glucagon-like-peptide-1 and Insulin-Resistance

Results from observational studies suggest an association of red meat intake with risk of type 2 diabetes mellitus (T2D). However, results from randomized controlled trials (RCTs) have not clearly supported a mechanistic link between red meat intake and T2D risk factors. Therefore, a systematic review and meta-analysis were conducted on RCTs evaluating the effects of diets containing red meat (beef, pork, lamb, etc.), compared to diets with lower or no red meat, on markers of glucose homeostasis in adults.. A search of PubMed and CENTRAL yielded 21 relevant RCTs. Pooled estimates were expressed as standardized mean differences (SMDs) between the red meat intervention and the comparator intervention with less or no red meat.. Compared to diets with reduced or no red meat intake, there was no significant impact of red meat intake on insulin sensitivity (SMD: -0.11; 95% CI: -0.39, 0.16), insulin resistance (SMD: 0.11; 95% CI: -0.24, 0.45), fasting glucose (SMD: 0.13; 95% CI: -0.04, 0.29), fasting insulin (SMD: 0.08; 95% CI: -0.16, 0.32), glycated hemoglobin (HbA1c; SMD: 0.10; 95% CI: -0.37, 0.58), pancreatic beta-cell function (SMD: -0.13; 95% CI: -0.37, 0.10), or glucagon-like peptide-1 (GLP-1; SMD: 0.10; 95% CI: -0.37, 0.58). Red meat intake modestly reduced postprandial glucose (SMD: -0.44; 95% CI: -0.67, -0.22; P < 0.001) compared to meals with reduced or no red meat intake. The quality of evidence was low to moderate for all outcomes.. The results of this meta-analysis suggest red meat intake does not impact most glycemic and insulinemic risk factors for T2D. Further investigations are needed on other markers of glucose homeostasis to better understand whether a causal relationship exists between red meat intake and risk of T2D.. CRD42020176059.

Topics: Animals; Blood Glucose; Cattle; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Meat; Randomized Controlled Trials as Topic; Red Meat; Risk Factors; Sheep

Neprilysin (NEP) is a transmembrane zinc-dependent metalloproteinase that inactivates various peptide hormones including glucagon-like peptide 1 (GLP-1). NEP inhibitors may be effective in the management of type 2 diabetes mellitus (T2DM) by increasing the circulating level of GLP-1. However, acute-effect NEP inhibitors may lead to detrimental effects by increasing blood glucose independent of GLP-1. These findings suggest a controversial point regarding the potential role of NEP inhibitors on glucose homeostasis in T2DM patients. Therefore, this perspective aimed to clarify the controversial points concerning the role of NEP inhibitors on glucose homeostasis in T2DM. NEP inhibitors may lead to beneficial effects by inhibition of NEP, which is involved in the impairment of glucose homeostasis through modulation of insulin resistance. NEP increases dipeptidyl peptidase-4 (DPP4) activity and contributes to increasing active GLP-1 proteolysis so NEP inhibitors may improve glycemic control through increasing endogenous GLP-1 activity and reduction of DPP4 activity. Thus, NEP inhibitors could be effective alone or in combination with antidiabetic agents in treating T2DM patients. However, long-term and short-term effects of NEP inhibitors may lead to a detrimental effect on insulin sensitivity and glucose homeostasis through different mechanisms including augmentation of substrates and pancreatic amyloid deposition. These findings are confirmed in animal but not in humans. In conclusion, NEP inhibitors produce beneficial rather than detrimental effects on glucose homeostasis and insulin sensitivity in humans though most of the detrimental effects of NEP inhibitors are confirmed in animal studies.. 脑啡肽酶(NEP)是一种跨膜锌依赖性金属蛋白酶，可使包括胰高血糖素样肽1 (GLP-1)在内的多种肽类激素失活。NEP抑制剂可能通过提高循环GLP-1水平来有效治疗2型糖尿病(T2DM)。然而，NEP抑制剂的急性效应可能会造成血糖升高，产生有害作用，且与GLP-1无关。这些发现提示NEP抑制剂对T2DM患者血糖稳态的作用尚存有争议。本视角旨在阐明NEP抑制剂对T2DM糖稳态作用的争议点。NEP通过调节胰岛素抵抗(IR)参与糖稳态受损，NEP抑制剂可能通过抑制NEP发挥有益作用。NEP增加二肽基肽酶-4 (DPP4)活性并有助于增加GLP-1蛋白水解活性，而NEP抑制剂可能通过增加内源性GLP-1活性和降低DPP4活性来改善血糖控制。因此，NEP抑制剂可单独或联合降糖药物治疗T2DM患者。然而，NEP抑制剂的长期和短期作用机制可能不同，包括增强底物和胰腺淀粉样蛋白沉积，导致对胰岛素敏感性和葡萄糖稳态的有害影响。这些发现在动物中得到证实，但在人类中未得到证实。综上所述，NEP抑制剂对人体葡萄糖稳态和胰岛素敏感性产生有益而非有害的影响，尽管大多数有害影响已在动物研究中得到证实。.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Homeostasis; Humans; Hypoglycemic Agents; Insulin Resistance; Neprilysin

Despite Polycystic Ovary Syndrome (PCOS) is a very prevalent disorder among women of reproductive age, there is widespread agreement that until now, no pharmacological options are available to tackle the entire spectrum of clinical manifestations encountered in the clinical practice. Obesity and insulin resistance, which commonly characterized this syndrome, prompted the design of studies investigating the effects of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) in PCOS. Indeed, a very impressive number of randomized controlled clinical trials (RCTs) and systematic reviews provided robust evidence on the effectiveness of GLP-1RA in PCOS as a new, appealing approach, producing both satisfactory and permanent weight loss, and improvement of insulin resistance at the same time. However, most of the subjects included in the RCTs are PCOS patients with obesity/overweight, whereas a portion of PCOS women, which can even reach 50%, might present a lean phenotype. Moreover, some benefits on clinical and metabolic features of PCOS may not have fully emerged due to the low or medium doses employed in the vast majority of the current studies. Thus, pitfalls in the methodology of these studies have led sometimes to misleading results. In addition, some aspects of GLP-1 beyond weight loss, such as preclinical evidence on GLP-1 effects in directly modulating the hypothalamus-pituitary-gonadal axis, or the effects of GLP-1RA on clinical and biochemical expression of hyperandrogenism, still deserve a greater insight, especially in light of a possible therapeutic use in PCOS women independently of obesity. Aim of this review is to further unravel the possible role of GLP-1 in PCOS pathogenesis, tempting to provide additional supports to the rationale of treatment with GLP-1RA in the management of PCOS also independent of weight loss. For this purpose, the outcomes of RCTs investigating in PCOS the anthropometric and metabolic changes have been treated separately to better underpin the effects of GLP-1 RA, in particular liraglutide, beyond weight loss.

Topics: Body Weight; Female; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Liraglutide; Obesity; Polycystic Ovary Syndrome; Weight Loss

In Covid-19, variations in fasting blood glucose are considered a distinct risk element for a bad prognosis and outcome in Covid-19 patients. Tirazepatide (TZT), a dual glucagon-like peptide-1 (GLP-1)and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist may be effective in managing Covid-19-induced hyperglycemia in diabetic and non-diabetic patients. The beneficial effect of TZT in T2DM and obesity is related to direct activation of GIP and GLP-1 receptors with subsequent improvement of insulin sensitivity and reduction of body weight. TZT improves endothelial dysfunction (ED) and associated inflammatory changes through modulation of glucose homeostasis, insulin sensitivity, and pro-inflammatory biomarkers release. TZT, through activation of the GLP-1 receptor, may produce beneficial effects against Covid-19 severity since GLP-1 receptor agonists (GLP-1RAs) have anti-inflammatory and pulmoprotective implications in Covid-19. Therefore, GLP-1RAs could effectively treat severely affected Covid-19 diabetic and non-diabetic patients. Notably, using GLP-1RAs in T2DM patients prevents glucose variability, a common finding in Covid-19 patients. Therefore, GLP-1RAs like TZT could be a therapeutic strategy in T2DM patients with Covid-19 to prevent glucose variability-induced complications. In Covid-19, the inflammatory signaling pathways are highly activated, resulting in hyperinflammation. GLP-1RAs reduce inflammatory biomarkers like IL-6, CRP, and ferritin in Covid-19 patients. Therefore, GLP-1RAs like TZ may be effective in Covid-19 patients by reducing the inflammatory burden. The anti-obesogenic effect of TZT may reduce Covid-19 severity by ameliorating body weight and adiposity. Furthermore, Covid-19 may induce substantial alterations in gut microbiota. GLP-1RA preserves gut microbiota and prevents intestinal dysbiosis. Herein, TZT, like other GLP-1RA, may attenuate Covid-19-induced gut microbiota alterations and, by this mechanism, may mitigate intestinal inflammation and systemic complications in Covid-19 patients with either T2DM or obesity. As opposed to that, glucose-dependent insulinotropic polypeptide (GIP) was reduced in obese and T2DM patients. However, activation of GIP-1R by TZT in T2DM patients improves glucose homeostasis. Thus, TZT, through activation of both GIP and GLP-1, may reduce obesity-mediated inflammation. In Covid-19, GIP response to the meal is impaired, leading to postprandial hyperglycemia and abnormal glucose hom

Topics: Blood Glucose; Body Weight; COVID-19; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hyperglycemia; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Obesity; SARS-CoV-2; Tumor Necrosis Factor-alpha

The long-acting glucagon-like peptide-1 receptor (GLP1R) agonist, semaglutide and the unimolecular glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP1R dual-agonist, tirzepatide have been successfully introduced as therapeutic options for patients with Type-2 diabetes (T2DM) and obesity. Proglucagon-derived peptides from phylogenetically ancient fish act as naturally occurring dual agonists at the GLP1R and the glucagon receptor (GCGR) with lamprey GLP-1 and paddlefish glucagon being the most potent and effective in stimulating insulin release from BRIN-BD11 clonal β-cells. These peptides were also the most effective in lowering blood glucose and elevating plasma insulin concentrations when administered intraperitoneally to overnight-fasted mice together with a glucose load. Zebrafish GIP acts as a dual agonist at the GIPR and GLP1R receptors. Studies with the high fat-fed mouse, an animal model with obesity, impaired glucose-tolerance and insulin-resistance, have shown that twice-daily administration of the long-acting analogs [D-Ala

Topics: Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Eating; Fish Proteins; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Obesity; Proglucagon

Recent studies discuss the evidence of lesser degrees of hyperglycemia contribution to cardiovascular disease (CVD) than impaired glucose tolerance. Indeed, the biggest risk for CVD seems to shift to glucose intolerance in humans with insulin resistance. Although there is a connection between abnormal insulin signaling and heart dysfunction in diabetics, there is also a relation between cardiac insulin resistance and aging heart failure (HF). Moreover, studies have revealed that HF is associated with generalized insulin resistance. Recent clinical outcomes parallel to the experimental data undertaken with antihyperglycemic drugs have shown their beneficial effects on the cardiovascular system through a direct effect on the myocardium, beyond their ability to lower blood glucose levels and their receptor-associated actions. In this regard, several new-class drugs, such as glucagon-like peptide 1 receptor agonists (GLP-1Ra) and sodium-glucose cotransport 2 inhibitors (SGLT2i), can improve cardiac health beyond their ability to control glycemia. In recent years, great improvements have been made toward the possibility of direct heart-targeting effects including modulation of the expression of specific cardiac genes in vivo for therapeutic purposes. However, many questions remain unanswered, regarding their therapeutic effects on cardiomyocytes in heart failure, although there are various cellular levels studies with these drugs. There are also some important comparative studies on the role of SGLT2i versus GLP-1Ra in patients with and without CVD as well as with or without hyperglycemia. Here, we sought to summarize and interpret the available evidence from clinical studies focusing on the effects of either GLP-1Ra or SGLT-2i or their combinations on cardiac structure and function. Furthermore, we documented data from experimental studies, at systemic, organ, and cellular levels. Overall, one can summarize that both clinical and experimental data support that either SGLT2i or GLP-1R agonists have similar benefits as cardioprotective agents in patients with or without impaired glucose tolerance.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose Intolerance; Heart Failure; Humans; Hypoglycemic Agents; Insulin Resistance; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce glycaemia and weight and improve insulin resistance (IR). Three electronic databases (Medline, Embase, PubMed) were searched from inception until March 2021. We selected randomized controlled trials comparing GLP-1 RAs and SGLT-2 inhibitors with control in adult NAFLD patients with or without T2DM. Network meta-analyses were performed using fixed and random effect models, and the mean difference (MD) with corresponding 95% confidence intervals (CI) were determined. The within-study risk of bias was assessed with the Cochrane collaborative risk assessment tool RoB.. 25 studies with 1595 patients were included in this network meta-analysis. Among them, there were 448 patients, in 6 studies, who were not comorbid with T2DM. Following a mean treatment duration of 28.86 weeks, compared with the control group, GLP-1 RAs decreased the HOMA-IR (MD [95%CI]; -1.573[-2.523 to -0.495]), visceral fat (-0.637[-0.992 to -0.284]), weight (-2.394[-4.625 to -0.164]), fasting blood sugar (-0.662[-1.377 to -0.021]) and triglyceride (- 0.610[-1.056 to -0.188]). On the basis of existing studies, SGLT-2 inhibitors showed no statistically significant improvement in the above indicators. Compared with SGLT-2 inhibitors, GLP-1 RAs decreased visceral fat (-0.560[-0.961 to -0.131]) and triglyceride (-0.607[-1.095 to -0.117]) significantly.. GLP-1 RAs effectively improve IR in NAFLD, whereas SGLT-2 inhibitors show no apparent effect.. PROSPERO https://www.crd.york.ac.uk/PROSPERO/, CRD42021251704.

Topics: Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Network Meta-Analysis; Non-alcoholic Fatty Liver Disease; Sodium-Glucose Transporter 2 Inhibitors; Triglycerides

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder among women of reproductive age. The incidence ranges from approx. 6% to 20%. PCOS is characterized by a spectrum of symptoms and clinical features that includes ovarian dysfunction, clinical and/or biochemical hyperandrogenism, and ultrasound evidence of morphologically polycystic ovaries. Obesity is present in 40-70% of patients with the syndrome. Adiposity is involved in exacerbating the negative effects of insulin resistance, hyperinsulinaemia, and hyperandrogenaemia in the course of PCOS. Therefore, it is essential to maintain normal weight or effectively treat overweight/obesity in patients suffering from this endocrinopathy. Apart from diet and lifestyle interventions, an appropriate pharmacological or surgical treatment should be selected for the individual patient. Evidence-based data have unequivocally proven the validity of the use of glucagon-like peptide 1 (GLP-1) analogues in the treatment of overweight/obese patients with PCOS. The result of the GLP-1 therapy is not only a reduction of body weight but also an improvement in insulin resistance and a decrease in hyperandrogenaemia. It also seems that this treatment method increases spontaneous and in-vitro pregnancy rates. Therefore, the GLP-1 treatment of obese PCOS women is a new therapeutic opportunity not only for weight loss but also for a wide range of benefits. This review summarizes and discusses findings regarding obesity and its relation to hyperandrogenism and insulin resistance in PCOS, with special attention paid to the pharmacological treatment of adiposity with GLP-1 analogues.

Topics: Female; Glucagon-Like Peptide 1; Humans; Hyperandrogenism; Insulin Resistance; Obesity; Overweight; Polycystic Ovary Syndrome

Non-alcoholic steatohepatitis (NASH) is a progressive form of Non-alcoholic fatty liver disease (NAFLD), which slowly progresses toward cirrhosis and finally leads to the development of hepatocellular carcinoma. Obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome are major risk factors contributing to NAFLD. Targeting these risk factors is a rational option for inhibiting NASH progression. In addition, NASH could be treated with therapies that target the metabolic abnormalities causing disease pathogenesis (such as de novo lipogenesis and insulin resistance) as well with medications targeting downstream processes such as cellular damage, apoptosis, inflammation, and fibrosis. Glucagon-like peptide (GLP-1), is an incretin hormone dysregulated in both experimental and clinical NASH, which triggers many signaling pathways including fibroblast growth factor (FGF) that augments NASH pathogenesis. Growing evidence indicates that GLP-1 in concert with FGF-21 plays crucial roles in the conservation of glucose and lipid homeostasis in metabolic disorders. In line, GLP-1 stimulation improves hepatic ballooning, steatosis, and fibrosis in NASH. A recent clinical trial on NASH patients showed that the upregulation of FGF-21 decreases liver fibrosis and hepatic steatosis, thus improving the pathogenesis of NASH. Hence, therapeutic targeting of the GLP-1/FGF axis could be therapeutically beneficial for the remission of NASH. This review outlines the significance of the GLP-1/FGF-21 axis in experimental and clinical NASH and highlights the activity of modulators targeting this axis as potential salutary agents for the treatment of NASH.

Topics: Diabetes Mellitus, Type 2; Fibroblast Growth Factors; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin Resistance; Lipids; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease

Obesity in women of reproductive age has a number of adverse metabolic effects, including Type II Diabetes (T2D), dyslipidemia, and cardiovascular disease. It is associated with increased menstrual irregularity, ovulatory dysfunction, development of insulin resistance and infertility. In women, estradiol is not only critical for reproductive function, but they also control food intake and energy expenditure. Food intake is known to change during the menstrual cycle in humans. This change in food intake is largely mediated by estradiol, which acts directly upon anorexigenic and orexigenic neurons, largely in the hypothalamus. Estradiol also acts indirectly with peripheral mediators such as glucagon like peptide-1 (GLP-1). Like estradiol, GLP-1 acts on receptors at the hypothalamus. This review describes the physiological and pathophysiological mechanisms governing the actions of estradiol during the menstrual cycle on food intake and energy expenditure and how estradiol acts with other weight-controlling molecules such as GLP-1. GLP-1 analogs have proven to be effective both to manage obesity and T2D in women. This review also highlights the relationship between steroid hormones and women's mental health. It explains how a decline or imbalance in estradiol levels affects insulin sensitivity in the brain. This can cause cerebral insulin resistance, which contributes to the development of conditions such as Parkinson's or Alzheimer's disease. The proper use of both estradiol and GLP-1 analogs can help to manage obesity and preserve an optimal mental health in women by reducing the mechanisms that trigger neurodegenerative disorders.

Topics: Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Estradiol; Female; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Obesity

The use of nutritional interventions for managing diabetes is one of the effective strategies aimed at reducing the global prevalence of the condition, which is on the rise. Almonds are the most consumed tree nut and they are known to be rich sources of protein, monounsaturated fatty acids, essential minerals, and dietary fibre. Therefore, the aim of this review was to evaluate the effects of almonds on gut microbiota, glycometabolism, and inflammatory parameters in patients with type 2 diabetes.. This systematic review and meta-analysis was carried out according to the preferred reporting items for systematic review and meta-analysis (PRISMA). EBSCOhost, which encompasses the Health Sciences Research Databases; Google Scholar; EMBASE; and the reference lists of articles were searched based on population, intervention, control, outcome, and study (PICOS) framework. Searches were carried out from database inception until 1 August 2021 based on medical subject headings (MesH) and synonyms. The meta-analysis was carried out with the Review Manager (RevMan) 5.3 software.. Nine randomised studies were included in the systematic review and eight were used for the meta-analysis. The results would suggest that almond-based diets have significant effects in promoting the growth of short-chain fatty acid (SCFA)-producing gut microbiota. Furthermore, the meta-analysis showed that almond-based diets were effective in significantly lowering (. The findings of this systematic review and meta-analysis have shown that almond-based diets may be effective in promoting short-chain fatty acid-producing bacteria and lowering glycated haemoglobin and body mass index in patients with type 2 diabetes compared with control. However, the effects of almonds were not significant (

Topics: Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glycated Hemoglobin; Homeostasis; Humans; Inflammation; Insulin; Insulin Resistance; Prunus dulcis; Publication Bias; Randomized Controlled Trials as Topic; Risk; Tumor Necrosis Factor-alpha

Besides insulin-mediated transport of glucose into the cells, an important role is also played by the non-insulin-mediated transport. This latter process is called glucose effectiveness (acronym S

Topics: Administration, Intravenous; Adult; Aged; Animals; Biological Transport; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male; Mice; Middle Aged

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.

Topics: Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Signal Transduction

Topics: Alzheimer Disease; Animals; Brain; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin; Insulin Resistance; Parkinson Disease; Receptors, Gastrointestinal Hormone

Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine-tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin-mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon-like peptide 1 (GLP-1) receptors. GLP-1, in addition to its well-characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP-1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP-1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP-1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP-1 in cardiac as well as skeletal muscle function.. 肌肉微血管系统对骨骼肌和心肌的健康和功能起着至关重要的调节作用。它为血浆间隙和肌肉间质之间的底物交换提供内皮表面积。胰岛素微调肌肉微血管灌注, 以调节自身在肌肉中的活动, 并为肌肉提供氧气和营养。具体地说, 胰岛素增加了肌肉微血管灌注, 使得更多的胰岛素转运到毛细血管周边的肌肉细胞, 然后通过其自身的透皮转运到达肌肉间质。在2型糖尿病中, 肌肉微血管对胰岛素的反应迟钝, 毛细血管稀疏。毛细血管密度的减少和胰岛素介导的毛细血管募集的降低, 都会导致可用于底物交换的内皮表面积减少。血管系统表达丰富的胰高血糖素样肽-1(GLP-1)受体。GLP-1可以改善内皮功能, 增加肌肉微血管灌注, 并刺激血管生成。重要的是, 这些作用在胰岛素抵抗状态下得以保留。因此, 使用GLP-1受体激动剂治疗胰岛素抵抗患者, 可能会改善骨骼肌和心肌微血管灌注, 增加肌肉的毛细血管, 从而改善氧、营养物质和胰岛素等激素向心肌细胞的输送。GLP-1的这些作用影响骨骼肌和心肌功能以及生物系统, 如功能性运动能力。涉及使用GLP-1受体激动剂的临床前研究和临床试验已经显示了有益的心血管效应, 并改善了2型糖尿病的心血管结局。未来的研究应该进一步研究GLP-1在心肌和骨骼肌功能中的不同作用.

Topics: Coronary Vessels; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Muscle, Skeletal; Myocardium; Regional Blood Flow

Despite plenty of currently available information on metabolic syndrome (MetS) in children and adolescents, there are still uncertainties regarding definition, prevention, management and treatment of MetS in children. The first approach to MetS in children consists of lifestyle interventions (nutritional education, physical activity). These recommendations are often difficult to achieve, especially for adolescents, therefore, there is usually a lack of successful outcomes. A pharmacological intervention in obese children may be needed in some cases, with the aim to improve the effects of these primary prevention interventions. Metformin seems to be safe and presents evident positive effects on insulin sensitivity, but long-term and consistent data are still missing to establish its role in the pediatric population and the possible effectiveness of other emergent treatments such as glucagon-like peptide-1 analogues, dipeptidylpeptidase-4 inhibitors, dual inhibitors of SGLT1 and SGLT2 and weight loss drugs. Bariatric surgery might be helpful in selected cases. The aim of this review is to present the most recent available treatments for the main components of metabolic syndrome, with a focus on insulin resistance. A short mention of management of congenital forms of insulin resistance will be included too.

Topics: Adolescent; Anti-Obesity Agents; Bariatric Surgery; Cardiovascular Diseases; Child; Dipeptidyl-Peptidase IV Inhibitors; Exercise; Forecasting; Glucagon-Like Peptide 1; Glycemic Index; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Metabolic Syndrome; Metformin; Non-alcoholic Fatty Liver Disease; Nutrition Assessment; Pediatric Obesity; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2 Inhibitors

The linkage of neurodegenerative diseases with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), including oxidative stress, mitochondrial dysfunction, excessive inflammatory responses and abnormal protein processing, and the correlation between cerebrovascular diseases and hyperglycemia has opened a new window for novel therapeutics for these cognitive disorders. Various antidiabetic agents have been studied for their potential treatment of cognitive disorders, among which the dipeptidyl peptidase-4 (DPP-4) inhibitors have been investigated more recently. So far, DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models, and cognitive benefits in diabetic patients with or without cognitive impairments. This review aims to summarize the potential mechanisms, advantages and limitations, and currently available evidence for developing DPP-4 inhibitors as a treatment of cognitive disorders.

Topics: Animals; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin Resistance

Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues.

Topics: Animals; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Oxidative Stress

The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases.. Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Bone and Bones; Bone Diseases, Metabolic; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Cellular Senescence; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor I; Mesenchymal Stem Cells; Obesity; Parathyroid Hormone; Receptor for Advanced Glycation End Products; Receptor, Insulin

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.

Topics: Antioxidants; Chalcones; Chenodeoxycholic Acid; Cytoprotection; Glucagon-Like Peptide 1; Humans; Imidazoles; Insulin Resistance; Metformin; Non-alcoholic Fatty Liver Disease; Patient Selection; Pharmaceutical Preparations; Propionates; Sulfoxides; Thiazolidinediones

Dysglycaemia (i.e. type 2 diabetes mellitus or impaired glucose tolerance) is not only common in patients with cardiovascular disease but increases the risk for future cardiovascular complications. Hyperglycaemia, the hallmark of diabetes, has since long been considered to be the link between diabetes and cardiovascular disease. Diabetes is, however, a complex, multifactorial disorder to which, for example, insulin resistance, endothelial dysfunction and factors such as increased thrombogenicity, hypertension and dyslipidaemia contribute. Thus, treatment needs to be multifactorial and to take cardiovascular aspects into account. Life-style adjustments are, together with blood pressure, lipid and glucose control, important parts of such management. Recent trial data reveal a beneficial effect on cardiovascular prognosis and mortality of blood glucose lowering agents belonging to the classes: sodium-glucose-transporter 2 inhibitors and glucagon-like peptide 1 agonists. The precise mechanisms by which certain sodium-glucose-transporter 2 inhibitors and glucagon-like peptide receptor agonists lead to these beneficial effects are only partly understood. An important impact of the benefits of sodium-glucose-transporter 2 inhibitors is a reduction in heart failure while glucagon-like peptide receptor agonists may retard the development of atherosclerotic vascular disease or stabilising plaques. Although there has been a considerable improvement in the prognosis for people with atherosclerotic diseases over the last decades there is still a gap between those with dysglycaemia, who are at higher risk, than those without dysglycaemia. This residual risk is reasonably related to two major factors: a demand for improved management and a need for new and improved therapeutic opportunities of type 2 diabetes, both routes to an improved prognosis that are at hands. This review is a comprehensive description of the possibilities to improve the prognosis for patients with dysglycaemia by a multifactorial management according to the most recent European guidelines issued in 2019 by the European Society of Cardiology in collaboration with the European Association for the Study of Diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Europe; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Resistance; Practice Guidelines as Topic; Prognosis; Risk Factors; Risk Reduction Behavior; Sodium-Glucose Transporter 2 Inhibitors

Considering conflicting results on the consequences of all types of obesity surgery, we were to summarize them via a systematic review.. Electronic literature search was done via scientific search engines. After the removal of duplicates and selection of articles of interest, 771 studies were included.. Insulin resistance indicators were significantly improved after bariatric surgery. Leptin was also significantly decreased while adiponectin was significantly increased. Although the level of metabolic hormones changed after bariatric surgery, they were not statistically significant. Inflammation indicators were significantly decreased. Significant reduction was also detected in PAI-1 and sICAM-1.. Bariatric surgery is beneficial in morbidly obese patients. Although treating obesity in a surgical way may cause some complications, the weight loss is generally safe and effective.

Topics: Adiponectin; Bariatric Surgery; C-Reactive Protein; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Interleukin-6; Leptin; Obesity, Morbid; Peptide YY; Plasminogen Activator Inhibitor 1; Tumor Necrosis Factor-alpha

Mammalian adipose tissue is traditionally categorized into white and brown relating to their function and morphology: while white serves as an energy storage, brown adipose tissue acts as the heat generator maintaining the core body temperature. The most recently identified type of fat, beige adipocyte tissue, resembles brown fat by morphology and function but is developmentally more related to white. The synthesis of beige fat, so-called browning of white fat, has developed into a topical issue in diabetes and metabolism research. This is due to its favorable effect on whole-body energy metabolism and the fact that it can be recruited during adult life. Indeed, brown and beige adipose tissues have been demonstrated to play a role in glucose homeostasis, insulin sensitivity, and lipid metabolism-all factors related to pathogenesis of type 2 diabetes. Many agents capable of initiating browning have been identified so far and tested widely in humans and animal models including in vitro and in vivo experiments. Interestingly, several agents demonstrated to have browning activity are in fact secreted as adipokines from brown and beige fat tissue, suggesting a physiological relevance both in beige adipocyte recruitment processes and in maintenance of metabolic homeostasis. The newest findings on agents driving beige fat recruitment, their mechanisms, and implications on type 2 diabetes are discussed in this review.

Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Lipotropic Agents; Melatonin; Natriuretic Peptides; Thermogenesis; Tretinoin

The current absence of effective treatments for Alzheimer's disease (AD) and Parkinson's disease (PD) reflects an incomplete knowledge of the underlying disease processes. Considerable efforts have been made to investigate the central pathological features of these diseases, giving rise to numerous attempts to develop compounds that interfere with such features. However, further characterization of the molecular targets within the interconnected AD and PD pathways is still required. Impaired brain insulin signaling has emerged as a feature that contributes to neuronal dysfunction in both AD and PD, leading to strategies aiming at restoring this pathway in the brain. Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for treatment of type 2 diabetes mellitus have been tested and have shown encouraging protective actions in experimental models of AD and PD as well as in initial clinical trials. We review studies revealing the neuroprotective actions of GLP-1 analogues in pre-clinical models of AD and PD and promising results from recent clinical trials.

Topics: Alzheimer Disease; Animals; Brain; Clinical Trials as Topic; Disease Models, Animal; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Neuroprotective Agents; Parkinson Disease

Non-alcoholic fatty liver disease (NAFLD) is a continuum of disorders that can range from simple steatosis to non-alcoholic steatohepatitis (NASH). As a complex metabolic disorder, the pathophysiology of NAFLD is incompletely understood. Recently glucagon-like peptide (GLP)-1 and -2 signalling has been implicated in the pathogenesis of NAFLD. The role of these gut hormones in the hepatic abnormalities is complicated by lack of consensus on the presence of GLP-1 and GLP-2 receptors within the liver. Nevertheless, GLP-1 and GLP-2 receptor agonists have been associated with alterations in lipid metabolism and hepatic and systemic inflammation, pathological abnormalities characteristic of NAFLD. Treatment with GLP-1 analogues has been shown to reverse features of NAFLD including insulin resistance, and alterations in hepatic de novo lipogenesis and reactive oxygen species. In this review, we provide an overview of the role of GLP-1 and GLP-2 in lipid homeostasis and metabolic disease including NAFLD and NASH.

Topics: Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-2 Receptor; Glucagon-Like Peptides; Humans; Insulin Resistance; Lipid Metabolism; Lipids; Lipogenesis; Lipoproteins; Liraglutide; Liver; Non-alcoholic Fatty Liver Disease; Peptides; Signal Transduction

Numerous micro-organisms naturally reside in the human body assuming a symbiotic, or, at times, even a dysbiotic relationship with the host. These microbial populations are referred to as the human microbiota. Host microbial populations are an important mediator of gastro-intestinal mucosal permeability, bile acid metabolism, short-chain fatty acids synthesis, fermentation of dietary polysaccharides and FXR/TGR5 signaling. Variations in the composition and function of gut microbiota have been observed in type 2 diabetes mellitus, insulin resistance and obesity, as well as in inflammatory bowel diseases. The microbial imbalance induced by such pathological processes is described as dysbiosis. In this review, we describe the pathophysiological links between type 2 diabetes mellitus and gut microbiota, explore the effect of anti-diabetic drugs on gut microbiota and suggest possible therapeutic targets.

Topics: alpha-Glucosidases; Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dysbiosis; Fermentation; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Metformin; Mice; Obesity; Permeability; Polysaccharides; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors

Nonalcoholic fatty liver disease (NAFLD), the most prevalent cause of chronic liver disease worldwide, is strongly associated with obesity and insulin resistance.. Significant weight loss can improve NAFLD and nonalcoholic steatohepatitis (NASH). Diet and exercise that result in a sustained body weight reduction of 7-10% can improve liver fat content, NASH, and fibrosis. Vitamin E can be considered in patients with biopsy-proven NASH without diabetes, though caution must be used in those with prostate cancer. Pioglitazone improves liver histology, including fibrosis, and can be considered in patients with or without diabetes. Glucagon-like peptide-1 (GLP-1) antagonists may be beneficial in NASH, but more studies are needed before they can be recommended. Bariatric surgery, with resultant weight loss, can result in improvement in liver fat and inflammation. NAFLD treatment includes diet and exercise with a target 7-10% weight reduction. Treatment goals include improvements in liver fat content, liver inflammation, and fibrosis.

Topics: Bariatric Surgery; Body Weight; Diet; Exercise; Glucagon-Like Peptide 1; Humans; Inflammation; Insulin Resistance; Liver; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Obesity; Pioglitazone; Prostatic Neoplasms; Vitamin E; Weight Loss

GLP-1 and GLP-2 are gut-derived hormones used in the treatment of diabetes type-2 and short bowel syndrome, respectively. GLP-1 attenuates insulin resistance and GLP-2 reduces enterocyte apoptosis and enhances crypt cell proliferation in the small intestine. In addition, both hormones have vasoactive effects and may be useful in situations with impaired microcirculation. The aim of this systematic review was to provide an overview of the potential effects of GLP-1 and GLP-2 on microcirculation. A systematic search was performed independently by two authors in the following databases: PubMed, EMBASE, Cochrane library, Scopus, and Web of Science. Of 1111 screened papers, 20 studies were included in this review: 16 studies in animals, three in humans, and one in humans and rats. The studies were few and heterogeneous and had a high risk of bias. However, it seems that GLP-1 regulates the pancreatic, skeletal, and cardiac muscle flow, indicating a role in the glucose homeostasis, while GLP-2 acts primarily in the regulation of the microcirculation of the mid-intestine. These findings may be useful in gastrointestinal surgery and in situations with impaired microcirculation of the gut.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Insulin Resistance; Microcirculation; Rats

Roux-en-Y gastric bypass (RYGB) is an effective treatment for diabetes. Glucagon-like peptide-1 (GLP-1) is a gut hormone that is important to glucose homeostasis.. This study aimed to assess GLP-1 level and its predictors after RYGB.. The study design was a meta-analysis. The data sources were MEDLINE, EMBASE, Web of Science, and the Cochrane Databases. The study selection composed of studies with pre- and post-RYGB levels. The main outcomes were as follows: Primary outcome was the change in postprandial GLP-1 levels after RYGB. Secondary outcomes included the changes in fasting glucose, fasting insulin, and fasting GLP-1 levels after RYGB. Meta-regression to determine predictors of changes in GLP-1 levels was performed. Outcomes were reported using Hedge's g.. Twenty-four studies with 368 patients were included. Postprandial GLP-1 levels increased after RYGB (Hedge's g = 1.29, p < 0.0001), while fasting GLP-1 did not change (p = 0.23). Peak postprandial GLP-1 levels gave the most consistent results (I. Postprandial GLP-1 levels increase after RYGB, while fasting levels remain unchanged. Shorter Roux limb length is associated with greater increase in postprandial GLP-1, which may lead to better glycemic control in this population.

Topics: Blood Glucose; Fasting; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Obesity, Morbid; Postprandial Period; Treatment Outcome; Weight Loss

Bariatric surgery is very effective in achieving and maintaining weight loss but it is also associated with improvement of obesity metabolic complications, primarily type 2 diabetes (T2D). Remission of T2D or at least a net improvement of glycemic control persists for at least 5 years. The bypass of duodenum and of the first portion of the jejunum up to the Treitz ligament as in Roux-en-Y Gastric Bypass (RYGB), or the bypass of the duodenum, the entire jejunum and the first tract of the ileum, such as in Bilio-Pancreatic Diversion (BPD), achieve different results on insulin sensitivity. Insulin resistance is the major driver of T2D manifesting long before insulin secretion failure. In fact, T2D development can be prevented by treatment with insulin sensitizing agents. Interestingly, RYGB improves hepatic insulin sensitivity while BPD ameliorates whole-body insulin sensitivity. Two major theories have been advocated to explain the early remission of T2D following RYGB or BPD before a meaningful weight loss takes place, the foregut and the hindgut hypotheses. The former holds that the bypass of the proximal intestine, i.e. duodenum and jejunum, prevents the secretion of signals - including nervous transmitters and hormones - promoting insulin resistance, the latter instead states that the delivery of nutrients directly into the ileum stimulates the secretion of hormones improving glucose disposal. The most studied candidate is Glucagon Like Peptide 1 (GLP1). However, while there is unambiguous evidence that GLP-1 stimulates insulin secretion, its direct action in lowering insulin resistance, independently of the effect on weight loss secondary to its satiety action, is utterly controversial. In this review we examine the effects on T2D and gastrointestinal peptide secretion produced by different types of metabolic surgery and by minimally invasive endoscopic surgery, whose utilization for the treatment of obesity and T2D is gaining wider interest and acceptance.

Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Obesity; Remission Induction

In type 2 diabetes mellitus there is an overproduction of chylomicron in the postprandial state that is associated with increased cardiovascular risk. Current evidence points out a leading role of enterocyte in dyslipidemia of type 2 diabetes mellitus, since it increases the production of apolipoprotein B-48 in response to a raise in plasma free fatty acids and glucose. The chylomicron metabolism is regulated by many factors apart from ingested fat, including hormonal and metabolic elements. More recently, studies about the role of gut hormones, have demonstrated that glucagon-like peptide-1 decreases the production of apolipoprotein B-48 and glucagon-like peptide-2 enhances it. Insulin acutely inhibits intestinal chylomicron production in healthy humans, whereas this acute inhibitory effect on apolipoprotein B-48 production is blunted in type 2 diabetes mellitus. Understanding these emerging regulators of intestinal chylomicron secretion may offer new mechanisms of control for its metabolism and provide novel therapeutic strategies focalized in type 2 diabetes mellitus postprandial hyperlipidemia with the reduction of cardiovascular disease risk.

Topics: Chylomicrons; Diabetes Mellitus, Type 2; Dyslipidemias; Enterocytes; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Postprandial Period; Triglycerides

Capsaicin, the major active constituent of chilli, is an agonist on transient receptor potential vanilloid channel 1 (TRPV1). TRPV1 is present on many metabolically active tissues, making it a potentially relevant target for metabolic interventions. Insulin resistance and obesity, being the major components of metabolic syndrome, increase the risk for the development of cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. In vitro and pre-clinical studies have established the effectiveness of low-dose dietary capsaicin in attenuating metabolic disorders. These responses of capsaicin are mediated through activation of TRPV1, which can then modulate processes such as browning of adipocytes, and activation of metabolic modulators including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α (PPARα), uncoupling protein 1 (UCP1), and glucagon-like peptide 1 (GLP-1). Modulation of these pathways by capsaicin can increase fat oxidation, improve insulin sensitivity, decrease body fat, and improve heart and liver function. Identifying suitable ways of administering capsaicin at an effective dose would warrant its clinical use through the activation of TRPV1. This review highlights the mechanistic options to improve metabolic syndrome with capsaicin.

Topics: Adipocytes; Adipose Tissue; AMP-Activated Protein Kinases; Animals; Capsaicin; Diabetes Mellitus, Type 2; Diet; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; PPAR alpha; TRPV Cation Channels; Uncoupling Protein 1

As well known to the scientific community, Alzheimer's disease (AD) is an irreversible neurodegenerative disease that ends up with impairment of memory and cognition due to neuronal and synapse loss. Patient's quality of life can be enhanced by targeting neurogenesis as a therapeutic paradigm. Moreover, several research evidences support the concept that AD is a type of metabolic disorder mediated by impairment in brain insulin responsiveness and energy metabolism. Growing evidence suggests that endogenous peptides such as glucagon-like peptide-1 (GLP-1) and stromal-derived factor-1α (SDF-1α) provide neuroprotection across a range of experimental models of AD. So, preserving functional activity of SDF-1α and GLP-1 by dipeptidyl peptidase-4 inhibition will enhance the homing/recruitment of brain resident and nonresident circulating stem cells/progenitor cells, a noninvasive approach for promoting neurogenesis. So, herewith we provide this in support of dipeptidyl peptidase-4 inhibitors as a new target of attention for treating AD.

Topics: Alzheimer Disease; Animals; Brain; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Memory; Neuronal Plasticity

Alzheimer's disease (AD), characterized by the aggregation of amyloid-β (Aβ) protein and neuroinflammation, is the most common neurodegenerative disease globally. Previous studies have reported that some AD patients show impaired glucose utilization in brain, leading to cognitive decline. Recently, diabetes-induced dementia has been called "type 3 diabetes", based on features in common with those of type 2 diabetes and the progression of AD. Impaired glucose uptake and insulin resistance in the brain are important issues in type 3 diabetes, because these problems ultimately aggravate memory dysfunction in the brain. Glucagon-like peptide 1 (GLP-1) has been known to act as a critical controller of the glucose metabolism. Several studies have demonstrated that GLP-1 alleviates learning and memory dysfunction by enhancing the regulation of glucose in the AD brain. However, the specific actions of GLP-1 in the AD brain are not fully understood. Here, we review evidences related to the role of GLP-1 in type 3 diabetes.

Topics: Animals; Brain; Dementia; Diabetes Complications; Disease Susceptibility; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Neurogenesis

Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Post-mortem analyses of Alzheimer disease (AD) subjects revealed insulin resistance in the brain, suggesting a role of this condition in cognitive deficits observed in AD. In this review, we focus on the glucagon-like peptide-1 (GLP-1) signaling pathway, whose role in the brain is collecting increasing attention because of its association with insulin signaling activation. Areas covered: The role of GLP-1-mediated effects in the brain and how they are affected along the progression of AD pathology is discussed. Furthermore, we provide a comprehensive discussion about the use of GLP-1 mimetics drugs, which have been developed as a treatment for T2DM but seem to possess a number of other physiological properties, including neuroprotective and anti-inflammatory effects, that may be useful to slow AD progression. Expert commentary: The repurposing of antidiabetic drugs for the modulation of brain insulin resistance in AD appears to be of great interest. The beneficial effects on synaptogenesis, neurogenesis, and cell repair as well as the reduction of the chronic inflammatory response, and most importantly the reduction of amyloid plaques in the brain indicate that these drugs have promise as novel treatments for AD.

Topics: Alzheimer Disease; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Molecular Targeted Therapy; Signal Transduction

Surgical interventions for weight-related diseases (SWRD) may have substantial and sustainable effect on weight reduction, also leading to a higher remission rate of type 2 diabetes (T2D) mellitus than any other medical treatment or lifestyle intervention. The resolution of T2D after Roux-en-Y gastric bypass (RYGB) typically occurs too quickly to be accounted for by weight loss alone, suggesting that these operations have a direct impact on glucose homeostasis. The mechanisms underlying these beneficial effects however remain unclear. Recent research suggests that changes in the concentrations of plasma bile acids might contribute to these metabolic changes after surgery. In this review, we aimed to outline the potential role of bile acids in SWRD. We systematically reviewed MEDLINE, SCOPUS, and Web of Science for articles reporting the effect of SWRD on outcomes published between 1969 and 2016. We found that changes in circulating bile acids after surgery may play a major role through activation of the farnesoid X receptor A (FXRA), the fibroblast growth factor 19 (FGF19), and the G protein-coupled bile acid receptor (TGR5). Bile acid concentration increased significantly after RYGB. Some studies suggest that a transitory decrease occurs at 1 week post-surgery, followed by a gradual increase. Most studies have shown the increase to be proportionate by all bile acid subtypes. Bile acids can regulate glucose metabolism through the expression of TGR5 receptor in L cells, resulting in a release of glucagon-like peptide 1 (GLP-1). It may also induce the synthesis and secretion of FGF19 in ileal cells, thereby improving insulin sensitivity and regulating glucose metabolism. All the present SWRD are involved with changes in food stimulation to the stomach. This implies that discovering and developing the antagonists to TGR5 and FXRA may effectively control metabolic syndrome and the elucidation of the mechanisms underlying the physiological effects related to weight loss and T2D remission after surgery may help to identify new drug targets.

Topics: Bile Acids and Salts; Diabetes Mellitus, Type 2; Fibroblast Growth Factors; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Obesity, Morbid

Obesity is one of the major challenges for public health in 21st century, with 1.9 billion people being considered as overweight and 600 million as obese. There are certain diseases such as type 2 diabetes, hypertension, cardiovascular disease, and several forms of cancer which were found to be associated with obesity. Therefore, understanding the key molecular mechanisms involved in the pathogenesis of obesity could be beneficial for the development of a therapeutic approach. Hormones such as ghrelin, glucagon like peptide 1 (GLP-1) peptide YY (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK) secreted by an endocrine organ gut, have an intense impact on energy balance and maintenance of homeostasis by inducing satiety and meal termination. Glucose and energy homeostasis are also affected by lipid sensing in which different organs respond in different ways. However, there is one common mechanism i.e. formation of esterified lipids (long chain fatty acyl CoAs) and the activation of protein kinase C δ (PKC δ) involved in all these organs. The possible role of gut microbiota and obesity has been addressed by several researchers in recent years, indicating the possible therapeutic approach toward the management of obesity by the introduction of an external living system such as a probiotic. The proposed mechanism behind this activity is attributed by metabolites produced by gut microbial organisms. Thus, this review summarizes the role of various physiological factors such as gut hormone and lipid sensing involved in various tissues and organ and most important by the role of gut microbiota in weight management.

Topics: Adipose Tissue; Brain; Cholecystokinin; Cholesterol, VLDL; Gastrointestinal Hormones; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Lipid Metabolism; Obesity; PPAR gamma

Growing evidence suggests that agonists of the glucagon-like peptide 1 (GLP-1) receptor provide neuroprotection across a range of experimental models of Parkinson's disease (PD) and, recently, a small proof-of-concept, open-label human trial of exenatide in the treatment moderate severity PD appeared to show persistent improvements in motor and cognitive function. The underlying mechanisms of action remain unclear, but as evidence for the potential use of GLP-1 agonists in treating several neurodegenerative disease mounts, and with several clinical trials of GLP-1 analogues in PD and Alzheimer's disease (AD) currently underway, here we review the molecular mechanisms underlying the neuroprotective effects of GLP-1 analogues in the laboratory and their potential therapeutic utility with particular relevance to PD and PD dementia (PDD).

Topics: Alzheimer Disease; Animals; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin Resistance; Learning; Mitochondria; Neurogenesis; Parkinson Disease; Proto-Oncogene Proteins c-akt; Signal Transduction

Roux-en Y gastric bypass is a highly effective bariatric/metabolic surgical procedure that can induce robust weight loss and even remission of type 2 diabetes. One of the characteristic consequences of Roux-en Y gastric bypass is the expedited nutrient delivery to the distal small intestine, where L-cells are abundant and bile acid reabsorption occurs. To examine the role of the distal small intestine in isolation from other components of Roux-en Y gastric bypass, the ileal transposition (IT) surgery has been used in various rat models. IT relocates the distal ileal segment to the upper jejunum distal to the ligament of Treitz without any other alterations in the gastrointestinal anatomy. Therefore, IT exposes the distal ileal tissue to ingested nutrients after a meal faster than the normal condition. Although there is some inconsistency in the effect of IT according to different types of rat models and different types of surgical protocols, IT typically improved glucose tolerance, increased insulin sensitivity and induced weight loss, and the findings were more prominent in obese diabetic rats. Suggested mechanisms for the metabolic improvements after IT include increased L-cell secretion (e.g., glucagon-like peptides and peptide YY), altered bile acid metabolism, altered host-microbial interaction, attenuated metabolic endotoxemia and many others. Based on the effect of IT, we can conclude that the contribution of the distal small intestine to the metabolic benefits of bariatric/metabolic surgery is quite considerable. By unveiling the mechanism of action of IT, we might revolutionize the treatment for obesity and type 2 diabetes.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Endotoxemia; Enteroendocrine Cells; Gastric Bypass; Gastrointestinal Microbiome; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Ileum; Insulin; Insulin Resistance; Insulin Secretion; Rats

The polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. It is diagnosed by the presence of hyperandrogenemia, insulin resistance (IR), obesity and other endocrine or metabolic disorders. Exenatide (EX) is a kind of glucagon-like peptide, which is a new option for patients with diabetes mellitus. We present a patient with infertility for PCOS. She was overweight and her medical history included IR, right-sided ovarian mucinous cystadenomas, and left-sided teratoma. Although she had been treated with ovarian surgery, clomiphene citrate and gonadotropins, weight loss and metformin, which have been effective for dominant follicle development, she still failed to conceive. Then EX was initiated to intervene for 2 months. EX treatment was successful to improve IR; after that the infertile woman with PCOS became pregnant. EX improves IR and reproduction capacity in PCOS patients, reducing insulin level and ameliorating endocrine disorders, thereby improving ovarian function, promoting follicle development, and providing new avenues for the treatment of infertility with PCOS.

Topics: Adult; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Infertility, Female; Insulin Resistance; Peptides; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Reproductive Techniques, Assisted; Venoms

Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

Topics: Adrenal Cortex; Animals; Corticotropin-Releasing Hormone; Diabetes Mellitus; Female; Fetal Development; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucocorticoids; Humans; Hypothalamo-Hypophyseal System; Incretins; Insulin Resistance; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Stress, Physiological

The increased prevalence of type 2 diabetes follows the increased prevalence of obesity. Both diseases share common pathophysiological pathways; obesity is in most cases the first step, whereas diabetes is the second one. Weight gain occurs during the treatment of diabetes with drugs causing endogenous or exogenous hyperinsulinemia. Insulin and sulfonylurea are making patients more obese and more insulin resistant. Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) and sodium/glucose cotransporter 2 inhibitors (SGLT2 inhibitors) are antidiabetic drugs with weight loss property. GLP-1 agonists mimic an incretin action. They release insulin after a meal during hyperglycemia and suppress glucagon. The weight loss effect is a consequence of central action increased satiety. Some of GLP-1 agonists weight loss is a result of decelerated gastric emptying rate. SGLT2 inhibitors block sodium glucose cotransporter in proximal tubule brush border and produce glucose excretion with urinary loss. Urinary glucose leak results in calories and weight loss. Even a modest weight loss has positive outcome on metabolic features of diabetic patient; such drugs have important role in treatment of type 2 diabetic patients. However, there are some still unresolved questions. The weight loss they produce is modest. Those drugs are expensive and not available to many diabetic patients, they are significantly more expensive compared to "traditional" hypoglycemic drugs. The hypoglycemic endpoint of GLP-1 agonists and SGLT2 inhibitors often requires adding another antidiabetic drug. The most radical and most effective therapy of type 2 diabetes and obesity is bariatric surgery having significant number of diabetes remission.

Topics: Anti-Obesity Agents; Bariatric Surgery; Biological Transport; Clinical Trials as Topic; Comorbidity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose; Glycosuria; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Kidney Tubules, Proximal; Microvilli; Multicenter Studies as Topic; Obesity; Peptides; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Venoms; Weight Loss

Obesity is now a major international health concern. It is increasingly common in young women with reproductive, metabolic and psychological health impacts. Reproductive health impacts are often poorly appreciated and include polycystic ovary syndrome (PCOS), infertility and pregnancy complications. PCOS is the most common endocrine condition in women and is underpinned by hormonal disturbances including insulin resistance and hyperandrogenism. Obesity exacerbates hormonal and clinical features of PCOS and women with PCOS appear at higher risk of obesity, with multiple underlying mechanisms linking the conditions. Lifestyle intervention is first line in management of PCOS to both prevent weight gain and induce weight loss; however improved engagement and sustainability remain challenges with the need for more research. Medications like metformin, orlistat, GLP1 agonists and bariatric surgery have been used with the need for large scale randomised clinical trials to define their roles.

Topics: Adipokines; Bariatric Surgery; Combined Modality Therapy; Comorbidity; Diet, Reducing; Exercise Therapy; Female; Glucagon-Like Peptide 1; Gonadal Steroid Hormones; Humans; Hyperandrogenism; Inflammation; Insulin Resistance; Lactones; Life Style; Metformin; Models, Biological; Motivation; Obesity; Obesity, Abdominal; Orlistat; Polycystic Ovary Syndrome; Prevalence; Sympathetic Nervous System; Weight Loss

Type 2 diabetes is often treated with a class of drugs referred to as glucagon-like peptide-1 (GLP-1) analogs. GLP-1 is a peptide secreted by the gut that acts through only one known receptor, the GLP-1 receptor. The primary function of GLP-1 is thought to be lowering of postprandial glucose levels. Indeed, medications utilizing this system, including the long-acting GLP-1 analogs liraglutide and exenatide, are beneficial in reducing both blood sugars and body weight. GLP-1 analogs were long presumed to affect glucose control through their ability to increase insulin levels through peripheral action on beta cells. However, multiple lines of data point to the ability of GLP-1 to act within the brain to alter glucose regulation. In this review we will discuss the evidence for a central GLP-1 system and the effects of GLP-1 in the brain on regulating multiple facets of glucose homeostasis including glucose tolerance, insulin production, insulin sensitivity, hepatic glucose production, muscle glucose uptake, and connections of the central GLP-1 system to the gut. Although the evidence indicates that GLP-1 receptors in the brain are not necessary for physiologic control of glucose regulation, we discuss the research showing a strong effect of acute manipulation of the central GLP-1 system on glucose control and how it is relevant to type 2 diabetic patients.

Topics: Animals; Brain; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells

The realization that low-glycemic index diets were formulated using resistant starch led to more than a decade of research on the health effects of resistant starch. Determination of the metabolizable energy of the resistant starch product allowed for the performance of isocaloric studies. Fermentation of resistant starch in rodent studies results in what appears to be a healthier gut, demonstrated by increased amounts of short-chain fatty acids, an apparent positive change in the microbiota, and increased gene expression for gene products involved in normal healthy proliferation and apoptosis of potential cancer cells. Additionally, consumption of resistant starch was associated with reduced abdominal fat and improved insulin sensitivity. Increased serum glucagon-like peptide 1 (GLP-1) likely plays a role in promoting these health benefits. One rodent study that did not use isocaloric diets demonstrated that the use of resistant starch at 8% of the weight of the diet reduced body fat. This appears to be approximately equivalent to the human fiber requirement. In human subjects, insulin sensitivity is increased with the feeding of resistant starch. However, only 1 of several studies reports an increase in serum GLP-1 associated with resistant starch added to the diet. This means that other mechanisms, such as increased intestinal gluconeogenesis or increased adiponectin, may be involved in the promotion of improved insulin sensitivity. Future research may confirm that there will be improved health if human individuals consume the requirement for dietary fiber and a large amount of the fiber is fermentable.

Topics: Abdominal Fat; Adiposity; Animals; Diet; Dietary Fiber; Fatty Acids, Volatile; Fermentation; Gastrointestinal Microbiome; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Obesity, Abdominal; Starch

Despite major advances in medical treatments, survival rates of chronic heart failure (CHF) have not significantly changed in the past 50 years, making it imperative to search for novel pathophysiological mechanisms and therapeutic targets. In this article, we summarize the current knowledge regarding the possibility to treat such anabolic deficiencies with hormone replacement therapy (HRT).. Mounting evidence supports the concept that CHF is a disease characterized not only by excessive neurohormonal activation but also by a reduced anabolic drive that carries functional and prognostic significance. The recent demonstration of overall beneficial effects of HRT in CHF may pave the way to slow the disease progression in patients with coexisting CHF and hormone deficiencies. The hypothesis is to identify a considerable subset of CHF patients also affected with hormone deficiency and to treat them with HRT.. Single or multiple HRT may in theory be performed in CHF. Such a novel approach may improve left ventricular architecture, function, and physical capacity as well as quality of life. Larger randomized, controlled trials are needed to confirm this working hypothesis.

Topics: Androgens; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Failure; Hormone Replacement Therapy; Human Growth Hormone; Humans; Hypoglycemic Agents; Insulin Resistance; Testosterone; Thyroxine

The widespread acceptance that increased dietary n-3 polyunsaturated fatty acids (PUFAs), especially α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), improve health is based on extensive studies in animals, isolated cells and humans. Visceral adiposity is part of the metabolic syndrome, together with insulin resistance, dyslipidemia, hypertension and inflammation. Alleviation of metabolic syndrome requires normalization of insulin release and responses. This review assesses our current knowledge of the mechanisms that allow n-3 PUFAs to improve insulin secretion and sensitivity. EPA has been more extensively studied than either ALA or DHA. The complex actions of EPA include increased G-protein-receptor-mediated release of glucagon-like peptide 1 (GLP-1) from enteroendocrine L-cells in the intestine, up-regulation of the apelin pathway and down-regulation of other control pathways to promote insulin secretion by the pancreatic β-cells, together with suppression of inflammatory responses to adipokines, inhibition of peroxisome proliferator-activated receptor α actions and prevention of decreased insulin-like growth factor-1 secretion to improve peripheral insulin responses. The receptors involved and the mechanisms of action probably differ for ALA and DHA, with antiobesity effects predominating for ALA and anti-inflammatory effects for DHA. Modifying both GLP-1 release and the actions of adipokines by n-3 PUFAs could lead to additive improvements in both insulin secretion and sensitivity.

Topics: Adipokines; alpha-Linolenic Acid; Animals; Disease Models, Animal; Docosahexaenoic Acids; Down-Regulation; Eicosapentaenoic Acid; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; PPAR alpha; Up-Regulation

Roux-en-Y gastric bypass (RYGB) surgery induces weight loss of 20-30% that is maintained for 20 years. In patients with type 2 diabetes, the glucose-lowering effect of RYGB is superior to conventional antidiabetic therapy and often occurs within days after surgery. The aim of the thesis was to investigate the physiological mechanisms responsible for improved glycaemic control with special focus on the early postoperative period. We therefore investigated insulin sensitivity, insulin clearance and pancreatic islet-cell function in patients with type 2 diabetes and in glucose tolerant subjects prior to and at 1 week, 3 months and 1 year after RYGB. Hepatic insulin sensitivity measured with a glucose tracer increased already 1 week after RYGB, whereas peripheral insulin sensitivity estimated with the hyperinsulinaemic euglycaemic clamp was unchanged. Concomitant increases in insulin clearance at 1 week further highlights the liver as an important organ responsible for the early effects on glucose metabolism after surgery since insulin predominantly is cleared by the liver. Rapid improvements in hepatic insulin sensitivity is a common observation after calorie restriction in obese patients and has been observed as early as after 48 hours in absence of major weight loss and changes in peripheral insulin sensitivity. Thus, calorie restriction is a likely explanation for our findings of early improvements in hepatic insulin sensitivity and insulin clearance after RYGB. Peripheral insulin sensitivity increased along with weight loss at 3 months and 1 year after RYGB. Beta-cell function increased after RYGB in patients with type 2 diabetes in response to oral glucose, whereas insulin secretion was unchanged in response to an intravenous (iv) glucose-glucagon test throughout the first year after surgery. In glucose tolerant subjects, the insulin response to iv glucose-glucagon declined after RYGB likely as an adaptation to increased insulin sensitivity. The secretion of glucagon-like peptide 1 (GLP-1) increased substantially in both groups in response to oral glucose, whereas the secretion of glucose-dependent insulinotropic poly-peptide (GIP) was largely unchanged postoperatively. The insulinotropic effects of the incretin hormones were preserved after surgery during iv infusion in glucose tolerant subjects. Increased insulin secretion postoperatively was thus linked to the oral and not the iv route of administration highlighting the importance of the changed gast

Topics: Anastomosis, Roux-en-Y; Blood Glucose; Body Mass Index; Denmark; Female; Follow-Up Studies; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Insulin-Secreting Cells; Male; Obesity, Morbid; Quality of Life; Treatment Outcome; Weight Loss

The management of type 1 diabetes remains a challenge for clinicians. Current practice is to administer insulin analogues to best mimic normal physiological insulin profiles. However, despite our best efforts the majority of individuals with type 1 diabetes continue to suffer from suboptimal glucose control, significant hypoglycemia and microvascular tissue complications of the disease. There is thus a significant unmet need in the treatment of T1DM to obtain better glycemic control.. We discuss the use of α-glucosidase inhibitors, dipeptidyl-peptidase inhibitors, glucagon-like peptide 1 agonists, biguanides, thiazolidinediones and sodium glucose co-transporter 2 inhibitors in individuals with T1DM.. Non-insulin therapies present a unique and exciting adjunctive treatment for individuals with type 1 diabetes. Although data are scarce, the classes of medications discussed help to lower glucose, decrease glycemic excursions and in some cases improve body weight, along with allowing dose reductions in total daily insulin. Glucagon-like peptide 1 agonists and sodium glucose co-transporter 2 inhibitors, in particular, have been demonstrated to provide clinical improvements in individuals with T1DM and we feel their use can be explored in obese, insulin-resistant patients with T1DM, those with frequent and significant glycemic excursions or individuals with persistently elevated hemoglobin A1c.

Topics: Biguanides; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin Resistance; Obesity; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

Alzheimer's disease (AD) is an age-related neurodegenerative disease leading over the course of decades to the most common form of dementia. Many of its pathologic features and cognitive deficits may be due in part to brain insulin resistance recently demonstrated in the insulin receptor→insulin receptor substrate-1 (IRS-1) signaling pathway. The proximal cause of such resistance in AD dementia and amnestic mild cognitive impairment (aMCI) appears to be serine inhibition of IRS-1, a phenomenon likely due to microglial release of inflammatory cytokines triggered by oligomeric Aβ. Studies on animal models of AD and on human brain tissue from MCI cases at high risk of AD dementia have shown that brain insulin resistance and many other pathologic features and symptoms of AD may be greatly reduced or even reversed by treatment with FDA-approved glucagon-like peptide-1 (GLP-1) analogs such as liraglutide (Victoza). These findings call attention to the need for further basic, translational, and clinical studies on GLP-1 analogs as promising AD therapeutics.

Topics: Alzheimer Disease; Animals; Brain; Glucagon-Like Peptide 1; Humans; Insulin Resistance

Overproduction of hepatic apoB100-containing VLDL particles has been well documented in animal models and in humans with insulin resistance such as the metabolic syndrome and type 2 diabetes, and contributes to the typical dyslipidemia of these conditions. In addition, postprandial hyperlipidemia and elevated plasma concentrations of intestinal apoB48-containing chylomicron and chylomicron remnant particles have been demonstrated in insulin resistant states. Intestinal lipoprotein production is primarily determined by the amount of fat ingested and absorbed. Until approximately 10 years ago, however, relatively little attention was paid to the role of the intestine itself in regulating the production of triglyceride-rich lipoproteins (TRL) and its dysregulation in pathological states such as insulin resistance. We and others have shown that insulin resistant animal models and humans are characterized by overproduction of intestinal apoB48-containing lipoproteins. Whereas various factors are known to regulate hepatic lipoprotein particle production, less is known about factors that regulate the production of intestinal lipoprotein particles. Monosacharides, plasma free fatty acids (FFA), resveratrol, intestinal peptides (e.g. GLP-1 and GLP-2), and pancreatic hormones (e.g. insulin) have recently been shown to be important regulators of intestinal lipoprotein secretion. Available evidence in humans and animal models strongly supports the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of chylomicrons in fed and fasting states. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors contribute to the enhanced formation and secretion of TRL. Understanding the regulation of intestinal lipoprotein production is imperative for the development of new therapeutic strategies for the prevention and treatment of dyslipidemia. Here we review recent developments in this field and present evidence that intestinal lipoprotein production is a process with metabolic plasticity and that modulation of intestinal lipoprotein secretion may be a feasible therapeutic strategy in the treatment of dyslipidemia and possibly prevention of atherosclerosis.

Topics: Animals; Apolipoprotein B-100; Apolipoprotein B-48; Atherosclerosis; Bile Acids and Salts; Cholesterol; Chylomicrons; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Dyslipidemias; Exenatide; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Insulin; Insulin Resistance; Intestine, Small; Lipoproteins; Microbiota; Peptides; Receptors, Glucagon; Resveratrol; Secretory Rate; Stilbenes; Triglycerides; Venoms

The prevalence of Alzheimer's disease is increasing rapidly in the absence of truly effective therapies. A promising strategy for developing such therapies is the treatment of brain insulin resistance, a common and early feature of Alzheimer's disease, closely tied to cognitive decline and capable of promoting many biological abnormalities in the disorder. The proximal cause of brain insulin resistance appears to be neuronal elevation in the serine phosphorylation of IRS-1, most likely due to amyloid-β-triggered microglial release of proinflammatory cytokines. Preclinically, the first line of defense is behavior-lowering peripheral insulin resistance (e.g., physical exercise and a Mediterranean diet supplemented with foods rich in flavonoids, curcumin and ω-3 fatty acids). More potent remediation is required, however, at clinical stages. Fortunately, the US FDA-approved antidiabetics exenatide (Byetta; Amylin Pharmaceuticals, Inc., CA, USA) and liraglutide (Victoza; Novo Nordisk A/S, Bagsvaerd, Denmark) are showing much promise in reducing Alzheimer's disease pathology and in restoring normal brain insulin responsiveness and cognitive function.

Topics: Aging; Alzheimer Disease; Animals; Brain; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Models, Neurological; Nootropic Agents

Bariatric surgery has emerged as the most durably effective treatment of type 2 diabetes (DM). However, the mechanisms governing improvement in glucose homeostasis have yet to be fully elucidated. In this review we discuss the various types of surgical interventions and the multitude of factors that potentially mediate the effects on glycemia, such as altered delivery of nutrients to the distal ileum, duodenal exclusion, gut hormone changes, bile acid reabsorption, and amino acid metabolism. Accumulating evidence that some of these changes seem to be independent of weight loss questions the rationale of using body mass index as the major indication for surgery in diabetic patients. Understanding the complex mechanisms and interactions underlying improved glycemic control could lead to novel therapeutic targets and would also allow for greater individualization of therapy and optimization of surgical outcomes.

Topics: Bariatric Surgery; Body Mass Index; Caloric Restriction; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Homeostasis; Humans; Incretins; Insulin Resistance; Male; Obesity, Morbid; Peptide YY; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome; Weight Loss

Polycystic ovary syndrome (PCOS) is an endocrine disease of women in reproductive age. It is characterized by anovulation and hyperandrogenism. Most often patients with PCOS have metabolic abnormalities such as dyslipidemia, insulin resistance, and glucose intolerance. It is not surprising that obesity is high prevalent in PCOS. Over 60 % of PCOS women are obese or overweight. Modulation of appetite and energy intake is essential to maintain energy balance and body weight. The gastrointestinal tract, where nutrients are digested and absorbed, plays a central role in energy homeostasis. The signals from the gastrointestinal tract arise from the stomach (ghrelin release), proximal small intestine (CCK release), and distal small intestine (GLP-1 and PYY) in response to food. These hormones are recognized as "appetite regulatory hormones." Weight loss is the key in the treatments of obese/overweight patients with PCOS. However, current non-pharmacologic management of body weight is hard to achieve. This review highlighted the gastrointestinal hormones, and discussed the potential strategies aimed at modifying hormones for treatment in PCOS.

Topics: Cholecystokinin; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Peptide YY; Polycystic Ovary Syndrome

Insulin resistance and the metabolic syndrome are associated with fasting and postprandial dyslipidemia. This involves the hepatic and intestinal overproduction of very low density lipoproteins (VLDL) and chylomicron particles, respectively, which give rise to atherogenic remnants upon lipolysis in the circulation. Recently, the insulin secretagogue glucagon-like peptide-1 (GLP-1) has received attention not only as an anti-diabetic therapy for regulating glycaemia, but also as a regulator of lipid and lipoprotein metabolism. In fact, agents that raise endogenous bioactive levels of GLP-1 (dipeptidyl peptidase 4 inhibitors) and agents that directly stimulate GLP-1 receptors (GLP-1 receptor agonists) have been assessed in both preclinical and clinical trials for their ability to modulate plasma lipid parameters. Here we describe current evidence supporting a role for GLP-1 in preventing elevated intestinal chylomicron output and postprandial hypertriglyceridemia--an independent predictor of cardiovascular risk. Furthermore, we examine a role for GLP-1 in regulating fasting hepatic VLDL production and hindering the development of a potentially devastating comorbidity, hepatic steatosis. Possible mechanisms of action of GLP-1 are discussed including a reduction in intestinal absorption of dietary lipid and enhanced hepatic fatty acid oxidation or autophagy. Finally, we discuss the current controversy over whether these effects could occur via direct receptor stimulation or alternative, indirect pathways. We conclude that GLP- 1-based therapies appear promising in the management of diabetic dyslipidemia, and further studies are warranted to elucidate their mechanisms of action in both the intestine and liver.

Topics: Animals; Cardiovascular Diseases; Chylomicrons; Dyslipidemias; Fasting; Fatty Liver; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Intestinal Mucosa; Lipid Metabolism; Lipoproteins; Liver; Postprandial Period; Risk Factors; Triglycerides

Glucagon-like peptide-1 (GLP-1), is a hormone secreted by small intestine. Consumption of food or glucose stimulates synthesis and secretion of GLP-1 in the bloodstream, which in turn stimulates insulin secretion from pancreas and delays gastric emptying. Owing to the favorable spectrum of effects on reduction of hyperglycemia and body weight, GLP-1 mimetics are intensely pursued as therapies for the treatment of type 2 diabetes (T2DM). Even after intensive control of hyperglycemia, the propensity for cardiovascular disease cannot be totally negated in diabetic patients. A major reason for the cardiovascular disease risk in diabetic patients is underlying dyslipidemia, also termed as diabetic dyslipidemia. It is characterized by high concentrations of triglycerides and LDL cholesterol, and lowered HDL cholesterol in plasma, which are associated with hyperglycemia. Increased insulin resistance gives rise to increased free fatty acids in bloodstream, which is the main reason for the lipid changes appearing in diabetic dyslipidemia. The secondary complications like atherosclerosis and other cardiovascular diseases may be predicted with the blood concentrations of triglycerides and cholesterol, due to the correlation proven in clinic. Hence, new drugs that target diabetic dyslipidemia will always be useful in therapy. Apart from its actions on body weight and glucose, GLP-1 can also regulate cholesterol and triglycerides by numerous ways. Acute and long term treatment with either GLP-1 or its stable analogs reduced fasting as well as postprandial lipids in healthy as well as T2DM patients. GLP-1R signaling reduces VLDL-TG production rate from liver, reduces hepatic TG content by modulating key enzymes of lipid metabolism in liver, and impairs hepatocyte de novo lipogenesis and β-oxidation. GLP-1 can also modulate reverse cholesterol transport. Apart from these direct effects on lipid metabolism, GLP-1 also reduces atherosclerotic events by inhibiting expression of atherogenic inflammatory mediators, suppressing smooth muscle cell proliferation and stimulating NO production. This review mainly deliberates the association of GLP-1 in lipid regulation via lipid absorption, hepatic cholesterol metabolism, reverse cholesterol transport and progression of atherosclerosis.

Topics: Anticholesteremic Agents; Body Weight; Cholesterol; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin Resistance; Lipid Metabolism; Receptors, Glucagon; Risk Factors; Signal Transduction; Treatment Outcome; Triglycerides

Glucagon-like peptide-1 (GLP-1)-based therapies have demonstrated efficacy and safety in treating type 2 diabetes, which shares a similar pathophysiological mechanism with non-alcoholic fatty liver disease (NAFLD). Recent studies showed that glucose-induced GLP-1 secretion was decreased in patients with NAFLD and that the level of dipeptidyl peptidase-4, which inactivates intact GLP-1, was upregulated. Moreover, the expression of the GLP-1 receptor was downregulated in livers from patients with NAFLD, indicating an association of defective GLP-1 signalling with NAFLD. Notably, GLP-1-based therapies are reported to be effective in improving hepatic endpoints in patients with NAFLD, such as reducing hepatic fat content, hepatic steatosis and plasma transaminase levels, and preventing fibrosis. GLP-1-based therapies are beneficial for body weight control and glycaemic normalisation, which are important for the management of NAFLD. Moreover, clinical and preclinical studies showed that GLP-1-based agents might directly exert their actions on the liver through activation of functional GLP-1 receptors in hepatocytes. The possible mechanisms involve regulating gene expression that is associated with insulin resistance and lipid metabolism, and suppressing oxidative stress in the liver cells, thus preventing the development and progression of NAFLD. Based on these promising data, large-scale randomised controlled trials are warranted to assess the efficacy and safety of GLP-1-based therapies in treating NAFLD.

Topics: Animals; Antioxidants; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Insulin Resistance; Lipid Metabolism; Liver; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Receptors, Glucagon; Signal Transduction; Treatment Outcome

Type II diabetes (T2D) is a progressive condition affecting approximately 350 million adults worldwide. Whilst skeletal muscle insulin resistance and beta-cell dysfunction are recognised causes of T2D, progressive loss of lean muscle mass (reducing surface area for glucose disposal area) in tandem with ageing-related adiposity (i.e. sarcopenic obesity) also plays an important role in driving hyperglycaemia progression. The anabolic effects of nutrition on the muscle are driven by the uptake of amino acids, into skeletal muscle protein, and insulin plays a crucial role in regulating this. Meanwhile glucagon-like peptide (GLP-1) and glucose- dependent insulinotropic peptide (GIP) are incretin hormones released from the gut into the bloodstream in response to macronutrients, and have an established role in enhancing insulin secretion. Intriguingly, endocrine functions of incretins were recently shown to extend beyond classical insulinotropic effects, with GLP-1/GIP receptors being found in extra-pancreatic cells i.e., skeletal muscle and peripheral (muscle) microvasculature. Since, incretins have been shown to modulate blood flow and muscle glucose uptake in an insulin-independent manner, incretins may play a role in regulating nutrient-mediated modulation of muscle metabolism and microvascular tone, independently of their insulinotropic effects. In this review we will discuss the role of skeletal muscle in glucose homeostasis, disturbances related to insulin resistance, regulation of skeletal muscle metabolism, muscle microvascular abnormalities and disturbances of protein (PRO) metabolism seen in old age and T2D. We will also discuss the emerging non-insulinotropic role of GLP-1 in modulating skeletal muscle metabolism and microvascular blood flow.

Topics: Blood Flow Velocity; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Microcirculation; Muscle, Skeletal

The glucagon-like peptide-1 (GLP-1) mimetics are an established therapeutic option for patients with type 2 diabetes. However, the properties of the GLP-1 mimetics go beyond the strict metabolic control of the patients with diabetes. The neuroprotective effects of GLP-1 have been shown in recent studies opening new areas of research in neurodegenerative diseases such as Alzheimer's disease (AD), among others. AIM. Systematic review including experimental studies and human clinical trials demonstrating the neuroprotective properties of GLP-1 mimetics in AD.. The experimental studies that have been conducted in rodent models of AD have demonstrated the neuroprotective properties of GLP-1 in the central nervous system reducing beta-amyloid plaques, the oxidative stress and the inflammatory brain response. Clinical trials in patients with cognitive impairment and AD testing the effects of GLP-1 analogs have recently started.. The GLP-1 analogs have neuroprotective properties. Considering that type 2 diabetes is a risk factor for cognitive impairment and dementia, the benefits of GLP-1 mimetics on cognition must be considered. Likewise, the GLP-1 mimetics represent a promising treatment for neurodegenerative diseases such as AD.. Analogos del glucagon-like peptide-1 (GLP-1): una nueva estrategia de tratamiento para la enfermedad de Alzheimer?. Introduccion. Los analogos del glucagon-like peptide-1 (GLP-1) son una opcion terapeutica establecida en los pacientes con diabetes tipo 2. Sin embargo, las propiedades de los analogos del GLP-1 van mas alla del control estrictamente metabolico del paciente diabetico. Los efectos neuroprotectores de los analogos del GLP-1 se han puesto de manifiesto en estudios recientes y han abierto nuevos campos de investigacion en trastornos neurodegenerativos como la enfermedad de Alzheimer (EA), entre otros. Objetivo. Revision sistematica de los estudios experimentales y ensayos clinicos en humanos que demuestran las propiedades neuroprotectoras de los analogos del GLP-1 en la EA. Desarrollo. Los estudios experimentales que se han llevado a cabo en modelos de roedores con EA demuestran las propiedades neuroprotectoras de los analogos del GLP-1 sobre el sistema nervioso central que reducen las placas de beta-amiloide, el estres oxidativo y la respuesta inflamatoria cerebral. Recientemente se han puesto en marcha estudios con analogos del GLP-1 en humanos con deterioro cognitivo y EA. Conclusiones. Los analogos del GLP-1 presentan propiedades neuroprotectoras. Al considerarse la diabetes tipo 2 un factor de riesgo para el deterioro cognitivo y la demencia, deben considerarse los beneficios de los analogos del GLP-1 sobre la cognicion. Del mismo modo, los analogos del GLP-1 suponen un tratamiento prometedor en la EA.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Brain Chemistry; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Models, Neurological; Neuroprotective Agents; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Factors; Venoms

The hormone glucagon-like peptide (GLP-1) is secreted from gut endocrine L cells in response to ingested nutrients. The activities of GLP-1 include stimulating insulin gene expression and biosynthesis, improving β-cell proliferation, exogenesis, and survival. Additionally, it prevents β-cell apoptosis induced by a variety of cytotoxic agents. In extrapancreatic tissues, GLP-1 suppresses hunger, delays gastric emptying, acts as an ileal brake, and increases glucose uptake. The pleiotropic actions of GLP-1, especially its glucose-lowering effect, gave rise to the suggestion that it is a novel approach to insulin resistance treatment. Hormones secreted from the gut including GLP-1, which are involved in the regulation of insulin sensitivity and secretions, have been found to be affected by nutrient intake. In recent years, there has been a growing interest in the effect nutrients may have on GLP-1 secretion; some frequently studied dietary constituents include monounsaturated fatty acids, fructooligosaccharides, and glutamine. This review focuses on the influence that the carbohydrate, fat, and protein components of a meal may have on the GLP-1 postprandial responses.

Topics: Animals; Cell Proliferation; Diabetes Mellitus, Type 2; Dietary Fats; Dietary Fiber; Dietary Proteins; Gastric Emptying; Glucagon-Like Peptide 1; Glutamine; Humans; Insulin; Insulin Resistance; Non-Nutritive Sweeteners; Postprandial Period

Type 2 diabetes mellitus (T2DM) is a multisystem disease comprising numerous metabolic defects that contribute to the development of hyperglycemia. Although insulin resistance in the skeletal muscle and liver together with progressive beta cell failure are traditionally thought of as the core defects responsible for the development and progression of hyperglycemia, research over the past 2 decades has revealed a far more complex interaction of organs and tissues, with consequences for the fundamental understanding of the mechanisms of glucose disequilibrium and the nature of T2DM itself. Dysfunctions in the gastrointestinal tract, adipose tissue, pancreatic alpha cells, brain, and kidneys have all been described, and together with insights into the involvement of liver, muscle, and beta cells produce a more robust picture of T2DM. The function of the kidneys in abnormal glucose homeostasis is a striking example of this evolution in T2DM knowledge, as the role of glucose transporters in regulating plasma glucose levels and producing hyperglycemia has enhanced current understanding of T2DM. As pathophysiologic mechanisms and defects continue to be discovered, they offer an expansion of potential targets for treatment of T2DM.

Topics: Adipocytes; Appetite; Brain; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Humans; Insulin Resistance; Insulin-Secreting Cells; Kidney; Liver; Muscle, Skeletal; Obesity; Sodium-Glucose Transport Proteins

Topics: Diabetes Mellitus; Education, Medical, Continuing; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Practice Guidelines as Topic

Insulin resistance has been associated with the development of type 2 diabetes, obesity, hypertension, dyslipidemia, atherosclerosis, and thus with increased cardiovascular morbidity and mortality. Insulin resistance precedes the onset of type 2 diabetes by many years. Targeting the pathophysiologic defects that characterize the onset of diabetes is more likely to achieve a durable glucose control and to delay disease progression. Incretins are gut-derived peptides that stimulate in a glucose-dependent mechanism insulin secretion and action. Glucose-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors both decrease fasting and postprandial glucose levels. In addition, GLP-1 analogues promote weight loss and exert a favorable effect on several cardiovascular risk factors. Data from human and experimental studies implicate that GLP-1 analogues and to a less extend DPP-4 inhibitors enhance insulin sensitivity. This review summarizes the current knowledge regarding the impact of GLP-1 analogues and DPP-4 inhibitors on insulin resistance.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance

The concept of IL-6 as a deleterious interleukin was challenged by its anti-inflammatory actions.. The beneficial health effects of exercise and the crosstalk between insulin-sensitive tissues and insulin-producing cells are mediated by IL-6.. IL-6 displays pleiotropic functions in a tissue-specific and physiological context-dependent manner. There is evidence suggesting that IL-6 worsens insulin resistance in the liver and adipose tissue, while improving insulin sensitivity in the muscle. The effects of this cytokine are influenced by its acute or chronical presence, the latter being associated with insulin resistance. IL-6 has anti-inflammatory effects and a compensatory role in obesity by increasing islet GLP-1 production. The therapeutic approach of blocking IL-6 signal can be diabetogenic.

Topics: Anti-Inflammatory Agents; Enteroendocrine Cells; Exercise; Genetic Pleiotropy; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Interleukin-6; Intestines; Liver; Obesity; Pancreas

Current strategies for the treatment of type 2 diabetes mellitus promote individualized plans to achieve target glucose levels on a patient-by-patient basis while minimizing treatment related risks. Maintaining glycemic control over time is a significant challenge because of the progressive nature of diabetes as a result of declining β-cell function. This article identifies complications of non-insulin treatments for diabetes. The major classes of medications are reviewed with special focus on target population, mechanism of action, effect on weight, cardiovascular outcomes and additional class-specific side effects including effects on bone. Effects on β-cell function are also highlighted.

Topics: Biguanides; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Sulfonylurea Compounds; Thiazolidinediones

The glucagon-like peptide-1 receptors agonists (GLP1RA) are a relatively new class of drugs, used for management of type 2 diabetes. This review studies the characteristics of these drugs, focusing upon their mechanism of action, intra-class differences, and utility in clinical practice. It compares them with other incretin based therapies, the dipeptidyl peptidase-IV inhibitors, and predicts future developments in the use of these molecules, while highlighting the robust indications for the use of these drugs.

Topics: Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Receptors, Glucagon

In this article, we review the results that can be expected after significant weight loss in patients with type 2 diabetes mellitus. We provide consensus-based documentation supported by the American Diabetes Association, the European Association for the Study of Diabetes, and the International Diabetes Federation on the importance of physical exercise, metabolic-bariatric surgery, and drug therapy. Lastly, we report the results of studies published in the last few years on glucagon-like peptide-1 analogs and the new family of oral drugs known as gliflozins, specifically studies published on dapagliflozin.

Topics: Bariatric Surgery; Benzhydryl Compounds; Causality; Comorbidity; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Reducing; Disease Management; Evidence-Based Medicine; Exercise Therapy; Glucagon-Like Peptide 1; Glucosides; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Metabolic Syndrome; Obesity; Practice Guidelines as Topic; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

In this study, we review the efficacy and safety limitations of insulin-dependent oral antidiabetic agents. In terms of efficiency, the main drawback of metformin, sulfonylureas, gliptins and -to a lesser extent-glitazones is durability. No drug per se is able to maintain stable blood glucose control for years. Metformin, sulfonylureas and gliptins have demonstrated safety. Experience with the first two drug groups is more extensive. The main adverse effect of metformin is gastrointestinal discomfort. Major concerns related to the use of sulfonylureas are hypoglycemia and weight gain. The use of pioglitazone has been associated with an increased risk of bladder cancer, edema, heart failure, weight gain, and distal bone fractures in postmenopausal women. The most common adverse reactions associated with glucagon-like peptide-1 agonists are gastrointestinal discomfort that sometimes leads to treatment discontinuation.

Topics: Contraindications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Drug Tolerance; Fractures, Spontaneous; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Metformin; Pioglitazone; Sulfonylurea Compounds; Thiazolidinediones; Urinary Bladder Neoplasms; Weight Gain

Topics: Asian People; Bariatric Surgery; Diabetes Mellitus, Type 2; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Laparoscopy; Obesity, Morbid

Bariatric surgery managing/preventing complications of severe overweight is nowadays widely accepted as a mainstay in the treatment of morbid obesity. Its role is particularly important in type 2 diabetes developing on the base of long-standing significant overweight. The glycemic control improves within days-weeks after these surgeries, when weight loss and reduction of the visceral fat mass is barely detectable. This short term effect is probably due to an increased secretion of glucagon-like peptide and, as a consequence, an improvement in hepatic insulin sensitivity as well as the whole body glucose uptake. Besides the prolonged glucagon-like peptide effects, the favourable long term effect of these operations - lasting for 10 years even after surgery - is the decrease of visceral fat mass and elimination of harmful influence of cytokines produced by the fatty tissue. The article overviews the metabolic effects of these procedures, their undoubted advantages and potential risks.

Topics: Bariatric Surgery; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Humans; Hungary; Insulin; Insulin Resistance; Intra-Abdominal Fat; Male; Obesity, Morbid; Peptide YY; United States; Weight Loss

According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.

Topics: Alzheimer Disease; Biomimetics; Brain; Central Nervous System; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Liraglutide; Peptides; Venoms

Hyperglycaemia frequently occurs in the critically ill, in patients with diabetes, as well as those who were previously glucose-tolerant. The terminology 'stress hyperglycaemia' reflects the pathogenesis of the latter group, which may comprise up to 40% of critically ill patients. For comparable glucose concentrations during acute illness outcomes in stress hyperglycaemia appear to be worse than those in patients with type 2 diabetes. While several studies have evaluated the optimum glycaemic range in the critically ill, their interpretation in relation to clinical recommendations is somewhat limited, at least in part because patients with stress hyperglycaemia and known diabetes were grouped together, and the optimum glycaemic range was regarded as static, rather than dynamic, phenomenon. In addition to hyperglycaemia, there is increasing evidence that hypoglycaemia and glycaemic variability influence outcomes in the critically ill adversely. These three categories of disordered glucose metabolism can be referred to as dysglycaemia. While stress hyperglycaemia is most frequently managed by administration of short-acting insulin, guided by simple algorithms, this does not treat all dysglycaemic categories; rather the use of insulin increases the risk of hypoglycaemia and may exacerbate variability. The pathogenesis of stress hyperglycaemia is complex, but hyperglucagonaemia, relative insulin deficiency and insulin resistance appear to be important. Accordingly, novel agents that have a pathophysiological rationale and treat hyperglycaemia, but do not cause hypoglycaemia and limit glycaemic variability, are appealing. The potential use of glucagon-like peptide-1 (or its agonists) and dipeptyl-peptidase-4 inhibitors is reviewed.

Topics: Analysis of Variance; Biomarkers; Blood Glucose; Critical Illness; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Risk Factors

In prediabetes and diabetes, hyperglycemia is often accompanied by fasting and postprandial hyperlipidemia. Incretin-based therapies are in increasing clinical use for treating hyperglycemia, but recent evidence emphasizes their ability to improve lipoprotein abnormalities. This is significant as heightened postprandial chylomicron levels during insulin resistance contribute to atherogenic diabetic dyslipidemia. This review summarises the evidence supporting a beneficial effect of incretin-based therapies on diabetic dyslipidemia through modulation of intestinal lipoprotein metabolism.. Preclinical and clinical trials have involved administering dipeptidyl peptidase IV inhibitors and glucagon-like peptide-1 receptor (GLP-1R) agonists to healthy and insulin-resistant individuals. Results indicate that enhancing GLP-1R signalling decreases postprandial apoB48-containing triglyceride-rich lipoproteins. These effects may be direct or may be secondary to reduced gastric emptying, increased insulin secretion, or enhanced chylomicron clearance.. Enhancing GLP-1R activity improves intestinal lipoprotein metabolism. GLP-1-mediated control of postprandial chylomicron production may be lost in type 2 diabetes in which the incretin response is impaired and in which associated dyslipidemia involves an excess of atherogenic chylomicron remnants. Further human studies are needed to better establish the impact of incretin-based therapies on dyslipidemia, as this offers a major new therapeutic approach to reduce cardiovascular risk in type 2 diabetic patients.

Topics: Animals; Chylomicrons; Dyslipidemias; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Incretins; Insulin Resistance; Intestinal Absorption; Lipid Metabolism; Postprandial Period

Studies of patients going into diabetes remission after gastric bypass surgery have demonstrated the important role of the gut in glucose control. The improvement of type 2 diabetes after gastric bypass surgery occurs via weight dependent and weight independent mechanisms. The rapid improvement of glucose levels within days after the surgery, in relation to change of meal pattern, rapid nutrient transit, enhanced incretin release and improved incretin effect on insulin secretion, suggest mechanisms independent of weight loss. Alternatively, insulin sensitivity improves over time as a function of weight loss. The role of bile acids and microbiome in the metabolic improvement after bariatric surgery remains to be determined. While most patients after bariatric surgery experienced sustained weight loss and improved metabolism, small scale studies have shown weight regain and diabetes relapse, the mechanisms of which remain unknown.

Topics: Bariatric Surgery; Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Follow-Up Studies; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance; Malnutrition; Metagenome; Obesity; Recurrence; Weight Loss

With growing awareness that long-term hyperglycemia is directly implicated in the tissue damage characteristic of diabetes, there has been a corresponding increase in clinicians' willingness to employ intensive treatment to achieve euglycemia, which may require diabetes drugs in combination. The expanding array of drugs with different mechanisms of action calls for a clear method of classification to guide rational combination therapy. Contemporary and historical literature was surveyed to document changes in awareness of toxicity from hyperglycemia and consequent changes in treatment strategy. References were selected for clinical applicability and explanation of drug mechanisms of action, with the goal of proposing a useful schema for classification. Diabetes drugs may be classified in the following categories: insulin providers, which increase the supply of insulin through administration of exogenous human insulin or analogues or drugs that stimulate endogenous insulin secretion (sulfonylureas and meglitinides are direct insulin secretagogues, whereas glucagon- like peptide-1 analogues and dipeptidyl peptidase-4 inhibitors act to increase the supply of insulin); insulin sensitizers (metformin, thiazolidinediones), which offset the effects of insulin resistance; and insulin-independent drugs, which work in the gut to impede intestinal absorption of glucose into the circulation (α-glucosidase inhibitors) or in the kidney to prevent renal reabsorption of glucose back into the circulation (sodium-glucose cotransporter 2 inhibitors, currently investigational). Awareness of these categories facilitates rational combinations of drugs with differing mechanisms of action to address hyperglycemia from separate directions, in accordance with current treatment guidelines.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Sodium-Glucose Transporter 2; Sulfonylurea Compounds; Thiazolidinediones

Roux-en-Y gastric bypass (RYGB) greatly improves glycaemic control in morbidly obese patients with type 2 diabetes, in many even before significant weight loss. Understanding the responsible mechanisms may contribute to our knowledge of the pathophysiology of type 2 diabetes and help identify new drug targets or improve surgical techniques. This review summarises the present knowledge based on pathophysiological studies published during the last decade. Taken together, two main mechanisms seem to be responsible for the early improvement in glycaemic control after RYGB: (1) an increase in hepatic insulin sensitivity induced, at least in part, by energy restriction and (2) improved beta cell function associated with an exaggerated postprandial glucagon-like peptide 1 secretion owing to the altered transit of nutrients. Later a weight loss induced improvement in peripheral insulin sensitivity follows.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin Resistance; Insulin-Secreting Cells; Male; Obesity, Morbid; Time Factors; Treatment Outcome

Type 2 diabetes mellitus is increasing over time as result of the obesity epidemics. In fact, the prevalence of Type 2 diabetes across Europe in 2010 was estimated to be 8.2% of the population and its projection for 2030 sees figures of 10.1%. This increase in the number of diabetic individuals has also dramatically raised the health expense, with spending on diabetes in Europe in 2010 accounting for 10% of the total healthcare cost. A meta-analysis of the literature evidenced that the clinical and laboratory manifestations of Type 2 diabetes are resolved in 78.1%, and are improved in 86.6% of obese patients (body mass index >35 kg/m²) after bariatric surgery. However, a gradation of effects of different surgical techniques in improving glucose control does exist, with the largest and durable effects observed in prevalently malabsorptive procedures. The outcome of bariatric surgery on insulin sensitivity and secretion is different in relation to the type of operation performed. In fact, while Roux-en-Y Gastric Bypass enhances insulin secretion after a meal thus improving glucose metabolism, Bilio-Pancreatic Diversion acts through the amelioration of insulin sensitivity allowing a subsequent reduction of insulin hypersecretion, which is a typical feature of the insulin resistance state. Gastric banding action is mediated uniquely through the weight loss, and the effect of sleeve gastrectomy is still to be elucidated. Incretin secretion is dramatically increased under nutrient stimulation after gastric bypass leading, probably, to an overstimulation of pancreatic β-cells resulting in the increase of insulin secretion.

Topics: Animals; Bariatric Surgery; Body Mass Index; Diabetes Mellitus, Type 2; Gastric Mucosa; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Intestinal Mucosa; Obesity, Morbid

The endothelium is critical for multiple processes occurring on both sides of the vascular wall including regulation of blood flow, maintenance of blood fluidity and control of inflammation. Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and appears to be a critical determinant of cardiovascular events. It is frequently detected in the early stages of type 2 diabetes and even in pre-diabetes conditions. Risk factors for endothelial dysfunction are numerous and include among others fasting and postprandial hyperglycemia and hyperlipidemia, hypertension, obesity, insulin resistance and inflammation. Many of these conditions can be improved by synthetic glucagon like peptide 1 (GLP-1) mimetics or inhibitors of the main GLP-1 degrading enzyme dipeptidyl peptidase 4 (DPP-4). Acute increases in GLP-1 activity abolish endothelial dysfunction induced by high-fat meals or by hyperglycemia. In vitro and preliminary clinical studies also indicate that GLP-1 or GLP-1 agonists can improve endothelial function by direct action on endothelium. GLP-1 or GLP-1 mimetic effects appear to extend to both conduit arteries and the microvasculature, and may depend on activation of endothelial GLP-1 receptors and downstream nitric oxide production. Additional studies are necessary to confirm improvement of endothelial function after prolonged treatment with incretin based medications as well as the cardiovascular benefit of these agents.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Nitric Oxide Synthase Type III

Patients with acute myocardial infarction (AMI) frequently have abnormalities of glucose metabolism and insulin resistance, both of which are associated with a poor outcome. Glucagon-like peptide 1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties which not only controls glucose levels but also has potential beneficial actions on the ischaemic and failing heart. In this review we highlight the underlying pathophysiological mechanisms for the development of hyperglycaemia in AMI, speculate on the potential relationship between GLP-1 and sphingosine-1-phosphate, and review the literature on the role of GLP-1 as an important approach to treating hyperglycaemia in the setting of AMI.

Topics: Animals; Glucagon-Like Peptide 1; Glucose; Humans; Hyperglycemia; Insulin Resistance; Lysophospholipids; Myocardial Infarction; Sphingosine

One major risk factor of type 2 diabetes is the impairment of glucose-induced insulin secretion which is mediated by the individual genetic background and environmental factors. In addition to impairment of glucose-induced insulin secretion, impaired glucagon-like peptide (GLP)1-induced insulin secretion has been identified to be present in subjects with diabetes and impaired glucose tolerance, but little is known about its fundamental mechanisms. The state of GLP1 resistance is probably an important mechanism explaining the reduced incretin effect observed in type 2 diabetes. In this review, we address methods that can be used for the measurement of insulin secretion in response to GLP1 in humans, and studies showing that specific diabetes risk genes are associated with resistance of the secretory function of the β-cell in response to GLP1 administration. Furthermore, we discuss other factors that are associated with impaired GLP1-induced insulin secretion, for example, insulin resistance. Finally, we provide evidence that hyperglycaemia per se, the genetic background and their interaction result in the development of GLP1 resistance of the β-cell. We speculate that the response or the non-response to therapy with GLP1 analogues and/or dipeptidyl peptidase-4 (DPP-IV) inhibitors is critically dependent on GLP1 resistance.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Male

Type 2 diabetes mellitus (T2DM) is one of the most troubling chronic disease regarding the huge number of new cases diagnosed annually worldwide. Currently available oral antidiabetic drugs (OADs) attempt to correct the underlying pathophysiological dysfunctions leading to T2DM: insulin resistance for the insulin sensitizers (metformin and thiazolidinediones), and impaired insulin secretion for the insulin secretagogues (sulfonylureas, glinides and more recently incretin mimetics). Incretin-based therapies include GLP-1 receptor agonists that provide pharmacologic levels of GLP-1 receptor stimulation beyond those that would occur from the action of the native hormone alone, and dipeptidyl-peptidase-4 (DPP-4) inhibitors that preserve endogenous GLP-1 by decreasing its degradation by the DPP-4 enzyme. In 2012, the development of new OADs aims to target untapped pathophysiological aspects of the disease (kidney homeostasis, glucagon signalling, chronic low-grade inflammation) for tailoring glycaemic control in T2DM. SGLT-2 inhibitors are the most advanced new OADs that lower HbA1C by increasing glycosuria and lead to a moderate weight loss. Although there is genuine hope that the range of OADs can be extended, a long-term evaluation of side effects and true clinical benefits is necessary.

Topics: Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Glycosuria; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Receptors, G-Protein-Coupled; Receptors, Glucagon; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones

GLP-1 analogues have been proven to be effective in the treatment of type 2 diabetes mellitus. They stimulate insulin production and secretion, and suppress glucagon secretion, depending on the blood glucose level. They also have an effect on the brain, enhancing satiety, and on the gut, where they delay gastric emptying. Theoretically, in type 2 diabetes mellitus patients, the combination of a GLP-1 analogue with insulin seems attractive, because of the weight loss perceived in users of GLP-1 analogues in contrast to the weight gain seen in most patients starting insulin therapy, leading to even more insulin resistance. There are only a few randomised controlled trials which have studied this combination and several uncontrolled studies, which will be reviewed here.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Treatment Outcome

Regulatory role of the brain in energy expenditure, appetite, glucose metabolism, and central effects of insulin has been prominently studied. Certain neurons in the hypothalamus increase or decrease appetite via orexigenes and anorexigenes, regulating energy balance and food intake. Hypothalamus is the site of afferent and efferent stimuli between special nuclei and beta- and alpha cells, and it regulates induction/inhibition of glucose output from the liver. Incretines, produced in intestine and in certain brain cells (brain-gut hormones), link to special receptors in the hypothalamus. Central role of insulin has been proved both in animals and in humans. Insulin gets across the blood-brain barrier, links to special hypothalamic receptors, regulating peripheral glucose metabolism. Central glucose sensing, via "glucose-excited" and "glucose-inhibited" cells have outstanding role. Former are active in hyperglycaemia, latter in hypoglycaemia, via influencing beta- and alpha cells, independently of traditional metabolic pathways. Evidence of brain insulin resistance needs centrally acting drugs, paradigm changes in therapy and prevention of metabolic syndrome, diabetes, cardiovascular and oncological diseases.

Topics: Animals; Appetite Depressants; Appetite Regulation; Blood Glucose; Brain; Ceramides; Cognition; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hypothalamus; Incretins; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Metabolic Syndrome; Neuropeptides; Non-alcoholic Fatty Liver Disease; Oligopeptides; Orexins; Pyrrolidonecarboxylic Acid

The evolving concept of how nutrient excess and inflammation modulate metabolism provides new opportunities for strategies to correct the detrimental health consequences of obesity. In this review, we focus on the complex interplay among lipid overload, immune response, proinflammatory pathways and organelle dysfunction through which excess adiposity might lead to type 2 diabetes. We then consider evidence linking dysregulated CNS circuits to insulin resistance and results on nutrient-sensing pathways emerging from studies with calorie restriction. Subsequently, recent recommendations for the management of type 2 diabetes are discussed with emphasis on prevailing current therapeutic classes of biguanides, thiazolidinediones and incretin-based approaches.

Topics: Adipose Tissue; Caloric Restriction; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Hypoglycemic Agents; Inflammation; Insulin Resistance; Insulin-Secreting Cells; Metformin; Signal Transduction; Thiazolidines

The intestine is an important metabolic organ that has gained attention in recent years for the newly identified role that it plays in the pathophysiology of various metabolic diseases including obesity, insulin resistance and diabetes. Recent insights regarding the role of enteroendocrine hormones, such as GIP, GLP-1, and PYY in metabolic diseases, as well as the emerging role of the gut microbial community and gastric bypass bariatric surgeries in modulating metabolic function and dysfunction have sparked a wave of interest in understanding the mechanisms involved, in an effort to identify new therapeutics and novel regulators of metabolism. This review summarizes the current evidence that the gastrointestinal tract has a key role in the development of obesity, inflammation, insulin resistance and diabetes and discusses the possible players that can be targeted for therapeutic intervention.

Topics: Animals; Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Inflammation; Insulin Resistance; Metabolic Diseases; Metagenome; Obesity; Peptide YY

The increasing prevalence, variable pathogenesis, progressive natural history, and complications of type 2 diabetes emphasise the urgent need for new treatment strategies. Longacting (eg, once weekly) agonists of the glucagon-like-peptide-1 receptor are advanced in development, and they improve prandial insulin secretion, reduce excess glucagon production, and promote satiety. Trials of inhibitors of dipeptidyl peptidase 4, which enhance the effect of endogenous incretin hormones, are also nearing completion. Novel approaches to glycaemic regulation include use of inhibitors of the sodium-glucose cotransporter 2, which increase renal glucose elimination, and inhibitors of 11β-hydroxysteroid dehydrogenase 1, which reduce the glucocorticoid effects in liver and fat. Insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed. Early proof of principle has been shown for compounds that enhance and partly mimic insulin action and replicate some effects of bariatric surgery.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Allylamine; Anticholesteremic Agents; Bariatric Surgery; Bile Acids and Salts; Cardiovascular System; Colesevelam Hydrochloride; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucokinase; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liver; Obesity; Peptides; Randomized Controlled Trials as Topic; Receptors, Dopamine D2; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Venoms

Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities.

Topics: Adipose Tissue; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diabetic Retinopathy; Epigenesis, Genetic; Female; Fetal Development; Genetic Predisposition to Disease; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Life Style; Liver; Muscle, Skeletal; Myocardium; Obesity; Prediabetic State; Pregnancy

Metabolic and neurodegenerative disorders have a growing prevalence in Western countries. Available epidemiologic and neurobiological evidences support the existence of a pathophysiological link between these conditions. Glucagon-like peptide 1 (GLP-1), whose activity is reduced in insulin resistance, has been implicated in central nervous system function, including cognition, synaptic plasticity, and neurogenesis. We review the experimental researches suggesting that GLP-1 dysfunction might be a mediating factor between Type 2 diabetes mellitus (T2DM) and neurodegeneration. Drug treatments enhancing GLP-1 activity hold out hope for treatment and prevention of Alzheimer's disease (AD) and cognitive decline.

Topics: Animals; Cognition Disorders; Diabetes Mellitus, Type 2; Endocrinology; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Nerve Degeneration; Therapies, Investigational

Type 2 diabetes is making up to 90% of the all diabetic cases. In addition to insulin resistance, insufficient B-cell function also plays an important role in the pathogenesis of the disease. The insufficient production and secretion of insulin can be increased by secretagogue drugs, like sulfonylureas and incretin mimetics/enhancers. In recent years growing number of genetic failures of the B-cells has been detected. These genetic variants can influence the efficacy of secretagogue drugs. Some of these gene polymorphisms were identified in the genes encoding the KATP channel (KCNJ11 and ABCC8). These mutations are able either to reduce or increase the insulin secretion and can modify the insulin response to sulfonylurea treatment. Other polymorphisms were found on genes encoding enzymes or transcription factors. In recent years, the genetic variants of TCF7L2 and its clinical importance have been intensely studied. Authors give a summary of the above gene polymorphisms and their role in insulin secretion.

Topics: ATP-Binding Cassette Transporters; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin Secretion; KATP Channels; Mutation; Polymorphism, Genetic; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Compounds; Sulfonylurea Receptors

Topics: Animals; Diabetic Nephropathies; Drug Design; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Insulin Resistance; Metabolic Syndrome; Mice; Molecular Targeted Therapy; PPAR gamma; Rats; Thiazolidines

Glucose homeostasis is controlled primarily by the opposing actions of insulin and glucagon, hormones that are secreted by the islets of Langerhans from β-cells and α-cells and Δ-cells, their role in glucose homeostasis still needs identifying. Insulin secretion is increased in response to elevated blood glucose to maintain normoglycemia by stimulating glucose transport in muscles and adipocytes and reducing glucose production by inhibiting gluconeogenesis in the liver. Whereas glucagon secretion is suppressed by hyperglycemia, it is stimulated during hypoglycemia, promoting hepatic glucose production and ultimately raising blood glucose levels. Glucagon secretion from pancreatic α-cells is regulated by various mechanisms including glycemia, neural input, and secretion from neighboring β-cells. Glucagon primarily acts on liver to initiate glycogenolysis and gluconeogenesis, resulting in a rapid increase in endogenous production of glucose. With longer stimulation, glucagon action on the liver results in a glucose-sparing activation of free fatty acid oxidation and production of ketones.

Topics: Blood Glucose; Energy Metabolism; Glucagon; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans

The prevalence of obesity and diabetes is epidemic. Severe insulin resistance (defined as the need for > or = 200 units of insulin per day to achieve glycemic control) is commonly seen with obesity and can complicate diabetes management. The management of patients with diabetes who have severe insulin resistance is difficult, and at times frustrating, and requires a multifaceted approach. Weight loss is the best treatment option, which can be a challenging task for patients to achieve and maintain. Medications that decrease insulin needs like metformin, thiazolidinediones, or pramlintide may help, but some patients also need high doses of insulin. This article reviews these different treatment options and provides practical advice on weight loss, use of insulin sensitizers, and use of U-500 insulin.

Topics: Amyloid; Bariatric Surgery; Diabetes Mellitus; Diet, Reducing; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Exercise; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Liraglutide; Metformin; Obesity; Peptides; Thiazolidinediones; Treatment Failure; Venoms; Weight Loss

Obesity is a potent risk factor for the development and progression of type 2 diabetes, and weight loss is a key component of diabetes management. Bariatric surgery results in significant weight loss and remission of diabetes in most patients. After surgery, glycemic control is restored by a combination of enforced caloric restriction, enhanced insulin sensitivity, and increased insulin secretion.

Topics: Bariatric Surgery; Body Mass Index; Caloric Restriction; Diabetes Mellitus, Type 2; Disease Management; Disease Progression; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Risk Factors; Weight Loss

Progressive deterioration of β-cell function is a hallmark of type 2 diabetes mellitus (DM). Together with increasing insulin resistance in peripheral tissues (in both the liver and the skeletal muscle), the inability of pancreatic insulin secretion to manage fasting and postprandial glucose levels results in hyperglycemia. Currently available oral antidiabetes agents improve glycemic parameters, but no single drug addresses the numerous pathophysiologic defects known to contribute to hyperglycemia in patients with type 2 DM. Dysregulation in the incretin system is another component of the pathophysiologic processes that lead to DM. Agents used to correct defects in the incretin system, such as glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors, offer the potential to restore glucose-dependent insulin secretion and improve β-cell function. Glucagon-like peptide 1 receptor agonists also promote weight loss and provide beneficial effects on cardiovascular risk factors. A new approach that promotes the selection of pharmacotherapy for the treatment of patients with DM, with the goal of slowing or reversing the natural history of the disease, may be in order. Clinicians can select agents to address specific pathophysiologic defects to improve glycemia, with the hope of preventing the development of complications.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Insulin Resistance; Islets of Langerhans; Male; Risk Assessment; Treatment Outcome

In the adult, the pancreatic beta-cell mass adapts insulin secretion to meet long-term changes in insulin demand and, in particular, in the presence of insulin resistance that is either physiological, such as pregnancy, or pathophysiological, such as obesity. The failure of beta cells to compensate for insulin resistance is a major component of impaired glucose homeostasis and overt diabetes. This defect is clearly the consequence of a decline of insulin response to glucose due to functional beta-cell deficiency. It is also the consequence of an inability of the endocrine pancreas to adapt the beta-cell mass to insulin demand (pancreas plasticity), which eventually leads to a decrease in functional beta-cell mass. This idea has resulted in considerable attention being paid to the development of new therapeutic strategies aiming to preserve and/or regenerate functional beta-cell mass. The latter is governed by a constant balance between beta-cell growth (replication from pre-existing beta cells and neogenesis from precursor cells) and beta-cell death (mainly apoptosis). Disruption of this balance may lead to rapid and marked changes in beta-cell mass. Glucagon-like peptide-1 (GLP-1), an incretin, enhances beta-cell survival (by activating beta-cell proliferation and differentiation, and inhibiting beta-cell apoptosis), thus contributing to the long-term regulation of insulin secretion by maintaining a functional beta-cell mass. The development of drugs regulating this parameter will be the major challenge of the next few years in the management of type 2 diabetes.

Topics: Adaptation, Physiological; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells

The single-tablet combination of vildagliptin and metformin addresses key defects of type 2 diabetes for improved glycemic control. By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, vildagliptin raises the levels of the active incretin hormones, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. This leads to increased synthesis and release of insulin from the pancreatic beta cells and decreased release of glucagon from the pancreatic alpha cells. The combination tablet also contains metformin, which addresses insulin resistance. The complementary mechanisms of action of the two agents in combination have been shown to provide additive and sustained reductions in hemoglobin A(1c) compared with metformin monotherapy. In active-controlled trials, the vildagliptin-metformin combination has been shown to produce equivalent reductions in hemoglobin A(1c) to pioglitazone-metformin and glimepiride-metformin combinations, without significant risk of hypoglycemia and without causing weight gain. In clinical trials, the overall incidence of any adverse event was similar in patients randomized to vildagliptin plus metformin and placebo plus metformin. Available data support the use of vildagliptin in combination with metformin as a promising second-line treatment for the management of type 2 diabetes and this is reflected in the latest UK National Institute for Health and Clinical Excellence draft guideline for consultation on new agents for blood glucose control in type 2 diabetes.

Topics: Adamantane; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lipids; Metformin; Nitriles; Practice Guidelines as Topic; Pyrrolidines; Safety; Treatment Outcome; Vildagliptin

As a consequence of excess abdominal adiposity and genetic predisposition, type 2 diabetes is a progressive disease, often diagnosed after metabolic dysfunction has taken hold of multiple organ systems. Insulin deficiency, insulin resistance and impaired glucose homeostasis resulting from beta-cell dysfunction characterize the disease. Current treatment goals are often unmet due to insufficient treatment modalities. Even when combined, these treatment modalities are frequently limited by safety, tolerability, weight gain, edema and gastrointestinal intolerance. Recently, new therapeutic classes have become available for treatment. This review will examine the new therapeutic classes of incretin mimetics and enhancers in the treatment of type 2 diabetes.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Treatment Outcome

Obesity is associated with increased insulin resistance and is a well-recognized factor for the development of type 2 diabetes. Unfortunately, most diabetes therapies are associated with further weight gain, a most unwelcome characteristic, given the association of weight gain with deteriorating metabolic control, worsening cardiovascular profiles and decreased adherence to treatment. Therapies that effectively control glycaemia without weight gain or with concomitant weight loss are needed. The aim of this article was to review the existing preclinical and clinical evidences, showing that the family of glucagon-like peptide-1 (GLP-1)-based therapies fulfils these criteria by harnessing the beneficial properties of GLP-1, a naturally occurring incretin hormone with a strong blood glucose-lowering action and the ability to induce weight loss.

Topics: Animals; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Obesity; Weight Loss

Nonalcoholic fatty liver disease (NAFLD), first described in 1980, is now recognized as one of the most common causes of elevated liver enzymes and chronic liver disease in Western countries. The incidence of NAFLD in both adults and children is rising, in conjunction with the burgeoning epidemics of obesity and type 2 diabetes mellitus. NAFLD often coexists with other sequelae of the metabolic syndrome: central obesity, type 2 diabetes, hypertension, and hyperlipidemia. NAFLD encompasses a spectrum of pathologic liver diseases ranging from simple hepatic steatosis to a predominant lobular necro-inflammation, with or without centrilobular fibrosis (called nonalcoholic steatohepatitis or NASH). NASH can progress to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Though the natural history of NASH is still not clearly defined, it has been observed to progress to cirrhosis in 15%-220% of those affected. Insulin resistance is nearly universal in NASH and is thought to play an important role in its pathogenesis leading to dysregulated lipid metabolism. The prevalence of insulin resistance is reported in the general population to be approaching 45%, suggesting that NAFLD and NASH will contin nue to be an important public health concern. To date, NASH has proven to be a difficult disease to treat. Front-line therapy with lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain long term. Given that insulin resistance plays a dominant role in the pathogenesis, many studies have examined the use of insulin sensitizers: the biguanides (metformin), thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone), glucagon-like peptide-1-receptor agonists, or incretins (exenatide)in NASH. This review will provide an overview of insulin resistance in NAFLD and provide a detailed summary on the clinical data regarding the use of insulin sensitizers in NASH.

Topics: Fatty Liver; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Prevalence; Thiazolidinediones; Triglycerides

The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

Topics: Adipokines; Adrenal Glands; Adult; Androgens; Cushing Syndrome; Diabetes Mellitus, Type 2; Endocrine System; Estrogens; Fatty Liver; Female; Glucagon-Like Peptide 1; Gonadal Steroid Hormones; Humans; Hyperlipidemias; Hypothalamus; Hypothyroidism; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Obesity; Pancreas; Pituitary Gland; Polycystic Ovary Syndrome; Postmenopause; Thyroid Gland

Obesity plays a key role in the pathophysiology of type 2 diabetes (T2DM), and weight loss is a major objective, although difficult to achieve with medical treatments. Bariatric surgery has proven its efficacy in obtaining marked and sustained weight loss, and is also associated with a significant improvement in glucose control and even diabetes remission. Roux-en-Y gastric bypass appears to be more effective in diabetic patients than the restrictive gastroplasty procedure. This may be explained not only by greater weight reduction, but also by specific hormonal changes. Indeed, increased levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) may lead to improved beta-cell function and insulin secretion as well as reduced insulin resistance associated with weight loss. The presence of T2DM in obese individuals is a further argument to propose bariatric surgery, and even more so when diabetes is difficult to manage by medical means and other weight-related complications may occur. Bariatric surgery is associated with a better cardiovascular prognosis and reduced mortality, even though acute and long-term complications are present. The observation that surgical rerouting of nutrients triggers changes in the release of incretin hormones that, in turn, ameliorate the diabetic state in the absence of weight loss has led to the recent development of innovative surgical procedures. Thus, bariatric surgery may be said to be progressing towards so-called 'metabolic surgery', which merits further evaluation in patients with T2DM within a multidisciplinary approach that involves both surgeons and endocrinologists.

Topics: Bariatric Surgery; Diabetes Mellitus, Type 2; Gastric Bypass; Gastroplasty; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Obesity, Morbid; Prognosis; Risk Factors; Weight Loss

Endothelial dysfunction is a major characteristic of the atherosclerotic process and can be used to predict the outcome of cardiovascular disease in humans. Together with obesity and insulin resistance, such dysfunction is common among patients with type 2 diabetes and may explain their poor prognosis in connection with such a disease. Insulin resistance in skeletal muscle, adipose tissue, and the liver, a well-characterized feature of obesity and type 2 diabetes, contributes to the impairment of glucose homeostasis. Furthermore, the myocardial muscle can also be resistant to insulin, which might, at least in part, explain the frequent development of heart failure in individuals suffering from type 2 diabetes. The relationship between insulin resistance and endothelial dysfunction has prompted investigations, which reveal that regular exercise, dietary changes, and/or pharmacological agents can both increase insulin sensitivity and improve endothelial function. Glucagon-like peptide-1, an incretin, lowers blood levels of glucose and offers a promising new approach to the treatment of type 2 diabetes mellitus. Its extensive extra-pancreatic effects, including a favorable influence on cardiovascular parameters, are extremely interesting in this connection. The potential pharmacological effects of glucagon-like peptide-1 and its analogues on the endothelium and the heart are discussed in the present review.

Topics: Endothelium; Glucagon-Like Peptide 1; Heart Failure; Humans; Hyperglycemia; Insulin; Insulin Resistance

Glucagon-like peptide-1 (GLP-1), a gastrointestinal hormone mainly produced in the post-prandial state, reduces blood glucose through the stimulation of insulin secretion and the inhibition of glucagon release. Long-acting GLP-1 receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors which increase GLP-1 levels, are used as hypoglycemic treatments in type 2 diabetes. This paper aims at reviewing the potential benefit of those treatments in the prevention of cardiovascular risk in type 2 diabetic patients.. Experimental studies have shown that GLP-1 has several potentially beneficial actions on cardiovascular risk. Some of those, such as protection from myocardial ischemic damage and improvement of cardiac function, have also been demonstrated in humans. However, the equivalence of GLP-1 agonists and DPP-4 inhibitors with GLP-1, with respect to cardiovascular risk profile, cannot be assumed or taken for granted. Drugs of those two classes have been shown to effectively reduce glycated hemoglobin and to have a specific effect on post-prandial glucose; furthermore, they seem to reduce blood pressure and to have some favorable effects on lipid profiles. Additionally, GLP-1 agonists induce weight loss in diabetic patients.. The profile of action of GLP-1 receptor agonists and DPP-4 inhibitors suggests the possibility of an actual reduction in cardiovascular risk, which needs to be confirmed by large long-term clinical trials.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Rate; Humans; Incretins; Insulin Resistance; Myocardial Contraction; Myocardial Ischemia; Risk Factors

The prevalence of obesity and the metabolic syndrome (MS) is on the rise, and subsequently the hepatic manifestation of MS, nonalcoholic fatty liver disease (NAFLD), has become a common entity in clinical practice. Most patients with NAFLD face medical complications related to their underlying MS in other organ systems; however, a small but significant group of patients with the more aggressive form of fatty liver, nonalcoholic steatohepatitis (NASH), are at risk of developing cirrhosis and hepatocellular carcinoma. As patients are generally asymptomatic, often their disease goes unrecognized. This is particularly true for NASH, where liver biopsy is currently required to make the diagnosis. Once diagnosed, no one treatment has been shown to be universally efficacious and those that are of benefit are not without side effects. Effective treatment regimens directed at both decreasing insulin resistance as well as the processes leading to necroinflammation and hepatic fibrosis have been investigated and include lifestyle modification, surgical therapies, and pharmacotherapy. This review focuses on current and potential future therapies for NASH.

Topics: Animals; Antioxidants; Bariatric Surgery; Body Mass Index; Cannabinoids; Cholagogues and Choleretics; Comorbidity; Fatty Liver; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Insulin Resistance; Lactones; Life Style; Metformin; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones; Treatment Outcome; Ursodeoxycholic Acid; Weight Loss

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Middle Aged; Nurse Practitioners; Patient Selection; Primary Health Care

Vildagliptin is a potent, selective and reversible inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for rapid inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). GLP-1 and GIP are important for the maintenance of normal glucose homeostasis as they enhance the sensitivity of insulin (beta-cell) and glucagon (alpha-cell) secretion to glucose. The delicate balance that is achieved by the incretin hormones is disturbed in type 2 diabetes mellitus (T2DM). Mechanistic studies of vildagliptin performed to characterise the effects of DPP-4 inhibition on pancreatic islet function and glucose metabolism have found that vildagliptin produces dose-dependent reductions in DPP-4; these result in persistent levels of active GLP-1 and GIP in the circulation leading to improved beta-cell sensitivity to glucose and glucose-dependent insulin secretion, and improved alpha-cell sensitivity to glucose and reduction in inappropriate glucagon secretion. These islet effects in turn lead to a reduction of the inappropriate endogenous glucose production and glucose utilisation during meals, resulting in improved glucose tolerance, and to a reduction of the inappropriate endogenous glucose production during the postabsorptive period that contributes to a reduced fasting hyperglycaemia. These islet effects are associated with improved insulin sensitivity and reduced meal-related hypertriglyceridaemia. In contrast, the GLP-1 effect of significantly delaying gastric emptying was not evident with vildagliptin treatment. The metabolic benefits of vildagliptin observed in T2DM are also evident in subjects with impaired glucose tolerance. Hence, vildagliptin improves glucose metabolism mainly by improving islet function.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Emptying; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Islets of Langerhans; Lipid Metabolism; Liver; Nitriles; Pyrrolidines; Vildagliptin

Excessive postprandial lipemia is highly prevalent in obese and insulin-resistant/type 2 diabetic individuals and substantially increases the risk of atherosclerosis and cardiovascular disease. This article will review our current understanding of the link between insulin resistance and intestinal lipoprotein overproduction and highlight some of the key recent findings in the field.. Emerging evidence from several animal models of insulin resistance as well as insulin-resistant humans clearly supports the link between insulin resistance and aberrant intestinal lipoprotein metabolism. In insulin-resistant states, elevated free fatty acid flux into the intestine, downregulation of intestinal insulin signaling and upregulation of microsomal triglyceride transfer protein all appear to stimulate intestinal lipoprotein production. Gut peptides, GLP-1 and GLP-2, may be important regulators of intestinal lipid absorption and lipoprotein production.. Available evidence in humans and animal models strongly favors the concept that the small intestine is not merely an absorptive organ but rather plays an active role in regulating the rate of production of triglyceride-rich lipoproteins. Metabolic signals in insulin resistance and type 2 diabetes and in some cases an aberrant intestinal response to these factors all contribute to the enhanced formation and secretion of triglyceride-rich lipoproteins.

Topics: Animals; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Insulin Resistance; Intestinal Mucosa; Lipoproteins; Liver; Models, Animal

The incretins are peptide hormones produced by special cell types of the intestines, which are secreted following ingestion of foods, indirectly, through a complex mechanism, by decreasing postprandial blood glucose levels participate in the regulation of the glucose homeostasis. The article beside of summarizing the physiological aspects of the two most important incretins, the glucagon-like peptide (GLP)-1 and glucose-dependent insulinotrope polypeptide (GIP), gives a detailed overview of multifaceted effects of GLP-1 and their potential application in the therapy of type 2 diabetes mellitus. The human GLP-1 because of its very short half-life is not suitable for therapeutic use. However, by inhibition its degradation, by suppression of activity of the serine peptidase type enzyme dipeptidyl peptidase (DPP) IV, its effect can be prolonged. Compounds with this effect have been synthetised, as well as drugs resistant to DPP IV, not being identical with the structure of the human GLP-1, but having agonist effect on its receptor could also be manufactured. Members of the first group are called incretin (GLP-1) enhancers, while of the second one incretin mimetics. Two of the enhancers, the sita- and vildagliptin, and one representative of the incretin mimetics, the exenatide after encouraging preclinical and human experiences have also been registered and introduced in the clinical practice. Their potential place in the treatment of type 2 diabetes is not exactly outlined at present. Though there are arguments underlining their early use in the glucose lowering drug treatment of type 2 diabetes, their application as part of a combination therapy seems to be a real indication.

Topics: Adamantane; Adenosine Deaminase; Adenosine Deaminase Inhibitors; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glycoproteins; Humans; Hypoglycemic Agents; Insulin Resistance; Intestinal Mucosa; Nitriles; Peptide Hormones; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a new class of oral antihyperglycemic agents to treat patients with type 2 diabetes. DPP-4 inhibitors improve fasting and postprandial glycemic control without hypoglycemia or weight gain. This article focuses on the physiology, clinical pharmacology, tolerability, and clinical utility of the DPP-4 inhibitor sitagliptin in the management of type 2 diabetes.

Topics: Animals; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Protease Inhibitors; Pyrazines; Sitagliptin Phosphate; Triazoles

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Insulin; Insulin Resistance; Insulin Secretion; Rats

Insulin sensitivity and insulin secretion are reciprocally related such that insulin resistance is adapted by increased insulin secretion to maintain normal glucose and lipid homeostasis. The relation between insulin sensitivity and secretion is curvilinear and mathematically best described as a hyperbolic relation. Several potential mediators have been suggested to be signals for the beta cells to respond to insulin resistance such as glucose, free fatty acids, autonomic nerves, fat-derived hormones and the gut hormone glucagon-like peptide-1 (GLP-1). Failure of these signals or of the pancreatic beta cells to adequately adapt insulin secretion in relation to insulin sensitivity results in inappropriate insulin levels, impaired glucose intolerance (IGT) and type 2 diabetes. Therefore, treatment of IGT and type 2 diabetes should aim at restoring the normal relation between insulin sensitivity and secretion. Such treatment includes stimulation of insulin secretion (sulphonylureas, repaglinide and nateglinide) and insulin sensitivity (metformin and thiazolidinediones), as well as treatment aimed at supporting the signals mediating the islet adaptation (cholinergic agonists and GLP-1). Both, for correct understanding of diabetes pathophysiology and for development of novel treatment modalities, therefore, the non-linear inverse relation between insulin sensitivity and secretion needs to be acknowledged.

Topics: Adaptation, Physiological; Animals; Blood Glucose; Cholinergic Agonists; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Metformin; Peptide Fragments; Protein Precursors; Sulfonylurea Compounds

The glucoincretins, glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), are intestinal peptides secreted in response to glucose or lipid intake. Data on isolated intestinal tissues, dietary treatments and knockout mice strongly suggest that GIP and GLP-1 secretion requires glucose and lipid metabolism by intestinal cells. However, incretin secretion can also be induced by non-digestible carbohydrates and involves the autonomic nervous system and endocrine factors such as GIP itself and cholecystokinin. The classical pharmacological approach and the recent use of knockout mice for the incretin receptors have shown that a remarkable feature of incretins is the ability to stimulate insulin secretion in the presence of hyperglycaemia only, hence avoiding any hypoglycaemic episode. This important role is the basis of ongoing clinical trials using GLP-1 analogues. Since most of the data concern GLP-1, we will focus on this incretin. In addition, GLP-1 is involved in glucose sensing by the autonomic nervous system of the hepato-portal vein controlling muscle glucose utilization and indirectly insulin secretion. GLP-1 has been shown to decrease glucagon secretion, food intake and gastric emptying, preventing excessive hyperglycaemia and overfeeding. Another remarkable feature of GLP-1 is its secretion by the brain. Recently, elegant data showed that cerebral GLP-1 is involved in cognition and memory. Experiments using knockout mice suggest that the lack of the GIP receptor prevents diet-induced obesity. Consequently, macronutrients controlling intestinal glucose and lipid metabolism would control incretin secretion and would consequently be beneficial for health. The control of incretin secretion represents a major goal for new therapeutic as well as nutrition strategies for treating and/or reducing the risk of hyperglycaemic syndromes, excessive body weight and thus improvement of well-being.

Topics: Animals; Autonomic Nervous System; Blood Glucose; Dietary Fiber; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Intestinal Mucosa; Inulin; Mice; Peptide Fragments; Protein Precursors; Receptors, Gastrointestinal Hormone; Receptors, Glucagon

The prevalence of type 2 diabetes mellitus (T2DM) and obesity in the western world is steadily increasing. Bariatric surgery is an effective treatment of T2DM in obese patients. The mechanism by which weight loss surgery improves glucose metabolism and insulin resistance remains controversial. In this review, we propose that two mechanisms participate in the improvement of glucose metabolism and insulin resistance observed following weight loss and bariatric surgery: caloric restriction and weight loss. Nutrients modulate insulin secretion through the entero-insular axis. Fat mass participates in glucose metabolism through the release of adipocytokines. T2DM improves after restrictive and bypass procedures, and combinations of restrictive and bypass procedures in morbidly obese patients. Restrictive procedures decrease caloric and nutrient intake, decreasing the stimulation of the entero-insular axis. Gastric bypass (GBP) operations may also affect the entero-insular axis by diverting nutrients away from the proximal GI tract and delivering incompletely digested nutrients to the distal GI tract. GBP and biliopancreatic diversion combine both restrictive and bypass mechanisms. All procedures lead to weight loss and decrease in the fat mass. Decrease in fat mass significantly affects circulating levels of adipocytokines, which favorably impact insulin resistance. The data reviewed here suggest that all forms of weight loss surgery lead to caloric restriction, weight loss, decrease in fat mass and improvement in T2DM. This suggests that improvements in glucose metabolism and insulin resistance following bariatric surgery result in the short-term from decreased stimulation of the entero-insular axis by decreased caloric intake and in the long-term by decreased fat mass and resulting changes in release of adipocytokines. Observed changes in glucose metabolism and insulin resistance following bariatric surgery do not require the posit of novel regulatory mechanisms.

Topics: Biomarkers; Blood Glucose; Body Mass Index; Caloric Restriction; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Male; Obesity, Morbid; Peptide Fragments; Peptide Hormones; Prognosis; Protein Precursors; Treatment Outcome; Weight Loss

Upon ingestion of food, the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are synthesised and secreted by specialised gut cells. GLP-1 is also produced in the pancreatic islets and the central nervous system. Both incretins bind to specific G-protein-coupled receptors that are distributed throughout the body. Incretins potentiate meal-induced insulin production and secretion by the beta-cells and lower the blood glucose level in the presence of hyperglycaemia. GLP-1 and GIP stimulate beta-cell proliferation and differentiation, whereas GLP-1 only inhibits gastric emptying and glucagon secretion, reduces food intake and improves insulin sensitivity. Insulin-resistant and type-2 diabetic patients have an impaired incretin response to meal ingestion. However, the insulinotropic action of exogenous GLP-1, but not that of GIP, is preserved in these subjects. After parenteral administration, GLP-1 has an extremely short duration of action because it is rapidly degraded by the ubiquitous enzyme dipeptidyl peptidase IV (DPPIV). To prolong GLP-1 bioactivity, DPPIV-resistant GLP-1 analogues, DPPIV inhibitors and exenatide, a long-acting synthetic GLP-1 receptor agonist derived from the Gila monster hormone exendin-4, have been developed. Enhancement of incretin action seems a rational and promising option for the treatment of type-2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Enzyme Inhibitors; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Peptide Fragments; Protein Precursors

Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Under some conditions of hyperglycemic challenge, insulin levels are lower in older people, suggesting beta-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, beta-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired beta-cell compensation to age-related insulin resistance may predispose older people to develop postchallenge hyperglycemia and type 2 diabetes. An improved understanding of the metabolic alterations associated with aging is essential for the development of preventive and therapeutic interventions in this population at high risk for glucose intolerance.

Topics: Adult; Aged; Aged, 80 and over; Aging; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Middle Aged; Nutrition Surveys; Peptide Fragments

Type 2 diabetes is reaching epidemic proportions worldwide, fueled by the increasing prevalence of obesity as many populations adopt a western lifestyle. Secondary complications affecting both the microvascular and macrovascular systems are responsible for premature mortality in Type 2 diabetes, with two thirds or more dying of cardiovascular disease. Two interacting metabolic defects, insulin resistance and beta-cell dysfunction are present in Type 2 diabetes. It is now recognised that insulin resistance is central to a cluster of metabolic abnormalities--called the insulin resistance syndrome--that are responsible for the excess of cardiovascular disease. Older antidiabetic agents such as the sulfonylureas, metformin and insulin are more effective than lifestyle modification in reducing microvascular complications of Type 2 diabetes, but overall do not reduce cardiovascular risk. Metformin, although no more effective as a glucose-lowering agent than sulfonylureas or insulin, does significantly reduce cardiovascular disease, probably as a result of its weak insulin-sensitising action. The newly-marketed thiazolidinedione insulin-sensitising antidiabetic agents also improve multiple biomarkers of cardiovascular risk, suggesting that novel approaches to insulin sensitisation will not only provide effective long-term glycaemic control but improve cardiovascular outcomes in Type 2 diabetes. Multiple therapeutic targets within the insulin signalling cascade are being explored, together with follow-up compounds to the first generation thiazolidinediones. These initiatives, together with developments in beta(3)-adrenoceptor agonists, 11 beta-hydroxysteroid dehydrogenase Type 1 inhibitors and modulators of the glucagon-like peptide 1 axis, all of which also potentially enhance insulin sensitivity, are critically evaluated.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adrenergic beta-3 Receptor Agonists; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Hydroxysteroid Dehydrogenases; Hypoglycemic Agents; Insulin; Insulin Resistance; Islets of Langerhans; Metformin; Peptide Fragments; Protein Precursors; Randomized Controlled Trials as Topic; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Thiazoles; Transcription Factors

Type 2 diabetes is associated with insulin resistance in peripheral tissues, such as muscle and fat, impaired glucose-stimulated insulin secretion from pancreatic beta-cells and elevated hepatic gluconeogenesis. Current pharmacotherapy does not adequately address the metabolic defects underlying this disease. Thus, novel targets are being explored that enhance insulin action at target tissues, stimulate carbohydrate and fat catabolism, decrease endogenous glucose production and increase pancreatic beta-cell neogenesis and glucose-dependent insulin secretion. This article reviews recent developments in research on several of these targets, namely acetyl-CoA carboxylase 2 (ACC2), I kappa kinase (IKK) beta, dipeptidyl peptidase IV (DPP-IV) and glucagon-like peptide-1 receptor (GLP-1R).

Topics: Acetyl-CoA Carboxylase; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Fatty Acids, Nonesterified; Glucagon; Glucagon-Like Peptide 1; I-kappa B Kinase; Insulin Resistance; Peptide Fragments; Protein Precursors; Protein Serine-Threonine Kinases

Glucagon-like peptide-1 (GLP-1), an intestinal gut hormone, is rapidly emerging as a new therapeutic agent for the treatment of diabetes mellitus. GLP-1, released from intestinal L-cells, is renowned for its potent stimulation of insulin biosynthesis and release from pancreatic b-cells. Exogenous administration of GLP-1 to subjects with type 2 diabetes results in the normalization of plasma glucose concentrations, in part, as a result of augmented glucose-stimulated insulin secretion. However, it is now recognized that GLP-1 has several other anti-diabetic actions that collectively improve the type 2 diabetic phenotype, and may also prove beneficial in the treatment of type 1 diabetes. These effects include the deceleration of gastric emptying and promotion of satiety, thereby reducing the availability of nutrients for absorption and reducing the requirement for insulin secretion. GLP-1 also reduces plasma glucose levels by suppressing glucagon secretion from pancreatic a-cells and potentially by improving insulin sensitivity in peripheral tissues. Further-more, GLP-1 upregulates expression of b-cell genes (GLUT2, glucokinase, insulin, and PDX-1) and promotes b-cell neogenesis and differentiation of ductal cells into insulin secreting cells. Although initial clinical trials indicate GLP-1 has excellent therapeutic potential, its relatively short-lived biological activity and delivery difficulties limit its appeal. Several approaches that are currently being explored to overcome these limitations include mobilizing endogenous GLP-1 release, preserving the biological activity of the native peptide, and developing GLP-1 analogues with extended durations of action.

Topics: Animals; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Administration Routes; Gastric Emptying; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Intestine, Small; Islets of Langerhans; Peptide Fragments; Protein Precursors; Rats; Receptors, Glucagon; Satiety Response; Signal Transduction

This review describes the latest approaches towards using gene therapy as a treatment for non-insulin dependent diabetes mellitus (NIDDM; Type 2 diabetes). We examine attempts to directly deliver the insulin gene to non-beta-cells, to improve insulin secretion from existing beta-cells and to develop ex vivo approaches to implanting genetically modified cells. Future research into the pathology of non-insulin dependent diabetes, combined with the latest developments in gene delivery systems, may potentially make gene therapy an attractive alternative NIDDM treatment in the future.

Topics: Adult; Animals; Antigens, Neoplasm; Biomarkers, Tumor; Blood Glucose; Cell Transplantation; Diabetes Mellitus, Type 2; Gene Expression Regulation; Genes, Synthetic; Genetic Therapy; Genetic Vectors; Glucagon; Glucagon-Like Peptide 1; Glucokinase; Glucose Transporter Type 2; Homeodomain Proteins; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Lectins, C-Type; Mice; Middle Aged; Monosaccharide Transport Proteins; Muscle Contraction; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pancreatitis-Associated Proteins; Peptide Fragments; Promoter Regions, Genetic; Protein Precursors; Proteins; Rats; Trans-Activators

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Liver; Liver Diseases; Peptide Fragments; Receptor, Insulin

Basic research on the cellular mechanisms that control the expression of the gene encoding glucagon has led to the discovery of proglucagon. This precursor is processed by tissue-specific proteolysis to produce glucagon in pancreatic alpha-cells and a glucagon-like peptide-1 (GLP-1) in the intestine. GLP-1 is a hormone that is released by intestinal cells into the circulation in response to food intake. GLP-1 and gastric inhibitory peptide (GIP) which has also been termed glucose-dependent insulinotropic peptide appear to account for most of the incretin effect in the augmentation of glucose-stimulated insulin secretion. These two hormones have specific beta-cell receptors that are coupled to GTP binding proteins to induce production of cyclic AMP and activation of cyclic AMP-dependent protein kinase. It is proposed that at least one factor contributing to the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) is desensitization of the GLP-1 receptor on beta-cells. At pharmacological doses, infusion of GLP-1, but not of GLP, can improve and enhance postprandial insulin response in NIDDM patients. Agonists of GLP-1 receptor have been proposed as new potential therapeutic agents in NIDDM patients. The observations that GLP-1 induces both secretion and production of insulin, and that its activities are mainly glucose-dependent, led to the suggestion that GLP-1 may present a unique advantage over sulfonylurea drugs in the treatment of NIDDM.

Topics: Diabetes Mellitus, Type 2; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Peptide Fragments; Protein Precursors; Receptors, Glucagon

In subjects with type 2 diabetes, both defects of insulin secretion and insulin resistance contribute to the development of hyperglycaemia. The major goals of treatment are to optimise blood glucose control, and normalise the associated lipid disturbances and elevated blood pressure. Pharmacologic treatment is often necessary. This paper discusses new forms of oral treatment for subjects with type 2 diabetes. These include a new sulphonylurea compound glimepiride (Amaryl), which binds to a different protein of the putative sulphonylurea receptor than glibenclamide, and seems to have a lower risk of hypoglycaemia. A new class of drugs with insulin secretory capacity, of which repaglinide (NovoNorm) is the leading compound, is now in phase III clinical trials. Alpha-glucosidase inhibitors reversibly inhibit alpha-glucosidase enzymes in the small intestine, which delays cleavage of oligo- and disaccharides to monosaccharides. This leads to a delayed and reduced blood glucose rise after a meal. Two compounds are in development or have been marketed, ie, miglitol and acarbose (Glucobay). Another new class of drugs is the thiazolidine-diones, which seem to work by enhancing insulin action. The 'insulin sensitising' effects of the leading compounds, troglitazone and BRL 49653C, do not involve any effect on insulin secretion. These drugs also seem to beneficially influence serum cholesterol and triglyceride levels. Oral antihyperglycaemic agents can be used only during a limited period of time in most patients, after which the diabetic state 'worsens' and insulin therapy has to be started. In this light, two new forms of treatment which require subcutaneous injections are also discussed: the synthetic human amylin analogue AC137 (pramlintide) and glucagon-like peptide-1 (7-36)-amide, a strong glucose-dependent stimulator of insulin secretion. It remains to be seen whether these compounds can be developed further for clinical use in patients with diabetes.

Topics: Amyloid; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islet Amyloid Polypeptide; Peptide Fragments; Protein Precursors; Sulfonylurea Compounds

In the submitted review the author discusses two substances secreted into the circulation which can similarly as insulin lower the blood sugar level. These substances are IGF-I (insulin-like growth factor I) and GLP (glucagon-like peptide). While in case of the former it is not certain whether it participates in the glucose homeostasis, this is beyond doubt in the latter. IGF-I prepared by the recombinant technique can be used therapeutically in cases of insulin resistance caused by a receptor or postreceptor disorder, because it may act via its own receptor. Side-effects after larger doses are a problem. GLP-1, the use of which would be useful in type 2 diabetics as it stimulates insulin secretion, is not used so far in therapy because hitherto prepared preparations have a very short period of a effectiveness.

Topics: Blood Glucose; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Pancreatic Hormones; Peptide Fragments; Peptides; Protein Precursors

Topics: Amyloid; Animals; Base Sequence; Carrier Proteins; Chromosome Mapping; Cloning, Molecular; Diabetes Mellitus, Type 2; DNA, Mitochondrial; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Glucagon; Glucagon-Like Peptide 1; Glucokinase; Glucose Transporter Type 4; Glycogen Synthase; Humans; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Molecular Sequence Data; Monosaccharide Transport Proteins; Muscle Proteins; Neoplasm Proteins; Peptide Fragments; Protein Precursors; Receptor, Insulin; Selection, Genetic; Tumor Suppressor Proteins

The aim of this study was to determine the effects of regular exposure to certain low- or no-calorie sweeteners (LNCS) on glucose tolerance and glucagon-like peptide 1 (GLP-1) release in healthy individuals.. It was designed as a randomized, single-blinded, controlled study. Healthy and normoglycemic adults who did not have regular consumption of LNCS were recruited. Participants underwent a 75-g oral glucose tolerance test (OGTT) at baseline and were randomly assigned to consume 330 mL water sweetened with saccharine, sucralose, or aspartame + acesulfame-K (Asp+Ace-K), or plain water for the control group, daily for 4 wk. Fasting plasma glucose, insulin, GLP-1, and glycated hemoglobin A. Of the participants enrolled in the study, 42 (age, 21.24 ± 2.26 y; body mass index, 20.65 ± 2.88 kg/m. These results suggest that regular consumption of LNCS-sweetened water similar to doses consumed in daily life over 4 wk had no significant effect on glycemic response, insulin sensitivity, GLP-1 release, and body weight in healthy individuals. This trial was registered at www.. gov as NCT04904133.

Topics: Adolescent; Adult; Aspartame; Blood Glucose; Body Weight; Female; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Sweetening Agents; Water; Young Adult

Survival under selective pressure is driven by the ability of our brain to use sensory information to our advantage to control physiological needs. To that end, neural circuits receive and integrate external environmental cues and internal metabolic signals to form learned sensory associations, consequently motivating and adapting our behaviour. The dopaminergic midbrain plays a crucial role in learning adaptive behaviour and is particularly sensitive to peripheral metabolic signals, including intestinal peptides, such as glucagon-like peptide 1 (GLP-1). In a single-blinded, randomized, controlled, crossover basic human functional magnetic resonance imaging study relying on a computational model of the adaptive learning process underlying behavioural responses, we show that adaptive learning is reduced when metabolic sensing is impaired in obesity, as indexed by reduced insulin sensitivity (participants: N = 30 with normal insulin sensitivity; N = 24 with impaired insulin sensitivity). Treatment with the GLP-1 receptor agonist liraglutide normalizes impaired learning of sensory associations in men and women with obesity. Collectively, our findings reveal that GLP-1 receptor activation modulates associative learning in people with obesity via its central effects within the mesoaccumbens pathway. These findings provide evidence for how metabolic signals can act as neuromodulators to adapt our behaviour to our body's internal state and how GLP-1 receptor agonists work in clinics.

Topics: Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin Resistance; Liraglutide; Male; Obesity

Evidence is emerging that interdaily meal pattern variability potentially affects response such as thermic effect of food (TEF), macronutrient metabolism, and appetite.. To investigate the effect of irregular meal pattern on TEF, glucose, insulin, lipid profile, and appetite regulation in women who are overweight or with obesity and confirmed insulin resistance.. In a randomized crossover trial, 9 women [mean ± SD BMI (in kg/m2): 33.3 ± 3.1] with confirmed insulin resistance consumed a regular (14 d; 6 meals/d) and an irregular (14 d; 3-9 meals/d) meal pattern separated by a 14-d washout interval. Identical foods were provided during the interventions, and at the start and end of each meal pattern, participants attended the laboratory after an overnight fast. Energy expenditure, glucose, insulin, lipids, adiponectin, leptin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin were measured at baseline and for 3 h after consumption of a test drink, after which an ad libitum test meal was offered. Subjective appetite ratings were recorded before and after the test drink, after the ad libitum meal, and during the intervention. Continuous interstitial glucose monitoring was undertaken for 7 consecutive days during each intervention.. TEF (over 3 h) was significantly lower postirregular intervention compared with postregular (97.7 ± 19.2 kJ*3 h in postregular visit and 76.7 ± 35.2 kJ*3 h in postirregular visit, paired t test, P = 0.048). Differences in HOMA-IR between the 2 interventions (3.3 ± 1.7 and 3.6 ± 1.6 in postregular and postirregular meal pattern, respectively) were not significant. Net incremental AUC for GLP-1 concentrations (over 3 h) for the postregular meal pattern were higher (864.9 ± 456.1 pmol/L*3 h) than the postirregular meal pattern (487.6 ± 271.7 pmol/L*3 h, paired t test, P = 0.005).. Following a 14-d period of an irregular meal pattern, TEF was significantly less than following a regular meal pattern, potentially compromising weight management if sustained long term. This study was registered at www.clinicaltrials.gov as NCT02582606.

Topics: Adiponectin; Adolescent; Adult; Appetite; Blood Glucose; Blood Glucose Self-Monitoring; Energy Metabolism; Feeding Behavior; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Lipids; Meals; Middle Aged; Obesity; Overweight; Peptide YY; Thermogenesis; Young Adult

Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic. In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of. A single dose of. NTR-NL6630.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Clostridiales; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptide 1; Glycemic Control; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Transcriptome

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment is a therapeutic approach for type 2 diabetes mellitus (T2DM). Some reports have shown that SGLT2i treatment improves insulin resistance; however, few studies have evaluated insulin resistance by the glucose clamp method. Hepatic insulin clearance (HIC) is a new pathophysiological mechanism of T2DM. The effect of SGLT2i treatment on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i treatment on insulin resistance, insulin secretion, incretin levels, body composition, and hepatic insulin clearance. We conducted a meal tolerance test (MTT) and a hyperinsulinemic-euglycemic clamp test in 9 T2DM patients. Ipragliflozin (50 mg/day) was administered, and the MTT and clamp test were performed after 4 months. We calculated HIC as the postprandial C-peptide AUC-to-insulin AUC ratio. We also measured GLP-1, GIP, and glucagon levels during the MTT. Body weight and HbA1c were decreased, although not significantly, after 4 months of treatment. Postprandial glucose, fasting insulin and postprandial insulin were significantly decreased. Insulin resistance with the glucose clamp was not changed, but the HOMA-IR and insulin sensitivity indices were significantly improved. Incretin and glucagon levels were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. The FIB-4 index and fatty liver index were significantly reduced. The HOMA-beta and insulinogenic indices were not changed, but the C-peptide index was significantly increased. Although the number of patients was small, these results suggested that SGLT2i treatment improved liver function, decreased hepatic insulin resistance, and increased hepatic insulin clearance, despite the small weight reduction.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucosides; Humans; Insulin; Insulin Resistance; Japan; Liver; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Thiophenes; Time Factors; Treatment Outcome

To evaluate the potential for glycaemic, renal and vascular benefits of bromocriptine quick release (BCQR) in adolescents and adults with type 1 diabetes.. Forty adolescents and 40 adults with type 1 diabetes aged 12-60 years old were enrolled in a double-blind, placebo-controlled, random order crossover study of 4 weeks of treatment in the morning with BCQR (titrated weekly from 0.8 mg to 1.6 mg to 3.2 mg, minimum dose 1.6 mg). Study assessments after each phase included blood pressure (BP), lipids, peripheral arterial stiffness and autonomic function, mixed meal tolerance test, continuous glucose monitoring (CGM), creatinine, estimated glomerular filtration rate, estimated insulin sensitivity, insulin dose and indirect calorimetry.. Adolescents displayed baseline hyperglycaemia, insulin resistance, metabolic dysfunction and increased renal filtration compared with adults. In both age groups, continuous glucose monitoring measures, estimated insulin sensitivity and insulin dose did not differ with BCQR treatment. In adolescents, BCQR decreased systolic BP, diastolic BP and triangular index and increased serum creatinine. In adults, systolic BP, mean arterial pressure, systemic vascular resistance, and mixed meal tolerance test glucose and glucagon-like peptide 1 areas under the curve were lower, and the orthostatic drop in systolic BP was greater with BCQR.. Greater hyperglycaemia, insulin resistance, metabolic dysfunction and renal hyperfiltration in adolescents argues for increased attention during this high-risk age period. Although BCQR had little impact on glycaemia or insulin sensitivity, initial vascular and renal responses suggest potential benefits of BCQR in adolescents and adults with type 1 diabetes requiring further study.

Topics: Adolescent; Adult; Blood Glucose; Blood Glucose Self-Monitoring; Bromocriptine; Child; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 1; Double-Blind Method; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Insulin Resistance; Lipids; Middle Aged; Young Adult

Epidemiologic studies have revealed that consuming green tea or coffee reduces diabetes risk. We evaluated the effects of the combined consumption of green tea catechins and coffee chlorogenic acids (GTC+CCA) on postprandial glucose, the insulin incretin response, and insulin sensitivity. Eleven healthy men were recruited for this randomized, double-blinded, placebo-controlled crossover trial. The participants consumed a GTC+CCA-enriched beverage (620 mg GTC, 373 mg CCA, and 119 mg caffeine/day) for three weeks; the placebo beverages (PLA) contained no GTC or CCA (PLA: 0 mg GTC, 0 mg CCA, and 119 mg caffeine/day). Postprandial glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) responses were measured at baseline and after treatments. GTC+CCA consumption for three weeks showed a significant treatment-by-time interaction on glucose changes after the ingestion of high-fat and high-carbohydrate meals, however, it did not affect fasting glucose levels. Insulin sensitivity was enhanced by GCT+CCA compared with PLA. GTC+CCA consumption resulted in a significant increase in postprandial GLP-1 and a decrease in GIP compared to PLA. Consuming a combination of GTC and CCA for three weeks significantly improved postprandial glycemic control, GLP-1 response, and postprandial insulin sensitivity in healthy individuals and may be effective in preventing diabetes.

Topics: Blood Glucose; Catechin; Chlorogenic Acid; Cross-Over Studies; Diabetes Mellitus; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Male; Postprandial Period; Tea

Granular study of metabolic responses to alterations in the ratio of dietary macro-nutrients can enhance our understanding of how dietary modifications influence patients with impaired glycemic control. In order to study the effect of diets enriched in fat or carbohydrates, fifteen healthy, normal-weight volunteers received, in a cross-over design, and in a randomized unblinded order, two weeks of an iso-caloric high-fat diet (HFD: 60E% from fat) and a high-carbohydrate diet (HCD: 60E% from carbohydrates). A mixed meal test (MMT) was performed at the end of each dietary period to examine glucose clearance kinetics and insulin and incretin hormone levels, as well as plasma metabolomic profiles. The MMT induced almost identical glycemia and insulinemia following the HFD or HCD. GLP-1 levels were higher after the HFD vs. HCD, whereas GIP did not differ. The HFD, compared to the HCD, increased the levels of several metabolomic markers of risk for the development of insulin resistance, e.g., branched-chain amino acid (valine and leucine), creatine and α-hydroxybutyric acid levels. In normal-weight, healthy volunteers, two weeks of the HFD vs. HCD showed similar profiles of meal-induced glycemia and insulinemia. Despite this, the HFD showed a metabolomic pattern implying a risk for a metabolic shift towards impaired insulin sensitivity in the long run.

Topics: Adaptation, Physiological; Adult; Appetite; Blood Glucose; Cross-Over Studies; Diabetes Mellitus; Diet, High-Fat; Dietary Carbohydrates; Discriminant Analysis; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycemic Control; Healthy Volunteers; Humans; Incretins; Insulin; Insulin Resistance; Least-Squares Analysis; Male; Metabolome; Risk Factors

Fructose compared to glucose has adverse effects on metabolic function, but endocrine responses to oral sucrose vs glucose is not well understood.. We investigated how oral sucrose vs glucose affected appetite-regulating hormones, and how biological factors (body mass index [BMI], insulin sensitivity, sex) influence endocrine responses to these 2 types of sugar.. Sixty-nine adults (29 men; 23.22 ± 3.74 years; BMI 27.03 ± 4.96 kg/m2) completed the study. On 2 occasions, participants consumed 300-mL drinks containing 75 g of glucose or sucrose. Blood was sampled at baseline, 10, 35, and 120 minutes post drink for plasma glucose, insulin, glucagon-like peptide (GLP-1)(7-36), peptide YY (PYY)total, and acyl-ghrelin measures. Hormone levels were compared between conditions using a linear mixed model. Interaction models were performed, and results were stratified to assess how biological factors influence endocrine responses.. Sucrose vs glucose ingestion provoked a less robust rise in glucose (P < .001), insulin (P < .001), GLP-1 (P < .001), and PYY (P = .02), whereas acyl-ghrelin suppression was similar between the sugars. We found BMI status by sugar interactions for glucose (P = .01) and PYY (P = .03); obese individuals had smaller increases in glucose and PYY levels after consuming sucrose vs glucose. There were interactions between insulin sensitivity and sugar for glucose (P = .003) and insulin (P = .04), and a sex by sugar interaction for GLP-1 (P = .01); men demonstrated smaller increases in GLP-1 in response to oral sucrose vs glucose.. Sucrose is less efficient at signaling postprandial satiation than glucose, and biological factors influence differential hormone responses to sucrose vs glucose consumption.

Topics: Administration, Oral; Adolescent; Adult; Appetite; Appetite Regulation; Blood Glucose; Body Mass Index; Down-Regulation; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Obesity; Peptide YY; Satiation; Sex Characteristics; South Carolina; Sucrose; Young Adult

The alpha-glucosidase inhibitor acarbose is believed to reduce plasma glucose by delaying hydrolysis of carbohydrates. Acarbose-induced transfer of carbohydrates to the distal parts of the intestine increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9-39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes.. In a double-blinded, placebo-controlled, randomized, crossover study, 15 participants with metformin-treated type 2 diabetes (age: 57-85 years, HbA1c: 40-74 mmol/mol) were subjected to two 14-day treatment periods with acarbose or placebo, respectively, separated by a 6-week wash-out period. At the end of each period, two randomized 4-h liquid mixed meal tests with concomitant infusion of exendin(9-39)NH2 and saline, respectively, were performed.. Compared to placebo, acarbose increased postprandial GLP-1 concentrations and decreased postprandial glucose. We observed no absolute difference in the exendin(9-39)NH2-induced increase in postprandial glucose excursions between placebo and acarbose periods, but relatively, postprandial glucose was increased by 119 ± 116% (mean ± s.d.) during exendin(9-39)NH2 infusion in the acarbose period vs a 39 ± 27% increase during the placebo period (P = 0.0163).. We confirm that acarbose treatment stimulates postprandial GLP-1 secretion in patients with type 2 diabetes. Using exendin(9-39)NH2, we did not see an impact of acarbose-induced GLP-1 secretion on absolute measures of postprandial glucose tolerance, but relatively, the effect of exendin(9-39)NH2 was most pronounced during acarbose treatment.

Topics: Acarbose; Aged; Aged, 80 and over; Blood Glucose; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Placebos; Postprandial Period

GIP was proposed to play a key role in the development of non- alcoholic fatty liver disease (NAFLD) in response to sugar intake. Isomaltulose, is a 1,6-linked glucose-fructose dimer which improves glucose homeostasis and prevents NAFLD compared to 1,2-linked sucrose by reducing glucose-dependent insulinotropic peptide (GIP) in mice. We compared effects of sucrose vs. isomaltulose on GIP and glucagon-like peptide-1 (GLP-1) secretion, hepatic insulin clearance (HIC) and insulin sensitivity in normal (NGT), impaired glucose tolerant (IGT) and Type 2 diabetes mellitus (T2DM) participants. A randomized crossover study was performed in 15 NGT, 10 IGT and 10 T2DM subjects. In comparison to sucrose, peak glucose concentrations were reduced by 2.3, 2.1 and 2.5 mmol/l (all p < 0.05) and insulin levels were 88% (p < 0.01, NGT), 32% (p < 0.05, IGT) and 55% (T2DM) lower after the isomaltulose load. Postprandial GIP

Topics: Adult; Case-Control Studies; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Isomaltose; Liver; Male; Middle Aged; Sucrose

Obesity is associated with microvascular insulin resistance, which is characterized by impaired insulin-mediated microvascular recruitment. Glucagon-like peptide 1 (GLP-1) recruits skeletal and cardiac muscle microvasculature, and this action is preserved in insulin-resistant rodents. We aimed to examine whether GLP-1 recruits microvasculature and improves the action of insulin in obese humans.. Fifteen obese adults received intravenous infusion of either saline or GLP-1 (1.2 pmol/kg/min) for 150 min with or without a euglycemic insulin clamp (1 mU/kg/min) superimposed over the last 120 min. Skeletal and cardiac muscle microvascular blood volume (MBV), flow velocity and blood flow, brachial artery diameter and blood flow, and pulse wave velocity (PWV) were determined.. Insulin failed to change MBV or flow in either skeletal or cardiac muscle, confirming the presence of microvascular insulin resistance. GLP-1 infusion alone increased MBV by ∼30% and ∼40% in skeletal and cardiac muscle, respectively, with no change in flow velocity, leading to a significant increase in microvascular blood flow in both skeletal and cardiac muscle. Superimposition of insulin to GLP-1 infusion did not further increase MBV or flow in either skeletal or cardiac muscle but raised the steady-state glucose infusion rate by ∼20%. Insulin, GLP-1, and GLP-1 + insulin infusion did not alter brachial artery diameter and blood flow or PWV. The vasodilatory actions of GLP-1 are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes.. In obese humans with microvascular insulin resistance, GLP-1's vasodilatory actions are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes.

Topics: Administration, Intravenous; Adult; Blood Glucose; Brachial Artery; Coronary Vessels; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Heart; Humans; Insulin Resistance; Male; Microvessels; Muscle, Skeletal; Myocardium; Obesity; Pulse Wave Analysis; Vascular Resistance; Vasodilation; Vasodilator Agents

To compare endocrine responses to intermittent vs continuous enteral nutrition provision during short-term bed rest.. Intermittent enteral nutrition attenuates the progressive rise in plasma leptin and insulinemia seen with continuous feeding during bed rest, suggesting that continuous feeding increases insulin requirements to maintain euglycemia. This raises the possibility that hepatic insulin sensitivity is impaired to a greater extent with continuous versus intermittent feeding during bed rest. To attenuate endocrine and metabolic changes with enteral feeding, an intermittent feeding strategy may, therefore, be preferable to continuous provision of nutrition. This trial was registered on clinicaltrials.gov as NCT02521025.

Topics: Adult; Bed Rest; Blood Glucose; Enteral Nutrition; Female; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Rest

The effect of nonnutritive sweeteners on appetite is controversial. Some studies have found changes in certain appetite control hormones with sucralose intake that may be through interaction with sweet taste receptors located in the intestine.. The aim of this study was to evaluate whether sucralose consumption could produce changes in fasting plasma concentrations of appetite-regulating hormones, including glucagon-like peptide 1, ghrelin, peptide tyrosine tyrosine, and leptin, and secondarily in insulin resistance.. A 2-week parallel randomized clinical trial with an additional visit conducted 1 week after dosing termination.. Sixty healthy, normal-weight individuals, without habitual consumption of nonnutritive sweeteners were recruited from July 2015 to March 2017 in Mexico City.. Daily sucralose consumption at 15% of the acceptable daily intake by using commercial sachets added to food. The control group followed the same protocol without an intervention.. Fasting concentrations of appetite regulating hormones before and after the intervention. Fasting glucose and insulin concentrations were measured to assess insulin resistance as a secondary outcome.. Basal and final concentrations were compared using Wilcoxon matched-pairs test and Mann-Whitney U test for analysis between groups. Repeated measures analysis of variance was used to evaluate changes in the homeostasis model assessment of insulin resistance.. Sucralose was not associated with changes in any of the hormones measured. One week postintervention, an incremental change (P=0.04) in the homeostasis model assessment of insulin resistance was found in the intervention group.. Sucralose intake is not associated with changes in fasting concentrations of glucagon-like peptide 1, ghrelin, peptide tyrosine tyrosine, or leptin. An increase in the homeostasis model assessment of insulin resistance observed only at 1 week postdosing is of unknown clinical significance, if any.

Topics: Adult; Appetite; Blood Glucose; Diet; Dipeptides; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Male; Mexico; Sucrose

Glucagon-like peptide-1 (GLP-1) is an incretin hormone used therapeutically in type 2 diabetes and obesity. The interplay between ambient free fatty acids (FFAs) and GLP-1 remains unclear. Acipimox suppresses adipose tissue lipolysis via activation of the PUMA-G (also known as HCA2 and GPR109a) receptor.. To investigate whether lowering of serum FFA level with acipimox affects GLP-1 secretion.. Two randomized crossover studies were performed in human subjects. Rat intestine was perfused intra-arterially and intraluminally, and l-cells were incubated with acipimox.. The participants were healthy overweight subjects and hypopituitary adult patients.. The overweight participants received acipimox 250 mg 60 minutes before an oral glucose test. The hypopituitary patients received acipimox 250 mg 12, 9, and 2 hours before and during the metabolic study day, when they were studied in the basal state and during a hyperinsulinemic euglycemic clamp.. Acipimox suppressed FFA but did not affect insulin in the clinical trials. In overweight subjects, the GLP-1 increase after the oral glucose tolerance test (area under the curve) was more than doubled [4119 ± 607 pmol/L × min (Acipimox) vs 1973 ± 375 pmol/L × min (control), P = 0.004]. In hypopituitary patients, acipimox improved insulin sensitivity (4.7 ± 0.8 mg glucose/kg/min (Acipimox) vs 3.1 ± 0.5 mg glucose/kg/min (control), P = 0.005], and GLP-1 concentrations increased ~40%. An inverse correlation between FFA and GLP-1 concentrations existed in both trials. In rat intestine, acipimox did not affect GLP-1 secretion, and l-cells did not consistently express the putative receptor for acipimox.. Acipimox treatment increases systemic GLP-1 levels in both obese subjects and hypopituitary patients. Our in vitro data indicate that the underlying mechanisms are indirect.

Topics: Adult; Animals; Blood Glucose; Cells, Cultured; Cross-Over Studies; Enteroendocrine Cells; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypolipidemic Agents; Hypopituitarism; Insulin Resistance; Intestinal Mucosa; Lipolysis; Male; Middle Aged; Overweight; Pilot Projects; Primary Cell Culture; Pyrazines; Rats

Bile acids, glucagon-like peptide-1 (GLP-1), and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1, and FGF19. First, we investigated the postprandial response to 40-h fast. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. We performed two separate observational randomized crossover studies on healthy, lean men. In

Topics: Bile Acids and Salts; Blood Glucose; Cross-Over Studies; Deoxycholic Acid; Dietary Supplements; Energy Metabolism; Fasting; Fibroblast Growth Factors; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Postprandial Period; Young Adult

It is known that the macronutrient content of a meal has different impacts on the postprandial satiety and appetite hormonal responses. Whether obesity interacts with such nutrient-dependent responses is not well characterized. We examined the postprandial appetite and satiety hormonal responses after a high-protein (HP), high-carbohydrate (HC), or high-fat (HF) mixed meal. This was a randomized cross-over study of 9 lean insulin-sensitive (mean±SEM HOMA-IR 0.83±0.10) and 9 obese insulin-resistant (HOMA-IR 4.34±0.41) young (age 21-40 years), normoglycaemic Chinese men. We measured fasting and postprandial plasma concentration of glucose, insulin, active glucagon-like peptide-1 (GLP-1), total peptide-YY (PYY), and acyl-ghrelin in response to HP, HF, or HC meals. Overall postprandial plasma insulin response was more robust in the lean compared to obese subjects. The postprandial GLP-1 response after HF or HP meal was higher than HC meal in both lean and obese subjects. In obese subjects, HF meal induced higher response in postprandial PYY compared to HC meal. HP and HF meals also suppressed ghrelin greater compared to HC meal in the obese than lean subjects. In conclusion, a high-protein or high-fat meal induces a more favorable postprandial satiety and appetite hormonal response than a high-carbohydrate meal in obese insulin-resistant subjects.

Topics: Adult; Asian People; Blood Glucose; Cross-Over Studies; Diet, High-Fat; Diet, High-Protein; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Obesity; Peptide YY; Postprandial Period; Satiety Response; Singapore; Young Adult

Emerging evidence shows that non-nutritive sweeteners might induce glucose intolerance. This study aims to determine the effects of chronic exposure to sucralose on glycemic response, insulin secretion and sensitivity, and glucagon-like peptide-1 (GLP-1) release in healthy subjects.. Healthy volunteers who did not use non-nutritive sweeteners and were normoglycemia after oral glucose tolerance test (OGTT) were recruited. Subjects underwent a 75-g OGTT on two separate occasions, preceded by blindly consuming pills containing either 200 mg sucralose or placebo for 4 wk in a randomized crossover trial. Plasma glucose, insulin, and active GLP-1 levels were obtained after ingesting 75-g glucose. On the following day, intravenous glucose tolerance test (IVGTT) was performed to evaluate the acute insulin response (AIR).. The continuous exposure to sucralose reduced AIR, decreased insulin sensitivity, and enhanced GLP-1 release in healthy subjects. However, the clinical significance of these results needs to be investigated in longer follow-up studies.

Topics: Adult; Area Under Curve; Blood Glucose; Cross-Over Studies; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Male; Sucrose; Sweetening Agents; Young Adult

Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved.. In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses.. Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin correlated positively with its fasting level (r = 0.9, p<0.001). The postprandial responses of GIHs and appetite hormones were similar after both diet regimens.. Both hypocaloric diet regimens reduced fasting leptin and GIP and postprandial response of GIP comparably. The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Eating only breakfast and lunch increased fasting plasma ghrelin more than the same caloric restriction split into six meals. The changes in fasting ghrelin correlated negatively with the decrease in body weight. These results suggest that for type 2 diabetic patients on a hypocaloric diet, eating larger breakfast and lunch may be more efficient than six smaller meals during the day.

Topics: Adult; Aged; Body Weight; Caloric Restriction; Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Insulin Resistance; Leptin; Male; Meals; Middle Aged; Pancreatic Polypeptide; Peptide YY; Time Factors; Treatment Outcome

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS,

Topics: Adult; Biomarkers; Blood Glucose; C-Peptide; Dietary Carbohydrates; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Meals; Postprandial Period; Time Factors

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released in response to food intake. It is unclear how meals high in protein (HP) and monounsaturated fat (HMF) affect GLP-1 response.. To examine the effect of a HP versus a HMF meal on GLP-1 response.. Twenty-four overweight/obese participants consumed two meals (HP: 31.9 % energy from protein; HMF: 35.2 % fat and 20.7 % monounsaturated fat) in a random order. Both meals contained the same energy and carbohydrate content. GLP-1, insulin, glucagon, C-peptide, and glucose were assessed from blood drawn in the fasting and postprandial states. The effect of meal condition on hormone and glucose responses and appetite ratings were assessed by repeated measures analysis.. Statistically significant (p < 0.01) time by meal condition effect was observed on active GLP-1, total GLP-1, insulin, C-peptide, and glucagon, but not glucose (p = 0.83). Area under the curve was significantly higher during the HP versus the HMF meal conditions for active GLP-1 (23.7 %; p = 0.0007), total GLP-1 (12.2 %; p < 0.0001), insulin (54.4 %; p < 0.0001), C-peptide (14.8 %; p < 0.0001), and glucagon (40.7 %; p < 0.0001). Blood glucose was not different between the HP versus HMF conditions (-4.8 %; p = 0.11). Insulin sensitivity was higher during the HMF versus HP conditions (Matsuda index mean difference: 16.3 %; p = 0.007). Appetite ratings were not different by meal condition.. GLP-1 and insulin responses were higher during the HP condition. However, no difference was found in blood glucose between conditions, and insulin sensitivity was higher during the HMF condition, indicating that a HMF meal may be optimal at regulating blood glucose in overweight/obese individuals without type 2 diabetes.

Topics: Adolescent; Adult; Aged; Appetite; Blood Glucose; Body Mass Index; C-Peptide; Cross-Over Studies; Exercise; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Meals; Mental Recall; Middle Aged; Obesity; Overweight; Postprandial Period; Young Adult

Although different hypotheses have been proposed, the underlying mechanism(s) of the weight loss induced by laparoscopic sleeve gastrectomy (LSG) is still unknown. The aim of this study was to determine whether eating the same meal at different rates (fast vs. slow feeding) evokes different post-prandial anorexigenic gut peptide responses in ten obese patients undergoing LSG. Circulating levels of GLP-1, PYY, glucose, insulin and triglycerides were measured before and 3 months after LSG. Visual analogue scales were used to evaluate the subjective feelings of hunger and satiety. Irrespective of the operative state, either fast or slow feeding did not stimulate GLP-1 release (vs. 0 min); plasma levels of PYY were increased (vs. 0 min) by fast and slow feeding only after LSG. There were no differences in post-prandial levels of GLP-1 when comparing fast to slow feeding or pre-to-post-operative state. Plasma levels of PYY after fast or slow feeding were higher in post, rather than pre-operative state, with no differences when comparing PYY release after fast and slow feeding. Hunger and satiety were decreased and increased, respectively, (vs. 0 min) by food intake. Fast feeding evoked a higher satiety than slow feeding in both pre- and post-operative states, with no differences in hunger. In both pre- and post-operative states, there were similar responses for hunger and satiety after food intake. Finally, LSG improved insulin resistance after either fast or slow feeding. These (negative) findings would suggest a negligible contribution of the anorexigenic gut peptide responses in LSG-induced weight loss.

Topics: Adult; Appetite Regulation; Body Mass Index; Combined Modality Therapy; Diet, Reducing; Enteroendocrine Cells; Feeding Behavior; Female; Gastrectomy; Gastroplasty; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Italy; Laparoscopy; Male; Middle Aged; Obesity, Morbid; Peptide YY; Postprandial Period; Time Factors; Weight Loss

We aimed to investigate the effects of gemigliptin, a dipeptidyl peptidase-4 inhibitor, on postprandial lipoprotein levels and endotoxemia in a randomized, double-blind, placebo-controlled, crossover study. Ten people with type 2 diabetes mellitus (T2DM), inadequately controlled with oral antidiabetic medications and/or lifestyle modification, were randomized to gemigliptin or placebo for 4 weeks. At the end of each treatment phase, the study participants underwent a high-fat meal tolerance test and needle aspiration of abdominal subcutaneous adipose tissue. The median (range) fasting and total area under the curve of apolipoprotein B48 (ApoB48) were significantly lower with gemigliptin than with placebo (2.9 [1.5-15.8] µg/mL vs 4.2 [1.3-23.4] µg/mL; P = .020; 35.3 [14.4-87.4] µg/mL × hour vs 42.2 [17.5-109.0] µg/mL × hour; P = .020, respectively), whereas apolipoprotein B100 showed no significant difference. Serum endotoxin levels were undetectable in 70% of the samples, so we were not able to evaluate the effect of gemigliptin on endotoxemia. The gene expression of inflammatory cytokines in subcutaneous adipose tissue was not affected by gemigliptin. Gemigliptin reduced ApoB48 levels after a high-fat meal in participants with T2DM. Whether systemic endotoxin levels can be reduced by gemigliptin requires further investigation.

Topics: Adiponectin; Adult; Aged; Apolipoprotein B-100; Apolipoprotein B-48; Blood Glucose; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Cytokines; Diabetes Mellitus, Type 2; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Endotoxemia; Endotoxins; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Interleukin-6; Lipid Metabolism; Male; Middle Aged; Piperidones; Postprandial Period; Pyrimidines; RNA, Messenger; Subcutaneous Fat, Abdominal; Transcriptome; Triglycerides; Tumor Necrosis Factor-alpha

To investigate the effect of exenatide on glucose disposal, insulin secretion, ß-cell function, lipolysis and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions.. Patients were assigned to exenatide 10 µg twice daily (EXE, n = 15) or control (CT, n = 15) for 3 months. Patients received a meal test/tracer study (MTT) to measure endogenous glucose production (EGP), rate of oral glucose appearance (RaO), insulin secretion rate (ISR), ß-cell function, hepatic insulin resistance (HIR) and adipose tissue insulin resistance (AT-IR) and insulin sensitivity (IS).. Post treatment, the EXE group showed a significant reduction in body weight ( P < .001). The postmeal time-course of glucose, insulin and ISR showed a lower peak between 60 and 180 minutes in phase with a reduction in RaO ( P < .01). After an initial similar suppression, EGP resumed at higher rates between 60 and 180 minutes ( P = .02) in EXE vs CT, while total RaO and EGP were similar throughout the MTT. In EXE, the postmeal glucagon, GLP1 and GIP responses were reduced ( P < .05). Fasting and postprandial lipolysis and ß-cell function were unaltered by active treatment. HIR, AT-IR and IS were all improved after exenatide treatment ( P < .05).. In morbidly obese non-diabetic subjects, exenatide causes weight loss, decreased postprandial glycaemia and glucagon response without changes in ß-cell function. These effects are consequent upon delayed oral glucose appearance in the circulation. Exenatide treatment is also associated with an improvement in hepatic, adipose tissue and whole-body IS with no influence on postprandial lipolysis.

Topics: Adipose Tissue; Adult; Blood Glucose; Exenatide; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Lipolysis; Liver; Male; Middle Aged; Obesity, Morbid; Peptides; Postprandial Period; Venoms

The decline in insulin sensitivity (S. Thirteen adolescents with T1D (HbA1C 8.2 ± 0.1%) were admitted to perform afternoon exercise (four 15-min treadmill/5-min rest cycles of exercise) on two occasions within a 4-wk period. They were randomized to receive a drink containing either glutamine (0.25 g/kg) or placebo before exercise, at bedtime, and early morning in a double-blind, crossover design. Blood glucose was monitored overnight, and a hyperinsulinemic-euglycemic clamp was performed the following morning.. Oral glutamine supplementation decreases blood glucose in adolescents with T1D after exercise. Insulin sensitivity, however, was unaltered during the euglycemic clamp. Although the mechanisms involved remain to be elucidated, studies to explore the potential use of glutamine to improve blood glucose control are needed.

Topics: Adolescent; Blood Glucose; Body Mass Index; Cross-Over Studies; Diabetes Mellitus, Type 1; Dietary Supplements; Double-Blind Method; Exercise; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glutamine; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male

High-amylose maize resistant starch type 2 (HAM-RS2) stimulates gut-derived satiety peptides and reduces adiposity in animals. Human studies have not supported these findings despite improvements in glucose homeostasis and insulin sensitivity after HAM-RS2 intake which can lower adiposity-related disease risk. The primary objective of this study was to evaluate the impact of HAM-RS2 consumption on blood glucose homeostasis in overweight, healthy adults. We also examined changes in biomarkers of satiety (glucagon-like peptide-1 [GLP-1], peptide YY [PYY], and leptin) and body composition determined by anthropometrics and dual-energy x-ray absorptiometry, dietary intake, and subjective satiety measured by a visual analogue scale following HAM-RS2 consumption.. Using a randomized-controlled, parallel-arm, double-blind design, 18 overweight, healthy adults consumed either muffins enriched with 30 g HAM-RS2 (n = 11) or 0 g HAM-RS2 (control; n = 7) daily for 6 weeks. The HAM-RS2 and control muffins were similar in total calories and available carbohydrate.. At baseline, total PYY concentrations were significantly higher 120 min following the consumption of study muffins in the HAM-RS2 group than control group (P = 0.043). Within the HAM-RS2 group, the area under the curve (AUC) glucose (P = 0.028), AUC leptin (P = 0.022), and postprandial 120-min leptin (P = 0.028) decreased independent of changes in body composition or overall energy intake at the end of 6 weeks. Fasting total PYY increased (P = 0.033) in the HAM-RS2 group, but changes in insulin or total GLP-1 were not observed. Mean overall change in subjective satiety score did not correlate with mean AUC biomarker changes suggesting the satiety peptides did not elicit a satiation response or change in overall total caloric intake. The metabolic response from HAM-RS2 occurred despite the habitual intake of a moderate-to-high-fat diet (mean range 34.5% to 39.4% of total calories).. Consuming 30 g HAM-RS2 daily for 6 weeks can improve glucose homeostasis, lower leptin concentrations, and increase fasting PYY in healthy overweight adults without impacting body composition and may aid in the prevention of chronic disease. However, between-group differences in biomarkers were not observed and future research is warranted before specific recommendations can be made.. None.

Topics: Absorptiometry, Photon; Adiposity; Adolescent; Adult; Biomarkers; Blood Glucose; Diet, High-Fat; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Overweight; Peptide YY; Postprandial Period; Satiation; Starch; Young Adult; Zea mays

Specific combinations of dietary fiber (DF) have been observed to result in improved glucose tolerance at a subsequent standardized breakfast. Arabinoxylan oligosaccharides (AXOS) are considered as DF with prebiotic potential, but so far no studies have investigated their metabolic effects in humans. This randomized cross-over study evaluated the overnight impact of breads containing AXOS-rich wheat bran extract and resistant starch (RS, Hi-Maize), separately or combined, on glucose tolerance, related metabolic parameters and markers of gut fermentation in healthy subjects.. Evening reference and test products were: (1) reference white wheat flour bread (WWB), WWB supplemented with (2) AXOS and RS (WWB + AXOS + RS), (3) an increased content of either AXOS (WWB + hiAXOS) or (4) RS (WWB + hiRS). At the subsequent standardized breakfast, blood was sampled for 3 h to monitor glucose, insulin, nonesterified fatty acids, glucagon-like peptide (GLP)-1 and GLP-2. Breath hydrogen (H2) and short chain fatty acids (SCFA) were measured as markers of gut fermentation, and subjective appetite was rated using visual analog scales.. Dose-dependent decreases in glucose responses were observed with increased AXOS over the duration of 3 h. Insulin sensitivity index was improved in the morning after the WWB + hiAXOS evening meal. An increase in breath H2 concentration and circulating SCFA was observed in the morning after both evening meals containing AXOS.. The present study indicates that AXOS have the potential of improving glucose tolerance in an overnight perspective and suggested mechanisms are improved insulin sensitivity and increased gut fermentation.

Topics: Adult; Appetite; Biomarkers; Blood Glucose; Body Mass Index; Bread; Breakfast; Breath Tests; Cross-Over Studies; Dietary Fiber; Fatty Acids, Nonesterified; Fatty Acids, Volatile; Female; Fermentation; Flour; Food, Fortified; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Male; Oligosaccharides; Postprandial Period; Prebiotics; Starch; Xylans; Young Adult

Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.. Fourteen patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.. Liraglutide reduced BMI (-1.9 vs. +0.04kg/m(2); p<0.001), HbA1c (-0.3 vs. +0.3%; p<0.01), cholesterol-LDL (-0.7 vs. +0.05mmol/L; p<0.01), ALT (-54 vs. -4.0IU/L; p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).. Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.

Topics: Adult; Aged; Body Mass Index; Double-Blind Method; Drug Monitoring; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Liraglutide; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome

Fermentable carbohydrates (FCHO) have been shown to improve insulin sensitivity in normoglycaemic and insulin-resistant subjects. However, there are no data on subjects with prediabetes. We aimed to investigate the effect of the FCHO inulin, on glucose homeostasis in subjects with prediabetes.. In a double-blind and placebo-controlled crossover study, 40 volunteers with prediabetes were randomly allocated to take 30 g/day of inulin or cellulose for 2 weeks in a crossover trial, following a 4-week dose-escalation run-in. Fasting insulin and glucose were measured for all subjects. Fifteen of the 40 subjects also underwent a meal tolerance test to assess insulin sensitivity, free fatty acids and glucagon-like peptide-1 concentrations. A subanalysis was carried out to examine any differences between the prediabetes subtypes.. Inulin was associated with a significant increase in (0-30 min)incremental AUC (iAUC) for insulin (treatment: p < 0.04) and (0-60 min)iAUC for insulin (treatment: p < 0.04) compared to control. There was a significant reduction in insulin resistance measured by the homeostatic model assessment in the isolated-impaired fasting glucose (p < 0.05) but not in the isolated-impaired glucose tolerance groups (p = 0.59).. The FCHO, inulin, may have unique metabolic effects that are of particular benefit to people at risk of diabetes, which warrant further investigation.

Topics: Aged; Blood Glucose; Body Mass Index; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Inulin; Male; Middle Aged; Prediabetic State; Risk Factors

Activation of free fatty acid receptor (FFAR)2 and FFAR3 via colonic short-chain fatty acids, particularly propionate, are postulated to explain observed inverse associations between dietary fiber intake and body weight. Propionate is reported as the predominant colonic fermentation product from l-rhamnose, a natural monosaccharide that resists digestion and absorption reaching the colon intact, while effects of long-chain inulin on appetite have not been extensively investigated. In this single-blind randomized crossover study, healthy unrestrained eaters (n = 13) ingested 25.5 g/d l-rhamnose, 22.4 g/d inulin or no supplement (control) alongside a standardized breakfast and lunch, following a 6-d run-in to investigate if appetite was inhibited. Postprandial qualitative appetite, breath hydrogen, and plasma glucose, insulin, triglycerides and non-esterified fatty acids were assessed for 420 min, then an ad libitum meal was provided. Significant treatment x time effects were found for postprandial insulin (P = 0.009) and non-esterified fatty acids (P = 0.046) with a significantly lower insulin response for l-rhamnose (P = 0.023) than control. No differences between treatments were found for quantitative and qualitative appetite measures, although significant treatment x time effects for meal desire (P = 0.008) and desire to eat sweet (P = 0.036) were found. Breath hydrogen was significantly higher with inulin (P = 0.001) and l-rhamnose (P = 0.009) than control, indicating colonic fermentation. These findings suggest l-rhamnose may inhibit postprandial insulin secretion, however neither l-rhamnose or inulin influenced appetite.

Topics: Adolescent; Adult; Appetite; Blood Glucose; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Colon; Cross-Over Studies; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Dietary Proteins; Dietary Supplements; Energy Intake; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Inulin; Male; Middle Aged; Peptide YY; Postprandial Period; Propionates; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Rhamnose; Single-Blind Method; Waist Circumference; Young Adult

The objective of this study was to determine the postprandial change in free fatty acid (FFA) profiles in subjects with impaired fasting glucose (IFG), and to evaluate the effect of low glycemic index (GI) load on postprandial FFA profiles and inflammation.. First, 50 IFG and 50 healthy subjects were recruited; and 2 -h postprandial changes in FFA profiles were determined. Second, the 50 IFG subjects then received three different loads: glucose load (GL), high glycemic index (HGI) load and low glycemic index (LGI) load, respectively. FFA profile, glucose, insulin, glucagon-like peptide 1 (GLP-1) and inflammatory biomarkers were assayed at 0, 30, 60, 90 and 120 min.. Postprandial stearic acid (C18:0) increased compared with baseline in all subjects, whereas the change in postprandial C18:0 was more marked in IFG subjects than in healthy subjects. Compared with subjects who received the GL and HGI load, the area under the curve for insulin, GLP-1, C18:0 and tumor necrosis factor-alpha significantly decreased and adiponectin increased in subjects who received the LGI load.. The rise in postprandial C18:0 in IFG subjects was inhibited by LGI load.

Topics: Adiponectin; Adult; Aged; Blood Glucose; Dietary Carbohydrates; Fasting; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Glucose; Glycemic Index; Glycemic Load; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Postprandial Period; Prediabetic State; Stearic Acids; Tumor Necrosis Factor-alpha

The changes in blood glucose concentrations that result from an oral glucose challenge are dependent on the rate of gastric emptying, the rate of glucose absorption and the rate of insulin-driven metabolism that include the incretins, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The rate of insulin-driven metabolism is clearly altered in obese subjects, but it is controversial which of these factors is predominant. We aimed to quantify gastric emptying, plasma insulin, C-peptide, glucagon and glucose responses, as well as incretin hormone secretions in obese subjects and healthy controls during increasing glucose loads.. The study was conducted as a randomized, double-blind, parallel-group trial in a hospital research unit. A total of 12 normal weight (6 men and 6 women) and 12 non-diabetic obese (BMI > 30, 6 men and 6 women) participants took part in the study. Subjects received intragastric loads of 10 g, 25 g and 75 g glucose dissolved in 300 ml tap water.. Main outcome measures were plasma GLP-1 and GIP, plasma glucagon, glucose, insulin, C-peptide and gastric emptying. The primary findings are: i) insulin resistance (P < 0.001) and hyperinsulinemia (P < 0.001); ii) decreased insulin disposal (P < 0.001); iii) trend for reduced GLP-1 responses at 75 g glucose; and iv) increased fasting glucagon levels (P < 0.001) in obese subjects.. It seems that, rather than changes in incretin secretion, fasting hyperglucagonemia and consequent hyperglycemia play a role in reduced disposal of insulin, contributing to hyperinsulinemia and insulin resistance.. ClinicalTrials.gov NCT01875575.

Topics: Adult; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Case-Control Studies; Diabetes Mellitus; Double-Blind Method; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Young Adult

Administration of ghrelin inhibits the acute insulin response to glucose and worsens IV glucose tolerance in healthy subjects. Evidence from preclinical studies suggests that ghrelin may have differential effects on glucose metabolism during fasting and feeding. Our objective was to test the effects of ghrelin on glucose and insulin responses during a meal tolerance test.. Acyl ghrelin (0.26 and 2.0 μg/kg/h) or saline was infused in 13 healthy subjects on three separate occasions in randomized order. Ghrelin was infused for 45 minutes to achieve steady-state levels and continued for 240 minutes after ingestion of a liquid test meal. Primary outcomes were area under the curve for glucose and insulin secretion.. We found that ghrelin infusions of 0.26 and 2.0 μg/kg/h raised steady-state plasma total ghrelin levels to 1.7- and 4.8-fold above fasting concentrations, but did not alter fasting plasma glucose or insulin levels. During the meal tolerance test, ghrelin decreased insulin sensitivity, impaired β-cell function, and induced glucose intolerance. The high-dose ghrelin infusion also raised postprandial glucagon like peptide 1 secretion without affecting glucose dependent insulinotropic polypeptide, glucagon, or peptide YY concentrations.. We conclude that both physiologic and pharmacologic doses of ghrelin worsen the glucose and β-cell responses to meal ingestion in healthy humans. The increase in postprandial glucagon like peptide 1 secretion by ghrelin suggests a novel enteroendocrine connection, but does not mitigate the glucose intolerance.

Topics: Adult; Blood Glucose; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Peptide YY; Postprandial Period; Young Adult

The role of the different factors associated with fatty liver is still poorly defined. We evaluated the relationships between liver fat content (LF) and metabolic, inflammatory and nutritional factors in a homogeneous cohort of individuals at high cardio-metabolic risk.. In 70 individuals with high waist circumference and at least one more criterion for metabolic syndrome enrolled in a nutritional intervention study, LF was evaluated at baseline by hepatic/renal echo intensity ratio (H/R), together with dietary habits (7-day dietary record), insulin sensitivity and β-cell function (fasting and OGTT-derived indices), fasting and postprandial plasma GLP-1 and lipoproteins, and plasma inflammatory markers. H/R correlated positively with fasting and OGTT plasma glucose and insulin concentrations, HOMA-IR and β-cell function, and IL-4, IL-17, IFN-γ, TNF-α, FGF and GCSF plasma concentrations (p < 0.05 for all), and negatively with insulin sensitivity (OGIS), dietary, polyphenols and fiber (p < 0.05 for all). By multiple stepwise regression analysis, the best predictors of H/R were OGIS (β = -0.352 p = 0.001), postprandial GLP-1 (β = -0.344; p = 0.001), HDL-cholesterol (β = -0.323; p = 0.002) and IFN-γ (β = 0.205; p = 0.036).. A comprehensive evaluation of factors associated with liver fat, in a homogeneous population at high cardio-metabolic risk, indicated a pathogenic combination of the same pathways underlying the atherosclerotic process, namely whole body insulin sensitivity and inflammation. The higher predictive value of postprandial variables suggests that liver fat is essentially a postprandial phenomenon, with a relevant role possibly played by GLP-1.. NCT01154478.

Topics: Adaptive Immunity; Adult; Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Cross-Sectional Studies; Diet Records; Feeding Behavior; Female; Glucagon-Like Peptide 1; Humans; Inflammation Mediators; Insulin; Insulin Resistance; Interferon-gamma; Italy; Liver; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Nutritional Status; Postprandial Period; Regression Analysis; Risk Assessment; Risk Factors; Time Factors

Obesity induces insulin resistance (IR), the key etiologic defect of type 2 diabetes mellitus (T2DM). Therefore, an incidence of obesity-induced diabetes is expected to decrease if obesity is controlled. Although Metformin is currently one of the main treatment options for T2DM in obese patients, resulting in an average of 5% weight loss, adequate weight control in all patients cannot be achieved with Metformin alone. Thus, additional therapies with a weight loss effect, such as acupuncture, may improve the effectiveness of Metformin.Subjective:We designed this randomized clinical trial (RCT) to compare the effects of Metformin monotherapy with that of Metformin and acupuncture combined therapy on weight loss and insulin sensitivity among overweight/obese T2DM patients, to understand whether acupuncture plus Metformin is a better approach than Metformin only on treating diabetes. To understand whether acupuncture can be an insulin sensitizer and, if so, its therapeutic mechanism.. Our results show that Metformin and acupuncture combined therapy significantly improves body weight, body mass index (BMI), fasting blood sugar (FBS), fasting insulin (FINS), homeostasis model assessment (HOMA) index, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, adiponectin, glucagon-like peptide-1 (GLP-1), resistin, serotonin, free fatty acids (FFAs), triglyceride (TG), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc) and ceramides.. Consequently, Metformin and acupuncture combined therapy is more effective than Metformin only, proving that acupuncture is an insulin sensitizer and is able to improve insulin sensitivity possibly by reducing body weight and inflammation, while improving lipid metabolism and adipokines. As a result, electro-acupuncture (EA) might be useful in controlling the ongoing epidemics in obesity and T2DM.

Topics: Acupuncture Therapy; Adiponectin; Adult; Biomarkers; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Interleukin-6; Leptin; Male; Metformin; Obesity; Resistin; Serotonin; Triglycerides; Tumor Necrosis Factor-alpha; Weight Loss

Bile acids (BAs) are increasingly recognised as metabolic regulators, potentially improving insulin sensitivity following bariatric surgery. However, physiological relevance of such observations remains unknown. Hence, we analysed serum BA composition and associated gut-derived hormone levels following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). 74 non-smoking men (45-55 yr) with MetS were randomised to a lifestyle-induced weight loss program (supervision via telemonitoring) or to a control arm. Before and after a 6 months intervention period clinical and laboratory parameters, body composition, serum BA profile, FGF-19, and GLP-1 concentrations were determined in fasting blood samples. 30 participants in the control and 33 participants in the treatment arm completed the study and were included in the data analysis. In participants of the treatment arm lifestyle-induced weight loss resulted in markedly improved insulin sensitivity. Serum levels of BA species and total GLP-1 decreased, while FGF-19 remained stable. Serum BA composition changed towards an increased 12α-hydroxylated/non-12α-hydroxylated ratio. None of these parameters changed in participants of the control arm. Our results demonstrate that improved metabolic control by lifestyle modifications lowers serum levels of BAs and GLP-1 and changes serum BA composition towards an increased 12α/non-12α ratio (ICTRP Trial Number: U1111-1158-3672).

Topics: Bile Acids and Salts; Blood Glucose; Body Mass Index; Body Weight; Fasting; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Prospective Studies; Weight Loss

To compare directly the impact of glucagon-like peptide-1 secretion on glucose metabolism in individuals with Type 2 diabetes listed for Roux-en-Y gastric bypass surgery, randomized to be studied before and 7 days after undergoing Roux-en-Y gastric bypass or after following a very-low-calorie diet.. A semi-solid meal test was used to investigate glucose, insulin and glucagon-like peptide-1 response. Insulin secretion in response to intravenous glucose and arginine stimulus was measured. Hepatic and pancreatic fat content was quantified using magnetic resonance imaging.. The decrease in fat mass was almost identical in the Roux-en-Y gastric bypass and the very-low-calorie diet groups (3.0±0.3 and 3.0±0.7kg). The early rise in plasma glucose level and in acute insulin secretion were greater after Roux-en-Y gastric bypass than after a very-low-calorie diet; however, the early rise in glucagon-like peptide-1 was disproportionately greater (sevenfold) after Roux-en-Y gastric bypass than after a very-low-calorie diet. This did not translate into a greater improvement in fasting glucose level or area under the curve for glucose. The reduction in liver fat was greater after Roux-en-Y gastric bypass (29.8±3.7 vs 18.6±4.0%) and the relationships between weight loss and reduction in liver fat differed between the Roux-en-Y gastric bypass group and the very-low-calorie diet group.. This study shows that gastroenterostomy increases the rate of nutrient absorption, bringing about a commensurately rapid rise in insulin level; however, there was no association with the large post-meal rise in glucagon-like peptide-1, and post-meal glucose homeostasis was similar in the Roux-en-Y gastric bypass and very-low-calorie diet groups. (Clinical trials registry number: ISRCTN11969319.).

Topics: Adipose Tissue; Adult; Aged; Amino Acids; Arginine; Blood Glucose; Body Composition; Caloric Restriction; Chromium; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Insulin Secretion; Lipase; Liver; Male; Membrane Proteins; Middle Aged; Nicotinic Acids; Pancreas; Triglycerides

Postprandial hyperinsulinemia, hyperglycemia, and insulin resistance increase the risk of type 2 diabetes (T2D) and cardiovascular disease mortality. Postprandial hyperinsulinemia and hyperglycemia also occur in metabolically healthy subjects consuming high-carbohydrate diets particularly after evening meals and when carbohydrate loads follow acute exercise. We hypothesized the involvement of dietary carbohydrate load, especially when timed after exercise, and mediation by the glucose-dependent insulinotropic peptide (GIP) in this phenomenon, as this incretin promotes insulin secretion after carbohydrate intake in insulin-sensitive, but not in insulin-resistant states.. Four groups of eight metabolically healthy weight-matched postmenopausal women were provided with three isocaloric meals (a pre-trial meal and two meals during the trial day) containing either 30% or 60% carbohydrate, with and without two-hours of moderate-intensity exercise before the last two meals. Plasma glucose, insulin, glucagon, GIP, glucagon-like peptide 1 (GLP-1), free fatty acids (FFAs), and D-3-hydroxybutyrate concentrations were measured during 4-h postprandial periods and 3-h exercise periods, and their areas under the curve (AUCs) were analyzed by mixed-model ANOVA, and insulin resistance during fasting and meal tolerance tests within each diet was estimated using homeostasis-model assessment (HOMA-IR).. The third low-carbohydrate meal, but not the high-carbohydrate meal, reduced: (1) evening insulin AUC by 39% without exercise and by 31% after exercise; (2) GIP AUC by 48% without exercise and by 45% after exercise, and (3) evening insulin resistance by 37% without exercise and by 24% after exercise. Pre-meal exercise did not alter insulin-, GIP- and HOMA-IR- lowering effects of low-carbohydrate diet, but exacerbated evening hyperglycemia.. Evening postprandial insulin and GIP responses and insulin resistance declined by over 30% after three meals that limited daily carbohydrate intake to 30% compared to no such changes after three 60%-carbohydrate meals, an effect that was independent of pre-meal exercise. The parallel timing and magnitude of postprandial insulin and GIP changes suggest their dependence on a delayed intestinal adaptation to a low-carbohydrate diet. Pre-meal exercise exacerbated glucose intolerance with both diets most likely due to impairment of insulin signaling by pre-meal elevation of FFAs.

Topics: 3-Hydroxybutyric Acid; Aged; Blood Glucose; Dietary Carbohydrates; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Middle Aged; Postprandial Period; Sedentary Behavior

Intake of sugar-sweetened beverages (SSB) may contribute to cardiovascular risk. The aim of this study was to investigate whether functional sugars with low compared to high glycemic index (GI) have beneficial effects on arterial stiffness during a period of low-physical activity. In a controlled cross-over dietary intervention (55% CHO, 30% fat, 15% protein), 13 healthy men (age: 23.7 ± 2.2 years, body mass index: 23.6 ± 1.9 kg/m²) completed 2 × 1 week of low physical activity following 1 week of normal physical activity (2363 ± 900 vs. 11,375 ± 3124 steps/day). During inactive phases participants consumed either low-GI (isomaltulose) or high-GI SSB (maltodextrin-sucrose), providing 20% of energy requirements. Postprandial vasodilatation (augmentation index, AIx), insulin sensitivity (IS) and Glucagon-like-peptide 1 (GLP-1) responses were measured during a meal test before and after SSB-intervention. Compared to maltodextrin-sucrose-SSB, postprandial vasodilatation was prolonged (AIx after 120 min: 9.9% ± 4.3% vs. 11.4% ± 3.7%,

Topics: Adult; Beverages; Cardiovascular Diseases; Cross-Over Studies; Dietary Carbohydrates; Dietary Sucrose; Exercise; Germany; Glucagon-Like Peptide 1; Glucose Intolerance; Glycemic Index; Humans; Insulin Resistance; Isomaltose; Male; Polysaccharides; Postprandial Period; Risk Factors; Sedentary Behavior; Single-Blind Method; Vascular Stiffness; Vasodilation

This study aims to assess the clinical and physiological effects of Roux-en-Y gastric bypass (RYGBP) on type 2 diabetes associated with mild obesity (body mass index [BMI] 30-34.9 kg/m(2)) over 24 months postsurgery.. In this prospective trial, 36 mildly obese subjects (19 males) with type 2 diabetes using oral antidiabetic drugs with (n = 24) or without insulin (n = 12) underwent RYGBP. Follow-up was conducted at baseline and 3, 6, 12, and 24 months postsurgery. The following endpoints were considered: changes in HbA1c, fasting glucose and insulin, antidiabetic therapy, BMI, oral glucose insulin sensitivity [OGIS, from meal tolerance test (MTT)], beta-cell secretory function [ΔCP(0-30)/ΔGlu(0-30) (ΔC-peptide/Δglucose ratio, MTT 0-30 min), disposition index (DI = OGIS [Symbol: see text] ΔCP(0-30)/ΔGlu(0-30)], glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) [incremental area under the curve (AUCi)], adiponectin, C-reactive protein, and lipids.. All subjects achieved normal-to-overweight BMI after 3 months. Over 24 months, 31/36 (86 %) subjects presented HbA1c <7 % [complete and partial remission of diabetes in 9/36 (22 %) and 1/36 (3 %), respectively]. Since 3 months postsurgery, improvements were observed in OGIS [290 (174) to 373 (77) ml/min/m(2), P = 0.009], ΔCP(0-30)/ΔGlu(0-30) [0.24 (0.19) to 0.52 (0.34) ng/mg, P = 0.001], DI [7.16 (8.53) to 19.8 (15.4) (ng/mg) (ml/min/m(2)), P = 0.001], GLP-1 AUCi [0.56 (0.64) to 3.97 (3.86) ng/dl [Symbol: see text] 10 min [Symbol: see text] 103, P = 0.000], and GIP AUCi [30.2 (12.6) to 27.0 (20.2) ng/dl [Symbol: see text] 10 min [Symbol: see text] 103, P = 0.004]. At baseline and after 12 months, subjects with diabetes nonremission had longer diabetes duration, higher HbA1c, lower beta-cell secretory function, and higher first 30-min GIP AUCi, compared with those with remission.. RYGBP improves the glucose metabolism in subjects with type 2 diabetes and mild obesity. This effect is associated with improvement of insulin sensitivity, beta-cell secretory function, and incretin secretion.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Severity of Illness Index

Gut hormones change with weight loss in adults but are not well studied in obese youth.. The primary aim was to evaluate how gut hormones and subjective appetite measure change with dietary weight loss in obese adolescents.. Participants were a subset of those taking part in the 'Eat Smart Study'. They were aged 10-17 years with body mass index (BMI) > 90th centile and were randomized to one of three groups: wait-listed control, structured reduced carbohydrate or structured low-fat dietary intervention for 12 weeks. Outcomes were fasting glucose, insulin, leptin, adiponectin, total amylin, acylated ghrelin, active glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP) and total peptide tyrosine-tyrosine. Pre- and postprandial subjective sensations of appetite were assessed using visual analogue scales.. Of 87 'Eat Smart' participants, 74 participated in this sub-study. The mean (standard deviation) BMI z-score was 2.1 (0.4) in the intervention groups at week 12 compared with 2.2 (0.4) in the control group. Fasting insulin (P = 0.05) and leptin (P = 0.03) levels decreased, while adiponectin levels increased (P = 0.05) in the intervention groups compared with control. The intervention groups were not significantly different from each other. A decrease in BMI z-score at week 12 was associated with decreased fasting insulin (P < 0.001), homeostatic model of assessment-insulin resistance (P < 0.001), leptin (P < 0.001), total amylin (P = 0.03), GIP (P = 0.01), PP (P = 0.02) and increased adiponectin (P < 0.001). There was no significant difference in appetite sensations.. Modest weight loss in obese adolescents leads to changes in some adipokines and gut hormones that may favour weight regain.

Topics: Adiponectin; Adolescent; Adult; Appetite; Body Mass Index; Body Weight; Fasting; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Male; Pediatric Obesity; Peptide YY; Postprandial Period; Weight Loss

There is evidence for health benefits from 'Palaeolithic' diets; however, there are a few data on the acute effects of rationally designed Palaeolithic-type meals. In the present study, we used Palaeolithic diet principles to construct meals comprising readily available ingredients: fish and a variety of plants, selected to be rich in fibre and phyto-nutrients. We investigated the acute effects of two Palaeolithic-type meals (PAL 1 and PAL 2) and a reference meal based on WHO guidelines (REF), on blood glucose control, gut hormone responses and appetite regulation. Using a randomised cross-over trial design, healthy subjects were given three meals on separate occasions. PAL2 and REF were matched for energy, protein, fat and carbohydrates; PAL1 contained more protein and energy. Plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) concentrations were measured over a period of 180 min. Satiation was assessed using electronic visual analogue scale (EVAS) scores. GLP-1 and PYY concentrations were significantly increased across 180 min for both PAL1 (P= 0·001 and P< 0·001) and PAL2 (P= 0·011 and P= 0·003) compared with the REF. Concomitant EVAS scores showed increased satiety. By contrast, GIP concentration was significantly suppressed. Positive incremental AUC over 120 min for glucose and insulin did not differ between the meals. Consumption of meals based on Palaeolithic diet principles resulted in significant increases in incretin and anorectic gut hormones and increased perceived satiety. Surprisingly, this was independent of the energy or protein content of the meal and therefore suggests potential benefits for reduced risk of obesity.

Topics: Adolescent; Adult; Blood Glucose; Cohort Studies; Cross-Over Studies; Diet, Paleolithic; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male; Meals; Patient Compliance; Peptide YY; Postprandial Period; Satiety Response; Time Factors; Up-Regulation; Young Adult

Glucagon-like peptide-1 (GLP-1) is an insulinotropic factor made in the gastrointestinal tract that is essential for normal glucose tolerance. Infusion of GLP-1 increases insulin secretion in both diabetic and nondiabetic humans. However, the degree to which people vary in their β-cell sensitivity to GLP-1 and the factors contributing to this variability have not been reported.. The objective was to measure the sensitivity of insulin secretion to GLP-1 in cohorts of lean and obese subjects across a broad range of insulin sensitivity.. Insulin secretion was measured during clamped hyperglycemia (7.2 mmol/L) and graded GLP-1 infusion in young, healthy subjects, and GLP-1 sensitivity was computed from the insulin secretion rate (ISR) during progressive increases in plasma GLP-1.. All subjects had fasting glucose values <5.2 mm. The obese subjects were insulin resistant compared to the lean group (homeostasis model of assessment 2 for insulin resistance: obese, 2.6 ± 0.5; lean, 0.8 ± 0.1; P < .001). ISR increased linearly in both cohorts with escalating doses of GLP-1, but the slope of ISR in response to GLP-1 was greater in the obese than in the lean subjects (obese, 0.17 ± 0.03 nmol/min/pm; lean, 0.05 ± 0.01 nmol/min/pm; P < .001). There was a significant association of β-cell GLP-1 sensitivity and insulin resistance (r = 0.83; P < .001), and after correction for homeostasis model of assessment 2 for insulin resistance, the slopes of ISR vs GLP-1 concentration did not differ in the two cohorts (obese, 0.08 ± 0.01; lean, 0.08 ± 0.01; P = .98). However, within the entire study group, β-cell GLP-1 sensitivity corrected for insulin resistance varied nearly 10-fold.. Insulin secretion in response to GLP-1 is proportional to insulin resistance in healthy subjects. However, there is considerable variability in the sensitivity of the β-cell to GLP-1 that is independent of insulin sensitivity.

Topics: Adult; Blood Glucose; Drug Resistance; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Health; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Obesity; Thinness; Young Adult

It is not known whether calorie restriction (CR) has additive benefits to those from exercise (EX)-induced weight loss. We hypothesized that weight loss from CR and EX (CREX) improves insulin sensitivity more than matched weight loss induced by EX or CR alone and that the incretin system may be involved in adaptations to CR.. Sedentary, overweight men and women (n = 52, 45-65 years of age) were randomized to undergo 6-8% weight loss by using CR, EX, or CREX. Glucose, insulin, C-peptide, insulin sensitivity, and incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) were measured during frequently sampled oral glucose tolerance tests (FSOGTTs). Incretin effects on insulin secretion were measured by comparing insulin secretion rates from the FSOGTTs to those from a glycemia-matched glucose infusion.. Despite similar weight losses in all groups, insulin sensitivity index values increased twofold more in the CREX group (2.09 ± 0.35 μM/kg/pM × 100) than in the CR (0.89 ± 0.39 μM/kg/pM × 100) and EX (1.04 ± 0.39 μM/kg/pM × 100) groups. Postprandial GLP-1 concentrations decreased only in the CR group (P = 0.04); GIP concentrations decreased in all groups. Incretin effects on insulin secretion were unchanged.. CR and EX have additive beneficial effects on glucoregulation. Furthermore, the adaptations to CR may involve reductions in postprandial GLP-1 concentrations. These findings underscore the importance of promoting both CR and EX for optimal health. However, because data from participants who withdrew from the study and from those who did not adhere to the intervention were excluded, the results may be limited to individuals who are capable of adhering to a healthy lifestyle intervention.

Topics: Adaptation, Physiological; Aged; Blood Glucose; C-Peptide; Caloric Restriction; Energy Intake; Energy Metabolism; Exercise Therapy; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Life Style; Male; Middle Aged; Overweight; Postprandial Period; Weight Loss

Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular (CV) risk markers. In this study our aim was to assess the effects of six months treatment with liraglutide 1.8 mg od on obesity, and CV risk markers, particularly platelet function, in young obese women with PCOS compared to controls of similar age and weight.. Carotid intima-media wall thickness (cIMT) was measured by B-mode ultrasonography, platelet function by flow cytometry, clot structure/lysis by turbidimetric assays and endothelial function by ELISA and post-ischaemic reactive hyperemia (RHI). Data presented as mean change (6-month - baseline) ± standard deviation.. Nineteen obese women with PCOS and 17 controls, of similar age and weight, were recruited; baseline atherothrombotic risk markers did not differ between the two groups. Twenty five (69.4%) participants completed the study (13 PCOS, 12 controls). At six months, weight was significantly reduced by 3.0 ± 4.2 and 3.8 ± 3.4 kg in the PCOS and control groups, respectively; with no significant difference between the two groups, P = 0.56. Similarly, HOMA-IR, triglyceride, hsCRP, urinary isoprostanes, serum endothelial adhesion markers (sP-selectin, sICAM and sVCAM), and clot lysis area were equally significantly reduced in both groups compared to baseline. Basal platelet P-selectin expression was significantly reduced at six months in controls -0.17 ± 0.26 but not PCOS -0.12 ± 0.28; between groups difference, 95% confidence interval = -0.14 - 0.26, P = 0.41. No significant changes were noted in cIMT or RHI.. Six months treatment with liraglutide (1.8 mg od) equally affected young obese women with PCOS and controls. In both groups, liraglutide treatment was associated with 3-4% weight loss and significant reduction in atherothrombosis markers including inflammation, endothelial function and clotting. Our data support the use of liraglutide as weight loss medication in simple obesity and suggest a potential beneficial effect on platelet function and atherothrombotic risk at 6 months of treatment.. Clinical trial reg. no. ISRCTN48560305. Date of registration 22/05/2012.

Topics: Adolescent; Adult; Blood Platelets; Cardiovascular Diseases; Carotid Intima-Media Thickness; Female; Fibrinolysis; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Middle Aged; Polycystic Ovary Syndrome; Risk Factors; Young Adult

Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA1c at 1 year after RYGB. β-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA1c in both groups, independent of weight loss. Weight loss and preserved β-cell function both predominantly determine the greatest glycemic benefit after RYGB.

Topics: Adiponectin; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Obesity; Treatment Outcome; Weight Loss

Dietary polyphenols and long chain n-3 polyunsaturated fatty acids (LCn3) are associated with lower cardiovascular risk. This may relate to their influence on glucose metabolism and diabetes risk. We evaluated the effects of diets naturally rich in polyphenols and/or LCn3 of marine origin on glucose metabolism in people at high cardiometabolic risk.. According to a 2 × 2 factorial design, individuals with high waist circumference and at least one more component of the metabolic syndrome were recruited at the obesity outpatient clinic. Eighty-six participants were randomly assigned by MINIM software to an isoenergetic diet: (1) control, low in LCn3 and polyphenol (analysed n = 20); (2) rich in LCn3 (n = 19); (3) rich in polyphenols (n = 19); or (4) rich in LCn3 and polyphenols (n = 19). The assigned diets were known for the participants and blinded for people doing measurements. Before and after the 8 week intervention, participants underwent a 3 h OGTT and a test meal with a similar composition as the assigned diet for the evaluation of plasma glucose, insulin and glucagon-like peptide 1 (GLP-1) concentrations, and indices of insulin sensitivity and beta cell function.. During OGTT, polyphenols significantly reduced plasma glucose total AUC (p = 0.038) and increased early insulin secretion (p = 0.048), while LCn3 significantly reduced beta cell function (p = 0.031) (two-factor ANOVA). Moreover, polyphenols improved post-challenge oral glucose insulin sensitivity (OGIS; p = 0.05 vs control diet by post hoc ANOVA). At test meal, LCn3 significantly reduced GLP-1 total postprandial AUC (p < 0.001; two-factor ANOVA).. Diets naturally rich in polyphenols reduce blood glucose response, likely by increasing early insulin secretion and insulin sensitivity. These effects may favourably influence diabetes and cardiovascular risk. The implications of the decrease in insulin secretion and postprandial GLP-1 observed with diets rich in marine LCn3 need further clarification.. ClinicalTrials.gov NCT01154478.. The trial was funded by European Community's Seventh Framework Programme FP7/2009-2012 under grant agreement FP7-KBBE-222639, Etherpaths Project and 'Ministero Istruzione Università e Ricerca' PRIN 2010-2011 - 2010JCWWKM.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diet; Fatty Acids, Omega-3; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Metabolic Diseases; Middle Aged; Obesity; Patient Compliance; Polyphenols; Waist Circumference

Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release of glucagon-like peptides (GLP)-1 and -2.. A prospective, double-blind, randomized trial was performed in 21 glucose-tolerant humans (11 lean: age 49 ± 7 years, BMI 23.6 ± 1.7 kg/m(2); 10 obese: age 51 ± 7 years, BMI 35.5 ± 4.9 kg/m(2)). Participants ingested 10(10) b.i.d. L. reuteri SD5865 or placebo over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess incretin effect and GLP-1 and GLP-2 secretion, and euglycemic-hyperinsulinemic clamps with [6,6-(2)H2]glucose were used to measure peripheral insulin sensitivity and endogenous glucose production. Muscle and hepatic lipid contents were assessed by (1)H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays.. In glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2 release by 76% (P < 0.01) and 43% (P < 0.01), respectively, compared with placebo, along with 49% higher insulin (P < 0.05) and 55% higher C-peptide secretion (P < 0.05). However, the intervention did not alter peripheral and hepatic insulin sensitivity, body mass, ectopic fat content, or circulating cytokines.. Enrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may serve as a novel therapeutic approach to improve glucose-dependent insulin release.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Limosilactobacillus reuteri; Male; Middle Aged; Obesity; Oxidative Stress; Pilot Projects; Probiotics; Prospective Studies; Protein Precursors

The effects of twice-daily GLP-1 analogue injections added on continuous subcutaneous insulin infusion (CSII) in patients with poorly controlled type 2 diabetes (T2DM) were unknown. After optimization of blood glucose in the first 3 days by CSII during hospitalization, patients with poorly controlled T2DM were randomized to receive CSII combined with injections of exenatide or placebo for another 3 days. A total of 51 patients (30 in exenatide and 21 in placebo groups) with mean A1C 11% were studied. There was no difference in mean glucose but a significant higher standard deviation of plasma glucose (SDPG) was found in the exenatide group (50.51 ± 2.43 vs. 41.49 ± 3.00 mg/dl, p = 0.027). The improvement of incremental area under the curve (AUC) of glucose and insulinogenic index (Insulin 0-peak/ Glucose 0-peak) in 75 g oral glucose tolerance test was prominent in the exenatide group (p < 0.01). The adiponectin level was significantly increased with exenatide added on (0.39 ± 0.32 vs. -1.62 ± 0.97 μg/mL, in exenatide and placebo groups, respectively, p = 0.045). In conclusion, the add-on of GLP-1 analogue to CSII increased glucose variability and the β - cell response in patients with poorly controlled T2DM.

Topics: Adiponectin; Biomarkers; Blood Glucose; C-Peptide; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endpoint Determination; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Peptides; Risk Factors; Venoms

The Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve β-cell function in prediabetes or early type 2 diabetes.. β-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95-125 mg/dL (5.3-6.9 mmol/L), OGTT 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA1c 5.8-7.0% (40-53 mmol/mol), and BMI 25-40 kg/m(2). Adult surgical protocol criteria are similar, except for fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), BMI 30-40 kg/m(2), HbA1c <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose ≥90 mg/dL (≥5.0 mmol/L), 2-h glucose ≥140 mg/dL (≥7.8 mmol/L), HbA1c ≤8.0% (≤64 mmol/mol), BMI >85th percentile and ≤50 kg/m(2), 10-19 years of age, and diabetes <6 months.. Primary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points.. RISE is determining whether medication or surgical intervention strategies can mitigate progressive β-cell dysfunction in adults and youth with prediabetes or early type 2 diabetes.

Topics: Adolescent; Adult; Aged; Arginine; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gastroplasty; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liraglutide; Male; Metformin; Middle Aged; Prediabetic State; Young Adult

Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.. This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40-70 years old, overweight (BMI 27-40 kg/m(2)) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n = 35) or matching placebo (n = 33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.. Liraglutide treatment (n = 24) significantly (p ≤ 0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs -4% [-11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs -0.5% (-15, 14]), and decreased insulin clearance rate (-3.5% [-11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n = 25). The liraglutide-treated group also had significantly (p ≤ 0.03) lower day-long glucose (-8.2% [-11, -6] vs -0.1 [-3, 2]) and NEFA concentrations (-14 [-20, -8] vs -2.1 [-10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p ≤ 0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.. A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.. ClinicalTrials.gov NCT01784965 FUNDING: The study was funded by the ADA.

Topics: Adult; Aged; Blood Glucose; Diet, Reducing; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liraglutide; Male; Middle Aged; Obesity; Prediabetic State; Weight Loss

The aim of this study is to investigate the effect of green tea extract on patients with type 2 diabetes mellitus and lipid abnormalities on glycemic and lipid profiles, and hormone peptides by a double-blinded, randomized and placebo-controlled clinical trial. This trial enrolled 92 subjects with type 2 diabetes mellitus and lipid abnormalities randomized into 2 arms, each arm comprising 46 participants. Of the participants, 39 in therapeutic arm took 500 mg green tea extract, three times a day, while 38 in control arm took cellulose with the same dose and frequency to complete the 16-week study. Anthropometrics measurements, glycemic and lipid profiles, safety parameters, and obesity-related hormone peptides were analyzed at screening and after 16-week course. Within-group comparisons showed that green tea extract caused a significant decrease in triglyceride and homeostasis model assessment of insulin resistance index after 16 weeks. Green tea extract also increased significantly high density lipoprotein cholesterol. The HOMA-IR index decreased from 5.4±3.9 to 3.5±2.0 in therapeutic arm only. Adiponectin, apolipoprotein A1, and apolipoprotein B100 increased significantly in both arms, but only glucagon-like peptide 1 increased in the therapeutic arm. However, only decreasing trend in triglyceride was found in between-group comparison. Our study suggested that green tea extract significantly improved insulin resistance and increased glucagon-like peptide 1 only in within-group comparison. The potential effects of green tea extract on insulin resistance and glucagon-like peptide 1 warrant further investigation.. ClinicalTrials.gov NCT01360567.

Topics: Demography; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Lipids; Male; Middle Aged; Placebos; Plant Extracts

Gut microbiota modifiers may have beneficial effects of non-alcoholic fatty liver disease (NAFLD) but randomised controlled trials (RCT) are lacking in children.. To perform a double-blind RCT of VSL#3 vs. placebo in obese children with biopsy-proven NAFLD.. Of 48 randomised children, 44 (22 VSL#3 and 22 placebo) completed the study. The main outcome was the change in fatty liver severity at 4 months as detected by ultrasonography. Secondary outcomes were the changes in triglycerides, insulin resistance as detected by the homoeostasis model assessment (HOMA), alanine transaminase (ALT), body mass index (BMI), glucagon-like peptide 1 (GLP-1) and activated GLP-1 (aGLP-1). Ordinal and linear models with cluster confidence intervals were used to evaluate the efficacy of VSL#3 vs. placebo at 4 months.. At baseline, moderate and severe NAFLD were present in 64% and 36% of PLA children and in 55% and 45% of VSL#3 children. The probability that children supplemented with VSL#3 had none, light, moderate or severe FL at the end of the study was 21%, 70%, 9% and 0% respectively with corresponding values of 0%, 7%, 76% and 17% for the placebo group (P < 0.001). No between-group differences were detected in triglycerides, HOMA and ALT while BMI decreased and GLP-1 and aGLP1 increased in the VSL#3 group (P < 0.001 for all comparisons).. A 4-month supplement of VSL#3 significantly improves NAFLD in children. The VSL#3-dependent GLP-1 increase could be responsible for these beneficial effects. Trial identifier: NCT01650025 (www.clinicaltrial.gov).

Topics: Alanine Transaminase; Biopsy; Body Mass Index; Child; Dietary Supplements; Double-Blind Method; Fatty Liver; Female; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Male; Non-alcoholic Fatty Liver Disease; Obesity; Probiotics; Severity of Illness Index; Treatment Outcome; Ultrasonography

To estimate the impact of aging and diabetes on insulin sensitivity, beta-cell function, adipocytokines, and incretin production.. Hyperglycemic clamps, arginine tests and meal tolerance tests were performed in 50 non-obese subjects to measure insulin sensitivity (IS) and insulin secretion as well as plasma levels of glucagon, GLP-1 and GIP. Patients with diabetes and healthy control subjects were divided into the following groups: middle-aged type 2 diabetes (MA-DM), aged Type 2 diabetes (A-DM) and middle-aged or aged subjects with normal glucose tolerance (MA-NGT or A-NGT).. IS, as determined by the homeostasis model assessment, glucose infusion rate, and oral glucose insulin sensitivity, was reduced in the aged and DM groups compared with MA-NGT, but it was similar in the MA-DM and A-DM groups. Insulinogenic index, first and second phase insulin secretion and the disposition indices, but not insulin response to arginine, were reduced in the aged and DM groups. Postprandial glucagon production was higher in MA-DM compared to MA-NGT. Whereas the GLP-1 production was reduced in A-DM, no differences between groups were observed in GIP production.. In non-obese subjects, diabetes and aging impair insulin sensitivity. Insulin production is reduced by aging, and diabetes exacerbates this condition. Aging associated defects superimposed diabetic physiopathology, particularly regarding GLP-1 production. On the other hand, the glucose-independent secretion of insulin was preserved. Knowledge of the complex relationship between aging and diabetes could support the development of physiopathological and pharmacological based therapies.

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Aging; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Down-Regulation; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Pancreas; Postprandial Period; Up-Regulation

The role of gastrointestinal (GI) hormones in the pathophysiology of obesity is unclear, although they are involved in the regulation of satiation and glucose metabolism. To (i) examine glucagon-like peptide 1 (GLP-1), amylin, ghrelin, and glucagon responses to a meal in obese adolescents and to (ii) test which GI peptides are associated with insulin resistance are presented.. A total of 16 obese (body mass index (BMI) ≥ 97th percentile for age and gender) and 14 control (BMI between 25th and 75th percentiles) adolescents were included. Subjects were instructed to eat a test meal (490 kcal). Plasma samples were collected for hormone and glucose analysis.. Obese adolescents were insulin resistant as expressed by the Homeostasis Model Assessment (HOMA) index and had significantly increased fasting glucagon and amylin levels compared to the control group (P = 0.003 and 0.044, respectively). In response to the meal, the increase in GLP-1 levels was reduced in obese adolescents (P < 0.001). In contrast, amylin secretion was significantly increased in the obese population compared to the control group (P < 0.005).. Obese adolescents have increased fasting glucagon and amylin levels and attenuated post-prandial GLP-1 concentrations compared with the control group. These factors could contribute to the metabolic syndrome.

Topics: Adolescent; Body Mass Index; Child; Female; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Male; Meals; Metabolic Syndrome; Pediatric Obesity; Postprandial Period; Satiation

To examine whether a pistachio-rich diet reduces the prediabetes stage and improves its metabolic risk profile.. Prediabetic subjects were recruited to participate in this Spanish randomized clinical trial between 20 September 2011 and 4 February 2013. In a crossover manner, 54 subjects consumed two diets, each for 4 months: a pistachio-supplemented diet (PD) and a control diet (CD). A 2-week washout period separated study periods. Diets were isocaloric and matched for protein, fiber, and saturated fatty acids. A total of 55% of the CD calories came from carbohydrates and 30% from fat, whereas for the PD, these percentages were 50 and 35%, respectively (including 57 g/day of pistachios).. Fasting glucose, insulin, and HOMA of insulin resistance decreased significantly after the PD compared with the CD. Other cardiometabolic risk markers such as fibrinogen, oxidized LDL, and platelet factor 4 significantly decreased under the PD compared with the CD (P < 0.05), whereas glucagon-like peptide-1 increased. Interleukin-6 mRNA and resistin gene expression decreased by 9 and 6%, respectively, in lymphocytes after the pistachio intervention (P < 0.05, for PD vs. CD). SLC2A4 expression increased by 69% in CD (P = 0.03, for PD vs. CD). Cellular glucose uptake by lymphocytes decreased by 78.78% during the PD (P = 0.01, PD vs. CD).. Chronic pistachio consumption is emerging as a useful nutritional strategy for the prediabetic state. Data suggest that pistachios have a glucose- and insulin-lowering effect, promote a healthier metabolic profile, and reverse certain metabolic deleterious consequences of prediabetes.

Topics: Cross-Over Studies; Diet; Fasting; Female; Glucagon-Like Peptide 1; Glucose; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Lipoproteins, LDL; Male; Middle Aged; Pistacia; Prediabetic State

Clinical studies evaluating the effects of medications on β-cell function in type 2 diabetes (T2DM) are compromised by an inability to determine the actual baseline degree of β-cell dysfunction independent of the reversible dysfunction induced by hyperglycemia (glucotoxicity). Short-term intensive insulin therapy (IIT) is a strategy for eliminating glucotoxicity before randomization. This study determined whether liraglutide can preserve β-cell function over 48 weeks in early T2DM following initial elimination of glucotoxicity with IIT.. In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years' duration and an A1C of 6.8 ± 0.8% (51 ± 8.7 mmol/mol) completed 4 weeks of IIT before randomization to daily subcutaneous liraglutide or placebo injection, with serial assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test performed every 12 weeks.. The primary outcome of baseline-adjusted ISSI-2 at 48 weeks was higher in the liraglutide group than in the placebo group (339.8 ± 27.8 vs. 229.3 ± 28.4, P = 0.008). Baseline-adjusted HbA1c at 48 weeks was lower in the liraglutide group (6.2 ± 0.1% vs. 6.6 ± 0.1%, P = 0.055) (44 ± 1.1 vs. 49 ± 1.1 mmol/mol). At each quarterly assessment, >50% of participants on liraglutide had an HbA1c ≤6.0% (42 mmol/mol) and glucose tolerance in the nondiabetic range. Despite this level of glycemic control, no difference was found in the incidence of hypoglycemia between the liraglutide and placebo groups (P = 0.61). Two weeks after stopping treatment, however, the beneficial effect on ISSI-2 of liraglutide versus placebo was entirely lost (191.9 ± 24.7 vs. 238.1 ± 25.2, P = 0.20).. Liraglutide provides robust enhancement of β-cell function that is sustained over 48 weeks in early T2DM but lost upon cessation of therapy.

Topics: Adult; Aged; Blood Glucose; Cytoprotection; Diabetes Mellitus, Type 2; Disease Progression; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liraglutide; Male; Middle Aged

To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on β-cell function and body composition.. This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA1c 9.7 ± 1%) and moderate obesity (BMI 36 ± 2 kg/m(2)) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of β-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months.. Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA1c of 6.7 ± 1.2% for gastric bypass, 7.1 ± 0.8% for sleeve gastrectomy, and 8.4 ± 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy (-16 vs. -10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. β-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, β-cell function inversely correlated with truncal fat and prandial free fatty acid levels.. Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic β-cell function and reduces truncal fat, thus reversing the core defects in diabetes.

Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Obesity; Weight Loss

Gastric bypass surgery (GBP) results in the rapid resolution of type 2 diabetes. Most studies aiming to explain the underlying mechanisms are limited to data obtained after a postsurgical recovery period, making assessment of confounding influences from, for example, weight loss and altered nutrient intake difficult.. To examine the impact of GBP on hormonal and metabolite profiles under conditions of identical nutrient intake independent of weight loss, we studied GBP patients fitted with a gastrostomy tube to enable the administration of nutrients to bypassed segments of the gut. Thus, this model allowed us to simulate partially the preoperative condition and compare this with the postoperative situation in the same patient.. Patients (n = 4) were first given a mixed meal test (MMT) orally and then via the gastrostomy tube, preceded by overnight and 2-hour fasting, respectively. Blood samples were assessed for hormones and metabolites.. The oral MMT yielded 4.6-fold increase in plasma insulin (P < .05), 2-fold in glucagon-like peptide-1 (P < .05), and 2.5-fold in glucose-dependent insulinotropic peptide (P < .05) plasma levels, compared with the gastrostomy MMT. The changes in hormone levels were accompanied by elevated branched-chain amino acid levels (1.4-2-fold, P < .05) and suppressed fatty acid levels (∼50%, P < .05).. These data, comparing identical nutrient delivery, demonstrate markedly higher incretin and insulin responses after oral MMT than after gastric MMT, thereby providing a potential explanation for the rapid remission of type 2 diabetes observed after GBP. The simultaneous increase in branched-chain amino acid questions its role as a marker for insulin resistance.

Topics: Adult; Amino Acids, Branched-Chain; Biomarkers; Body Mass Index; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrostomy; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Meals; Obesity, Morbid; Postoperative Period; Postprandial Period

The aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD.. We randomized 68 older individuals (mean age, 58±8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed.. Eleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P=0.26). Subjects who continued to use liraglutide (n=24) lost twice as much weight as those using placebo (n=27; 6.8 vs. 3.3 kg; P<0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (-3.2 vs. 0.2 mmol/L; P<0.001) and significantly (P≤0.04) greater lowering of systolic blood pressure (-8.1 vs. -2.6 mmHg), fasting glucose (-0.5 vs. 0 mmol/L), and triglyceride (-0.4 vs. -0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. -0.9 bpm; P=0.001).. The addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.

Topics: Body Weight; Caloric Restriction; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Male; Middle Aged; Obesity; Overweight; Prediabetic State; Triglycerides; Weight Loss

Roux-en-Y gastric bypass (RYGB) improves glycaemic control in part by increasing postprandial insulin secretion through exaggerated glucagon-like peptide (GLP)-1 release. However, it is unknown whether islet cell responsiveness to i.v. glucose, non-glucose (arginine) and incretin hormones, including GLP-1, is altered.. Eleven severely obese glucose-tolerant individuals underwent three hyperglycaemic clamps with arginine bolus and co-infusion of either GLP-1, glucose-dependent insulinotropic polypeptide (GIP) or saline before, and at 1 week and 3 months after RYGB. In addition, an OGTT was performed before and 3 months after surgery.. After RYGB, insulin sensitivity improved at 1 week and 3 months, while insulin stimulation and glucagon suppression in response to the clamp with saline co-infusion were largely unaltered. The influence of i.v. GLP-1 and GIP on insulin and glucagon secretion was also unchanged postoperatively. In response to the postoperative OGTT at 3 months, insulin and GLP-1, but not GIP, secretion increased. Furthermore, the glucose profile during the OGTT was altered, with a substantial reduction in 2 h plasma glucose and a paradoxical hypersecretion of glucagon.. After RYGB, insulin hypersecretion is linked to the oral, but not the i.v., route of administration and is associated with exaggerated release and preserved insulinotropic action of GLP-1, while both the secretion and action of GIP are unchanged. The results highlight the importance of increased GLP-1 secretion for improving postoperative glucose metabolism.. ClinicalTrials.gov NCT01559779.

Topics: Adult; Blood Glucose; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Male; Obesity, Morbid; Pancreas; Peptide Fragments; Postprandial Period; Treatment Outcome

Secreted frizzled-related protein-5 (Sfrp5) is a novel adipocyte-secreted hormone that has been shown to link obesity with diabetes. Studies in mice have revealed that Sfrp5 represents a potential target for the control of obesity-linked abnormalities in glucose homeostasis.. Our objective was to gain insight into the physiological role of circulating Sfrp5 in humans.. We conducted a series of cross-sectional and interventional studies of the general population and outpatients of the Internal Medicine Department at the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Subjects included 104 healthy subjects, 101 with impaired glucose tolerance, and 112 with newly diagnosed type 2 diabetes mellitus and, in a separate study, 30 healthy women, and 32 women with polycystic ovarian syndrome (PCOS). Oral glucose tolerance test and euglycemic-hyperinsulinemic clamp were performed to assess glucose tolerance and insulin sensitivity.. Circulating Sfrp5 was significantly lower in both impaired glucose intolerance and newly diagnosed type 2 diabetes mellitus than in individuals with normal glucose tolerance (P < 0.01). Overweight/obese subjects had significantly lower Sfrp5 levels than lean individuals (P < 0.01), but females had higher Sfrp5 levels than males (P < 0.05). In a separate study, Sfrp5 levels were lower in PCOS women than healthy women (P < 0.05). Moreover, circulating Sfrp5 correlated with markers of adiposity, including body mass index, waist-to-hip ratio, percent body fat, homeostasis model assessment of insulin resistance, lipid profile, and adiponectin. Hyperglycemia decreased circulating Sfrp5 levels, whereas liraglutide increased Sfrp5 levels. In the euglycemic-hyperinsulinemic state, circulating Sfrp5 was significantly decreased in healthy women but not in PCOS women.. We conclude that circulating Sfrp5 is likely to play a major role in insulin resistance in humans.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Eye Proteins; Female; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Male; Membrane Proteins; Metabolic Diseases; Middle Aged; Obesity

We designed an experiment to examine the effect of bile acid sequestration with Colesevelam on fasting and postprandial glucose metabolism in type 2 diabetes. To do so, we tested the hypothesis that Colesevelam increases the disposition index (DI), and this increase is associated with increased glucagon-like peptide-1 (GLP-1) concentrations. Thirty-eight subjects on metformin monotherapy were studied using a double-blind, placebo-controlled, parallel-group design. Subjects were studied before and after 12 weeks of Colesevelam or placebo using a labeled triple-tracer mixed meal to measure the rate of meal appearance (Meal Ra), endogenous glucose production (EGP), and glucose disappearance (Rd). Insulin sensitivity and β-cell responsivity indices were estimated using the oral minimal model and then used to calculate DI. Therapy with Colesevelam was associated with a decrease in fasting (7.0 ± 0.2 vs. 6.6 ± 0.2 mmol/L; P = 0.004) and postprandial glucose concentrations (3,145 ± 138 vs. 2,896 ± 127 mmol/6 h; P = 0.01) in the absence of a change in insulin concentrations. Minimal model-derived indices of insulin secretion and action were unchanged. Postprandial GLP-1 concentrations were not altered by Colesevelam. Although EGP and Rd were unchanged, integrated Meal Ra was decreased by Colesevelam (5,191 ± 204 vs. 5,817 ± 204 μmol/kg/6 h; P = 0.04), suggesting increased splanchnic sequestration of meal-derived glucose.

Topics: Allylamine; Anticholesteremic Agents; Blood Glucose; C-Peptide; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Postprandial Period

Zinc-α2-glycoprotein (ZAG) has been proposed to play a role in the pathogenesis of insulin resistance. Previous studies in humans and in rodents have produced conflicting results regarding the link between ZAG and insulin resistance. The objective of this study was to examine the relationships between ZAG and insulin resistance in cross-sectional and interventional studies.. Serum ZAG (determined with ELISA) was compared with various parameters related to insulin resistance in subjects with normal glucose tolerance, impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes mellitus (T2DM), and in women with or without polycystic ovary syndrome (PCOS). Euglycemic-hyperinsulinemic clamps were performed in healthy and PCOS women. Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of ZAG. The effect of a glucagon-like peptide-1 agonist on ZAG was studied in a 12-week liraglutide treatment trial.. Circulating ZAG was lower in patients with IGT and newly diagnosed T2DM than in controls. Circulating ZAG correlated positively with HDL cholesterol and adiponectin, and correlated inversely with BMI, waist-to-hip ratio, body fat percentage, triglycerides, fasting blood glucose, fasting insulin, HbA1c, and homeostasis model assessment of insulin resistance (HOMA-IR). On multivariate analysis, ZAG was independently associated with BMI, HOMA-IR, and adiponectin. ZAG mRNA and protein were decreased in adipose tissue of T2DM patients. Moreover, circulating ZAG levels were lower in women with PCOS than in women with high insulin sensitivity. Liraglutide treatment for 12 weeks significantly increased circulating ZAG levels.. We conclude that ZAG may be an adipokine associated with insulin resistance.

Topics: Adipokines; Adult; Aged; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Liraglutide; Male; Middle Aged; Polycystic Ovary Syndrome; Seminal Plasma Proteins; Zn-Alpha-2-Glycoprotein

Aging is associated with deteriorating glucose tolerance. Studies assessing glucose tolerance and subsequent insulin and incretin hormone release often fail to take into account the rate of gastric emptying when evaluating these responses.. Our objective was to determine the comparative effects of variations in the small intestinal glucose load on the glycemic, insulinemic, and incretin responses in healthy young and older subjects.. Twelve healthy young (six males, six females; age 22.2±2.3 yr) and 12 older (six males, six females; age 68.7±1.0 yr) subjects had measurements of blood glucose, serum insulin and plasma incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] and calculations of insulin resistance (homeostatic model assessment) and β-cell function corrected for insulin sensitivity, before and during intraduodenal infusions of glucose at 1, 2, or 3 kcal/min or saline for 60 minutes. The study was double-blinded and randomized, and performed in the Discipline of Medicine at the Royal Adelaide Hospital.. At baseline, blood glucose and serum insulin were slightly higher in the older subjects (P<0.001), whereas GLP-1 and GIP were comparable between groups. In both groups, the glycemic, insulinemic, and GLP-1 responses were dependent on the duodenal glucose load in a nonlinear fashion (P<0.001). The glycemic response was greater (P<0.001) in the older subjects, whereas GLP-1 and GIP responses were comparable between groups. The older subjects were more insulin resistant (P<0.001) and had impaired β-cell function, particularly at higher glucose loads (P<0.05).. When glucose is infused into the small intestine at equal rates in healthy young and older subjects, GLP-1 and GIP responses are comparable, indicating that impaired incretin secretion does not account for age-related glucose intolerance.

Topics: Age Factors; Aged; Blood Glucose; Double-Blind Method; Duodenum; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin; Insulin Resistance; Male; Postprandial Period; Young Adult

The insulinotropic effect of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) is impaired in patients with type 2 diabetes. It remains unclear whether this impairment is a primary pathophysiological trait or a consequence of developing diabetes. Therefore, we aimed to investigate the insulinotropic effect of GIP and GLP-1 compared with placebo before and after 12 d of glucose homeostatic dysregulation in healthy subjects.. The insulinotropic effect was measured using hyperglycemic clamps and infusion of physiological doses of GIP, GLP-1, or saline in 10 healthy Caucasian males before and after intervention using a high-calorie diet, sedentary lifestyle, and administration of prednisolone (37.5 mg once daily) for 12 d.. The intervention resulted in increased insulin resistance according to the homeostatic model assessment (1.2 ± 0.2 vs. 2.6 ± 0.5, P = 0.01), and glucose tolerance deteriorated as assessed by the area under curve for plasma glucose during a 75-g oral glucose tolerance test (730 ± 30 vs. 846 ± 57 mm for 2 h, P = 0.021). The subjects compensated for the change in insulin resistance by significantly increasing their postintervention insulin responses during saline infusion by 2.9 ± 0.5-fold (P = 0.001) but were unable to do so in response to incretin hormones (which caused insignificant increases of only 1.78 ± 0.3 and 1.38 ± 0.3-fold, P value not significant).. These data show that impairment of the insulinotropic effect of both GIP and GLP-1 can be induced in healthy male subjects without risk factors for type 2 diabetes, indicating that the reduced insulinotropic effect of the incretin hormones observed in type 2 diabetes most likely is a consequence of insulin resistance and glucose intolerance rather than a primary event causing the disease.

Topics: Adult; Blood Glucose; C-Peptide; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Infusions, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Kinetics; Male; Severity of Illness Index; Young Adult

We studied the metabolic effects of 48-h GLP-1 treatment in insulin resistant heart failure patients.In a randomized placebo-controlled double-blinded cross-over study, 11 non-diabetic HF patients with IHD received 48-h GLP-1 and placebo-infusion. We applied OGTT, hyperinsulinemic clamp, indirect calorimetry, forearm, and tracer methods.7 insulin resistant HF (EF 28%±2) patients completed the protocol. GLP-1 decreased plasma glucose levels (p=0.048) and improved glucose tolerance. 4 patients had hypoglycemic events during GLP-1 vs. none during placebo. GLP-1 treatment tended to increase whole body protein turnover (p=0.08) but did not cause muscle wasting. No significant changes in circulating levels of insulin, glucagon, free fatty acids or insulin sensitivity were detected.GLP-1 treatment decreased glucose levels and increased glucose tolerance in insulin resistant HF patients with IHD. Hypoglycemia was common and may limit the use of GLP-1 in these patients. Insulin sensitivity, lipid-, and protein metabolism remained unchanged.Data were collected at the examinational laboratories of Department of Endocrinology and Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

Topics: Blood Glucose; Calorimetry, Indirect; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Fatty Acids, Nonesterified; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Heart Failure; Humans; Insulin; Insulin Resistance; Male; Middle Aged

Our aim was to study the potential mechanisms responsible for the improvement in glucose control in Type 2 diabetes (T2D) within days after Roux-en-Y gastric bypass (RYGB). Thirteen obese subjects with T2D and twelve matched subjects with normal glucose tolerance (NGT) were examined during a liquid meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), β-cell glucose sensitivity (β-GS), and disposition index (D(β-GS): β-GS × 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 ± 2.3, 1 wk: 7.0 ± 1.2 (P < 0.001)], and insulin concentrations decreased significantly in both groups. At 129 min, glucose concentrations decreased in T2D [Pre: 11.4 ± 3, 1 wk: 8.2 ± 2 (P = 0.003)] but not in NGT. HOMA-IR decreased by 50% in both groups. β-GS increased in T2D [Pre: 1.03 ± 0.49, 1 wk: 1.70 ± 1.2, (P = 0.012)] but did not change in NGT. The increase in DI(β-GS) was 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion was unchanged, while GLP-1 secretion increased more than 10-fold in both groups. The changes induced by RYGB were sustained or further enhanced 3 mo and 1 yr after surgery. Improvement in glycemic control in T2D after RYGB occurs within days after surgery and is associated with increased insulin sensitivity and improved β-cell function, the latter of which may be explained by dramatic increases in GLP-1 secretion.

Topics: Adult; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hyperglycemia; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Obesity; Obesity, Morbid; Postprandial Period; Time Factors

To compare duodenal-jejunal bypass (DJB) with standard medical care in nonobese patients with type 2 diabetes and evaluate surgically induced endocrine and metabolic changes.. Eighteen patients submitted to a DJB procedure met the following criteria: overweight, diabetes diagnosis less than 15 years, current insulin treatment, residual β-cell function, and absence of autoimmunity. Patients who refused surgical treatment received standard medical care (control group). At baseline, 3, 6, and 12 months after surgery, insulin sensitivity and production of glucagon-like peptide-1 and glucose-insulinotropic polypeptide were assessed during a meal tolerance test. Fasting adipocytokines and dipeptidyl-peptidase-4 concentrations were measured.. The mean age of the patients was 50 (5) years, time of diagnosis: 9 (2) years, time of insulin usage: 6 (5) months, fasting glucose: 9.9 (2.5) mmol/dL, and HbA1c (glycosylated hemoglobin) level: 8.9% (1.2%). Duodenal-jejunal bypass group showed greater reductions in fasting glucose (22% vs 6% in control group, P < 0.05) and daily insulin requirement (93% vs 15%, P < 0.01). Twelve patients from DJB group stopped using insulin and showed improvements in insulin sensitivity and β-cell function (P < 0.01), and reductions in glucose-insulinotropic polypeptide levels (P < 0.001), glucagon during the first 30 minutes after meal (P < 0.05), and leptin levels (P < 0.05). Dipeptidyl-peptidase-4 levels increased after surgery (P < 0.01), but glucagon-like peptide-1 levels did not change.. Duodenal-jejunal bypass improved insulin sensitivity and β-cell function and reduced glucose-insulinotropic polypeptide, leptin, and glucagon production. Hence, DJB resulted in better glycemic control and reduction in insulin requirement but DJB did not result in remission of diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Dipeptidyl Peptidase 4; Duodenum; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Humans; Incretins; Insulin Resistance; Jejunum; Middle Aged

Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500-600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women.. Seventeen overweight women (BMI > 28) were recruited to the study. Glucose, insulin and lipid metabolism were evaluated by euglycemic clamp technique, indirect calorimetry and an oral glucose tolerance test (OGTT). Insulin sensitivity was calculated as glucose disposal rate (GDR) and insulin sensitivity index (ISI), and also by HOMA-IR. Insulin secretion rate (ISR) was calculated from plasma C-peptide measurements. Secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) was measured during an oral glucose tolerance test. Abdominal fat distribution was assessed by dual x-ray absorptiometry scan and computed tomography.. Ten women completed the intervention. The subjects lost an average 11% of their baseline weight. There was a significant loss of subcutaneous abdominal fatty tissue (p < 0.01) and intra-abdominal fatty tissue (p =0.05). Whole body (HOMA-IR) (p < 0.05) insulin sensitivity increased significantly, but peripheral (ISI) insulin sensitivity was unaltered after weight loss. GIP increased (p < 0.05) and GLP-1 was unaltered after the dietary intervention. Insulin responses did not differ before and after dietary intervention, however, a significant increase in insulin clearance (p < 0.05) was observed. The weight loss resulted in a significant decrease in free testosterone.. A VLCD is an effective weight loss treatment, which results in an immediate improvement in several metabolic parameters.

Topics: Adult; Androgens; Body Composition; Body Weight; Caloric Restriction; Dihydrotestosterone; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Intra-Abdominal Fat; Lipid Mobilization; Obesity; Testosterone; Treatment Outcome; Young Adult

Supplementing preoperative carbohydrate drinks with glutamine may lead to benefits in addition to reducing insulin resistance, but amino acids may delay gastric emptying (GE). The effects of supplementing a preoperative carbohydrate drink (CCD) with glutamine or lipid on GE were studied.. Ten healthy male volunteers ingested 410 ml of one of three isocaloric-isovolumetric carbohydrate-based drinks labelled with (99m)Tc-DTPA: CCD (preOp(®), Nutricia, UK, 50 g carbohydrate), CCD/G (preOp(®), 36 g carbohydrate + 15 g glutamine) or CCD/L (preOp(®), 36 g carbohydrate + 7 g lipid) in this randomized, blinded, three-way crossover study. After baseline measurements, GE was measured scintigraphically and blood sampled for insulin, glucose and glucagon-like peptide 1 (GLP-1) at 20 min intervals for 240 min.. Mean (95% CI) T(90) GE times for CCD, CCD/G and CCD/L were 101 (87-115), 95 (84-107) and 87 (72-102) min, respectively. At 40 min postprandially, mean (SEM) concentrations of glucose (mmol/l) and insulin (mIU/l) were 7.5 (0.5) and 35 (5) for CCD; 6.2 (0.2) and 28 (4) for CCD/G; and 7 (0.3) and 31 (5) for CCD/L, respectively. There were no differences in postprandial GLP-1 concentrations.. Glutamine and lipid supplementation did not prolong the GE of CCD but did 'blunt' postprandial glucose and insulin responses, independent of GLP-1 concentrations. Registered under ClinicalTrials.gov Identifier no. NCT00943020.

Topics: Adolescent; Adult; Beverages; Blood Glucose; Carbohydrate Metabolism; Carbohydrates; Cross-Over Studies; Dietary Supplements; Eating; Ethnicity; Gastric Emptying; Glucagon-Like Peptide 1; Glutamine; Humans; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Preoperative Care; Single-Blind Method; Technetium Tc 99m Pentetate; White People; Young Adult

Glucocorticoids (GCs) are regarded as diabetogenic because they impair insulin sensitivity and islet-cell function. This study assessed whether treatment with the glucagon-like peptide receptor agonist (GLP-1 RA) exenatide (EXE) could prevent GC-induced glucose intolerance.. A randomized, placebo-controlled, double-blind, crossover study in eight healthy men (age: 23.5 [20.0-28.3] years; BMI: 26.4 [24.3-28.0] kg/m(2)) was conducted. Participants received three therapeutic regimens for 2 consecutive days: 1) 80 mg of oral prednisolone (PRED) every day (q.d.) and intravenous (IV) EXE infusion (PRED+EXE); 2) 80 mg of oral PRED q.d. and IV saline infusion (PRED+SAL); and 3) oral placebo-PRED q.d. and intravenous saline infusion (PLB+SAL). On day 1, glucose tolerance was assessed during a meal challenge test. On day 2, participants underwent a clamp procedure to measure insulin secretion and insulin sensitivity.. PRED+SAL treatment increased postprandial glucose levels (vs. PLB+SAL, P = 0.012), which was prevented by concomitant EXE (vs. PLB+SAL, P = NS). EXE reduced PRED-induced hyperglucagonemia during the meal challenge (P = 0.018) and decreased gastric emptying (vs. PRED+SAL, P = 0.028; vs. PLB+SAL, P = 0.046). PRED+SAL decreased first-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL, P = 0.017 and P = 0.05, respectively), whereas PRED+EXE improved first- and second-phase glucose- and arginine-stimulated C-peptide secretion (vs. PLB+SAL; P = 0.017, 0.012, and 0.093, respectively).. The GLP-1 RA EXE prevented PRED-induced glucose intolerance and islet-cell dysfunction in healthy humans. Incretin-based therapies should be explored as a potential strategy to prevent steroid diabetes.

Topics: Adolescent; Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Exenatide; Glucagon-Like Peptide 1; Glucocorticoids; Glucose Clamp Technique; Glucose Intolerance; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Male; Peptides; Prednisone; Venoms; Young Adult

The effects of medical and surgical treatments for obesity on glucose metabolism and glucagon-like peptide 1 (GLP-1) levels independent of weight loss remain unclear. This study aims to assess plasma glucose levels, insulin sensitivity and secretion, and GLP-1 levels before and after sleeve gastrectomy (SG) or medical treatment (MED) for obesity.. This study is a prospective, controlled, non-randomised study. Two groups of non-diabetic obese patients with similar BMIs, including a SG group (BMI, 35.5 ± 0.9 kg/m(2); n = 6) and a MED group (BMI, 37.7 ± 1.9 kg/m(2); n = 6) and a group of lean subjects (BMI, 21.7 ± 0.7 kg/m(2); n = 8).. Plasma glucose, insulin, and total GLP-1 levels at fasting and after the intake of a standard liquid meal at baseline and at 2 months post-intervention. At baseline, total GLP-1 levels were similar, but obese patients had lower insulin sensitivity and higher insulin secretion than lean subjects. At 2 months post-intervention, SG and MED patients achieved similar weight loss (14.4 ± 0.8%, 15.3 ± 0.9%, respectively). Insulin sensitivity increased in SG and MED patients; however, postprandial insulin secretion decreased after MED, but not after SG. The incremental area under the curve of GLP-1 increased after SG (P = 0.04), but not after MED.. Weight loss by medical or surgical treatment improved insulin sensitivity. However, only MED corrected the hyperinsulinemic postprandial state associated to obesity. Postprandial GLP-1 levels increased significantly after SG without duodenal exclusion, which may explain why insulin secretion did not decrease following this surgery.

Topics: Adult; Blood Glucose; Diet, Reducing; Exercise Therapy; Female; Gastrectomy; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Obesity; Prospective Studies; Treatment Outcome; Weight Loss

The surgical treatment of obesity ameliorates metabolic abnormalities in patients with type 2 diabetes. The objective of this study was to evaluate the early effects of Roux-en-Y gastric bypass (RYGB) on metabolic and hormonal parameters in patients with type 2 diabetes (T2DM).. Ten patients with T2DM (BMI, 39.7 ± 1.9) were evaluated before and 7, 30, and 90 days after RYGB. A meal test was performed, and plasma insulin, glucose, glucagon, and glucagon-like-peptide 1 (GLP-1) levels were measured at fasting and postprandially.. Seven days after RYGB, a significant reduction was observed in HOMA-IR index from 7.8 ± 5.5 to 2.6 ± 1.7; p < 0.05 was associated with a nonsignificant reduction in body weight. The insulin and GLP-1 curves began to show a peak at 30 min after food ingestion, while there was a progressive decrease in glucagon and blood glucose levels throughout the meal test. Thirty and 90 days after RYGB, along with progressive weight loss, blood glucose and hormonal changes remained in the same direction and became more expressive with the post-meal insulin curve suggesting recovery of the first phase of insulin secretion and with the increase in insulinogenic index, denoting improvement in β-cell function. Furthermore, a positive correlation was found between changes in GLP-1 and insulin levels measured at 30 min after meal (r = 0.6; p = 0.000).. Our data suggest that the RYGB surgery, beyond weight loss, induces early beneficial hormonal changes which favor glycemic control in type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Prospective Studies; Treatment Outcome; Weight Loss

Hyperglycemia resolves quickly after bariatric surgery, but the underlying mechanism and the most effective type of surgery remains unclear.. To examine glucose metabolism and beta-cell function in patients with type 2 diabetes mellitus (T2DM) after two types of bariatric intervention; Roux-en-Y gastric bypass (RYGB) and gastric restrictive (GR) surgery.. Prospective, nonrandomized, repeated-measures, 4-week, longitudinal clinical trial.. In all, 16 T2DM patients (9 males and 7 females, 52+/-14 years, 47+/-9 kg m(-2), HbA1c 7.2+/-1.1%) undergoing either RYGB (N=9) or GR (N=7) surgery.. Glucose, insulin secretion, insulin sensitivity at baseline, and 1 and 4 weeks post-surgery, using hyperglycemic clamps and C-peptide modeling kinetics; glucose, insulin secretion and gut-peptide responses to mixed meal tolerance test (MMTT) at baseline and 4 weeks post-surgery.. At 1 week post-surgery, both groups experienced a similar weight loss and reduction in fasting glucose (P<0.01). However, insulin sensitivity increased only after RYGB, (P<0.05). At 4 weeks post-surgery, weight loss remained similar for both groups, but fasting glucose was normalized only after RYGB (95+/-3 mg 100 ml(-1)). Insulin sensitivity improved after RYGB (P<0.01) and did not change with GR, whereas the disposition index remained unchanged after RYGB and increased 30% after GR (P=0.10). The MMTT elicited a robust increase in insulin secretion, glucagon-like peptide-1 (GLP-1) levels and beta-cell sensitivity to glucose only after RYGB (P<0.05).. RYGB provides a more rapid improvement in glucose regulation compared with GR. This improvement is accompanied by enhanced insulin sensitivity and beta-cell responsiveness to glucose, in part because of an incretin effect.

Topics: Bariatric Surgery; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Weight Loss

Many of the metabolic benefits of Roux-en-Y gastric bypass (RYGB) occur before weight loss. In this study we investigated the influence of caloric restriction on the improvements in the metabolic responses that occur within the 1st week after RYGB. RESEARCH METHODS AND DESIGN: A mixed meal was administered to nine subjects before and after RYGB (average 4 +/- 0.5 days) and to nine matched, obese subjects before and after 4 days of the post-RYGB diet.. Weight loss in both groups was minimal; the RYGB subjects lost 1.4 +/- 5.3 kg (P = 0.46) vs. 2.2 +/- 1.0 kg (P = 0.004) in the calorically restricted group. Insulin resistance (homeostasis model assessment of insulin resistance) improved with both RYGB (5.0 +/- 3.1 to 3.3 +/- 2.1; P = 0.03) and caloric restriction (4.8 +/- 4.1 to 3.6 +/- 4.1; P = 0.004). The insulin response to a mixed meal was blunted in both the RYGB and caloric restriction groups (113 +/- 67 to 65 +/- 33 and 85 +/- 59 to 65 +/- 56 nmol x l(-1) x min(-1), respectively; P < 0.05) without a change in the glucose response. Glucagon-like peptide 1 levels increased (9.2 +/- 8.6 to 12.2 +/- 5.5 pg x l(-1) x min(-1); P = 0.04) and peaked higher (45.2 +/- 37.3 to 84.8 +/- 33.0 pg/ml; P = 0.01) in response to a mixed meal after RYGB, but incretin responses were not altered after caloric restriction.. These data suggest that an improvement in insulin resistance in the 1st week after RYGB is primarily due to caloric restriction, and the enhanced incretin response after RYGB does not improve postprandial glucose homeostasis during this time.

Topics: Adipokines; Adult; Blood Glucose; Caloric Restriction; Combined Modality Therapy; Eating; Fasting; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Postoperative Period; Weight Loss

A variety of dietary fibers have been shown to alter satiety hormone gene expression and secretion. The objective of this study was to examine plasma satiety hormone concentrations in healthy subjects consuming either PolyGlycopleX (PGX) or control (skim milk powder) for 21 days.. A randomized, double-blind, placebo-controlled clinical study was conducted in 54 healthy male and female adults. Participants consumed 5 g per day of PGX or control for 1 week followed by 2 additional weeks of 10 g per day of assigned product (n=27 per group). Primary outcomes measured at three visits (V1, V2 and V3) were plasma active glucagon-like peptide-1 (GLP-1) total ghrelin, peptide YY (PYY) and insulin.. There was a significant effect of visit for fasting PYY with control participants experiencing decreased PYY levels over time while PGX prevented this decline. When stratified by body mass index (BMI), PGX increased fasting PYY levels from week 1 to week 3 compared with control in participants with BMI <23 kg/m(2). There was a significant effect of visit for fasting ghrelin with levels decreasing in both PGX and control groups over time. No differences were detected in fasting GLP-1 levels. Although there was a 14% reduction in fasting insulin between V1 and V3 with PGX this was not significantly different from control.. PGX is a highly viscous, functional fiber that modifies satiety hormone secretion in healthy adults. Its' potential to act similarly in overweight adults warrants investigation.

Topics: Adolescent; Adult; Alginates; Body Mass Index; Dietary Fiber; Dietary Supplements; Double-Blind Method; Drug Combinations; Female; Ghrelin; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Overweight; Peptide YY; Polysaccharides, Bacterial; Time Factors; Young Adult

To determine whether altered GLP-1 activity contributes to the abnormal endogenous glucose production (EGP) and insulin secretion characteristic of people with impaired fasting glucose (IFG).. People with IFG (n=10) and normal glucose tolerance (NGT; n=13) underwent assessment of EGP (via [6,6-(2)H(2)]-glucose infusion). Parameters of whole body insulin action and secretion were estimated by IVGTT and OGTT. Measures of EGP and insulin secretion were made before and after sitagliptin administration.. EGP was not different at baseline (glucose R(a); 1.47+/-0.08 vs. 1.46+/-0.05mg/kg/min, IFG vs. NGT, p=0.93). However, when differences in circulating insulin were accounted for (EGPXSSPI; 20.2+/-2.1 vs. 14.4+/-1.0AU, vs. NGT, p=0.03) the hepatic insulin resistance index was significantly higher in IFG. Baseline insulin action (S(i); 2.3+/-0.1x10(-4)/microU/ml vs. 3.5+/-0.4x10(-4)/microU/ml, p=0.01, IFG vs. NGT) and secretion (DI; 587+/-81x10(-4)/min vs. 1171+/-226x10(-4)/min, p=0.04, IFG vs. NGT) were impaired in IFG when evaluated by the IVGTT, but not by OGTT (insulin sensitivity 4.52+/-1.08x10(-4)dl/kg/min vs. 6.73+/-1.16x10(-4)dl/kg/min, IFG vs. NGT, p=0.16; indices of basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and total (Phi(t)) insulin secretion, p>0.07). Sitagliptin did not change EGP or insulin secretion in either group.. Incretin action maintained insulin secretion, but not hepatic insulin action, in people with IFG.

Topics: Aged; Blood Glucose; Body Mass Index; C-Peptide; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liver; Male; Middle Aged; Pyrazines; Severity of Illness Index; Sitagliptin Phosphate; Triazoles

Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% Vo(2 max)) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 +/- 190, post: 1,269 +/- 70, kcal/day; n = 9) diet on the GIP response to glucose in older (66.8 +/- 1.5 yr), obese (34.4 +/- 1.7 kg/m(2)) adults with impaired glucose tolerance. In addition to GIP, plasma PYY(3-36), insulin, and glucose responses were measured during a 3-h, 75-g oral glucose tolerance test. Both interventions led to a significant improvement in Vo(2 max) (P < 0.05). Weight loss (kg) was significant in both groups but was greater after EX-HYPO (-8.3 +/- 1.1 vs. -2.8 +/- 0.5, P = 0.002). The glucose-stimulated insulin response was reduced after EX-HYPO (P = 0.02), as was the glucose-stimulated GIP response (P < 0.05). Furthermore, after the intervention, changes in insulin (DeltaI(0-30)/DeltaG(0-30)) and GIP (Delta(0-30)) secretion were correlated (r = 0.69, P = 0.05). The PYY(3-36) (Delta(0-30)) response to glucose was increased after both interventions (P < 0.05). We conclude that 1) a combination of caloric restriction and exercise reduces the GIP response to ingested glucose, 2) GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions, and 3) the increased PYY(3-36) response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin-resistant adults.

Topics: Aged; Blood Glucose; Body Mass Index; Diet, Reducing; Eating; Exercise; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Obesity; Peptide Fragments; Peptide YY; Physical Fitness; Satiety Response

To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled intravenous glucose tolerance test.. The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity.. Fourteen weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine-stimulated insulin secretion during hyperglycaemia.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Islets of Langerhans; Liraglutide; Male; Middle Aged; Receptors, Glucagon; Treatment Outcome

To study the effects of three weight-maintenance diets with different macronutrient composition on carbohydrate, lipid metabolism, insulin and incretin levels in insulin-resistant subjects.. A prospective study was performed in eleven (7 W, 4 M) offspring of obese and type 2 diabetes patients. Subjects had a BMI > 25 Kg/m2, waist circumference (men/women) > 102/88, HBA1c < 6.5% and were regarded as insulin-resistant after an OGTT (Matsuda ISIm <4). They were randomly divided into three groups and underwent three dietary periods each of 28 days in a crossover design: a) diet high in saturated fat (SAT), b) diet rich in monounsaturated fat (MUFA; Mediterranean diet) and c) diet rich in carbohydrate (CHO).. Body weight and resting energy expenditure did not changed during the three dietary periods. Fasting serum glucose concentrations fell during MUFA-rich and CHO-rich diets compared with high-SAT diets (5.02 +/- 0.1, 5.03 +/- 0.1, 5.50 +/- 0.2 mmol/L, respectively. Anova < 0.05). The MUFA-rich diet improved insulin sensitivity, as indicated by lower homeostasis model analysis-insulin resistance (HOMA-ir), compared with CHO-rich and high-SAT diets (2.32 +/- 0.3, 2.52 +/- 0.4, 2.72 +/- 0.4, respectively, Anova < 0.01). After a MUFA-rich and high-SAT breakfasts (443 kcal) the postprandial integrated area under curve (AUC) of glucose and insulin were lowered compared with isocaloric CHO-rich breakfast (7.8 +/- 1.3, 5.84 +/- 1.2, 11.9 +/- 2.7 mmol . 180 min/L, Anova < 0.05; and 1004 +/- 147, 1253 +/- 140, 2667 +/- 329 pmol . 180 min/L, Anova <0.01, respectively); while the integrated glucagon-like peptide-1 response increased with MUFA and SAT breakfasts compared with isocaloric CHO-rich meals (4.22 +/- 0.7, 4.34 +/- 1.1, 1.85 +/- 1.1, respectively, Anova < 0.05). Fasting and postprandial HDL cholesterol concentrations rose with MUFA-rich diets, and the AUCs of triacylglycerol fell with the CHO-rich diet. Similarly fasting proinsulin (PI) concentration fell, while stimulated ratio PI/I was not changed by MUFA-rich diet.. Weight maintenance with a MUFA-rich diet improves HOMA-ir and fasting proinsulin levels in insulin-resistant subjects. Ingestion of a virgin olive oil-based breakfast decreased postprandial glucose and insulin concentrations, and increased HDL-C and GLP-1 concentrations as compared with CHO-rich diet.

Topics: Analysis of Variance; Area Under Curve; Blood Glucose; Calorimetry, Indirect; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Fats; Dietary Fats, Unsaturated; Fatty Acids; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Obesity; Postprandial Period; Prospective Studies

Glucagon-like peptide 1 (GLP-1) is potentially a very attractive agent for treating type 2 diabetes. We explored the effect of short-term (1 week) treatment with a GLP-1 derivative, liraglutide (NN2211), on 24-h dynamics in glycemia and circulating free fatty acids, islet cell hormone profiles, and gastric emptying during meals using acetaminophen. Furthermore, fasting endogenous glucose release and gluconeogenesis (3-(3)H-glucose infusion and (2)H(2)O ingestion, respectively) were determined, and aspects of pancreatic islet cell function were elucidated on the subsequent day using homeostasis model assessment and first- and second-phase insulin response during a hyperglycemic clamp (plasma glucose approximately 16 mmol/l), and, finally, on top of hyperglycemia, an arginine stimulation test was performed. For accomplishing this, 13 patients with type 2 diabetes were examined in a double-blind, placebo-controlled crossover design. Liraglutide (6 micro g/kg) was administered subcutaneously once daily. Liraglutide significantly reduced the 24-h area under the curve for glucose (P = 0.01) and glucagon (P = 0.04), whereas the area under the curve for circulating free fatty acids was unaltered. Twenty-four-hour insulin secretion rates as assessed by deconvolution of serum C-peptide concentrations were unchanged, indicating a relative increase. Gastric emptying was not influenced at the dose of liraglutide used. Fasting endogenous glucose release was decreased (P = 0.04) as a result of a reduced glycogenolysis (P = 0.01), whereas gluconeogenesis was unaltered. First-phase insulin response and the insulin response to an arginine stimulation test with the presence of hyperglycemia were markedly increased (P < 0.001), whereas the proinsulin/insulin ratio fell (P = 0.001). The disposition index (peak insulin concentration after intravenous bolus of glucose multiplied by insulin sensitivity as assessed by homeostasis model assessment) almost doubled during liraglutide treatment (P < 0.01). Both during hyperglycemia per se and after arginine exposure, the glucagon responses were reduced during liraglutide administration (P < 0.01 and P = 0.01). Thus, 1 week's treatment with a single daily dose of the GLP-1 derivative liraglutide, operating through several different mechanisms including an ameliorated pancreatic islet cell function in individuals with type 2 diabetes, improves glycemic control throughout 24 h of daily living, i.e., prandial and nocturnal periods. This

Topics: Circadian Rhythm; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose; Hormones; Humans; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Liraglutide; Male; Middle Aged

Glucagon-like peptide-1-(7-36)-amide (GLP-1) is involved in satiety control and glucose homeostasis. Animal studies suggest a physiological role for GLP-1 in water and salt homeostasis. This study's aim was to define the effects of GLP-1 on water and sodium excretion in both healthy and obese men. Fifteen healthy subjects and 16 obese men (mean body mass index, 36 kg/m2) were examined in a double-blind, placebo-controlled, crossover study to demonstrate the effects of a 3-h infusion of GLP-1 on urinary sodium excretion, urinary output, and the glomerular filtration rate after an i.v. 9.9-g salt load. Infusion of GLP-1 evoked a dose-dependent increase in urinary sodium excretion in healthy subjects (from 74 +/- 8 to 143 +/- 18 mmol/180 min, P = 0.0013). In obese men, there was a significant increase in urinary sodium excretion (from 59 to 96 mmol/180 min, P = 0.015), a decrease in urinary H+ secretion (from 1.1 to 0.3 pmol/180 min, P = 0.013), and a 6% decrease in the glomerular filtration rate (from 151 +/- 8 to 142 +/- 8 ml/min, P = 0.022). Intravenous infusions of GLP-1 enhance sodium excretion, reduce H+ secretion, and reduce glomerular hyperfiltration in obese men. These findings suggest an action at the proximal renal tubule and a potential renoprotective effect.

Topics: Adult; Blood Glucose; Cross-Over Studies; Double-Blind Method; Drinking; Glomerular Filtration Rate; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Kidney Tubules, Proximal; Male; Natriuresis; Obesity; Peptide Fragments; Protein Precursors; Protons; Renin; Renin-Angiotensin System; Sodium; Thirst; Urine

The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is being examined as a potential new agent for treatment in type 2 diabetic patients. Whereas the insulinotropic properties of this peptide are well established, another property of the hormone, an insulinomimetic effect per se, is controversial. In the normal glucose-tolerant lean state, it is difficult to demonstrate an insulinomimetic effect. The current study was conducted to examine whether GLP-1 has insulinomimetic effect in the obese state. Ten obese volunteers (body mass index, 34.6 +/- 0.8 kg/m(2)), whose ages were 32.5 +/- 3.0 yr, participated in two euglycemic clamp studies (n = 20 clamps) for 120 min. Five of the volunteers were females. The initial clamp was performed with a primed (0-10)-constant (10-60) infusion of GLP-1 at a final rate of 1.5 pmol x kg(-1) x min(-1). At 60 min, the GLP-1 infusion was terminated, and euglycemic was maintained from 60-120 min. After the GLP-1 study, each individual's plasma insulin level was measured. A second study was performed that was identical to the first, with the infusion of regular insulin in place of GLP-1. Insulin infusion rates were regulated in each individual to simulate plasma insulin levels produced during the GLP-1 infusion. The rate of disappearance of glucose was calculated for each subject. Fasting plasma insulin levels were similar between studies. In response to the GLP-1 infusion, with maintenance of plasma glucose level clamped at fasting level, significant increases in plasma insulin occurred in all subjects (P < 0.001). The insulin levels during the insulin infusion study were similar to that induced by GLP-1. The rate of disappearance of glucose (insulin-mediated glucose uptake) progressively increased in response to both the GLP-1 and insulin infusion. However, the rate of disappearance of glucose during the GLP-1 study was significantly higher (P = 0.033) than during the insulin study. We conclude that in insulin-resistant states, GLP-1 has insulinomimetic properties per se.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Obesity; Peptide Fragments; Protein Precursors

To investigate whether features of the insulin resistance syndrome are associated with altered incretin responses to food intake.. From a population-based study, 35 men were recruited, representing a wide spectrum of insulin sensitivity and body weight. Each subject underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. A mixed meal was given, and plasma levels of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), as well as insulin, glucagon, and glucose were measured.. Insulin resistance was associated with impaired GIP and GLP-1 responses to a mixed meal. The total area under the curve (AUC) of the GIP response after the mixed meal was associated with insulin sensitivity (r = 0.54, P < 0.01). There was a significant difference between the highest and the lowest tertile of insulin sensitivity (P < 0.05). GLP-1 levels 15 min after food intake were significantly lower in the most insulin-resistant tertile compared with the most insulin-sensitive tertile. During the first hour, the AUC of GLP-1 correlated significantly with insulin sensitivity (r = 0.47, P < 0.01). Multiple linear regression analysis showed that insulin resistance, but not obesity, was an independent predictor of these decreased incretin responses.. In insulin resistance, the GIP and GLP-1 responses to a mixed meal are impaired and are related to the degree of insulin resistance. Decreased incretin responsiveness may be of importance for the development of impaired glucose tolerance.

Topics: Adult; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; Eating; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Peptide Fragments; Postprandial Period; Protein Precursors; Regression Analysis

Characterization of beta-cell function in humans is essential for identifying genetic defects involved in abnormal insulin secretion and the pathogenesis of type 2 diabetes.. We designed a novel test assessing plasma insulin and C-peptide in response to 3 different secretagogues. Seven lean, healthy volunteers twice underwent a 200 min hyperglycaemic clamp (10 mmol L-1) with administration of GLP-1 (1.5 pmol. kg-1. min-1) starting at 120 min and an arginine bolus at 180 min. We determined glucose-induced first and second-phase insulin secretion, GLP-1-stimulated insulin secretion, arginine-stimulated insulin response (increase above prestimulus, DeltaIarg) and the maximal, i. e. highest absolute, insulin concentration (Imax). Insulin sensitivity was assessed during second-phase hyperglycaemia. On a third occasion 6 subjects additionally received an arginine bolus at > 25 mM blood glucose, a test hitherto claimed to provoke maximal insulin secretion.. Insulin levels increased from 46 +/- 11 pM to 566 +/- 202 pM at 120 min, to 5104 +/- 1179 pM at 180 min and to maximally 8361 +/- 1368 pM after arginine (all P < 0.001). The within subject coefficients of variation of the different secretion parameters ranged from 10 +/- 3% to 16 +/- 6%. Except for second-phase which failed to correlate significantly with DeltaIarg (r = 0.52, P = 0.23) and Imax (r = 0.75, P = 0.053) all phases of insulin secretion correlated with one another. The insulin concentration after the arginine bolus at > 25 mM glucose (n = 6) was 2773 +/- 855 pM vs. 7562 +/- 1168 pM for Imax (P = 0.003).. This novel insulin secretion test elicits a distinct pattern of plasma insulin concentrations in response to the secretagogues glucose, GLP-1 and arginine and is highly reproducible and can be used for differential characterization of islet function.

Topics: Adult; Arginine; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Peptide Fragments; Protein Precursors; Reproducibility of Results

Total parenteral nutrition (TPN) can lead to complications, such as glucose metabolism disorders. While TPN is associated with impairments in intestinal function, the gut barrier and mucosal immunity, the relationship between the gut microbiome and TPN-related glucose metabolism disorders remains to be explored. In a cohort of 256 participants with type 2 intestinal failure, we show that parenteral nutrition providing >80% of total energy induces insulin resistance and a higher risk of complications. Using various male mouse models, we demonstrate that changes in Lactobacillaceae and indole-3-acetic acid (IAA) levels underlie these complications. Lactobacillaceae and IAA levels decrease in TPN-treated mice and participants, while their abundances in the latter are negatively correlated with insulin resistance and serum lipopolysaccharide levels. Furthermore, IAA activates the aryl hydrocarbon receptor and increases glucagon-like peptide-1 secretion through upregulation of Gcg expression and increased stem cell differentiation towards L cells. Finally, liraglutide, a glucagon-like peptide-1 receptor agonist, completely prevents TPN-induced glucose metabolism disorders in mice. Thus, TPN induces glucose metabolism disorders by altering the gut microbiota and its metabolites.

Topics: Animals; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose; Insulin Resistance; Male; Mice; Parenteral Nutrition, Total

Type 2 diabetes (T2D) is a challenging health concern worldwide. A lifestyle intervention to treat T2D is difficult to adhere, and the effectiveness of approved medications such as metformin, thiazolidinediones (TZDs), and sulfonylureas are suboptimal. On the other hand, bariatric procedures such as Roux-en-Y gastric bypass (RYGB) are being recognized for their remarkable ability to achieve diabetes remission, although the underlying mechanism is not clear. Recent evidence points to branched-chain amino acids (BCAAs) as a potential contributor to glucose impairment and insulin resistance. RYGB has been shown to effectively lower plasma BCAAs in insulin-resistant or T2D patients that may help improve glycemic control, but the underlying mechanism for BCAA reduction is not understood. Hence, we attempted to explore the mechanism by which RYGB reduces BCAAs. To this end, we randomized diet-induced obese (DIO) mice into three groups that underwent either sham or RYGB surgery or food restriction to match the weight of RYGB mice. We also included regular chow-diet-fed healthy mice as an additional control group. Here, we show that compared to sham surgery, RYGB in DIO mice markedly lowered serum BCAAs most likely by rescuing BCAA breakdown in both liver and white adipose tissues. Importantly, the restored BCAA metabolism following RYGB was independent of caloric intake. Fasting insulin and HOMA-IR were decreased as expected, and serum valine was strongly associated with insulin resistance. While gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are postulated to mediate various surgery-induced metabolic benefits, mice lacking these hormonal signals (GLP-1R/Y2R double KO) were still able to effectively lower plasma BCAAs and improve glucose tolerance, similar to mice with intact GLP-1 and PYY signaling. On the other hand, mice deficient in fibroblast growth factor 21 (FGF21), another candidate hormone implicated in enhanced glucoregulatory action following RYGB, failed to decrease plasma BCAAs and normalize hepatic BCAA degradation following surgery. This is the first study using an animal model to successfully recapitulate the RYGB-led reduction of circulating BCAAs observed in humans. Our findings unmasked a critical role of FGF21 in mediating the rescue of BCAA metabolism following surgery. It would be interesting to explore the possibility of whether RYGB-induced improvement in glucose homeostasis is partly through decreased BCAAs.

Topics: Amino Acids, Branched-Chain; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Mice; Obesity

Obesity has emerged as a worldwide metabolic disease, given its rapid growth in global prevalence. Red ginseng extracts (RGS), one of the traditional processed products of ginseng, show the potential to improve the metabolic phenotype of obesity. However, the RGS mechanism for regulating obesity and late insulin resistance remains to be clarified.. This study aimed to emphasize the potential use of RGS in treatment of obesity and insulin resistance (IR) and explore the underlying mechanism affecting glucose and lipid metabolism improvements.. The role of RGS was evaluated in a high-fat diet (HFD) rodent model. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to characterize the glucose metabolism level. The expression of lipolysis proteins and uncoupling protein-1 (UCP-1) were investigated by western blot. Glucagon-like peptide-1 (GLP-1) and apical sodium-dependent bile acid transporter (ASBT) protein expression in the intestine were determined via immunofluorescence. UPLC-Q-TOF-MS were used to detect the alterations in bile acids (BAs) levels in serum, ileum, and inguinal white adipose tissue (iWAT). In addition, intestine-specific Tgr5 knockout mice were employed to verify the efficacy of RGS in improving obesity.. RGS treatment alleviated dietary-induced dyslipidemia and IR in obese mice in a dose-dependent manner and improved glucose and insulin tolerance, and energy expenditure. RGS treatment significantly reduced lipid deposition and induced GLP-1 secretion in the intestine of wild-type mice but not in Tgr5. Our results demonstrated that RGS significantly alleviated HFD-induced obesity and insulin resistance in mice. RGS intervention improved glucose metabolism, promoted lipolysis, and energy metabolism by activating TGR5 in the intestine. In addition, we found that activating intestinal TGR5 facilitated the localization of ASBT to the plasma membrane, which ultimately promoted the transport of BAs to regulate metabolic phenotype.

Topics: Animals; Bile Acids and Salts; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Insulin Resistance; Insulins; Intestines; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Receptors, G-Protein-Coupled; Signal Transduction

The pattern of the plasma glucose response curve during an oral glucose tolerance test (OGTT) is of prognostic significance with "biphasic" when compared with "monophasic" patterns being associated with greater insulin sensitivity/secretion and a reduced risk of progression to diabetes. The relationships of the glucose response curves with gastric emptying and incretin hormone secretion are not known.. Thirty-six adults (age > 65 years) without known diabetes consumed a 300 mL drink containing 75 g glucose and 150 mg C. At baseline, 22 participants had a "monophasic" and 14 a "biphasic" glucose response. The 1 h plasma glucose response curve was greater and the GLP-1 AUC. A biphasic curve is associated with a higher 60 min glucose response curve and increases in GLP-1, but no difference in either GIP or gastric emptying.

Topics: Aged; Blood Glucose; Gastric Emptying; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance

To determine the contribution of these regulators on glucose tolerance after bariatric surgery, an oral glucose tolerance test (OGTT) was performed before and 2 months after surgery in 9 RYGB and 7 SG subjects. Eight healthy subjects served as metabolic controls. Plasma glucose, insulin, C-peptide, GLP-1, and GIP were measured during each OGTT. Insulin sensitivity and secretion, glucose effectiveness, and glucose rate of appearance were determined via oral minimal models.. RYGB and SG resulted in similar weight reductions (13%, RYGB (. These results demonstrate that the early improvement in glucose tolerance in obese T2D after RYGB and SG surgeries is attributable mainly to increased insulin secretion and glucose effectiveness, while insulin sensitivity seems to play only a minor role. This trial is registered with NCT02713555.

Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Insulin Secretion; Obesity

In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses.. We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones).. Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β =  - 0.67, P-value = 1.88 × 10. The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP's effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.

Topics: African People; Blood Glucose; Complement Factor D; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Ghana; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Kenya; Mendelian Randomization Analysis; Risk Factors

Long-term sleep deprivation (SD) is a bad lifestyle habit, especially among specific occupational practitioners, characterized by circadian rhythm misalignment and abnormal sleep/wake cycles. SD is closely associated with an increased risk of metabolic disturbance, particularly obesity and insulin resistance. The incretin hormone, glucagon-like peptide-1 (GLP-1), is a critical insulin release determinant secreted by the intestinal L-cell upon food intake. Besides, the gut microbiota participates in metabolic homeostasis and regulates GLP-1 release in a circadian rhythm manner. As a commonly recognized intestinal probiotic,

Topics: Animals; Bifidobacterium; Blood Glucose; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Circadian Rhythm; Dietary Supplements; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Incretins; Insulin; Insulin Resistance; Macaca mulatta; Male; Sleep Deprivation; Treatment Outcome; Triglycerides

More than one-third of chronic pancreatitis patients will eventually develop diabetes, recently classified as post-chronic pancreatitis diabetes mellitus (PPDM-C). This study was aimed to investigate the pancreatic and gut hormone responses to a mixed meal test in PPDM-C patients, compared with non-diabetic chronic pancreatitis (CP), and type 2 diabetes patients or healthy controls.. Sixteen patients with PPDM-C, 12 with non-diabetic CP as well as 10 with type 2 diabetes and healthy controls were recruited. All participants underwent mixed meal tests, and blood samples were collected for measurements of blood glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, peptide YY, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Indices of insulin sensitivity and secretion were calculated. Repeated measures analysis of variance was performed.. Participants with PPDM-C exhibited decreases in both fasting and postprandial responses of C-peptide (P < 0.001), insulin (P < 0.001), ghrelin (P < 0.001) and PYY (P = 0.006) compared to participants with type 2 diabetes and healthy controls. Patients with CP showed blunted glucagon, PP and incretin reactions, while the responses were increased in patients with PPDM-C compared to controls. The level of insulin sensitivity was higher for PPDM-C than type 2 diabetes (P < 0.01), however the indices for early/late-phase and overall insulin secretion (P < 0.01) were lower.. Patients with PPDM-C are characterized by decreased C-peptide, insulin, ghrelin and PYY responses, and similar levels of glucagon, PP, GIP and GLP-1 compared to those with type 2 diabetes. The above findings, when confirmed in a larger population, may prove helpful to establish the diagnosis of PPDM-C, and should promote study on underlying pathophysiological mechanisms.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Pancreatitis, Chronic; Peptide YY

The early distinction of pancreatic cancer associated diabetes (PaCDM) in patients with elderly diabetes is critical. However, PaCDM and type 2 diabetes mellitus (T2DM) remain indistinguishable. We aim to address the differences between the pancreatic and gut endocrine hormones of patients with PaCDM and T2DM.. A total of 44 participants underwent mixed meal tolerance test (MMTT). Fasting and postprandial concentrations of insulin, C-peptide, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) were measured. Insulin sensitivity and secretion indices were calculated. One-way ANOVA with post-hoc analysis was used for statistical analysis.. Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared with T2DM. Baseline concentrations and AUCs differed. PaCDM patients showed lower insulin secretion capacity but better insulin sensitivity than T2DM patients. The peak concentration and AUC of PP in T2DM group were higher than healthy controls, but in accordance with PaCDM. PaCDM patients presented lower baseline GLP-1 concentration than T2DM patients. No between-group differences were found for glucagon and GIP.. PaCDM patients had a lower baseline and postprandial insulin and C-peptide secretion than T2DM patients. Reduced insulin secretion and improved peripheral sensitivity were found in PaCDM patients compared with T2DM.

Topics: Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Pancreatic Neoplasms

To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively.. Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36 (PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test.. Single or multiple dose GTS-21 (0.5-8.0 mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged.. α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Benzylidene Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Male; Mice; Mice, Knockout; Nicotinic Agonists; Pyridines; Sitagliptin Phosphate; Tyrosine

Peptide hormones play a crucial role in body weight and glucose homeostasis. In this study, we aimed to explore this association and recruited 43 obese and 31 age- and sex-matched lean participants. We assessed their body mass index (BMI), waist circumference (WC), waist-to-height ratio (WtHR), percentage body fat (PBF), fasting blood levels of peptide hormones (GLP-1, GLP-2, insulin, leptin, ghrelin, CCK, and PYY), fasting blood sugar (FBS), and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We tested the associations between peptide hormones and markers of obesity and insulin resistance (IR) by using the Independent-Samples

Topics: Adult; Body Mass Index; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Obesity; United Arab Emirates

Diabetes is expected to increase up to 700 million people worldwide with type 2 diabetes being the most frequent. The use of nutritional interventions is one of the most natural approaches for managing the disease. Minerals are of paramount importance in order to preserve and obtain good health and among them molybdenum is an essential component. There are no studies about the consumption of biofortified food with molybdenum on glucose homeostasis but recent studies in humans suggest that molybdenum could exert hypoglycemic effects. The present study aims to assess if consumption of lettuce biofortified with molybdenum influences glucose homeostasis and whether the effects would be due to changes in gastrointestinal hormone levels and specifically Peptide YY (PYY), Glucagon-Like Peptide 1 (GLP-1), Glucagon-Like Peptide 2 (GLP-2), and Gastric Inhibitory Polypeptide (GIP). A cohort of 24 people was supplemented with biofortified lettuce for 12 days. Blood and urine samples were obtained at baseline (T0) and after 12 days (T2) of supplementation. Blood was analyzed for glucose, insulin, insulin resistance, β-cell function, and insulin sensitivity, PYY, GLP-1, GLP-2 and GIP. Urine samples were tested for molybdenum concentration. The results showed that consumption of lettuce biofortified with molybdenum for 12 days did not affect beta cell function but significantly reduced fasting glucose, insulin, insulin resistance and increased insulin sensitivity in healthy people. Consumption of biofortified lettuce did not show any modification in urine concentration of molybdenum among the groups. These data suggest that consumption of lettuce biofortified with molybdenum improves glucose homeostasis and PYY and GIP are involved in the action mechanism.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Food, Fortified; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Lactuca; Molybdenum; Peptide YY

Cushing’s disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM−) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM− (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Insulin; Insulin Resistance; Meals; Pituitary ACTH Hypersecretion; Somatostatin

Metabolic Syndrome (MetS) represents a common dysmetabolic state in children with obesity. Although data in youth show a role of gut hormones (GH) in the risk of developing MetS, no data are available during the prepubertal age, especially across clusters of MetS.. We characterized components of MetS and changes in GH concentrations in 90 prepubertal children with obesity compared to 30 healthy age- and gender-matched peers. Children with obesity were divided into three groups according to the number of the components of MetS (group 1: 30 obese without components of MetS; group 2: 30 obese with 1 component of MetS; group 3: 30 obese with 2 or more components of MetS). Anthropometric parameters, blood pressure (BP), fasting insulin and glycemia, lipid profile, transaminases, and GH concentration were determined. Differences across the groups were evaluated by the Kruskal-Wallis test and post hoc analysis by Mann-Whitney test.. Fasting glycemia and insulin, HOMA-IR, triglycerides, and BP progressively increased and high-density lipoprotein progressively decreased across the groups of children with obesity compared to controls, showing worse values in group 3. GLP-1 and ghrelin values progressively decreased and obestatin progressively increased. The more components of the MetS were present, the further GH concentrations deviated from standard values.. Components of MetS and GH concentrations are impaired in prepubertal children with obesity compared to controls. The close association between progressive alterations in GH levels and increasing number of components of the MetS might indicate a role of these hormones in the determination of metabolic risk.

Topics: Adolescent; Blood Glucose; Body Mass Index; Child; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Lipoproteins, HDL; Metabolic Syndrome; Obesity; Transaminases; Triglycerides

We used a high-fat diet (HFD) and streptozotocin (STZ) to induce type 2 diabetic mellitus (T2DM) mice and evaluated the effect of banana peel dietary fibers (BP-DFs) as potential hypoglycemic agents. After 5 weeks of intervention with banana peel dietary fibers (BP-DFs), food intake was reduced, body weight was increased, blood lipids and glucose were reduced, fasting insulin and GLP-1 levels were increased, and liver and pancreatic tissue damage was reduced. Banana peel soluble dietary fiber (BP-SDF) has the most significant effect. The results of fecal microbiota analysis showed that BP-DFs could ameliorates gut microbiome dysbiosis, and all three types of dietary fibers have obvious effects. The results of fecal short-chain fatty acids (SCFAs) showed that the content of fecal SCFAs was increased after BP-DFs dietary intervention, and BP-SDF had the most obvious effect. RT-PCR experiment results show that BP-DFs can up-regulate the mRNA expression levels of PI3K, AKT, IRS-1, and FOXO1 in the liver of diabetic mice, which indicates that BD-DFs may play a role in improving insulin resistance and insulin signal transduction via the IRS/PI3K/AKT pathway, improving insulin resistance and insulin signal transduction. Our research may be extended to BP-DFs, especially BP-SDF, as the basis for potential dietary intervention to prevent or treat type 2 diabetic mellitus. This work supports future research studies of the anti-diabetic properties of BP-SDF in humans. PRACTICAL APPLICATIONS: Diabetes can lead to a variety of complications that have a huge impact on health. Dietary fiber may help in lowering blood sugar. Our experimental results showed that banana peel dietary fibers have the effect of reducing food intake, blood sugar, improving liver and pancreas function, increasing the abundance of intestinal flora, and improving the IRS/PI3K/AKT pathway in T2DM mice. Therefore, this study could provide a theoretical basis for the development of functional foods with banana peel dietary fiber.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Fiber; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Mice; Musa; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA, Messenger; Streptozocin

Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non-alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi-synthetic, long chain, structurally-engineered fatty acid-1024 (SEFA-1024), as a treatment for obesity-induced hyperglycemia, insulin-resistance, and fatty liver disease in rodent models. A single dose of SEFA-1024 was administered to evaluate glucose tolerance and active glucagon-like peptide 1 (GLP-1) in lean rats in the presence and absence of a DPP-4 inhibitor. The effects of SEFA-1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high-fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high-fat diet murine model. SEFA-1024 reversed obesity-associated insulin resistance and improved glycemic control. SEFA-1024 increased active GLP-1. In a long-term model of diet-induced obesity, SEFA-1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA-1024 is an enterohepatic-targeted, eicosapentaenoic acid derivative that reverses obesity-induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA-1024 works may include increasing aGLP-1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA-1024 may serve as a potential treatment for obesity-related diabetes and NAFLD.

Topics: Animals; Diabetes Mellitus; Diet, High-Fat; Fatty Acids; Glucagon-Like Peptide 1; Insulin Resistance; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Rats

GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 - which is rapidly degraded - modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1's anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production.. Syrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1. GLP-1. Our data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut-brain-liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.

Topics: Animals; Chylomicrons; Cricetinae; Glucagon-Like Peptide 1; Insulin Resistance; Lipoproteins; Mesocricetus; Mice; Mice, Inbred C57BL; Portal Vein

Worldwide, metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. MAFLD is associated with insulin resistance, type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Early diagnosis and management are vital to improving hepatic and cardiometabolic outcomes. Dietary change, weight loss, and structured exercise are the main treatment approaches for fatty liver disease. Since 2010, several investigational drug treatments failed to achieve regulatory approval due to mixed and unsatisfactory results. Although glucagon-like peptide 1 receptor agonists (GLP1-RAs) showed initial promise as therapeutic agents, metabolic liver damage can recur after monotherapy cessation. Dual incretin receptor agonists target the receptors for glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). Importantly, on May 13, 2022, the US Food and Drug Administration (FDA) approved tirzepatide as the first dual GLP-1 and GIP receptor agonist for the treatment of T2DM. Dual incretin receptor agonists induce weight loss and enhance hepatic lipid metabolism and systemic insulin sensitivity. Insulin resistance and hepatic steatosis are the main contributors to the development of MAFLD. Treatment with dual incretin analogs reduces hepatic steatosis, lobular inflammation, liver cell damage, fibrosis, and total liver triglyceride levels. The availability of dual incretin receptor agonists for patients with MAFLD may result in weight control, normalizing insulin sensitivity, and reducing or even reversing metabolic dysfunction and liver damage. This Editorial aims to provide an update and discuss how treatment with dual incretin receptor agonists may maintain normal glucose levels and weight and control MAFLD.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin Resistance; United States; Weight Loss

Impaired secretion of glucagon-like peptide-1 (GLP-1) among Caucasians contributes to reduced incretin effect in type 2 diabetes mellitus (T2DM) patients. However, studies emanating from East Asia suggested preserved GLP-1 levels in pre-diabetes (pre-DM) and T2DM. We aimed to resolve these conflicting findings by investigating GLP-1 levels during oral glucose tolerance test (OGTT) among Malay, Chinese, and Indian ethnicities with normal glucose tolerance (NGT), pre-DM, and T2DM. The association between total GLP-1 levels, insulin resistance, and insulin sensitivity, and GLP-1 predictors were also analyzed.. A total of 174 subjects were divided into NGT (n=58), pre-DM (n=54), and T2DM (n=62). Plasma total GLP-1 concentrations were measured at 0, 30, and 120 min during a 75-g OGTT. Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of insulin sensitivity (HOMA-IS), and triglyceride-glucose index (TyG) were calculated.. Total GLP-1 levels at fasting and 30 min were significantly higher in T2DM compared with pre-DM and NGT (27.18 ± 11.56 pmol/L vs. 21.99 ± 10.16 pmol/L vs. 16.24 ± 7.79 pmol/L, p=0.001; and 50.22 ± 18.03 pmol/L vs. 41.05 ± 17.68 pmol/L vs. 31.44 ± 22.59 pmol/L, p<0.001; respectively). Ethnicity was a significant determinant of AUC. This is the first study that showed GLP-1 responses are augmented as IR states increase. Fasting and post-OGTT GLP-1 levels are raised in T2DM and pre-DM compared to that in NGT. This raises a possibility of an adaptive compensatory response that has not been reported before. Among the three ethnic groups, the Indians has the highest IR and GLP-1 levels supporting the notion of an adaptive compensatory secretion of GLP-1.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Ethnicity; Fasting; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Prediabetic State; Triglycerides

This study intended to determine the associations between gut microbiota and glucose response in healthy individuals and analyze the connection between the gut microbiome and glucose-metabolism-related parameters.. Fecal bacterial composition and anthropometric, body composition, body fat distribution, and biochemical measures were analyzed. A 75-g oral glucose tolerance test (OGTT) was given to each participant to investigate changes in glucagon-like peptide 1 (GLP-1), insulin, and glucose. The whole body fat and the regions of interest of local body composition were analyzed using dual-energy X-ray absorptiometry (DEXA), and gut microbiota composition was assessed through variable regions (V3-V4) of the bacterial 16s ribosomal RNA gene using high-throughput sequencing techniques. Spearman correlation analysis was used to evaluate the association between gut microbiota and clinical and metabolic changes.. The number of operational taxonomic units (OTUs) demonstrated a reduction in the diversity and composition of gut microbiota associated with enhanced adiposity, dyslipidemia, insulin resistance, and hyperglycemia. The alpha diversity revealed that microbiota diversity, richness, and composition were higher in the African group and lower in the Chinese group. Principal coordinates analysis (PCoA) plots of beta diversity showed significant variability in gut microbial community structure between the two groups (. Our data suggest that there is an interaction between gut microbiota, host physiology, and glucometabolic pathways, and this could contribute to adiposity and pathophysiology of hyperlipidemia, insulin resistance, and hyperglycemia. These findings provide an important basis for determining the relation between the gut microbiota and the pathogenesis of various metabolic disorders.

Topics: China; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose; Humans; Hyperglycemia; Insulin Resistance; Insulins

Acarbose is one of the optimal drugs for patients with the first diagnosis of type 2 diabetes mellitus (T2DM). But what kind of emerging patients has the best therapeutic response to acarbose therapy has never been reported. To this end, we investigated predictors of acarbose therapeutic efficacy in newly diagnosed T2DM patients in China.. A total of 346 T2DM patients received acarbose monotherapy for 48 weeks as part of participating in the Study of Acarbose in Newly Diagnosed Patients with T2DM in China (MARCH study) from November 2008 to June 2011. Change in glycated hemoglobin (ΔHbA1c) served as a dependent variable while different baseline variables including sex, age, disease duration, weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), HbA1c, fasting plasma glucose (FPG), 2-h postprandial blood glucose (2 h PG), fasting insulin (FINS), 2-h postprandial insulin (2 h INS), early insulin secretion index (IGI), homeostasis model assessment of insulin resistance index (HOMA-IR), homeostasis model assessment of beta cell function (HOMA-B), area under the curve (AUC) of glucagon, insulin and GLP-1 were assessed as independent predictors. Step-wise multiple linear regression was employed for statistical analysis.. The results suggested that independent predictors of ΔHbA1c at 12 weeks included baseline body weight (β = - 0.012, P = 0.006), DBP (β = 0.010, P = 0.047), FPG (β = 0.111, P = 0.005) and 2 h PG (β = 0.042, P = 0.043). Independent predictors of ΔHbA1c at 24 weeks included disease duration (β = 0.040, P = 0.019) and FPG (β = 0.117, P = 0.001). Finally, independent predictor of ΔHbA1c at 48 weeks was disease duration (β = 0.038, P = 0.046).. Acarbose may be more effective in newly diagnosed T2DM patients with low FPG, low 2 h PG and obesity. The earlier T2DM is diagnosed and continuously treated with acarbose, the better the response to therapy.

Topics: Acarbose; Blood Glucose; China; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Insulins

In contrast to Western population, glucagon-like peptide-1 (GLP-1) levels are preserved in some East Asian population with type 2 diabetes (T2D), explaining why dipeptidyl peptidase-IV (DPP-IV) inhibitors are more effective in East Asians. We assessed whether differences in endogenous GLP-1 levels resulted in different treatment responses to DPP-IV inhibitors in prediabetes and T2D.. A prospective 12-week study using linagliptin 5mg once daily in 50 subjects (28 prediabetes and 22 T2D) who were stratified into high versus low fasting GLP-1 groups. A 75-g oral glucose tolerance test (OGTT) was performed at week 0 and 12. Primary outcomes were changes in HbA1c, fasting and post-OGTT glucose after 12 weeks. Secondary outcomes included changes in insulin resistance and beta cell function indices.. There was a greater HbA1c reduction in subjects with high GLP-1 compared to low GLP-1 levels in both the prediabetes and T2D populations [least-squares mean (LS-mean) change of -0.33% vs. -0.11% and -1.48% vs. -0.90% respectively)]. Linagliptin significantly reduced glucose excursion by 18% in high GLP-1 compared with 8% in low GLP-1 prediabetes groups. The reduction in glucose excursion was greater in high GLP-1 compared to low GLP-1 T2D by 30% and 21% respectively. There were significant LS-mean between-group differences in fasting glucose (-0.95 mmol/L), 2-hour glucose post-OGTT (-2.4 mmol/L) in the high GLP-1 T2D group. Improvement in insulin resistance indices were seen in the high GLP-1 T2D group while high GLP-1 prediabetes group demonstrated improvement in beta cell function indices. No incidence of hypoglycemia was reported.. Linagliptin resulted in a greater HbA1c reduction in the high GLP-1 prediabetes and T2D compared to low GLP-1 groups. Endogenous GLP-1 level play an important role in determining the efficacy of DPP-IV inhibitors irrespective of the abnormal glucose tolerance states.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Resistance; Linagliptin; Prediabetic State; Prospective Studies

Recently, the duodenum has garnered interest for its role in treating metabolic diseases, including type 2 diabetes (T2DM). Multiple sessions of external photobiomodulation (PBM) in previous animal studies suggested it resulted in improved hyperglycemia, glucose intolerance, and insulin resistance with a multifactorial mechanism of action, despite the target organ of PBM not being clearly proven. This study aimed to determine whether a single session of a duodenal light-emitting diode (LED) PBM may impact the T2DM treatment in an animal model.. Goto-Kakizaki rats as T2DM models were subjected to PBM through duodenal lumen irradiation, sham procedure, or control in 1-week pilot (630 nm, 850 nm, or 630/850 nm) and 4-week follow-up (630 nm or 630/850 nm) studies. Oral glucose tolerance tests; serum glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, and insulin levels; liver chemistry and histology; and gut microbiome in the PBM, sham control, and control groups were evaluated.. In the 1-week study, duodenal dual-wavelength (D, 630/850 nm) LED PBM showed improved glucose intolerance, alkaline phosphatase and cholesterol levels, and weight gain than other groups. The D-LED PBM group in the 4-week study also showed improved hyperglycemia and liver enzyme levels, with relatively preserved pancreatic islets and increased serum insulin and GLP-1 levels. Five genera (. A single session of D-LED PBM improved hyperglycemia and hepatic parameters through the change of serum insulin, insulin resistance, insulin expression in the pancreatic β-cells, and gut microbiome in T2DM animal models.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Duodenum; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Resistance; Liver; Rats

Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy.. We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp.. Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9-a GLP-1 receptor antagonist-worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates.. Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Diet, High-Fat; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Clamp Technique; Glucose Intolerance; Ibuprofen; Insulin; Insulin Resistance; Intestinal Diseases; Liver; Mice; Mice, Inbred C57BL

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are innovative drugs that effectively reduce glycemic levels and overweight in patients with type 2 diabetes mellitus (T2DM). However, the criteria for predicting the hypoglycemic effect of this group of drugs have not been practically defined.. To assess the factors contributing to the achievement the glycemia normalization in patients with diabetes mellitus and obesity by adding to antihyperglycemic therapy (AT) a drug from the GLP-1 RA group liraglutide 3.0 mg per day.. A single-center, prospective, non-randomized study was provided. The objects of the study were patients with T2DM and obesity (n=22). Liraglutide 3.0 mg per day was added to the current AT of patients. Initially, the parameters of carbohydrate metabolism, hormones of the incretin system on an empty stomach and during the mixed-meal test, insulin resistance using the euglycemic hyperinsulinemic clamp test, and body composition were studied. After 9 months of therapy, all studies were repeated and a search for possible predictors of the carbohydrate metabolism normalization was made.. The body mass index of patients decreased from 42.4 [37.7; 45.0] to 35.9 [33.0; 40.9] kg/m2. Fasting blood glucose and glycated hemoglobin levels decreased from 9.02 [7.40; 11.37] mmol/L and 7.85 [7.43; 8.65]% up to 5.90 [5.12; 6.18] mmol/L and 6.40 [5.90; 6.60]%, respectively. 14 (63.6%) patients reached normoglycemia. Insulin resistance according to the clamp test did not change over the study. Basal concentrations of oxyntomodulin, glycentin and the area under the GLP-1, oxyntomodulin, glycentin curve significantly decreased 9 months after liraglutide administration. The prognostic marker of the achievement of normoglycemia during therapy with liraglutide 3.0 mg/day is the level of endogenous GLP-15.5 pmol/L before the appointment of arGPP-1 therapy.. The concentration of endogenous GLP-1 before the appointment of liraglutide therapy at a dose of 3.0 mg per day can be used for prediction the drug hypoglycemic effect and achieving normoglycemia possibility.. Актуальность. Агонисты рецепторов глюкагоноподобного пептида-1 (арГПП-1) являются инновационными препаратами, эффективно снижающими уровень гликемии и избыточный вес у пациентов с сахарным диабетом 2-го типа (СД 2). Однако практически не определены критерии, позволяющие прогнозировать сахароснижающий эффект этой группы препаратов. Цель. Оценить факторы, способствующие достижению нормализации гликемии у пациентов с СД 2 и ожирением при добавлении к сахароснижающей терапии (СТ) препарата из группы арГПП-1 лираглутида 3,0 мг/сут. Материалы и методы. Проведено одноцентровое проспективное нерандомизированное исследование. Объектами исследования выступили пациенты с СД 2 и ожирением (n=22). К текущей СТ пациентов был добавлен лираглутид 3,0 мг/сут. Исходно исследованы показатели углеводного обмена, гормонов инкретиновой системы натощак и в течение теста со смешанной пищей, инсулинорезистентности с помощью эугликемического гиперинсулинемического клэмп-теста, композитного состава тела. Через 9 мес терапии повторены все исследования и проведен поиск возможных предикторов нормализации углеводного обмена. Результаты. Индекс массы тела пациентов снизился с 42,4 [37,7; 45,0] до 35,9 [33,0; 40,9] кг/м2. Уровни глюкозы крови натощак и гликированного гемоглобина снизились с 9,02 [7,40; 11,37] ммоль/л и 7,85 [7,43; 8,65]% до 5,90 [5,12; 6,18] ммоль/л и 6,40 [5,90; 6,60]% соответственно. Нормогликемии достигли 14 (63,6%) пациентов. Инсулинорезистентность, согласно клэмп-тесту, не изменилась на протяжении 9 мес исследования. Базальные концентрации оксинтомодулина, глицентина и площади под кривой ГПП-1, оксинтомодулина, глицентина значимо снизились через 9 мес после назначения лираглутида. Прогностическим маркером достижения нормогликемии при терапии лираглутидом 3,0 мг/сут является уровень эндогенного ГПП-15,5 пмоль/л до назначения терапии арГПП-1. Заключение. Концентрация эндогенного ГПП-1 до назначения терапии лираглутидом в дозе 3,0 мг/сут может быть использована для прогнозирования сахароснижающего эффекта препарата и возможности достижения нормогликемии.

Topics: Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Liraglutide; Obesity; Oxyntomodulin; Prognosis; Prospective Studies

Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone glucagon-like peptide-1 (GLP-1) and changes in levels of circulating bile acids. The levels of individual bile acids in the gastrointestinal (GI) tract after surgery have, however, remained largely unstudied. Using ultra-high performance liquid chromatography-mass spectrometry-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a Takeda G-protein receptor 5 (TGR5) agonist that increases Tgr5 expression and induces GLP-1 secretion. Furthermore, CA7S administration increases glucose tolerance in insulin-resistant mice in a TGR5-dependent manner. CA7S remains gut restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into the circulation. By studying changes in individual metabolites after surgery, the present study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.

Topics: Animals; Anti-Obesity Agents; Bariatric Surgery; Bile; Caco-2 Cells; Cholic Acid; Colon; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Tolerance Test; HEK293 Cells; Humans; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, G-Protein-Coupled; RNA, Small Interfering; Signal Transduction; Sulfates

The present study aimed to disclose a potent and selective GPR120 agonist LXT34 and its anti-diabetic effects.. Calcium mobilization assay was used to measure the agonistic potency and selectivity of LXT34 in GPR120 or GPR40-overexpression Chinese hamster ovary (CHO) cells. Glucagon-like peptide-1 (GLP-1) release and glucose-stimulated insulin secretion (GSIS) were evaluated in human colonic epithelial cell line NCI-H716 and mouse insulinoma cell line MIN6 by enzyme-linked immunosorbent assay (ELISA), respectively. The anti-inflammatory effect was determined in lipopolysaccharide (LPS)-induced murine macrophage cell line RAW264.7. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed to assess the anti-diabetic effects of LXT34 in db/db mice, and chronic inflammation in liver and adipose tissues were investigated using histomorphology, immunoblot and gene expression analysis.. LXT34 was a potent GPR120 agonist with negligible activity toward human and mouse GPR40. LXT34 could potentiate GSIS and suppress LPS-induced inflammation in macrophages. LXT34 not only markedly improved glucose tolerance and insulin resistance, but also distinctly reduced macrophages infiltration, pro-inflammatory cytokines expression and JNK phosphorylation of both liver and adipose tissues in db/db mice.. LXT34, a novel and potent GPR120-selective agonist, showed beneficial effects on improving glucose homeostasis in obesity-related type 2 diabetes.

Topics: Adipose Tissue; Animals; Chronic Disease; Glucagon-Like Peptide 1; Glucose; Inflammation; Insulin Resistance; Insulin Secretion; Lipopolysaccharides; Liver; Mice; Mice, Inbred C57BL; RAW 264.7 Cells; Receptors, G-Protein-Coupled

Beinaglutide has been approved for glucose lowering in type 2 diabetes mellitus (T2DM) in China. In addition to glycemic control, significant weight loss is observed from real world data. This study is designed to investigate the pharmacological and pharmacokinetic profiles of beinaglutide in different models.. The pharmacological efficacy of beinaglutide was evaluated in C57BL/6 and ob/ob mice after single administration. Pharmacokinetic profiles in mice were investigated after single or multiple administration. Sub-chronic pharmacological efficacy was investigated in ob/ob mice for two weeks treatment and diet-induced ob/ob mice model of nonalcoholic steatohepatitis (NASH) for four weeks treatment.. Beinaglutide could dose-dependently reduce the glucose levels and improve insulin secretion in glucose tolerance tests, inhibit food intake and gastric emptying after single administration. At higher doses, beinaglutide could inhibit food intake over 4 h, which results in weight loss in ob/ob mice after about two weeks treatment. No tachyphylaxis is observed for beinaglutide in food intake with repeated administration. In NASH model, beinaglutide could reduce liver weight and hepatic steatosis and improve insulin sensitivity. Signiant changes of gene levels were observed in fatty acid β-oxidation (Ppara, Acadl, Acox1), mitochondrial function (Mfn1, Mfn2), antioxidation (Sod2), Sirt1, and et al. SIGNIFICANCE: Our results characterize the pharmacological and pharmacokinetic profiles of beinaglutide in mice and supported that chronic use of beinaglutde could lead to weight loss and reduce hepatic steatosis, which suggest beinaglutide may be effective therapy for the treatment of obesity and NASH.

Topics: Animals; Antioxidants; Diabetes Complications; Diabetes Mellitus; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Liraglutide; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease; Obesity; Oxidation-Reduction; Peptide Fragments; PPAR alpha; Weight Loss

Aloe vera (L.) Burm. f. extract has been medicinally used for over 5000 years in different cultures for its curative and therapeutic properties ranging from dermatitis to diabetes. It has been demonstrated to alleviate diabetes through its protective effects on pancreatic islets and by improving insulin secretion.. To investigate the simultaneous effect of ethanolic A. vera gel extract on diabetes and obesogenic milieu in Streptozotocin-induced WNIN/GR-Ob mutant obese rats.. A total of 30 rats were grouped equally into WNIN/GR-Ob control (received water as a vehicle), WNIN/GR-Ob Diabetic rats (Streptozotocin-35 mg/kg bw), WNIN/GR-Ob Diabetic rats + Sitagliptin (10 mg/kg bw), WNIN/GR-Ob Diabetic rats + A. vera (300 mg/kg bw) and GR-Ob control + A. vera (300 mg/kg bw). After 4 weeks of treatment, fasting blood glucose, serum insulin, Homeostatic Model Assessment - Insulin Resistance and β-cell function, glucose-stimulated insulin secretion, Dipeptidyl peptidase-IV activity, and lipid profiles were studied. In addition, ultrastructural analysis of isolated islets and dual-energy X-ray absorptiometry analysis for body composition were also carried out.. The A. vera treated group showed a significant reduction (p < 0.05) in triglyceride, Very low-density lipoprotein levels, Triglyceride to High-density lipoprotein ratio as well as fasting blood glucose levels and DPP-IV activity with a concomitant increase in the serum insulin levels. The increase in IR was observed in both WNIN/GR-Ob control and diabetic rats with a significant decrease in β-cell function in the diabetic rats as per Homeostatic Model Assessment values. Oral administration of A. vera was effective in both reducing Homeostatic Model Assessment-Insulin Resistance and increasing Homeostatic Model Assessment-β values. Also, the treated group demonstrated preservation of islets and a significant increase (p < 0.05) in the diameter of β-cell as evident through Scanning electron microscope analysis. The increase in lean body mass was manifested in the treated group with a reduction in Fat percent in comparison with other groups.. The beneficial effects of A. vera in WNIN/GR-Ob strain may be attributed to its ability to lower lipid profile thus improve insulin sensitivity and/or modulating β-cell function. Thus, it has great therapeutic potential as an herbal remedy for the treatment of diabetes and associated adverse effects such as obesity. The exact mechanism underlying the observation needs to be investigated further to explore the anti-obesity and anti-diabetic properties of A. vera and advocate its potential application as alternative medicine.

Topics: Aloe; Animals; Anti-Obesity Agents; Blood Glucose; Body Composition; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Obesity; Plant Extracts; Rats, Mutant Strains; Sitagliptin Phosphate; Streptozocin

Bile acid has attracted attention as a signal transmission molecule in energy metabolism. Although a high-fat diet (HFD) or obesity is known to increase hepatic fat content and alter bile acid composition, the changes in bile acid composition due to HFD or obesity remain to be elucidated. We sought to examine the bile acid composition in high fat diet-induced non-alcoholic fatty liver disease (NAFLD) in obese diabetic rats. Eight-week-old male spontaneously diabetic Torii fatty (SDTF) rats or control rats were fed an HFD. Twelve weeks post the commencement of HFD, serum and hepatic bile acid compositions and serum GLP-1 levels, which is stimulated by the secondary bile acid deoxycholic acid (DCA), were measured. The correlation between the bile acid composition and serum GLP-1 levels was also examined. While serum and hepatic levels of cholic acid (CA), a primary bile acid, tended to decrease in HFD-fed control rats, they were significantly decreased in HFD-fed SDTF rats. Hepatic CYP8B1, which plays a role in CA synthesis, the mRNA levels were significantly decreased in HFD-fed control and SDTF rats. In contrast, while serum and hepatic DCA levels were not changed in HFD-fed control rats, they were decreased in HFD-fed SDTF rats. Hepatic DCA/CA did not change in HFD-fed SDTF rats, but significantly increased in HFD-fed control rats. While serum GLP-1 levels were not changed in SDTF rats, they were significantly increased in HFD-fed control rats. Hepatic DCA/CA tended to correlate with serum GLP-1 levels, which tended to negatively correlate with the hepatic triglyceride content in SDTF rats. These results indicate that relatively increased DCA might contribute to an increase in serum GLP-1 levels, which inhibits hepatic steatosis in NAFLD.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Fatty Acids; Gene Expression Regulation; Glucagon-Like Peptide 1; Insulin Resistance; Liver; Male; Non-alcoholic Fatty Liver Disease; Obesity; Rats, Sprague-Dawley; Triglycerides

Matrine (Mat), a bitter tastes compounds of derived from leguminosae such as Sophora flavescens and S. subprostrata, commonly used to improve obesity and diabetes.. Our study to demonstrate bitter substances can stimulate the Bitter taste receptors (TAS2Rs) or Calcium-sensing receptor (CaSR) to stimulate the secretion of GLP-1 to promote blood glucose regulation.. The diabetic mice and intestinal secretory cell model were established to evaluate the Mat on glucose metabolism, intestinal insulin secretion and GLP-1 secretion related substances. To clarify the mechanism of Mat in regulating GLP-1 secretion by immunofluorescence, calcium labeling, siRNA, and molecular docking.. The results showed that Mat could significantly improve glucose metabolism and increased insulin and GLP-1 secretion in diabetic mice and increased trisphosphate inositol (IP3) levels by affecting the expression of phospholipase C β2 (PLCβ2) and promote an increase in intracellular Ca2. Matrine is a typical bitter alkaloid could be used as an agonist of CaSR to stimulate the secretion of GLP-1 in the intestine, and it may be used as a potential drug for diabetes treatment.

Topics: Alkaloids; Animals; Cell Line; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Resistance; Intestines; Male; Matrines; Mice, Inbred C57BL; Molecular Docking Simulation; Phospholipase C beta; Quinolizines; Receptors, Calcium-Sensing; Receptors, G-Protein-Coupled

The intestines have been recognized as important tissues for metabolic regulation, including glycemic control, but their vital role in promoting the anti-diabetic effects of bitter melon, the fruit of

Topics: Cell Line; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Enterocytes; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Intestinal Mucosa; Momordica charantia; Plant Extracts

Topics: Animals; Blood Glucose; Body Weight; Down-Regulation; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin; Insulin Resistance; Intestine, Small; Liraglutide; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Pancreas; Quinolones; Rats; Signal Transduction; Thiophenes

/Objectives: The pathogenesis of hyperglycemia during acute pancreatitis (AP) remains unknown due to inaccessibility of human tissues and lack of animal models. We aimed to develop an animal model to study the mechanisms of hyperglycemia and impaired glucose tolerance in AP.. We injected ferrets with intraperitoneal cerulein (50 μg/kg, 9 hourly injections) or saline. Blood samples were collected for glucose (0, 4, 8, 12, 24h); TNF-α, IL-6 (6h); amylase, lipase, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) (24h). Animals underwent oral glucose tolerance test (OGTT), mixed meal tolerance test (MMTT) at 24h or 3 months, followed by harvesting pancreas for histopathology and immunostaining.. Cerulein-injected ferrets exhibited mild pancreatic edema, neutrophil infiltration, and elevations in serum amylase, lipase, TNF-α, IL-6, consistent with AP. Plasma glucose was significantly higher in ferrets with AP at all time points. Plasma glucagon, GLP-1 and PP were significantly higher in cerulein-injected animals, while plasma insulin was significantly lower compared to controls. OGTT and MMTT showed abnormal glycemic responses with higher area under the curve. The hypoglycemic response to insulin injection was completely lost, suggestive of insulin resistance. OGTT showed low plasma insulin; MMTT confirmed low insulin and GIP; abnormal OGTT and MMTT responses returned to normal 3 months after cerulein injection.. Acute cerulein injection causes mild acute pancreatitis in ferrets and hyperglycemia related to transient islet cell dysfunction and insulin resistance. The ferret cerulein model may contribute to the understanding of hyperglycemia in acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Blood Glucose; Ceruletide; Ferrets; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Insulin Resistance; Interleukin-6; Lipase; Pancreatitis; Tumor Necrosis Factor-alpha

Glucagon-like peptide-1 (GLP-1) receptor agonist treatment is beneficial for the human glucose metabolism, and GLP-1 secretion is greatly enhanced following Roux-en-Y gastric bypass (RYGB).. To elucidate the relationship between GLP-1 concentrations and insulin sensitivity in subjects with class II/III obesity without diabetes and to assess the relation between GLP-1 and the improvements in glucose metabolism following RYGB.. Clinical research facility in a university hospital.. We recruited 35 patients scheduled for RYGB and assessed their plasma GLP-1, insulin, and glucose responses to a high-fat mixed meal. Basal and insulin-mediated glucose fluxes were determined during a 2-step hyperinsulinemic-euglycemic clamp with stable isotope-labeled tracers. Out of 35 subjects, 10 were studied both before surgery and at 1 year of follow-up.. Plasma GLP-1 increased following the high-fat mixed meal. Postprandial GLP-1 excursions correlated positively with hepatic and peripheral insulin sensitivity, but not with body mass index. At 1 year after RYGB, participants had lost 24% ± 6% of their body weight. Plasma GLP-1, insulin, and glucose levels peaked earlier and higher after the mixed meal. The positive association between the postprandial GLP-1 response and peripheral insulin sensitivity persisted.. Postprandial GLP-1 concentrations correlate with insulin sensitivity in subjects with class II/III obesity without diabetes before and 1 year after RYGB. Increased GLP-1 signaling in postbariatric patients may, directly or indirectly, contribute to the observed improvements in insulin sensitivity and metabolic health.

Topics: Bariatric Surgery; Blood Glucose; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Obesity; Postprandial Period

Ca

Topics: Alstrom Syndrome; Animals; Blood Glucose; Calcium; Calcium Signaling; Diabetes Mellitus, Type 2; Disease Models, Animal; Endoplasmic Reticulum; Exenatide; Fluorescent Dyes; Fura-2; Glucagon-Like Peptide 1; Hepatocytes; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; Obesity; Palmitic Acid

Glucose curve shapes during oral glucose tolerance tests (OGTTs) are mainly classified as incessant increase, monophasic and biphasic. Youth with an incessant increase curve have worse β-cell function. The aim of this paper was to investigate the incessant increase curve in Chinese adults with type 2 diabetes (T2DM), and its association with β-cell function and gut hormone levels. Eighty-nine Chinese patients (59 males and 30 females) were included in this study with a mean age of 50.56 ± 16.00 years. They were all recently diagnosed with T2DM and underwent 180-min OGTTs. Data on demographics, β-cell function, and insulin sensitivity were also collected. Gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and ghrelin, were also detected during the OGTT. A total of 39.3 % of subjects had an incessant increase in the glucose response curve, while 59.6 % had a monophasic curve. Because only one curve was classified as biphasic, patients with a biphasic curve were omitted from further research. Lower plasma C-peptide, HOMA2-β, area under the curve (AUC) of C-peptide, and ratio of AUC of insulin to AUC of glucose were found in patients with incessant increase curves compared to those with monophasic curves (P < 0.05). Higher glycated hemoglobin (HbA

Topics: Adult; Aged; Asian People; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged

Topics: Bariatric Surgery; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Obesity; Postprandial Period

MYC is a transcription factor with broad biological functions, notably in the control of cell proliferation. Here, we show that intestinal MYC regulates systemic metabolism. We find that MYC expression is increased in ileum biopsies from individuals with obesity and positively correlates with body mass index. Intestine-specific reduction of MYC in mice improves high-fat-diet-induced obesity, insulin resistance, hepatic steatosis and steatohepatitis. Mechanistically, reduced expression of MYC in the intestine promotes glucagon-like peptide-1 (GLP-1) production and secretion. Moreover, we identify Cers4, encoding ceramide synthase 4, catalysing de novo ceramide synthesis, as a MYC target gene. Finally, we show that administration of the MYC inhibitor 10058-F4 has beneficial effects on high-fat-diet-induced metabolic disorders, and is accompanied by increased GLP-1 and reduced ceramide levels in serum. This study positions intestinal MYC as a putative drug target against metabolic diseases, including non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

Topics: Animals; Biomarkers; Diet, High-Fat; Disease Models, Animal; Disease Susceptibility; Glucagon-Like Peptide 1; Humans; Ilium; Insulin Resistance; Intestinal Mucosa; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Proto-Oncogene Proteins c-myc

Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma.

Topics: Adult; Adverse Childhood Experiences; Antipsychotic Agents; Biomarkers; C-Peptide; Female; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Plasminogen Activator Inhibitor 1; Psychotic Disorders; Resistin

Topics: AMP-Activated Protein Kinases; Animals; Blood Glucose; Cholecalciferol; Creatinine; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Hyperuricemia; Hypoglycemic Agents; Insulin Resistance; Kidney; Kidney Cortex; Male; Malondialdehyde; MAP Kinase Signaling System; NADP; Oxidative Stress; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Sirtuin 1; Sodium Chloride; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Urea; Uric Acid; Vildagliptin

Doxorubicin is a common chemotherapy treatment with numerous negative ramifications of use such as nephropathy and radiation-induced cardiotoxicity. Doxorubicin has been shown to cause overexpression of proinflammatory cytokines including MCP-1 and IL-1β via activation of the NF-κB pathway. Furthermore, apoptosis marked by dysregulation of the Bax/Bcl-2 ratio and oxidative stress and the production of reactive oxygen species (ROS) are also exacerbated by doxorubicin administration. Teneligliptin is part of the wider dipeptidyl peptidase-4 (DPP-4) inhibitor family which has until recently been almost exclusively used to treat type 2 diabetes mellitus. DPP-4 inhibitors such as teneligliptin control the overexpression of glucagon-like peptidase 1 (GLP-1) which has the downstream effects of general insulin resistance and high blood sugar levels. Our findings indicate a significant protective effect of teneligliptin against the aftereffects of doxorubicin as a chemotherapy treatment. This protective effect includes but is not limited to the reduction of inflammation and the mitigation of dysregulated apoptosis, as evidenced by reduced expression of IL-1β and MCP-1, inhibition of NF-κB activation, and improvement of the Bax/Bcl-2 ratio. The aim of the present study was to establish teneligliptin as a potentially useful agent for the treatment of radiation-induced cardiotoxicity, and our findings support this notion.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blood Glucose; Cell Line; Cell Survival; Chemokine CCL2; Dipeptidyl Peptidase 4; Doxorubicin; Glucagon-Like Peptide 1; Humans; Inflammation; Insulin Resistance; Interleukin-1beta; Myocytes, Cardiac; Oxidative Stress; Pyrazoles; Rats; Reactive Oxygen Species; Receptors, KIR3DL1; Thiazolidines

The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting.. Cross-sectional data were obtained from the Swedish population-based Malmö Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses.. Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found.. Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain.

Topics: Aged; Blood Glucose; Case-Control Studies; Cognition; Cross-Sectional Studies; Diabetes Mellitus; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycation End Products, Advanced; Humans; Insulin; Insulin Resistance; Male; Mental Status and Dementia Tests; Optical Imaging; Sweden

We aimed to determine the immediacy of exercise intervention on liver-specific metabolic processes in nonalcoholic fatty liver disease.. We undertook a short-term (7-d) exercise training study (60 min·d treadmill walking at 80%-85% of maximal heart rate) in obese adults (N = 13, 58 ± 3 yr, 34.3 ± 1.1 kg·m, >5% hepatic lipid by H-magnetic resonance spectroscopy). Insulin sensitivity index was estimated by oral glucose tolerance test using the Soonthorpun model. Hepatic insulin extraction (HIE) was calculated as the molar difference in area under the curve (AUC) for insulin and C-peptide (HIE = 1 - (AUCInsulin/AUCC-Pep)).. The increases in HIE, V˙O2max, and insulin sensitivity index after the intervention were 9.8%, 9.8%, and 34%, respectively (all, P < 0.05). Basal fat oxidation increased (pre: 47 ± 6 mg·min vs post: 65 ± 6 mg·min, P < 0.05) and carbohydrate oxidation decreased (pre: 160 ± 20 mg·min vs post: 112 ± 15 mg·min, P < 0.05) with exercise training. After the intervention, HIE correlated positively with adiponectin (r = 0.56, P < 0.05) and negatively with TNF-α (r = -0.78, P < 0.001).. By increasing HIE along with peripheral insulin sensitivity, aerobic exercise training rapidly reverses some of the underlying physiological mechanisms associated with nonalcoholic fatty liver disease, in a weight loss-independent manner. This reversal could potentially act through adipokine-related pathways.

Topics: Blood Glucose; C-Peptide; Carbohydrate Metabolism; Exercise; Glucagon-Like Peptide 1; Heart Rate; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Oxygen Consumption

Defects in incretin have been shown to be related to the pathogenesis of type 2 diabetes. Whether such a deficiency happens in gestational diabetes mellitus (GDM) remains to be confirmed. We assessed the association of fasting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) with GDM. We also studied the longitudinal circulation of these peptides during pregnancy and afterwards.. 53 women with GDM (30 managed with diet only (GDM-diet) and 23 treated with insulin (GDM-insulin)) and 43 pregnant women with normal glucose tolerance (NGDM) were studied, with GIP and GLP-1 levels measured at 24-28 weeks (E1), prior (E2) and after (E3) delivery, and postpuerperium (E4).. Basal GIP was shown to be low in GDM groups compared to NGDM in E1, and in E4 for GDM-diet. GLP-1 was low in GDM groups during pregnancy and afterwards. At E1, serum GIP and GLP-1 were inversely associated with GDM and participants with lower levels of GIP (<0.23 ng/mL) and GLP-1 (<0.38 ng/mL) had a 6 (95% CI 2.5-14.5)- and 7.6 (95% CI 3.0-19.1)-fold higher risk of developing GDM compared with the higher level, respectively. In the postpuerperium, when there is a drop in. There is an independent, inverse association between fasting incretins and higher risk of GDM. Furthermore, lowered levels of these peptides may play an important role in the abnormality of glucose regulation following pregnancy.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes, Gestational; Diet Therapy; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Logistic Models; Longitudinal Studies; Postpartum Period; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Prospective Studies

High-fat diets (HFD) have been widely associated with an increased risk of metabolic disorders and overweight. However, a high intake of sources that are rich in monounsaturated fatty acids has been suggested as a dietary agent that is able to positively influence energy metabolism and vascular function. The main objective of this study was to analyze the role of dietary fats on hepatic peptidases activities and metabolic disorders. Three diets: standard (S), HFD supplemented with virgin olive oil (VOO), and HFD supplemented with butter plus cholesterol (Bch), were administered over six months to male Wistar rats. Plasma and liver samples were collected for clinical biochemistry and aminopeptidase activities (AP) analysis. The expression of inducible nitric oxide synthase (iNOS) was also determined by Western blot in liver samples. The diet supplement with VOO did not induce obesity, in contrast to the Bch group. Though the VOO diet increased the time that was needed to return to the basal levels of plasma glucose, the fasting insulin/glucose ratio and HOMA2-%B index (a homeostasis model index of insulin secretion and valuation of β-cell usefulness (% β-cell secretion)) were improved. An increase of hepatic membrane-bound dipeptidyl-peptidase 4 (DPP4) activity was found only in VOO rats, even if no differences in fasting plasma glucagon-like peptide 1 (GLP-1) were obtained. Both HFDs induced changes in hepatic pyroglutamyl-AP in the soluble fraction, but only the Bch diet increased the soluble tyrosyl-AP. Angiotensinase activities that are implicated in the metabolism of angiotensin II (AngII) to AngIV increased in the VOO diet, which was in agreement with the higher activity of insulin-regulated-AP (IRAP) in this group. Otherwise, the diet that was enriched with butter increased soluble gamma-glutamyl transferase (GGT) and Leucyl-AP, iNOS expression in the liver, and plasma NO. In summary, VOO increased the hepatic activity of AP that were related to glucose metabolism (DPP4, angiotensinases, and IRAP). However, the Bch diet increased activities that are implicated in the control of food intake (Tyrosine-AP), the index of hepatic damage (Leucine-AP and GGT), and the expression of hepatic iNOS and plasma NO. Taken together, these results support that the source of fat in the diet affects several peptidases activities in the liver, which could be related to alterations in feeding behavior and glucose metabolism.

Topics: Animals; Diet, High-Fat; Dipeptidyl Peptidase 4; Energy Intake; Feeding Behavior; gamma-Glutamyltransferase; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin Resistance; Liver; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Obesity; Peptide Hydrolases; Pyroglutamyl-Peptidase I; Rats, Wistar

Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions in metabolic disorders including obesity and non-alcoholic fatty liver disease (NAFLD). Herein, we aimed to characterize the role and therapeutic potential of a newly identified peptide hormone in NAFLD.. Using bioinformatics, we identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we named 'metabolitin (MTL)'. We used ligand-receptor binding, receptor internalization, bioluminescence resonance energy transfer and Nano isothermal titration calorimetry assays to study the binding relationship between MTL and GPRC6A. For in vivo biological studies, wild-type mice kept on a high-fat diet (HFD) were injected or gavaged with MTL to study its function in NAFLD.. We confirmed that MTL binds to GPRC6A and OCN interacts with GPRC6A using in vitro biological studies. Both intraperitoneal and oral administration of MTL greatly improved NAFLD and insulin resistance in a mouse model. Interacting with GPRC6A expressed in intestines, MTL can significantly inhibit intestinal neurotensin secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by the 5'AMP-activated protein kinase pathway. In addition, glucagon like peptide-1 secretion was induced by MTL treatment.. Oral or intraperitoneal MTL significantly improves the symptoms of NAFLD by inhibiting lipid absorption and insulin resistance. MTL could be a potential therapeutic candidate for the treatment of NAFLD.. A novel murine peptide hormone, herein named 'metabolitin', inhibits fatty acid absorption and improves systemic insulin resistance in a murine model of obesity and non-alcoholic fatty liver disease. Thus, metabolitin has therapeutic potential for the treatment of patients with non-alcoholic fatty liver disease.

Topics: Animals; Dietary Fats; Disease Models, Animal; Glucagon-Like Peptide 1; Hypolipidemic Agents; Insulin Resistance; Intestinal Absorption; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Osteocalcin; Peptide Hormones; Receptors, G-Protein-Coupled; Signal Transduction; Treatment Outcome; Triglycerides

Topics: Animals; Blood Glucose; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucose Transporter Type 2; Humans; Insulin Resistance; Mice; Mitochondria; Renal Insufficiency; Shift Work Schedule

To investigate the effects of linagliptin treatment on hepatic energy metabolism and ER stress in high-fat-fed C57BL/6 mice.. Forty male C57BL/6 mice, three months of age, received a control diet (C, 10% of lipids as energy, n = 20) or high-fat diet (HF, 50% of lipids as energy, n = 20) for 10 weeks. The groups were randomly subdivided into four groups to receive linagliptin, for five weeks, at a dose of 30 mg/kg/day added to the diets: C, C-L, HF, and HF-L groups.. The HF group showed higher body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels than the C group, all of which were significantly diminished by linagliptin in the HF-L group. The HF group had higher hepatic steatosis than the C group, whereas linagliptin markedly reduced the hepatic steatosis (less 52%, P < 0.001). The expression of Sirt1 and Pgc1a was more significant in the HF-L group than in the HF group. Linagliptin also elicited enhanced GLP-1 concentrations and a reduction in the expression of the lipogenic genes Fas and Srebp1c. Besides, HF-L showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45 coupled with reduced apoptotic nuclei immunostaining.. Linagliptin caused a marked reduction in hepatic steatosis as a secondary effect of its glucose-lowering property. NAFLD countering involved reduced lipogenesis, increased beta-oxidation, and relief in endoplasmic reticulum stress, leading to reduced apoptosis and better preservation of the hepatic structure. Therefore, linagliptin may be used, preferably in diabetic patients, to avoid the progression of hepatic steatosis.

Topics: Animals; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Carbohydrate Metabolism; Diet, High-Fat; Eating; Endoplasmic Reticulum Stress; Fasting; Feeding Behavior; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Linagliptin; Lipid Droplets; Lipids; Lipogenesis; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Perilipin-2; Vascular Endothelial Growth Factor A

Roux-en-Y gastric bypass surgery (RYGB) can achieve long-term remission of type 2 diabetes. However, the specific molecular mechanism through which this occurs has remained largely elusive. Bile acid signaling through the nuclear hormone receptor farnesoid X receptor (FXR) exerts beneficial effects after sleeve gastrectomy (VSG), which has similar effects to RYGB. Therefore, we investigated whether FXR signaling is necessary to mediate glycemic control after RYGB.. RYGB or sham surgery was performed in high-fat diet-induced obese FXR-/- (knockout) and FXR+/+ (wild type) littermates. Sham-operated mice were fed ad libitum (S-AL) or by weight matching (S-WM) to RYGB mice via caloric restriction. Body weight, body composition, food intake, energy expenditure, glucose tolerance tests, insulin tolerance tests, and homeostatic model assessment of insulin resistance were performed.. RYGB surgery decreases body weight and fat mass in WT and FXR-KO mice. RYGB surgery has similar effects on food intake and energy expenditure independent of genotype. In addition, body weight-independent improvements in glucose control were attenuated in FXR -/- relative to FXR +/+ mice after RYGB. Furthermore, pharmacologic blockade of the glucagon-like peptide-1 receptor (GLP-1R) blunts the glucoregulatory effects of RYGB in FXR +/+ but not in FXR -/- mice at 4 weeks after surgery.. These results suggest that FXR signaling is not required for the weight loss up to 16 weeks after RYGB. Although most of the improvements in glucose homeostasis are secondary to RYGB-induced weight loss in wild type mice, FXR signaling contributes to glycemic control after RYGB in a body weight-independent manner, which might be mediated by an FXR-GLP-1 axis during the early postoperative period.

Topics: Animals; Blood Glucose; Body Composition; Body Weight; Diet, High-Fat; Energy Metabolism; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycemic Control; Homeostasis; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Obesity; Receptors, Cytoplasmic and Nuclear; Weight Loss

This study has examined the in vitro and in vivo anti-diabetic properties of the peptidase-resistant analogues [D-Ser

Topics: Amino Acid Sequence; Animals; Anti-Obesity Agents; Apoptosis; Blood Glucose; Body Weight; Cell Proliferation; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Transporter Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Neoplasm Proteins; Obesity; Receptors, Glucagon; Structure-Activity Relationship

The gut microbiota might critically modify metabolic disease development. Dietary fibers such as galacto-oligosaccharides (GOS) presumably stimulate bacteria beneficial for metabolic health. This study assesses the impact of GOS on obesity, glucose, and lipid metabolism.. Following Western-type diet feeding (C57BL/6 mice) with or without β-GOS (7% w/w, 15 weeks), body composition, glucose and insulin tolerance, lipid profiles, fat kinetics and microbiota composition are analyzed. GOS reduces body weight gain (p < 0.01), accumulation of epididymal (p < 0.05), perirenal (p < 0.01) fat, and insulin resistance (p < 0.01). GOS-fed mice have lower plasma cholesterol (p < 0.05), mainly within low-density lipoproteins, lower intestinal fat absorption (p < 0.01), more fecal neutral sterol excretion (p < 0.05) and higher intestinal GLP-1 expression (p < 0.01). Fecal bile acid excretion is lower (p < 0.01) in GOS-fed mice with significant compositional differences, namely decreased cholic, α-muricholic, and deoxycholic acid excretion, whereas hyodeoxycholic acid increased. Substantial changes in microbiota composition, conceivably beneficial for metabolic health, occurred upon GOS feeding.. GOS supplementation to a Western-type diet improves body weight gain, dyslipidemia, and insulin sensitivity, supporting a therapeutic potential of GOS for individuals at risk of developing metabolic syndrome.

Topics: Animals; Bile Acids and Salts; Body Weight; Diet, High-Fat; Diet, Western; Dietary Supplements; Dyslipidemias; Energy Metabolism; Feces; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Insulin Resistance; Male; Mice, Inbred C57BL; Obesity; Oligosaccharides; Sterols

The present study was aimed to investigate the mechanisms of salidroside (SAL) from Rhodiola wallichiana var. cholaensis on hypoglycemic and oxidative stress responses. The palmitate (PA)-induced GLUTag cells model and the glucosamine-induced insulin resistance model in HepG2 cells were built. SAL led to the up-regulation of the serum glucagon-like peptide 1 (GLP-1) level by facilitating the SCFAs production, the promotion of GLP-1 synthesis by improving p38 MAPK phosphorylation and regulating insulin resistance. Moreover, the production of reactive oxygen species (ROS) and the expression of MAPKs were down-regulated. Furthermore, SAL was found to be able to inhibit PA-induced apoptosis that down-regulates cleaved caspase-3 and Bax expressions, while up-regulating Bcl-2 expression and up-regulates the Bcl-2/Bax ratio in glucosamine induced insulin resistance model. Besides, SAL can also up-regulate the mTOR/p70S6k signaling pathway in the PA-induced GLUTag cells model. Our data demonstrated that SAL could reverse insulin resistance and stimulates the GLP-1 secretion by alleviating ROS-mediated activation of MAPKs signaling pathway and mitigating apoptosis. PRACTICAL APPLICATIONS: Our data showed that SAL could increase the GLP-1 level by stimulating the SCFAs production and p38 phosphorylation and facilitate the IR and GLP-1 synthesis by alleviating ROS-mediated activation of MAPKs signaling pathway and mitigating apoptosis. Furthermore, the SAL has also stimulated the mTOR/p70S6k signaling pathway in PA-induced GLUTag cells model. The results provided a possibility to employ SAL for diabetes treatment.

Topics: Apoptosis; Glucagon-Like Peptide 1; Glucosides; Humans; Insulin Resistance; Mitogen-Activated Protein Kinase Kinases; Phenols; Reactive Oxygen Species; Rhodiola; Signal Transduction

Methylglyoxal was shown to impair adipose tissue capillarization and insulin sensitivity in obese models. We hypothesized that glyoxalase-1 (GLO-1) activity could be diminished in the adipose tissue of type 2 diabetic obese patients. Moreover, we assessed whether such activity could be increased by GLP-1-based therapies in order to improve adipose tissue capillarization and insulin sensitivity. GLO-1 activity was assessed in visceral adipose tissue of a cohort of obese patients. The role of GLP-1 in modulating GLO-1 was assessed in type 2 diabetic GK rats submitted to sleeve gastrectomy or Liraglutide treatment, in the adipose tissue angiogenesis assay and in the HUVEC cell line. Glyoxalase-1 activity was decreased in visceral adipose tissue of pre-diabetic and diabetic obese patients, together with other markers of adipose tissue dysfunction and correlated with increased HbA1c levels. Decreased adipose tissue GLO-1 levels in GK rats were increased by sleeve gastrectomy and Liraglutide, being associated with overexpression of angiogenic and vasoactive factors, as well as insulin receptor phosphorylation (Tyr1161). Moreover, GLP-1 increased adipose tissue capillarization and HUVEC proliferation in a glyoxalase-dependent manner. Lower adipose tissue GLO-1 activity was observed in dysmetabolic patients, being a target for GLP-1 in improving adipose tissue capillarization and insulin sensitivity.

Topics: Adipose Tissue; Adult; Aged; Animals; Capillaries; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Gastrectomy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Human Umbilical Vein Endothelial Cells; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Lactoylglutathione Lyase; Liraglutide; Male; Middle Aged; Neovascularization, Physiologic; Obesity; Rats, Wistar; Signal Transduction

Konjac glucomannan (KGM) is a hypoglycemic polysaccharide with a wide range of molecular weights. But study on hypoglycemic effects of KGMs relate to molecular weight is limited. In this study, KGMs with high and medium molecular weights, and the degraded KGMs were analyzed with physicochemical properties, hypoglycemic effects and mechanisms. Results showed that as the molecular weight KGMs decreased, the viscosity decreased, molecular flexibility increased, while chemical groups, crystal structures and main chains showed little change. KGMs with medium molecular weights (KGM-M1, KGM-M2) showed better effects on increasing body weight, decreasing levels of fasting blood glucose, insulin resistance, total cholesterol and low density lipoprotein cholesterol, and enhancing integrity of pancreas and colon, than KGMs with high or low molecular weights (KGM-H, KGM-L) in type 2 diabetic rats. Mechanism analysis suggested that KGM-M1 and KGM-M2 had higher antioxidant and anti-inflammatory activities on elevating superoxide dismutase, decreasing malondialdehyde and tumor necrosis factor-α levels. Moreover, KGM-M1 and KGM-M2 increased gut microbiota diversity, Bacteroidetes/Firmicutes ratio and Muribaculaceae, decreased Romboutsia and Klebsiella, and improved 6 diabetic related metabolites. Combined, KGM-M1 and KGM-M2 showed higher hypoglycemic effects, due to regulatory activities of antioxidant, anti-inflammatory, intestinal microbiota, and relieved metabolic disorders.

Topics: Animals; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drinking Behavior; Fasting; Feces; Feeding Behavior; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Lipids; Magnetic Resonance Spectroscopy; Male; Mannans; Molecular Weight; Multivariate Analysis; Oxidative Stress; Phylogeny; Rats, Sprague-Dawley; Scattering, Radiation; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

The insulinotropic capacity of exogenous glucagon like peptide-1 (GLP-1) is reduced in type 2 diabetes and the insulin-resistant obese. We have tested the hypothesis that this response is the consequence of a reduced pancreatic GLP-1 receptor (GLP-1r) density in insulin-resistant obese animals.. GLP-1r density was measured in lean and insulin-resistant adult miniature pigs after the administration of a. GLP-1r binding potential in the obese pancreas was reduced by 75% compared with lean animals. Similar reductions were evident for fat tissue, but not for the duodenum. In the lean group, induced hyperinsulinemia reduced pancreatic GLP-1r density to a level comparable with that of the obese group. The reduction in blood to tissue transfer of the GLP-1r ligand paralleled that of tissue perfusion estimated using. These observations establish that a reduction in abdominal tissue perfusion and a lower GLP-1r density account for the diminished insulinotropic effect of GLP-1 agonists in type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin; Insulin Resistance; Pancreas; Swine

Resistant starch, a functional food ingredient, can improve the nutritional value of food products. In this study, the in vitro digestibility of starch from banana flour at four ripening stages was evaluated. The result showed that the resistant starch content of banana flour at ripening stage 1 was up to 81%. Furthermore, to explore the effect of resistant starch in the body, the in vivo digestibility of banana flour was investigated. The intake of banana flour at ripening stage 1 resulted in a nearly 70% decrease in the homeostasis model assessment of insulin resistance value, compared to that of the model group. By contrast, the genes related to glucokinase were upregulated by 66%, and the expression level of the insulin receptor gene was increased by more than 1.5 times that of the model group. Thus, natural banana flour has potential for controlling type 2 diabetes mellitus.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Digestion; Flour; Functional Food; Glucagon-Like Peptide 1; Homeostasis; Insulin Resistance; Lipids; Musa; Nutritive Value; Resistant Starch; Starch

Obese patients without diabetes present an interesting phenotype to explore protective mechanisms against type 2 diabetes (T2D) development. In our study we looked for specific hormonal features of obese patients without T2D.. We included 6 groups of patients with different metabolic profiles (n=212): controls with BMI25 kg/m2, HbA1c6%, age 30 years; patients with 25BMI30 kg/m2and HbA1c6%; patients with 25BMI30 kg/m2and HbA1c6%; patients with BMI30 kg/m2and HbA1c6% (+ Obesity - T2D) obese patients without T2D or prediabetes; patients with BMI30 kg/m2and newly-diagnosed T2D/prediabetes, HbA1c6%; patients with known history of T2D on glucose-lowering drugs with BMI30 kg/m2. Insulin, GLP-1, GIP were measured during glucose-tolerance test at 0, 30 and 120 minutes; insulin resistance (IR) was assessed by HOMA-IR.. Waist circumference was bigger in patients with obesity despite their metabolic profile comparing to patients without obesity (p0.001). Waist-to-hip ratio was similar in patients with different metabolic status. According to IR + Obesity - T2D group had intermediate position: IR was higher in that group comparing to people without obesity, but was less that in patients with obesity and HbA1c6% (p0.001). + Obesity - T2D group had the most potent baseline insulin secretion, assessed by НОМА-%band the highest postprandial secretion, measured by insulinogenic index among all patient groups with obesity (p0.001). There was no significant difference in GLP-1 secretion; GIP secretion was higher in patients with BMI30 kg/m2comparing to people with BMI30 kg/m2(p0.01).. Пациенты с ожирением без нарушений углеводного обмена представляет большой интерес для изучения механизмов, защищающих от развития сахарного диабета 2-го типа (СД 2). Цель.Проанализировать особенности гормональной секреции у лиц с ожирением без СД 2. Материалы и методы.В исследование включены 6 групп пациентов с различным метаболическим статусом (n=212): контрольная группа с индексом массы тела (ИМТ)25 кг/м2, гликированным гемоглобином (HbA1c)6%, возраст 30 лет; пациенты с ИМТ 25ИМТ30 кг/м2и HbA1c6%; пациенты с ИМТ 25ИМТ30 кг/м2и HbA1c6%; пациенты с ИМТ30 кг/м2и HbA1c6% (+ ожирение - СД) группа с ожирением без СД 2 и предиабета; пациенты с ИМТ30 кг/м2и впервые выявленным HbA1c6%; пациенты с известным СД 2 на сахароснижающих препаратах с ИМТ30 кг/м2. В ходе глюкозотолерантного теста (0, 30, 120 мин) определены инсулин, глюкозозависимый инсулинотропный полипептид 1-го типа, глюкозозависимый инсулинотропный полипептид, рассчитан показатель HOMA-IR. Результаты.Окружность талии отмечена больше у пациентов с ожирением вне зависимости от метаболических нарушений по сравнению с лицами без ожирения (p0,001). Соотношение окружностей талии и бедер не позволяло дифференцировать пациентов с разными метаболическими рисками. В группе + ожирение - СД инсулинорезистентность выше, чем у пациентов без ожирения, но ниже, чем у пациентов с ожирением и HbA1c6% (p0,001). Эта группа также имела наиболее высокие показатели базальной (НОМА-%) и стимулированной секреции инсулина (индекс инсулиногенности) среди всех пациентов с ИМТ30 кг/м2(p0,001). Секреция ГПП-1 не отличалась, секреция ГИП отмечена выше в группах с ИМТ30 кг/м2по сравнению с лицами с ИМТ30 кг/м2(p0,01). Заключение.Отличие фенотипа пациентов с ожирением без СД 2 от лиц с СД 2 заключалось в менее выраженной инсулинорезистентности и более сохранной базальной и стимулированной секреции инсулина, достаточной для поддержания нормогликемии.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Obesity

Topics: Adult; Aged; Female; Glucagon-Like Peptide 1; Hepacivirus; Hepatitis C; Humans; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged; Resistin; Severity of Illness Index

Topics: Adult; Aged; Cross-Sectional Studies; Fatty Acids, Volatile; Feces; Female; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Lipolysis; Male; Middle Aged; Young Adult

The present study investigated whether glucagon like peptide‑1 (GLP‑1) improves glucose uptake through glucose transporter type 4 (GLUT4), mediated by the activation of sirtuin 1 (SIRT1), in skeletal muscle cells with palmitate induced‑insulin resistance. The levels of glucose uptake, GLUT4, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP) were determined in human skeletal muscle myotubes (HSMMs) exposed to palmitate and GLP‑1. Then, to determine whether PKA/cAMP were downstream signals of GLP‑1, a PKA inhibitor was used. To determine whether SIRT‑1 contributes to GLP‑1 action in HSMMs with palmitate‑induced insulin resistance, the levels of peroxisome proliferator‑activated receptor γ coactivator 1α (PGC1α) deacetylation and SIRT‑1 activity were assessed using a SIRT1 inhibitor and small interfering RNA (siRNA). The phosphorylation levels of protein kinase B (Akt) and insulin receptor substrate 1 (IRS‑1) as insulin signaling pathways, were assessed in GLP‑1‑treated HSMMs exposed to palmitate. The influence of SIRT1 on the GLP‑1‑induced activation of insulin signaling pathway was determined using a SIRT1 inhibitor. GLP‑1 restored the palmitate‑induced reductions in the levels of glucose uptake, GLUT4 mRNA, GLUT4 promoter activity, and GLUT4 protein in HSMMs. PKA and cAMP, as GLP‑1 downstream signals, played a role in this process. GLP‑1 increased the deacetylation levels of PGC1α, and stimulated SIRT1 in HSMMs. Moreover, the SIRT1 inhibitor and siRNA of SIRT1 suppressed the effect of GLP‑1 on GLUT4 expression in HSMMs exposed to palmitate. The SIRT1 inhibitor also prevented the GLP‑1‑induced phosphorylation of IRS‑1 and Akt in palmitate‑treated HSMMs. The present findings suggest that in palmitate‑induced insulin‑resistant HSMM, GLP‑1 activates SIRT1 through the PKA/cAMP pathway, which in turn enhances glucose uptake through GLUT4 and the insulin signaling pathway.

Topics: Acetylation; Enzyme Activation; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Humans; Insulin Resistance; Models, Biological; Muscle, Skeletal; Palmitic Acid; Phosphorylation; Recombinant Proteins; Signal Transduction; Sirtuin 1

Insulin resistance is an independent negative predictor of outcome after elective surgery and increases mortality among surgical patients in intensive care. The incretin hormone glucagon-like peptide-1 (GLP-1) potentiates glucose-induced insulin release from the pancreas but may also increase insulin sensitivity in skeletal muscle and directly suppress hepatic glucose release. Here, we investigated whether a perioperative infusion of GLP-1 could counteract the development of insulin resistance after surgery. Pigs were randomly assigned to three groups; surgery/control, surgery/GLP-1, and sham/GLP-1. Both surgery groups underwent major abdominal surgery. Whole-body glucose disposal (WGD) and endogenous glucose release (EGR) were assessed preoperatively and postoperatively using D-[6,6-2H2]-glucose infusion in combination with hyperinsulinemic euglycemic step-clamping. In the surgery/control group, peripheral insulin sensitivity (i.e., WGD) was reduced by 44% relative to preoperative conditions, whereas the corresponding decline was only 9% for surgery/GLP-1 (P < 0.05). Hepatic insulin sensitivity (i.e., EGR) remained unchanged in the surgery/control group but was enhanced after GLP-1 infusion in both surgery and sham animals (40% and 104%, respectively, both P < 0.05). Intraoperative plasma glucose increased in surgery/control (∼20%) but remained unchanged in both groups receiving GLP-1 (P < 0.05). GLP-1 diminished an increase in postoperative glucagon levels but did not affect skeletal muscle glycogen or insulin signaling proteins after surgery. We show that GLP-1 improves intraoperative glycemic control, diminishes peripheral insulin resistance after surgery, and suppresses EGR. This study supports the use of GLP-1 to prevent development of postoperative insulin resistance.

Topics: Animals; Blood Glucose; Drug Evaluation, Preclinical; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glycogen; Incretins; Infusions, Intravenous; Insulin; Insulin Resistance; Liver; Muscle, Skeletal; Perioperative Care; Perioperative Period; Random Allocation; Surgical Procedures, Operative; Swine

The influential role of incretin hormones on glucose metabolism in patients with a history of Roux-en-Y gastric bypass (RYGB) has been investigated thoroughly, but there has been little examination of the effect of incretins and ectopic lipids on altered glucose profiles, especially severe hypoglycemia in pregnant women with RYGB.. In this prospective clinical study, an oral glucose tolerance test (OGTT), an intravenous glucose tolerance test (IVGTT), and continuous glucose monitoring (CGM) were conducted in 25 women with RYGB during pregnancy, 19 of normal weight (NW) and 19 with obesity (OB) between the 24th and the 28th weeks of pregnancy, and 3 to 6 months post-partum. Post-partum, the ectopic lipid content in the liver, heart, and skeletal muscle was analyzed using. RYGB patients presented with major fluctuations in glucose profiles, including a high occurrence of postprandial hyperglycemic spikes and hypoglycemic events during the day, as well as a high risk of hypoglycemic periods during the night (2.9 ± 1.1% vs. 0.1 ± 0.2% in the OB and vs. 0.8 ± 0.6% in the NW groups, p < 0.001). During the extended OGTT, RYGB patients presented with exaggerated expression of GLP-1, which was the main driver of the exaggerated risk of postprandial hypoglycemia in a time-lagged correlation analysis. Basal and dynamic GLP-1 levels were not related to insulin sensitivity, insulin secretion, or beta cell function and did not differ between pregnant women with and without GDM. A lower amount of liver fat (2.34 ± 5.22% vs.5.68 ± 4.42%, p = 0.015), which was positively related to insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR: rho = 0.61, p = 0.002) and beta-cell function (insulinogenic index: rho = 0.65, p = 0.001), was observed in the RYGB group after delivery in comparison to the OB group.. GLP-1 is mainly involved in the regulation of postprandial glucose metabolism and therefore especially in the development of postprandial hypoglycemia in pregnant RYGB patients, who are characterized by major alterations in glucose profiles, and thus in long-term regulation, multiple organ-related mechanisms, such as the lipid content in the liver, must be involved.

Topics: Adult; Anastomosis, Roux-en-Y; Blood Glucose; Diabetes, Gestational; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Incretins; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Lipids; Obesity; Pregnancy

The probiotic Lactobacillus gasseri SBT2055 (LG2055) has a protective effect against metabolic syndrome in rats and humans. Metabolic syndrome increases the risk of type 2 diabetes mellitus. In this study, Goto-Kakizaki rats were used as a diabetic model and fed diets containing LG2055-fermented or nonfermented skim milk for 4 wk. Indices of diabetes such as blood glucose levels, serum glucagon levels, plasma levels of insulin, C-peptide, and glucagon-like peptide-1, tissue glycogen contents, and pancreatic mRNA levels were measured. The plasma C-peptide levels and pancreatic mRNA levels of insulin genes (Ins1 and Ins2) and Pdx1 (a transcriptional factor of insulin genes) were increased in LG2055 diet-fed rats. The increase in insulin secretion corresponded to an improvement in serum and pancreatic inflammatory status, associated with decreases in serum levels of serum amyloid P and pancreatic levels of granulocyte colony-stimulating factor. Insulin resistance in Goto-Kakizaki rats was ameliorated by increased glycogen storage in the liver and quadriceps femoris muscles and decreased serum free fatty acid levels. This improvement may be related to the increased cecal production of short-chain fatty acids. In conclusion, dietary LG2055 improved insulin secretion in diabetic rats by improving the inflammatory status in the pancreas and serum.

Topics: Animals; Blood Glucose; Cecum; Diabetes Mellitus, Type 2; Diet; Fatty Acids, Volatile; Glucagon-Like Peptide 1; Glycogen; Humans; Insulin; Insulin Resistance; Insulin Secretion; Lactobacillus gasseri; Liver; Male; Muscle, Skeletal; Probiotics; Rats

Takeda G protein-coupled receptor 5 (TGR5) agonists induce systemic release of glucagon-like peptides (GLPs) from intestinal L cells, a potentially therapeutic action against metabolic diseases such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and Type 2 diabetes. Historically, TGR5 agonist use has been hindered by side effects, including inhibition of gallbladder emptying. Here, we characterize RDX8940, a novel, orally administered TGR5 agonist designed to have minimal systemic effects and investigate its activity in mice fed a Western diet, a model of NAFLD and mild insulin resistance. Agonist activity, binding selectivity, toxicity, solubility, and permeability of RDX8940 were characterized in standard in vitro models. RDX8940 pharmacokinetics and effects on GLP secretion, insulin sensitivity, and liver steatosis were assessed in C57BL/6 mice fed normal or Western diet chow and given single or repeated doses of RDX8940 or vehicle, with or without dipeptidyl peptidase-4 (DPP4) inhibitors. Gallbladder effects were assessed in CD-1 mice fed normal chow and given RDX8940 or a systemic TGR5 agonist or vehicle. Our results showed that RDX8940 is minimally systemic, potent, and selective, and induces incretin (GLP-1, GLP-2, and peptide YY) secretion. RDX8940-induced increases in plasma active GLP-1 (aGLP-1) levels were enhanced by repeated dosing and by coadministration of DPP4 inhibitors. RDX8940 increased hepatic exposure to aGLP-1 without requiring coadministration of a DPP4 inhibitor. In mice fed a Western diet, RDX8940 improved liver steatosis and insulin sensitivity. Unlike systemic TGR5 agonists, RDX8940 did not inhibit gallbladder emptying. These results indicate that RDX8940 may have therapeutic potential in patients with NAFLD/NASH. NEW & NOTEWORTHY Takeda G protein-coupled receptor 5 (TGR5) agonists have potential as a treatment for nonalcoholic steatohepatitis and nonalcoholic fatty liver disease (NAFLD) but have until now been associated with undesirable side effects associated with systemic TGR5 agonism, including blockade of gallbladder emptying. We demonstrate that RDX8940, a potent, selective, minimally systemic oral TGR5 agonist, improves liver steatosis and insulin sensitivity in a mouse model of NAFLD and does not inhibit gallbladder emptying in mice.

Topics: Animals; Diet, Western; Disease Models, Animal; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Resistance; Intestines; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Receptors, G-Protein-Coupled

Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) has launched a huge challenge to classic Roux-en-Y gastric bypass (RYGB). Our objective was to compare diabetes remission and micronutrient deficiency in a mildly obese diabetic rat model undergoing SADI-S versus RYGB.. Thirty adult male mildly obese diabetic rats were randomly assigned to sham (S), SADI-S, and RYGB groups. Body weight, food intake, fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), plasma insulin, GLP-1, and ghrelin levels were measured at indicated time points. Meanwhile, insulin sensitivity and pancreatic β cell function were assessed during OGTT. Finally, plasma micronutrient evaluation and islet β cell mass analysis were performed after all animals were sacrificed.. As compared to sham, the SADI-S and RYGB groups achieved almost equivalent efficacy in caloric restriction and FPG control without excessive weight loss. During OGTT, the SADI-S and RYGB groups also provided comparable effects on glycemic excursion, insulin sensitivity, and β cell function; however, only rats in the RYGB group showed significant changes in gut hormones, whereas the three groups were found to exhibit no significant difference in β cell mass. In addition, only vitamin E in the RYGB group was deficient as compared with the SADI-S and S groups.. In mildly obese diabetic rat, SADI-S and RYGB procedures have comparable efficacy in diabetes remission and risk of micronutrient deficiency. These data show that each of the surgery accomplishes diabetes improvements through both overlapping and distinct mechanisms requiring further investigation.

Topics: Anastomosis, Surgical; Animals; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenum; Eating; Gastrectomy; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose Tolerance Test; Ileum; Insulin Resistance; Insulin-Secreting Cells; Male; Micronutrients; Obesity; Random Allocation; Rats; Rats, Wistar; Remission Induction; Weight Loss

Macronutrient regulation of hyperphagia and adiposity in Prader-Willi syndrome (PWS) is poorly understood. We compared fasting and postprandial concentrations of hormones and metabolites in eight PWS children (age 9-18 years) fed, in random order, low carbohydrate, high-fat (LC, 15% carb; 65% fat; 20% protein) and low-fat, high carbohydrate (LF, 65% carb, 15% fat, 20% protein) diets matched for calories and protein.. Participants were randomized to consume either the LC or LF diet during a first hospital admission and the second diet during a subsequent admission. Blood samples were obtained after overnight fasting and 1 hour after a mixed meal.. Relative to subjects consuming the LF diet, subjects consuming the LC diet had: lower postprandial insulin concentrations (P = 0.02); higher fasting GLP-1 AND GIP concentrations and increased postprandial GLP-1 (P < 0.02); reduced ratio of fasting ghrelin to GLP-1 (P = 0.0078); increased FFA and fatty acid oxidation, as assessed by concentrations of even-chain acylcarnitines (P < 0.001); lower fasting TG and TG/HDL ratio (P < 0.01); and higher concentrations of branch chain amino acids (P < 0.01). There were no changes in glucose, PYY, or adiponectin. CRP, AST and ALT were all higher (P < 0.01) on the LC diet.. Increases in GLP-1 with low carbohydrate feeding and reductions in the ratio of ghrelin to GLP-1 might limit food intake and improve glycaemic control in PWS. Other potential benefits of carbohydrate restriction may include fat mobilization and oxidation and reductions in the TG/HDL ratio, a marker of insulin resistance. However, increases in CRP, AST and ALT necessitate longer-term studies of low carbohydrate efficacy and safety.

Topics: Adiposity; Adolescent; Amino Acids; Blood Glucose; Child; Fasting; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Peptide YY; Prader-Willi Syndrome

Gastric bypass with a proximal gastric pouch (Roux-en-Y gastric bypass) induces early diabetes remission. The effect of gastric bypass with a distal gastric pouch remains unknown.. To observe the effect on glucose tolerance and diabetes remission of gastric bypass with a distal gastric pouch.. A type 2 diabetes (T2D) model was created in 44 Sprague-Dawley (SD) rats that randomly underwent Roux-en-Y gastric bypass (RYGB, n = 8); gastric bypass with duodenal-jejunal transit (GB-DJT, n = 8); distal-pouch gastric bypass with duodenal-jejunal transit (DPGB-DJT, n = 8); distal-pouch gastric bypass with duodenal-jejunal bypass (DPGB-DJB, n = 8); sham (n = 6); and Roux-en-Y gastric bypass with esophageal re-anastomosis (RYGB-Er, n = 6) surgery. In the DPGB-DJT and the DPGB-DJB groups, the gastric pouch was created in the distal stomach. In the RYGB and the GB-DJT groups, the gastric pouch was created in the proximal stomach. An oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and mixed-meal tolerance test (MMTT) conducted preoperatively were repeated postoperatively.. GLP-1 AUC recorded preoperatively was significantly increased 8 weeks postoperatively in the RYGB, GB-DJT, and DPGB-DJB groups. Increased GLP-1 AUC in the DPGB-DJT did not reach statistical significance. Improved glucose tolerance in the RYGB and GB-DJT groups was significantly higher than DPGB-DJT group. DPGB-DJB did not improve glucose tolerance significantly. Gastrin level was increased significantly in the DPGB-DJT and DPGB-DJB groups.. In gastric bypass, creating the gastric pouch in the distal region of the stomach significantly impairs the glucose tolerance and diabetes remission in spite of the increased GLP-1 and insulin responses in T2D SD rat model, suggesting that bypassing the distal stomach may be the key mediator of early diabetes remission after RYGB.

Topics: Analysis of Variance; Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Insulin Resistance; Male; Obesity, Morbid; Rats; Rats, Sprague-Dawley; Remission Induction

Glucagon-like peptide-1 (GLP-1) an incretin hormone, is known to regulate the glucose-mediated insulin secretion. However, reduction in the level of GLP-1 is considered to be a major cause for the reduction of GLP-1-dependent insulin secretory response. Genistein an isoflavone, is an important polyphenol and has wide range of therapeutic potentials, but its therapeutic effects alone and/or in combination with metformin on GLP-1 secretion have not been investigated yet. Hence, we aimed to investigate the stimulatory action of genistein in combination with metformin on GLP-1 via downregulation of inflammatory mediators, hyperlipidemia and hyperglycemia in alloxan-induced diabetic rats. Diabetes was induced in experimental rats by single administration of alloxan intraperitoneally. Metformin (50 mg/kg/day), genistein (20 mg/kg/day) and combination of genistein and metformin was administered in alloxan-induced diabetic rats. We found that genistein alone and/or in combination with metformin significantly increased the serum level (P < 0.01) and tissue content (P < 0.05) of GLP-1 in intestine when compared with that of metformin-treated animals. Similarly, genistein alone and/or in combination with metformin also resulted in normoglycemia (P < 0.001), glucose tolerance (P < 0.01), insulin sensitivity (P < 0.0001), hyperlipidemia (P < 0.01), liver and kidney function biomarkers (P < 0.01) as compared to that of metformin-treated experimental animals. Moreover, genistein alone and/or in combination with metformin also downregulated the inflammatory responses by decreasing the levels of interleuin-6, tumor necrosis factor-α and C-reactive protein in serum (P < 0.05) and intestine (P < 0.001) more efficiently as compared to that of metformin-treated experimental animals. The downregulation of inflammatory responses in intestine, was positively associated with increased secretion of GLP-1 from intestine. Histopathology of pancreas and intestine also showed that genistein significantly improved the deleterious effects of alloxan on pancreas and intestine. Hence, our work provides new insights on the synergistic effects of genistein and metformin on GLP-1 secretion. This may significantly improve the perception for proposing new GLP-1-based synergistic approaches for the treatment of diabetes mellitus.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Down-Regulation; Genistein; Glucagon-Like Peptide 1; Hypoglycemic Agents; Inflammation Mediators; Insulin Resistance; Rats

GH and IGF-1 are crucial for attainment of normal body size and regulation of food intake, nutrient storage, and insulin sensitivity. Enteroendocrine connections exist between the GH-IGF-1 axis and insulin, ghrelin, and glucagon-like peptide 1 (GLP-1). The status of these connections in GH deficiency (GHD) is unknown.. To study the enteroendocrine connections before and after a standard meal test in a homogeneous population of adults with congenital untreated isolated GHD (IGHD) due to a mutation in the GHRH receptor gene.. In a cross-sectional study of 20 individuals with IGHD and 20 control subjects, we measured glucose, insulin, ghrelin, and GLP-1 before and 30, 60, 120, and 180 minutes after a standardized test meal. Homeostasis model assessment index of insulin resistance (HOMA-IR) and homeostasis model assessment (HOMA)-β were calculated. Participants scored feelings of hunger, fullness, and prospective food consumption on a visual analog scale.. Area under the curve (AUC) values of glucose, insulin, ghrelin, GLP-1, hunger, fullness, and prospective food consumption.. Fasting HOMA-IR and HOMA-β were lower in individuals with IGHD than in control subjects (P = 0.002 and P = 0.023, respectively). AUC was higher for hunger (P < 0.0001), glucose (P = 0.0157), ghrelin (P < 0.0001), and GLP-1 (P < 0.0001) and smaller for fullness (P < 0.0001) in individuals with IGHD compared with control subjects. There was no difference in AUC for prospective food consumption or insulin.. Untreated IGHD is associated with increased GLP-1 secretion and reduced postprandial ghrelin and hunger attenuation in response to a mixed meal. These enteroendocrine connections can result in a favorable outcome in terms of environmental adaptation and guaranteeing appropriate food intake and can confer metabolic benefits.

Topics: Adult; Area Under Curve; Blood Glucose; Case-Control Studies; Dwarfism, Pituitary; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Hunger; Insulin; Insulin Resistance; Male; Middle Aged; Mutation; Postprandial Period; Receptors, LHRH; Satiety Response

Bariatric surgery is associated with significant and sustained weight loss and improved metabolic outcomes. It is unclear if weight loss alone is the main mechanism of improved metabolic health. The purpose of this trial was to compare indices of appetite regulation, insulin sensitivity and energy intake (EI) between participants achieving 10 kg of weight loss via Roux-en-Y Gastric Bypass (RYGB) or dietary restriction (DIET); intake of a very low calorie liquid diet (800 kcal/d; 40% protein, 40% fat, 20% carbohydrate that matched the post-RYGB dietary protocol). Adults qualifying for bariatric surgery were studied before and after 10 kg of weight loss (RYGB [n = 6]) or DIET [n = 17]). Appetite (hunger, satiety, and prospective food consumption [PFC]), appetite-related hormones, and metabolites (ghrelin, PYY, GLP-1, insulin, glucose, free fatty acids [FFA], and triglycerides [TG]) were measured in the fasting state and every 30 min for 180 min following breakfast. Participants were provided lunch to evaluate acute ad libitum EI, which was similarly reduced in both groups from pre to post weight loss. Fasting ghrelin was reduced to a greater extent following RYGB compared to DIET (P = 0.04). Area under the curve (AUC) for ghrelin (P = 0.01), hunger (P < 0.01) and PFC (P < 0.01) increased after DIET compared to RYGB, following 10 kg weight loss. Satiety AUC increased after RYGB and decreased after DIET (P < 0.01). Glucose and insulin (fasting and AUC) decreased in both groups. FFA increased in both groups, with a greater increase in AUC seen after RYGB versus DIET (P = 0.02). In summary, appetite-related indices were altered in a manner that, if maintained, may promote a sustained reduction in energy intake with RYGB compared to DIET. Future work with a larger sample size and longer follow-up will be important to confirm and extend these findings.

Topics: Adult; Appetite; Appetite Regulation; Blood Glucose; Body Mass Index; Diet, Reducing; Energy Intake; Female; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Satiation; Weight Loss

Impaired insulin sensitivity (IS) and β-cell dysfunction result in hyperglycaemia in patients of acromegaly. However, alterations in incretins and their impact on glucose-insulin homeostasis in these patients still remain elusive. Twenty patients of active acromegaly (10 each, with and without diabetes) underwent hyperinsulinemic euglycaemic clamp and mixed meal test, before and after surgery, to measure indices of IS, β-cell function, GIP, GLP-1 and glucagon response. Immunohistochemistry (IHC) for GIP and GLP-1 was also done on intestinal biopsies of all acromegalics and healthy controls. Patients of acromegaly, irrespective of presence or absence of hyperglycaemia, had similar degree of insulin resistance, however patients with diabetes exhibited hyperglucagonemia, and compromised β-cell function despite significantly higher GIP levels. After surgery, indices of IS improved, GIP and glucagon levels decreased significantly in both the groups, while there was no significant change in indices of β-cell function in those with hyperglycaemia. IHC positivity for GIP, but not GLP-1, staining cells in duodenum and colon was significantly lower in acromegalics with diabetes as compared to healthy controls possibly because of high K-cell turnover. Chronic GH excess induces an equipoise insulin resistance in patients of acromegaly irrespective of their glycaemic status. Dysglycaemia in these patients is an outcome of β-cell dysfunction consequent to GIP resistance and hyperglucagonemia.

Topics: Acromegaly; Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Prospective Studies; Receptors, Gastrointestinal Hormone

Type 2 diabetes (T2DM) associated with non-alcoholic fatty liver disease (NAFLD) increases cardiovascular risk. Complex and subtle connections are established between hepatic dysfunction and adipose tissue hyperactivity. This relationship is mediated by insulin resistance, dyslipidemia and inflammation. Recently incretins have been involved in this connection including GLP-1 (glucagon-like peptide-1). The aim of this study is to establish interactions between the GLP-1 plasma levels and metabolic syndrome clusters and adipocytokines profile (leptin, adiponectin, resistin, TNFα and IL-6) in diabetic subjects with or without NAFLD. The study was undertaken on 320 adult subjects divided into four groups: NAFLD, DT2, NAFLD+DT2 and control. In all subjects, the metabolic syndrome clusters was investigated according to the NCEP/ATPIII criteria. Insulin resistance was evaluated by the Homa-IR model. The metabolic parameters were determined on Cobas® automated biochemical analysis. The adipocytokines are determined by immunoassay method on Elisa human reader - Biotek ELX 800. The NAFLD has been confirmed by abdominal ultrasound and by histology. Feeding and fasting plasma GLP-1 was assessed by Elisa method. The data revealed that insulin resistance (Homa-IR) is present in all groups. Homa-IR is negatively associated with plasma GLP-1 depletion in the NAFLD, DT2 and NAFLD+DT2 groups. Adiponectin levels are decreased in all groups as for GLP-1. At the opposite, leptin, resistin, TNFα and IL-6 levels show an inverse correlation with GLP-1. This study suggests that plasma GLP-1 can be considered as a transition and evolution biomarker between NAFLD and T2D. GLP-1 accurately reflects metabolic and inflammatory status, both in subjects with NAFLD only or with T2D only, before the diabetes - steatosis stage.

Topics: Adipokines; Adult; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Incretins; Insulin Resistance; Liver; Male; Metabolic Networks and Pathways; Metabolic Syndrome; Middle Aged; Non-alcoholic Fatty Liver Disease

BACKGROUND Nowadays, more than 170 million patients suffer from diabetes mellitus worldwide. This study aimed to investigate the effects of sleeve gastrectomy (SG) and ileal transposition (IT) surgery on the control of diabetes. MATERIAL AND METHODS Goto-Kakizaki rats were used to establish type 2 diabetes models and undergo SG or IT surgery. At 2 months post-surgery, insulin, glucose, triglycerides (TG), total cholesterol (TC), glucose tolerance, glucagon-like peptide-1 (GLP-1) levels, and insulin sensitivity were evaluated. RESULTS SG significantly shortened operative time and post-operative recovery time compared to IT surgery (P<0.05). SG and IT surgery resulted in significantly induced weight loss, significantly decreased levels of glucose, and significantly enhanced levels of Ghrelin compared the Sham surgery group (P<0.001). SG and IT surgery resulted in significantly increased GLP-1 levels compared to Sham surgery (P<0.001). SG resulted in better reduction of oral glucose tolerance test (OGTT) glucose compared to IT surgery (P<0.05). SG and IT surgery significantly upregulated insulin tolerance test (ITT) levels compared to Sham surgery (P<0.001). SG induced better reductions in TC and TG compared to IT surgery (P<0.05). CONCLUSIONS In non-obese rats with spontaneous diabetes, both SG and IT surgery were found to control diabetes by regulating body weight and levels of glucose, Ghrelin, GLP-1, OGTT glucose, insulin, TC, and TG. Moreover, SG demonstrated advantages of shorter operative time, shorter post-operative recovery time, and better control of diabetes compared to IT surgery.

Topics: Anastomosis, Surgical; Animals; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Ileum; Insulin; Insulin Resistance; Male; Rats; Rats, Inbred Strains; Weight Loss

Exenatide (Exe) is a glucagon-like peptide (GLP)-1 receptor agonist that enhances insulin secretion and is associated with induction of satiety with weight loss. As mitochondrial dysfunction and lipotoxicity are central features of nonalcoholic steatohepatitis (NASH), we tested whether Exe improved mitochondrial function in this setting. We studied C57BL/6J mice fed for 24 weeks either a control- or high-fructose, high-trans-fat (TFD)-diet (i.e., a NASH model previously validated by our laboratory). For the final 8 weeks, mice were treated with Exe (30 µg/kg/day) or vehicle. Mitochondrial metabolism was assessed by infusion of [13C3]propionate, [3,4-13C2]glucose and NMR-based 13C-isotopomer analysis. Exenatide significantly decreased fasting plasma glucose, free fatty acids and triglycerides, as well as adipose tissue insulin resistance. Moreover, Exe reduced 23% hepatic glucose production, 15% tri-carboxylic acid (TCA) cycle flux, 20% anaplerosis and 17% pyruvate cycling resulting in a significant 31% decrease in intrahepatic triglyceride content (P = 0.02). Exenatide improved the lipidomic profile and decreased hepatic lipid byproducts associated with insulin resistance and lipotoxicity, such as diacylglycerols (TFD: 111 ± 13 vs Exe: 64 ± 13 µmol/g protein, P = 0.03) and ceramides (TFD: 1.6 ± 0.1 vs Exe: 1.3 ± 0.1 µmol/g protein, P = 0.03). Exenatide lowered expression of hepatic lipogenic genes (Srebp1C, Cd36) and genes involved in inflammation and fibrosis (Tnfa, Timp1). In conclusion, in a diet-induced mouse model of NASH, Exe ameliorates mitochondrial TCA cycle flux and significantly decreases insulin resistance, steatosis and hepatocyte lipotoxicity. This may have significant clinical implications to the potential mechanism of action of GLP-1 receptor agonists in patients with NASH. Future studies should elucidate the relative contribution of direct vs indirect mechanisms at play.

Topics: Adipose Tissue; Animals; Blood Glucose; Citric Acid Cycle; Diet, High-Fat; Exenatide; Fatty Acids, Nonesterified; Fibrosis; Gene Expression Profiling; Glucagon-Like Peptide 1; Hepatocytes; Hypoglycemic Agents; Inflammation; Insulin Resistance; Lipid Metabolism; Lipidomics; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria; Non-alcoholic Fatty Liver Disease; Triglycerides

Alzheimer's disease (AD) is a multifactorial condition in which, along with amyloid-β (Aβ) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Aβ and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances.

Topics: Alzheimer Disease; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Disease Models, Animal; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Neuroimmunomodulation; Neuronal Plasticity; Neuroprotective Agents; Signal Transduction

New-onset diabetes frequently resolves after pancreaticoduodenectomy (PD). Glucagon-like peptide-1 (GLP-1) conceivably is involved as its release is enhanced by rapid gastric emptying and distal bowel exposure to nutrients. We aimed at studying factors associated with GLP-1 release after PD.. Fifteen PD subjects with distal gastrectomy (Whipple) and 15 with pylorus preservation were evaluated. A test meal containing 1 g paracetamol to measure gastric emptying was ingested. Blood for the measurement of paracetamol, glucose, insulin, and GLP-1 was drawn at baseline and 10, 20, 30, 60, 90, 120, 150, and 180 minutes thereafter. The Matsuda index of insulin sensitivity was calculated.. In univariate analysis, gastric emptying correlated with GLP-1. Glucagon-like peptide-1 responses to the modes of operation did not differ. Multiple regression analysis confirmed gastric emptying and Whipple versus pylorus-preserving pancreaticoduodenectomy as independent predictors of GLP-1 release. The Matsuda index of insulin sensitivity correlated with GLP-1 concentrations and inversely with body mass index. Patients after Whipple procedure revealed lower glycated hemoglobin as compared with pylorus-preserving pancreaticoduodenectomy.. Following PD, the postprandial GLP-1 release seems to be enhanced by rapid gastric emptying and to improve insulin sensitivity. Partial gastrectomy versus pylorus preservation enhanced the release of GLP-1, conceivably because of greater distal bowel exposure to undigested nutrients.

Topics: Adult; Aged; Blood Glucose; Female; Gastrectomy; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Pancreaticoduodenectomy; Postprandial Period; Young Adult

Diabetes is a chronic metabolic disease characterized by elevated blood glucose levels due to insulin resistance and β-cell dysfunction. This study aims to examine the effects of polysaccharides from adlay seeds (PAS) on hyperglycemia and gut microbiota in streptozocin (STZ)-induced diabetic mice. The administration of PAS in diabetic mice caused a significant decrease in the glucose level and serum levels of glycosylated hemoglobin (HbA1c). Similarly, PAS also showed decreased total cholesterol (TC) and triglyceride (TG) concentrations. Furthermore, a significant increase in the concentrations of glucagon-like peptide 1 (GLP-1) was observed. Unexpectedly, PAS reduced the concentrations of anti-amyloid beta (Aβ1-42) protein. Also, histopathological examination showed that PAS contributed to the reduction of STZ-lesioned pancreatic cells. Metformin treatment significantly reduced the diversity of the gut microbiota, while PAS treatment altered the diversity and composition of the microbiota. Collectively, our findings demonstrate that the hypoglycemic effects of PAS in type-2 diabetic mice (T2D) may be associated with the regulation of the intestinal microbiota and its metabolic pathways.

Topics: Amyloid beta-Peptides; Animals; Cholesterol; Coix; Diabetes Mellitus, Experimental; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred ICR; Pancreas; Peptide Fragments; Polysaccharides; RNA, Ribosomal, 16S; Seeds; Streptozocin; Triglycerides

The decrease in incretin effects is an important etiologic component of type 2 diabetes with unknown mechanisms. In an attempt to understand obesity-induced changes in liver oxygen homeostasis, we found that liver HIF-1α expression was increased mainly by soluble factors released from obese adipocytes, leading to decreased incretin effects. Deletion of hepatocyte HIF-1α protected obesity-induced glucose intolerance without changes in body weight, liver steatosis, or insulin resistance. In-depth mouse metabolic phenotyping revealed that obesity increased first-pass degradation of an incretin hormone GLP-1 with increased liver DPP4 expression and decreased sinusoidal blood flow rate, reducing active GLP-1 levels in peripheral circulation. Hepatocyte HIF-1α KO blocked these changes induced by obesity. Deletion of hepatocyte HIF-2α did not change liver DPP4 expression but improved hepatic steatosis. Our results identify a previously unknown pathway for obesity-induced impaired beta cell glucose response (incretin effects) and the development of glucose intolerance through inter-organ communications.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Transcription Factors; Diet, High-Fat; Dipeptidyl Peptidase 4; Fatty Liver; Glucagon-Like Peptide 1; Glucose; Hepatitis; Hepatocytes; Insulin Resistance; Liver; Male; Mice, Knockout; Obesity

TGR5 plays an important role in many physiological processes. However, the functions of TGR5 in the regulation of the glucose metabolism and insulin sensitivity in the skeletal muscles have not been fully elucidated. We synthesized MN6 as a potent and selective TGR5 agonist. Here, the effect of MN6 on insulin resistance in skeletal muscles was evaluated in diet-induced obese (DIO) mice and C2C12 myotubes, and the underlying mechanisms were explored.. The activation of MN6 on human and mouse TGR5 was evaluated by a cAMP assay in HEK293 cell lines stable expressing hTGR5/CRE or mTGR5/CRE cells. GLP-1 secretion was measured in NCI-H716 cells and CD1 mice. The acute and chronic effects of MN6 on regulating metabolic abnormalities were observed in ob/ob and DIO mice. 2-deoxyglucose uptake was examined in isolated skeletal muscles. Akt phosphorylation, glucose uptake and glycogen synthesis were examined to assess the effects of MN6 on palmitate-induced insulin resistance in C2C12 myotubes.. Our study identified that a TGR5 agonist could ameliorate insulin resistance by the cAMP/PKA pathway in skeletal muscles; this uncovered a new effect of the TGR5 agonist on regulating the glucose metabolism and insulin sensitivity in skeletal muscles and further strengthened its potential value for the treatment of type 2 diabetes.

Topics: Animals; Cyclopropanes; Diabetes Mellitus, Experimental; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; HEK293 Cells; Homeostasis; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Fibers, Skeletal; Muscle, Skeletal; Pyridines; Quinoxalines; Receptors, G-Protein-Coupled

A previous genome-wide association study linked overexpression of an ATP-binding cassette transporter, ABCC5, in humans with a susceptibility to developing type 2 diabetes with age. Specifically, ABCC5 gene overexpression was shown to be strongly associated with increased visceral fat mass and reduced peripheral insulin sensitivity. Currently, the role of ABCC5 in diabetes and obesity is unknown. This study reports the metabolic phenotyping of a global Abcc5 knockout mouse.. Abcc5. ABCC5 protein expression levels are inversely related to fat mass and appear to play a role in the regulation of GLP-1 secretion from enteroendocrine cells.

Topics: Adipose Tissue; Animals; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Insulin; Insulin Resistance; Male; Mice; Mice, Knockout; Multidrug Resistance-Associated Proteins

The gastric mucosa is an endocrine organ that regulates satiation pathways by expression of orexigenic and anorexigenic hormones. Vertical sleeve gastrectomy (VSG) excludes gastric mucosa and reduces gastric volume. Our study aimed to investigate the independent effects of altering gastric mucosa on obesity and its related comorbidities.. Gastric mucosa devitalization (GMD) of 70% of the stomach was achieved by argon plasma coagulation in a high-fat diet rat model and was compared with VSG and sham surgery. In an 8-week follow-up study, we quantified body weight, visceral adiposity, insulin resistance index, cholesterol profiles, and free fatty acid profiles by enzyme-linked immunosorbent assay (ELISA). Following a 2-hour oral glucose tolerance test, the kinetics of ghrelin, glucagon-like peptide-1, peptide YY, and serum and liver bile acid levels were measured. Liver lipid content was quantified by ELISA.. GMD resulted in significant reductions in body weight, visceral and subcutaneous adipose tissue, and hepatic steatosis as well as an improvement in lipid metabolism. GMD resulted in significant reductions in food intake and intestinal malabsorption of free fatty acids, both contributing to improved body composition and metabolic profile. Mechanistically, GMD resulted in a significant reduction in serum palmitate levels as well as an increase in serum and liver bile acid levels, known to alter glucose and lipid metabolism. Similar changes were noted when VSG rats were compared with sham surgery rats.. Devitalization of gastric mucosa, independent of altering gastric volume, was able to reduce obesity-related comorbidities. The gastric mucosa may be a potential target for treating obesity and its associated comorbidities.

Topics: Adiposity; Animals; Argon Plasma Coagulation; Bile Acids and Salts; Blood Glucose; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Nonesterified; Gastrectomy; Gastric Mucosa; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Lipid Metabolism; Liver; Male; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Stomach; Triglycerides

To investigate the role of glucagon-like peptide-1 analog (GLP-1) in high-fat diet-induced obesity-related glomerulopathy (ORG). Male C57BL/6 mice fed a high-fat diet for 12 wk were treated with GLP-1 (200 μg/kg) or 0.9% saline for 4 wk. Fasting blood glucose and insulin and the expression of podocin, nephrin, phosphoinositide 3-kinase (PI3K), glucose transporter type (Glut4), and microtubule-associated protein 1A/1B-light chain 3 (LC3) were assayed. Glomerular morphology and podocyte foot structure were evaluated by periodic acid-Schiff staining and electron microscopy. Podocytes were treated with 150 nM GLP-1 and incubated with 400 μM palmitic acid (PA) for 12 h. The effect on autophagy was assessed by podocyte-specific Glut4 siRNA. Insulin resistance and autophagy were assayed by immunofluorescence and Western blotting. The high-fat diet resulted in weight gain, ectopic glomerular lipid accumulation, increased insulin resistance, and fusion of podophyte foot processes. The decreased translocation of Glut4 to the plasma membrane and excess autophagy seen in mice fed a high-fat diet and in PA-treated cultured podocytes were attenuated by GLP-1. Podocyte-specific Glut4 siRNA promoted autophagy, and rapamycin-enhanced autophagy worsened the podocyte injury caused by PA. Excess autophagy in podocytes was induced by inhibition of Glut4 translocation to the plasma membrane and was involved in the pathology of ORG. GLP-1 restored insulin sensitivity and ameliorated renal injury by decreasing the level of autophagy.

Topics: Animals; Autophagy; Blood Glucose; Cell Line; Cytoprotection; Diet, High-Fat; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Insulin; Insulin Resistance; Kidney Diseases; Male; Mice, Inbred C57BL; Obesity; Palmitic Acid; Podocytes; Protein Transport; Signal Transduction; Sirolimus

Loss of glucose homeostasis during sepsis is associated with increased organ dysfunction and higher mortality. Novel therapeutic strategies to promote euglycemia in sepsis are needed. We have previously shown that early low-level intravenous (IV) dextrose suppresses pancreatic insulin secretion and induces insulin resistance in septic mice, resulting in profound hyperglycemia and worsened systemic inflammation. In this study, we hypothesized that administration of low-level dextrose via the enteral route would stimulate intestinal incretin hormone production, potentiate insulin secretion in a glucose-dependent manner, and thereby improve glycemic control in the acute phase of sepsis. We administered IV or enteral dextrose to 10-week-old male C57BL/6J mice exposed to bacterial endotoxin and measured incretin hormone release, glucose disposal, and proinflammatory cytokine production. Compared with IV administration, enteral dextrose increased circulating levels of the incretin hormone glucose-dependent insulinotropic peptide (GIP) associated with increased insulin release and insulin sensitivity, improved mean arterial pressure, and decreased proinflammatory cytokines in endotoxemic mice. Exogenous GIP rescued glucose metabolism, improved blood pressure, and increased insulin release in endotoxemic mice receiving IV dextrose, whereas pharmacologic inhibition of GIP signaling abrogated the beneficial effects of enteral dextrose. Thus, stimulation of endogenous GIP secretion by early enteral dextrose maintains glucose homeostasis and attenuates the systemic inflammatory response in endotoxemic mice and may provide a therapeutic target for improving glycemic control and clinical outcomes in patients with sepsis.

Topics: Animals; Endotoxemia; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Homeostasis; Incretins; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL

There is an ongoing debate on which procedure provides the best treatment for type 2 diabetes. Furthermore, the pathomechanisms of diabetes improvement of partly anatomically differing operations is not fully understood.. A loop duodenojejunostomy (DJOS) with exclusion of one third of intestinal length, a sleeve gastrectomy (SG), or a combination of DJOS + SG was performed in 8-week-old male ZDF rats. One, three, and six months after surgery, an oral glucose tolerance test and measurements of GLP-1, GIP, insulin, and bile acids were conducted.. After an initial (4 weeks) equal glucose control, DJOS and DJOS + SG showed significantly lower glucose levels than SG 3 and 6 months after surgery. There was sharp decline of insulin levels in SG animals over time, whereas insulin levels in DJOS and DJOS + SG were preserved. GIP levels were significantly larger in both groups containing a sleeve at all three time points, whereas GLP-1 was equal in all groups at all time. Bile acid levels were significantly higher in the DJOS compared to the SG group at all time points. Interestingly, the additional SG in the DJOS + SG group led to lower bile acid levels 1 and 6 months postoperatively.. The effect of SG on glucose control was transient, whereas a duodenal exclusion was the more effective procedure in this model due to a sustained pancreatic function with a preserved insulin secretion.

Topics: Anastomosis, Surgical; Animals; Bariatric Surgery; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenum; Gastrectomy; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Jejunum; Male; Obesity, Morbid; Rats; Rats, Zucker

Background Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic β-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, β-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance. Methods In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and β-cell insulin secretion functions. Results Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls ( p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or β-cell function (r = 0.50, p = 0.07). Discussion Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal β-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in mig

Topics: Adult; Blood Glucose; Chronic Disease; Cross-Sectional Studies; Female; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Insulin Resistance; Migraine Disorders; Neuropeptide Y

In this study, gamma-aminobutyric acid (GABA) enriched rice bran (ERB) was supplemented to obese rats to investigate the attenuation of metabolic syndromes induced by high-fat diet. ERB-containing diet stimulated butyrate and propionate production by promoting Anaerostipes, Anaerostipes sp., and associated synthesizing enzymes. This altered short-chain fatty acid (SCFA) distribution further enhanced circulatory levels of leptin and glucagon-like peptide-1, controlling food intake by downregulating orexigenic factors. Together with the enhanced fatty acid β-oxidation highlighted by Prkaa2, Ppara, and Scd1 expression via AMPK signaling pathway and nonalcoholic fatty liver disease pathway, energy expenditure was positively modulated. Serum lipid compositions showed ERB supplement exhibited a more efficient effect on lowering serum sphingolipids, which was closely associated with the status of insulin resistance. Consistently, genes of Ppp2r3b and Prkcg, involved in the function of ceramides in blocking insulin action, were also downregulated following ERB intervention. Enriched GABA and phenolic acids were supposed to be responsible for the health-beneficial effects.

Topics: Adipose Tissue; Animals; Ceramides; Diet; Diet, High-Fat; DNA; Energy Metabolism; Fatty Acids, Volatile; Food, Fortified; gamma-Aminobutyric Acid; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Insulin Resistance; Leptin; Liver; Male; Metabolic Syndrome; Obesity; Oryza; Rats; Rats, Sprague-Dawley; Seeds; Sphingolipids

Weight loss (WL) and altered gut hormonal levels are involved in glucose homeostasis after laparoscopic sleeve gastrectomy (LSG).. The aim of this study was to evaluate the time-related effects of WL, ghrelin, and glucacon-like peptide-1 (GLP-1) plasma concentrations on type 2 diabetes resolution after LSG.. University hospital, Italy.. Ninety-one patients who underwent LSG were investigated. Insulin secretion (insulinogenic index [IGI]), insulin resistance, plasma glucose level and percentage glycated hemoglobin using the oral glucose tolerance test were assessed before surgery, on postoperative day 3, and then at 6, 12, 24, and 36 months after LSG. At the same time points, WL, ghrelin, and GLP-1 levels were determined.. During follow-up, the resolution rate of type 2 diabetes was 9.4%, 42.3%, 71.8%, 81.2%, and 91.8%, respectively. Ghrelin plasma concentrations decreased significantly after LSG (271.5 ± 24.5 pg/mL versus 122.4 ± 23.4 pg/mL, P = .04). GLP-1 plasma concentrations increased significantly after LSG (1.7 ± 2.6 pg/mL versus 2.5 ± 3.4 pg/mL, P = .04). The percentage of excess weight loss and IGI presented a positive linear correlation (r) at all follow-up time points with a strong positive correlation at 12 and 24 months. A strong negative correlation between ghrelin and IGI was recorded during the first 3 days after LSG (r = -.9). GLP-1 and IGI presented a strong positive correlation at day 3 and 6 months (i.e., .8 and .8, respectively).. LSG may affect glucose homeostasis by 2 different time-related modes: a first step in which the hormonal changes play a predominant role in glucose homeostasis and a second step in which the percentage excess weight loss determines the metabolic results.

Topics: Adult; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Insulin Secretion; Laparoscopy; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Weight Loss; Young Adult

Three-dimensional (3D) pseudoislets (PIs) can be used for the study of insulin-producing β-cells in free-floating islet-like structures similar to that of primary islets. Previously, we demonstrated the ability of islet-derived endothelial cells (iECs) to induce PIs using murine insulinomas, where PI formation enhanced insulin production and glucose responsiveness. In this report, we examined the ability of iECs to spontaneously induce the formation of free-floating 3D PIs using the EndoC-βH1 human β-cell line murine MS1 iEC. Within 14 days, the coculturing of both cell types produced fully humanized EndoC-βH1 PIs with little to no contaminating murine iECs. The size and shape of these PIs were similar to primary human islets. iEC-induced PIs demonstrated reduced dysregulated insulin release under low glucose levels and higher insulin secretion in response to high glucose and exendin-4 [a glucagon-like peptide-1 (GLP-1) analog] compared with monolayer cells cultured alone. Interestingly, iEC-PIs were also better at glucose sensing in the presence of extendin-4 compared with PIs generated on a low-adhesion surface plate in the absence of iECs and showed an overall improvement in cell viability. iEC-induced PIs exhibited increased expression of key genes involved in glucose transport, glucose sensing, β-cell differentiation, and insulin processing, with a concomitant decrease in glucagon mRNA expression. The enhanced responsiveness to exendin-4 was associated with increased protein expression of GLP-1 receptor and phosphokinase A. This rapid coculture system provides an unlimited number of human PIs with improved insulin secretion and GLP-1 responsiveness for the study of β-cell biology.

Topics: Cells, Cultured; Coculture Techniques; Endothelial Cells; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Signal Transduction

Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent an important class of glucose-lowering drug for type 2 diabetes. DPP-4 enzyme activity has been observed to be significantly altered in type 2 diabetes. Here, the role of DPP-4 was examined in a high fat fed (HFF) mouse model of insulin resistance. HFF mice had an increased bodyweight (p < .01), were hyperglycaemic (p < .01) and hyperinsulinaemic (p < .05). Compared to normal diet, HFF mice exhibited increased plasma DPP-4 activity (p < .01). Tissue distribution patterns in lean and HFF mice demonstrated highest levels of DPP-4 activity in lung (20-26 μmol/min/mg protein) and small intestine (13-14 μmol/min/mg protein), and lowest activity in the spleen (3.8 μmol/min/mg protein). Modulation of DPP-4 activity by high fat feeding was observed in several tissues with increases in the lung (p < .05), liver (p < .05), kidney (p < .05) and pancreas (p < .05). With a high fat diet, DPP-4 gene expression was upregulated in the liver (p < .001) and downregulated in the pancreas (p < 0.001) and small intestine (p < .001). Immunohistochemical analysis revealed increased DPP-4 immunostaining localised primarily in the pancreatic islets of HFF mice (p < .01) with no change in islet GLP-1 expression. Treatment of HFF mice with metformin for 21-days resulted in inhibition of circulating DPP-4 activity (p < .05), decreased blood glucose (p < .05) and increased GLP-1 gene expression (p < .001). These data indicate that DPP-4 is modulated in a tissue specific manner and is dependent on physiological conditions such as hyperglycaemia and insulin resistance, suggesting a significant role in disorders such as diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet, High-Fat; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Metformin; Mice; Obesity

To investigate the physiological mechanisms leading to rapid improvement in diabetes after Roux-en-Y gastric bypass (RYGB) and specifically the contribution of the concurrent peri-operative dietary restrictions, which may also alter glucose metabolism.. In order to assess the differential contributions of diet and surgery to the mechanisms leading to the rapid improvement in diabetes after RYGB we enrolled 10 patients with type 2 diabetes scheduled to undergo RYGB. All patients underwent a 10-day inpatient supervised dietary intervention equivalent to the peri-operative diet (diet-only period), followed by, after a re-equilibration (washout) period, an identical period of pair-matched diet in conjunction with RYGB (diet and RYGB period). We conducted extensive metabolic assessments during a 6-hour mixed-meal challenge test, with stable isotope glucose tracer infusion performed before and after each intervention.. Similar improvements in glucose levels, β-cell function, insulin sensitivity and post-meal hepatic insulin resistance were observed with both interventions. Both interventions led to significant reductions in fasting and postprandial acyl ghrelin. The diet-only intervention induced greater improvements in basal hepatic glucose output and post-meal gastric inhibitory polypeptide (GIP) secretion. The diet and RYGB intervention induced significantly greater increases in post-meal glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and glucagon levels.. Strict peri-operative dietary restriction is a main contributor to the rapid improvement in glucose metabolism after RYGB. The RYGB-induced changes in the incretin hormones GLP-1 and PYY probably play a major role in long-term compliance with such major dietary restrictions through central and peripheral mechanisms.

Topics: Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liver; Male; Middle Aged; Obesity; Peptide YY; Postprandial Period; Remission Induction

To examine the effect of different feeding routes on appetite and metabolic responses after Roux-en-Y gastric bypass (RYGB).. A standard liquid meal was administered either orally, into the gastric remnant, or intraduodenally 6 months after RYGB. Changes in plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY), and appetite were measured pre- and postprandially.. Postprandial GLP-1 and PYY responses were similar, whereas glucose, insulin, and GIP levels differed markedly after oral versus intraduodenal feeding. Intraduodenal feeding prompted an intermediate appetite response (i.e., between oral and intragastric). For postprandial glucose, insulin, and GIP levels, the intraduodenal route was more similar to the intragastric than the oral route. Intragastric administration did not evoke changes in appetite, glucose, or insulin; however, it slightly increased GLP-1 and PYY and moderately increased GIP.. Appetite and metabolic responses after RYGB depend on the route by which nutrients enter the gastrointestinal tract.

Topics: Adult; Appetite; Blood Glucose; Duodenum; Enteral Nutrition; Female; Food; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastric Mucosa; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Meals; Obesity; Peptide YY; Postprandial Period; Stomach

Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function.. We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization.. GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies.. Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity.

Topics: Adipose Tissue, Brown; Adiposity; Animals; Exenatide; GABAergic Neurons; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypothalamus; Insulin Resistance; Lipogenesis; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Signal Transduction; Thermogenesis; Uncoupling Protein 1

To investigate the effects of sleeve gastrectomy (SG) on glucose metabolism and changes in glucagon-like peptide 1 (GLP-1) in Goto-Kakizaki (GK) rats.. GK rats were randomly assigned to one of three groups: SG, SG pair-fed plus sham surgery (PF-sham), and ad libitum-fed no surgery (control). Food intake, body weight, blood glucose, GLP-1 and insulin levels, and GLP-1 expression in the jejunum and ileum were compared.. The SG rats exhibited lower postoperative food intake, body weight, and fasting glucose than did the control rats (. Improvement of glucose metabolism by SG was associated with increased GLP-1 secretion. SG contributes to an increase in plasma GLP-1 levels via increased GLP-1 expression in the mucosa of the jejunum and/or ileum.

Topics: Animals; Blood Glucose; Body Weight; Eating; Gastrectomy; Glucagon-Like Peptide 1; Glucose Tolerance Test; Ileum; Insulin; Insulin Resistance; Jejunum; Male; Peptide Fragments; Rats

Type 2 diabetes mellitus (T2DM) is a major risk factor for ischemic stroke accompanied by vascular dysfunction and poor cerebrovascular outcome. Lixisenatide is a glucagon like peptide-1 (GLP-1) analog that is recently used for T2DM treatment with established neuroprotective properties. This study investigated and compared the neuroprotective effect of lixisenatide against glimepiride on diabetic rats subjected to global cerebral ischemia/reperfusion (I/R) injury. T2DM-induced adult male Wistar rats were administered lixisenatide or glimepiride prior to induction of global cerebral I/R-induced injury. Results showed a disturbance in oxidative stress parameters (catalase, reduced glutathione, and malondialdehyde) along with increasing in caspase-3 and tumor necrosis factor-alpha protein expressions in ischemic diabetic brain tissues. An upregulation of protein level of inducible nitric oxide (iNOS) synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit, NOX2 gene expression associated with significant suppression of endothelial nitric oxide synthase (eNOS) protein expression are recorded in carotid arteries of diabetic I/R-injured rats. Apart from ameliorating glucose intolerance and insulin resistance, lixisenatide was found to be superior to glimepiride as protective treatment in terms of enhancing behavioral/neurological functions and suppressing cerebral oxidative stress, inflammation, and apoptosis in cerebral I/R-injured diabetic rats. Unlike glimepiride, lixisenatide relieved carotid endothelial dysfunction by increasing eNOS expression. It also dampened vascular nitrosative/oxidative stress via suppression of iNOS and NADPH oxidase expressions. This study supposed that lixisenatide represents a more suitable anti-diabetic therapy for patients who are at risk of ischemic stroke, and even so, the mechanisms of lixisenatide-mediated vascular protection warrant further experimental and clinical investigations.

Topics: Animals; Brain Ischemia; Carotid Arteries; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Resistance; Male; NADPH Oxidase 2; NADPH Oxidases; Neuroprotective Agents; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Peptides; Rats, Wistar; Reperfusion Injury

Insulin secretion (IS) declines with age, which increases the risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in older adults. IS is regulated by the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Here we tested the hypotheses that incretin release is lower in older adults and that this decline is associated with β-cell dysfunction.. A total of 40 young (25 ± 3 years) and 53 older (74 ± 7 years) lean nondiabetic subjects underwent a 2-hour oral glucose tolerance test (OGTT). Based on the OGTT, subjects were divided into three groups: young subjects with normal glucose tolerance (Y-NGT; n = 40), older subjects with normal glucose tolerance (O-NGT; n = 32), and older subjects with IGT (O-IGT; n = 21).. Plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15 to 30 minutes. We quantitated insulin sensitivity (Matsuda index) and insulin secretory rate (ISR) by deconvolution of C-peptide with the calculation of β-cell glucose sensitivity.. Matsuda index, early phase ISR (0 to 30 minutes), and parameters of β-cell function were lower in O-IGT than in Y-NGT subjects but not in O-NGT subjects. GLP-1 concentrations were elevated in both older groups [GLP-1 area under the curve (AUC)0-120 was 2.8 ± 0.1 in Y-NGT, 3.8 ± 0.5 in O-NGT, and 3.7 ± 0.4 nmol/L∙120 minutes in O-IGT subjects; P < 0.05], whereas GIP secretion was higher in O-NGT than in Y-NGT subjects (GIP AUC0-120 was 4.7 ± 0.3 in Y-NGT, 6.0 ± 0.4 in O-NGT, and 4.8 ± 0.3 nmol/L∙120 minutes in O-IGT subjects; P < 0.05).. Aging is associated with an exaggerated GLP-1 secretory response. However, it was not sufficient to increase insulin first-phase release in O-IGT and overcome insulin resistance.

Topics: Adult; Aged; Aging; Blood Glucose; C-Peptide; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male

Roux-en-Y gastric bypass (RYGB) is effective for the treatment of type 2 diabetes mellitus; however, the mechanism remains unclear.. The effects of RYGB on postprandial responses to three different diets (low carbohydrate (CH)-rich diet, high CH-rich diet, and fat-rich diet) of different nutritional composition in a Goto-Kakizaki (GK) diabetic rat model were assessed by measuring glucose tolerance, insulin resistance, incretin responses, and bile acid (BA) metabolism.. GK-RYGB group rats lost weight and preferred low CH-rich diet, but there were no significant differences in BW among the different diets. Glucose tolerance and insulin resistance were improved in rats who underwent RYGB, together with higher levels of circulating BAs, plasma GLP-1, and PYY levels. GK-RYGB rats fed high CH-rich or fat-rich diet showed increased glucose level and insulin resistance, together with high plasma BA, GIP, and PYY levels compared to those fed a low CH-rich diet.. RYGB improves glucose tolerance and insulin resistance which may be related to BA metabolism and hormone levels, and the nutrient composition of the diet affects the treatment effect of RYGB on T2DM.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet; Gastric Bypass; Glucagon-Like Peptide 1; Insulin Resistance; Rats

Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell-specific

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Gastroplasty; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Obesity; Organ Specificity; Signal Transduction; Tissue Culture Techniques; Weight Loss

Gastric bypass surgery leads to profound changes in the secretion of gut hormones with effects on metabolism, appetite, and food intake. Here, we discuss their contributions to the improvement in glucose tolerance and the weight loss that results from the operations. We find that the improved glucose tolerance is due the following events: a negative energy balance and resulting weight loss, which improve first hepatic and later peripheral insulin sensitivity, in combination with increased postprandial insulin secretion elicited particularly by exaggerated glucagon-like peptide-1 responses. The weight loss is due to loss of appetite resulting in reduced energy intake, and we find it probable that this process is driven by exaggerated secretion of appetite-regulating gut hormones including, but probably not limited to, glucagon-like peptide-1 and peptide-YY. The increased secretion is due to an accelerated exposure to and absorption of nutrients in the small intestine. This places the weight loss and the gut hormones in key positions with respect to the metabolic improvements after bypass surgery.

Topics: Appetite; Bariatric Surgery; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dietary Proteins; Digestion; Eating; Gastric Bypass; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Intestinal Absorption; Nutrients; Obesity, Morbid; Peptide YY; Weight Loss

The mechanism by which Roux-en-Y Gastric Bypass (RYGB) increases the secretion of glucagon-like peptide-1 (GLP-1) remains incompletely defined. Here we investigated whether TGR5-mTORC1 signaling mediates the RYGB-induced alteration in GLP-1 production in mice and human beings.. Circulating bile acids, TGR5-mTORC1 signaling, GLP-1 synthesis and secretion were determined in lean or obese male C57BL/6 mice with or without RYGB operation, as well as in normal glycemic subjects, obese patients with type 2 diabetes before and after RYGB.. Positive relationships were observed among circulating bile acids, ileal mechanistic target of rapamycin complex 1 (mTORC1) signaling and GLP-1 during changes in energy status in the present study. RYGB increased circulating bile acids, ileal Takeda G protein-coupled receptor 5 (TGR5) and mTORC1 signaling activity, as well as GLP-1 production in both mice and human subjects. Inhibition of ileal mTORC1 signaling by rapamycin significantly attenuated the stimulation of bile acid secretion, TGR5 expression and GLP-1 synthesis induced by RYGB in lean and diet-induced obese mice. GLP-1 production and ileal TGR5-mTORC1 signaling were positively correlated with plasma deoxycholic acid (DCA) in mice. Treatment of STC-1 cells with DCA stimulated the production of GLP-1. This effect was associated with a significant enhancement of TGR5-mTORC1 signaling. siRNA knockdown of mTORC1 or TGR5 abolished the enhancement of GLP-1 synthesis induced by DCA. DCA increased interaction between mTOR-regulatory-associated protein of mechanistic target of rapamycin (Raptor) and TGR5 in STC-1 cells.. Deoxycholic acid-TGR5-mTORC1 signaling contributes to the up-regulation of GLP-1 production after RYGB.

Topics: Animals; Bile Acids and Salts; Blood Glucose; Deoxycholic Acid; Diabetes Mellitus, Type 2; Gastric Bypass; Gene Expression Regulation; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Obese; Middle Aged; Obesity; Receptors, G-Protein-Coupled; Signal Transduction

A growing body of evidence suggests a protective role of polyphenols and exercise training on the disorders of type 2 diabetes mellitus (T2DM). We aimed to assess the effect of the açaí seed extract (ASE) associated with exercise training on diabetic complications induced by high-fat (HF) diet plus streptozotocin (STZ) in rats. Type 2 diabetes was induced by feeding rats with HF diet (55% fat) for 5 weeks and a single dose of STZ (35 mg/kg i.p.). Control (C) and Diabetic (D) animals were subdivided into four groups each: Sedentary, Training, ASE Sedentary, and ASE Training. ASE (200 mg/kg/day) was administered by gavage and the exercise training was performed on a treadmill (30min/day; 5 days/week) for 4 weeks after the diabetes induction. In type 2 diabetic rats, the treatment with ASE reduced blood glucose, insulin resistance, leptin and IL-6 levels, lipid profile, and vascular dysfunction. ASE increased the expression of insulin signaling proteins in skeletal muscle and adipose tissue and plasma GLP-1 levels. ASE associated with exercise training potentiated the reduction of glycemia by decreasing TNF-α levels, increasing pAKT and adiponectin expressions in adipose tissue, and IR and pAMPK expressions in skeletal muscle of type 2 diabetic rats. In conclusion, ASE treatment has an antidiabetic effect in type 2 diabetic rats by activating the insulin-signaling pathway in muscle and adipose tissue, increasing GLP-1 levels, and an anti-inflammatory action. Exercise training potentiates the glucose-lowering effect of ASE by activating adiponectin-AMPK pathway and increasing IR expression.

Topics: Adipose Tissue; Animals; Blood Glucose; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diet, High-Fat; Drug Evaluation, Preclinical; Euterpe; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Resistance; Interleukin-6; Leptin; Lipids; Male; Muscle, Skeletal; Physical Conditioning, Animal; Phytotherapy; Plant Extracts; Random Allocation; Rats; Rats, Wistar; Seeds

Glucagon-like peptide 1 (GLP1) is produced by L cells in the intestine, and agonists of the GLP1 receptor are effective in the treatment of diabetes. Levels of GLP1 increase with numbers of L cells. Therefore, agents that increase numbers of L cell might be developed for treatment of diabetes. Ras homologue family member A (RhoA) signaling through Rho-associated coiled-coil-containing protein kinases 1 and 2 (ROCK1 and ROCK2) controls cell differentiation, but it is not clear whether this pathway regulates enteroendocrine differentiation in the intestinal epithelium. We investigated the effects of Y-27632, an inhibitor of ROCK1 and ROCK2, on L-cell differentiation.. We collected intestinal tissues from GLU-Venus, GPR41-RFP, and Neurog3-RFP mice, in which the endocrine lineage is fluorescently labeled, for in vitro culture and histologic analysis. Small intestine organoids derived from these mice were cultured with Y-27632 and we measured percentages of L cells, expression of intestinal cell-specific markers, and secretion of GLP1 in medium. Mice were fed a normal chow or a high-fat diet and given Y-27632 or saline (control) and blood samples were collected for measurement of GLP1, insulin, and glucose.. Incubation of intestinal organoids with Y-27632 increased numbers of L cells and secretion of GLP1. These increases were associated with upregulated expression of genes encoding intestinal hormones, neurogenin 3, neurogenic differentiation factor 1, forkhead box A1 and A2, and additional markers of secretory cells. Mice fed the normal chow diet and given Y-27632 had increased numbers of L cells in intestinal tissues, increased plasma levels of GLP1 and insulin, and lower blood levels of glucose compared with mice fed the normal chow diet and given saline. In mice with insulin resistance induced by the high-fat diet, administration of Y-27632 increased secretion of GLP1 and glucose tolerance compared with administration of saline.. In mouse intestinal organoids, an inhibitor of RhoA signaling increased the differentiation of the secretory lineage and the development of enteroendocrine cells. Inhibitors of RhoA signaling or other strategies to increase numbers of L cells might be developed for treatment of patients with type 2 diabetes or for increasing glucose tolerance.

Topics: Amides; Animals; Biomarkers; Blood Glucose; Cell Differentiation; Cell Lineage; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Ileum; Insulin; Insulin Resistance; Male; Mice, Inbred C57BL; Mice, Transgenic; Organoids; Phenotype; Protein Kinase Inhibitors; Pyridines; rho GTP-Binding Proteins; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Stem Cells; Time Factors; Tissue Culture Techniques

Fatty acid esters of hydroxylated fatty acids (FAHFAs) were discovered as a novel class of endogenous mammalian lipids whose profound effects on metabolism have been shown. In the current study, in vitro and in vivo the metabolic effects of two of these FAHFAs, namely palmitic acid-5- (or -9) -hydroxy-stearic acid (5- or 9-PAHSA, respectively) were profiled. In DIO mice fed with differentially composed low- or high-fat diets, acute and subchronic treatment with 5-PAHSA and 9-PAHSA alone, or in combination, did not significantly improve the deranged metabolic status. Neither racemic 5- or 9-PAHSA, nor the enantiomers were able to: (1) increase basal or insulin-stimulated glucose uptake in vitro, (2) stimulate GLP-1 release from GLUTag cells, or (3) induce GSIS in rat, mouse, or human islets or in a human pancreatic β cell line. Therefore, our data do not support the further development of PAHSAs or their derivatives for the control of insulin resistance and hyperglycemia.

Topics: Animals; Diet, Fat-Restricted; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; HEK293 Cells; Humans; Hyperglycemia; Insulin Resistance; Islets of Langerhans; Mice; Mice, Inbred C57BL; Models, Animal; Obesity; Palmitic Acid; Rats; Rats, Sprague-Dawley; Stearic Acids

Pancreatic lipidosis (nonalcoholic fatty pancreas disease, NAFPD) causes insulin resistance and dysfunction of pancreatic β-cells, with the risk of type 2 diabetes mellitus (T2DM). However, the prevalence and pathogenic factors associated with NAFPD are not clear. The aim of the study was to explore the prevalence of NAFPD in a Chinese adult population, and investigate factors associated with NAFPD aggravation.This was a cross-sectional study; 4419 subjects were enrolled for NAFPD screening and were divided into NAFPD (n = 488) and without NAFPD (n = 3930) groups. The sex, age, related concomitant diseases, general physical parameters, and serum glucose and lipid metabolism were compared between the 2 groups.The overall NAFPD prevalence was 11.05%, but increased with age. In those <55 years NAFPD prevalence was lower in females than males (P < .05), but prevalence was similar >55 years. Nonalcoholic fatty liver disease (NAFLD), T2DM, homeostasis model assessment-insulin resistance index, total cholesterol, triglyceride, lipoprotein, adiponectin, and glucagon-like peptide 1 (GLP-1) were the independent risk factors for NAFPD (P < .05). Analaysis of mild NAFPD (MN) and severe NAFPD (SN) subgroups, according to the extent of fat deposition, suggested that NAFLD, triglyceride, lipoprotein, and adiponectin were independent risk factors for NAFPD aggravation (P < .05).The NAFPD prevalence was about 11% in Chinese adults. Its development and progression was related to NAFLD, T2DM, insulin resistance, dyslipidemia, and GLP-1 levels. Severe NAFPD was associated with NAFLD and dyslipidemia.

Topics: Adiponectin; Adult; Age Factors; China; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Insulin Resistance; Lipoproteins; Male; Middle Aged; Overweight; Pancreatic Diseases; Prevalence; Risk Factors; Sex Factors; Triglycerides

Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes.. KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling.. We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone.. Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.

Topics: Animals; Body Weight; Cyclopentanes; Diabetes Mellitus, Type 2; Disease Models, Animal; Enteroendocrine Cells; Glucagon-Like Peptide 1; Humulus; Hypoglycemic Agents; Insulin Resistance; Intestinal Mucosa; Intestines; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Receptors, G-Protein-Coupled; Signal Transduction

Gain-of-function (GOF) mutations in the ATP-sensitive potassium (K

Topics: Animals; Blood Glucose; Cytokines; Diabetes Mellitus; Glucagon; Glucagon-Like Peptide 1; Glyburide; Inflammation; Insulin; Insulin Resistance; Leptin; Mice; Mice, Transgenic; Mutation; Potassium Channels, Inwardly Rectifying

Glucagon-like peptide 1 (GLP-1) levels may be reduced in type 2 diabetes, but whether a similar impairment exists in gestational diabetes mellitus (GDM) has not been established. We studied this in a prospective cohort study of pregnant women (

Topics: Adult; Blood Glucose; Diabetes, Gestational; Female; Gestational Age; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Pregnancy; Prospective Studies; Young Adult

Intermittent energy restriction (IER) involves short periods of severe energy restriction interspersed with periods of adequate energy intake, and can induce weight loss. Insulin sensitivity is impaired by short-term, complete energy restriction, but the effects of IER are not well known. In randomised order, fourteen lean men (age: 25 (sd 4) years; BMI: 24 (sd 2) kg/m2; body fat: 17 (4) %) consumed 24-h diets providing 100 % (10 441 (sd 812) kJ; energy balance (EB)) or 25 % (2622 (sd 204) kJ; energy restriction (ER)) of estimated energy requirements, followed by an oral glucose tolerance test (OGTT; 75 g of glucose drink) after fasting overnight. Plasma/serum glucose, insulin, NEFA, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and fibroblast growth factor 21 (FGF21) were assessed before and after (0 h) each 24-h dietary intervention, and throughout the 2-h OGTT. Homoeostatic model assessment of insulin resistance (HOMA2-IR) assessed the fasted response and incremental AUC (iAUC) or total AUC (tAUC) were calculated during the OGTT. At 0 h, HOMA2-IR was 23 % lower after ER compared with EB (P<0·05). During the OGTT, serum glucose iAUC (P<0·001), serum insulin iAUC (P<0·05) and plasma NEFA tAUC (P<0·01) were greater during ER, but GLP-1 (P=0·161), GIP (P=0·473) and FGF21 (P=0·497) tAUC were similar between trials. These results demonstrate that severe energy restriction acutely impairs postprandial glycaemic control in lean men, despite reducing HOMA2-IR. Chronic intervention studies are required to elucidate the long-term effects of IER on indices of insulin sensitivity, particularly in the absence of weight loss.

Topics: Adult; Area Under Curve; Blood Glucose; Caloric Restriction; Energy Intake; Energy Metabolism; Fasting; Fibroblast Growth Factors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Male; Obesity; Postprandial Period; Weight Loss; Young Adult

Obesity and type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and impaired glucagon-like peptide-1 (GLP-1) secretion/function. Lipotoxicity, a chronic elevation of free fatty acids in the blood, could affect insulin-signaling in many peripheral tissues. To date, the effects of lipotoxicity on the insulin receptor and insulin resistance in the intestinal L-cells need to be elucidated. Moreover, recent observations indicate that L-cells may be able to process not only GLP-1 but also glucagon from proglucagon. The aim of this study was to investigate the effects of chronic palmitate exposure on insulin pathways, GLP-1 secretion and glucagon synthesis in the GLUTag L-cell line. Cells were cultured in the presence/absence of palmitate (0.5 mM) for 24 h to mimic lipotoxicity. Palmitate treatment affected insulin-stimulated GLP-1 secretion, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. In our model lipotoxicity induced extracellular signal-regulated kinase (ERK 44/42) activation both in insulin stimulated and basal conditions and also up-regulated paired box 6 (PAX6) and proglucagon expression (

Topics: Cell Line; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Palmitates; Proprotein Convertase 2; Signal Transduction

Diabetes and obesity are characterized by glucose intolerance, fat deposition, inflammation, and dyslipidemia. Recent reports postulated that distinct gut microbiota alterations were observed in obese/diabetic subjects and modulating gut microbiota beneficially through specific probiotics could be a potential therapeutic option for type 2 diabetes/obesity. Therefore, we attempted to study the efficacy of probiotics of Indian gut origin (Lactobacillus plantarum MTCC5690 and Lactobacillus fermentum MTCC5689) along with a positive control, Lactobacillus rhamnosus (LGG) on glucose/lipid homeostasis in high-fat-diet-induced diabetic animal model.. C57BL/6J male mice were divided into seven groups (n = 6 per group) comprising feeding on: (1) Normal Pellet Diet (NPD), (2) High-Fat Diet (HFD), (3) HFD with LGG, (4) HFD with MTCC5690, (5) HFD with MTCC5689, (6) HFD with metformin, and 7) HFD with vildagliptin for a period of 6 months. Biochemical markers, glucose tolerance, insulin resistance, and GLP-1 and LPS levels were assessed by standard protocols. Gut integrity was measured by intestinal permeability test. Transcriptional levels of tight junction proteins (TJPs) were probed in small intestinal tissues while inflammatory signals and other pathway specific genes were profiled in liver, visceral adipose tissue, and skeletal muscle.. Mice fed with HFD became insulin resistant, glucose intolerant, hyperglycemic, and dyslipidemic. Diabetic mice were characterized to exhibit decreased levels of GLP-1, increased gut permeability, increased circulatory levels of LPS, decrease in the gene expression patterns of intestinal tight junction markers (occludin and ZO-1), and increased proinflammatory gene markers (TNFα and IL6) in visceral fat along with decreased mRNA expression of FIAF and adiponectin. Diabetic mice also exhibited increased mRNA expression of ER stress markers in skeletal muscle. In addition, liver from HFD-fed diabetic mice showed increased gene expressions of proinflammation, lipogenesis, and gluconeogenesis. Probiotic interventions (most prominently the MTCC5689) resisted insulin resistance and development of diabetes in mice under HFD feeding and beneficially modulated all the biochemical and molecular alterations in a mechanistic way in several tissues. The metabolic benefits offered by the probiotics were also more or less similar to that of standard drugs such as metformin and vildagliptin.. Native probiotic strains MTCC 5690 and MTCC 5689 appear to have potential against insulin resistance and type 2 diabetes with mechanistic, multiple tissue-specific mode of actions.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dyslipidemias; Endoplasmic Reticulum Stress; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose Intolerance; India; Inflammation; Insulin Resistance; Lactobacillus plantarum; Limosilactobacillus fermentum; Lipids; Lipogenesis; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Probiotics; Transcriptome

The gut environment has been considered to play a role in the development of nonalcoholic steatohepatitis (NASH). α-glucosidase inhibitors (α-GIs) delay carbohydrate absorption and may change the gut environment. We considered that the protective effect of α-GIs against NASH development is related to changes in the gut environment and thus investigated the effects of miglitol, an α-GI, on NASH development and the gut environment.. Mice were divided into three groups and fed a normal chow diet (NCD), a high-fat high-sucrose diet (HFHSD), or HFHSD plus 0.04% miglitol (HFHSD plus M) for 12 weeks.. Insulin resistance developed more in the HFHSD group than in the NCD group, whereas it was suppressed in the HFHSD plus M group. NASH was evaluated histologically, biochemically, and on the basis of messenger RNA expression levels. Miglitol treatment suppressed HFHSD-induced NASH development with the suppression of hepatic Toll-like receptor 4 expression, increased glucagon-like peptide 1 (GLP-1) concentration, and reduced lipopolysaccharide concentration in portal plasma. Regarding the gut environment, the intestinal transit time was shortened and colon inflammation was suppressed in the HFHSD plus M group compared with the HFHSD group. Regarding the gut microbiota, the abundances of Erysipelotrichaceae and Coriobacteriaceae were increased in the HFHSD group compared with the NCD group, whereas the increase was suppressed in the HFHSD plus M group.. We demonstrated that miglitol has a protective effect against HFHSD-induced NASH development. The increased GLP-1 secretion and the suppression of endotoxemia, associated with the changes in the gut environment, including the gut microbiota, could contribute to the underlying mechanisms.

Topics: 1-Deoxynojirimycin; Animals; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease

BACKGROUND Over the past few decades, bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), has become widely considered the most effective treatment for morbid obesity. In most cases, it results in enhanced glucose management in patients with obesity and type 2 diabetes (T2D), which is observed before significant weight loss. However, what accounts for this effect remains controversial. To gain insight into the benefits of RYGB in T2D, we investigated changes in the β-cell mass of obese rats following RYGB. MATERIAL AND METHODS RYGB or a sham operation was performed on obese rats that had been fed a high-fat diet (HFD) for 16 weeks. Then, the HFD was continued for 8 weeks in both groups. Additional normal chow diet (NCD) and obese groups were used as controls. RESULTS In the present study, RYGB induced improved glycemic control and enhanced β-cell function, which was reflected in a better glucose tolerance and a rapidly increased secretion of insulin and C-peptide after glucose administration. Consistently, rats in the RYGB group displayed increased β-cell mass and islet numbers, which were attributed in part to increased glucagon-like peptide 1 levels following RYGB. CONCLUSIONS Our data indicate that RYGB can improve b-cell function via increasing β-cell mass, which plays a key role in improved glycemic control after RYGB.

Topics: Animals; Bariatric Surgery; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Obesity; Obesity, Morbid; Rats; Rats, Sprague-Dawley; Weight Loss

This study was initiated to investigate the effects of Roux-en-Y gastric bypass (RYGB) surgery on hepatic glucose metabolism and hepatic expression of protein tyrosine phosphatase 1B (PTP1B) in obese rats.. Body weight, glucose, intraperitoneal glucose, insulin, and pyruvate tolerance tests were performed pre- and postoperatively, and plasma lipid, insulin and glucagon-like peptide 1 (GLP-1) were measured. The mRNA levels of G6Pase, Pepck, Gsk-3β and Gys-2, and the expression levels of PTP1B mRNA, protein, and other components of the insulin signaling pathway were measured by using RT-PCR and western blotting. The intracellular localization of PTP1B and hepatic glycogen deposition was also observed.. RYGB surgery-treated rats showed persistent weight loss, significantly improved glucose tolerance, pyruvate tolerance, and dyslipidemia, as well as increased insulin sensitivity, hepatic glycogen deposition and increased plasma GLP-1 in obese rats. RT-PCR analyses showed Pepck, G6Pase, and Gsk-3β mRNA to be significantly decreased, and Gys-2 mRNA to be significantly increased in liver tissue in the RYGB group (p < 0.05 vs. high-fat diet (HFD) or HFD + sham group); in addition, the expression of PTP1B were significantly decreased and insulin signaling were improved in the RYGB group (p < 0.05 vs. HFD or HFD + sham group).. RYGB can improve hepatic glucose metabolism and down-regulate PTP1B in obese rats. An increased circulating GLP-1 concentration may be correlated with the effects following RYGB in obese rats.

Topics: Animals; Blood Glucose; Body Weight; Down-Regulation; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Insulin; Insulin Resistance; Liver; Male; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Sprague-Dawley; RNA, Messenger

Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues as well as for pancreatic insulin secretion. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in β-cells, and AQP12, an aquaporin related to pancreatic damage, in the improvement of pancreatic function and steatosis after sleeve gastrectomy in diet-induced obese rats.. Male Wistar obese rats (n=125) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by sleeve-gastrectomized animals) interventions. The tissue distribution and expression of AQPs in the rat pancreas were analyzed by real-time PCR, western blotting and immunohistochemistry. The effect of ghrelin isoforms and glucagon-like peptide 1 (GLP-1) on insulin secretion, triacylglycerol (TG) accumulation and AQP expression was determined in vitro in RIN-m5F β-cells.. Sleeve gastrectomy reduced pancreatic β-cell apoptosis, steatosis and insulin secretion. Lower ghrelin and higher GLP-1 concentrations were also found after bariatric surgery. Acylated and desacyl ghrelin increased TG content, whereas GLP-1 increased insulin release in RIN-m5F β-cells. Sleeve gastrectomy was associated with an upregulation of AQP7 together with a normalization of the increased AQP12 levels in the rat pancreas. Interestingly, ghrelin and GLP-1 repressed AQP7 and AQP12 expression in RIN-m5F β-cells. AQP7 protein was negatively correlated with intracellular lipid accumulation in acylated ghrelin-treated cells and with insulin release in GLP-1-stimulated β-cells.. AQP7 upregulation in β-cells after sleeve gastrectomy contributes, in part, to the improvement of pancreatic steatosis and insulin secretion by increasing intracellular glycerol used for insulin release triggered by GLP-1 rather than for ghrelin-induced TG biosynthesis.

Topics: Animals; Aquaporins; Blotting, Western; Disease Models, Animal; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Immunohistochemistry; Insulin Resistance; Insulin-Secreting Cells; Male; Obesity; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Up-Regulation; Weight Loss

An increase of bile acids (BAs), fibroblast growth factor 19 (FGF19), and glucagon-like peptide 1 (GLP-1) has been implicated in metabolic improvements after Roux-en-Y gastric bypass and vertical sleeve gastrectomy. However, data are still conflicting regarding their role after laparoscopic adjustable gastric banding (LAGB).. To assess the fasting BA, FGF19, and GLP-1 concentrations in plasma before and after LAGB and to test for correlations with immunometabolic parameters. Furthermore, hepatic farnesoid X receptor (FXR) expression and regulation of FXR-dependent genes were analyzed.. Observational study at the University Hospital Innsbruck.. Twenty obese patients.. Fasting plasma samples were taken before, 3, 6, and 12 months after LAGB. Liver biopsies were obtained at surgery and after 6 months postoperatively.. BA profiles, GLP-1 and FGF19 levels, hepatic FXR expression and regulation of FXR target genes were determined.. Total, conjugated, and secondary BAs transiently increased 3 months after LAGB (P < 0.01). Only one BA, glycolithocholic acid sulfate, remained significantly elevated throughout the whole follow-up period (P < 0.05). GLP-1 had increased transiently 3 months after surgery (P < 0.01), whereas FGF19 levels increased continuously (P < 0.05). Insulin, homeostasis model assessment index, C-reactive protein, FGF19, and GLP-1 correlated positively with different BAs. No differences were seen in hepatic FXR expression and FXR-regulated genes.. Our study results, not only identified LAGB-induced changes in BAs and BA-induced hormones, but also revealed associations between changes in BA profile with GLP-1 and FGF19.

Topics: Adult; Bariatric Surgery; Bile Acids and Salts; C-Reactive Protein; Female; Fibroblast Growth Factors; Gene Expression Regulation; Glucagon-Like Peptide 1; Glycocholic Acid; Humans; Immunohistochemistry; Insulin; Insulin Resistance; Laparoscopy; Liver; Male; Obesity, Morbid; Real-Time Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear

To investigate factors causing diabetes recurrence after sleeve gastrectomy (SG) and duodenal-jejunal bypass (DJB).. SG and DJB were performed on rats with diabetes induced by high-fat diet (HFD) and streptozotocin (STZ). HFD was used to induce diabetes recurrence at 4 wk postoperatively. Body weight, oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), insulin signaling [IR, insulin receptor substrate (IRS)1, IRS2, phosphatidylinositol 3-kinase and AKT in liver and skeletal muscle], oral glucose stimulated insulin secretion, beta-cell morphology (mass, apoptosis and insulin secretion), glucagon-like peptide (GLP)-1, PYY and ghrelin were compared among SG rats with common low-fat diet (SG-LFD), SG with HFD (SG-HFD), DJB rats with LFD (DJB-LFD), DJB with HFD (DJB-HFD) and sham-operation with LFD (Sham) at targeted postoperative times.. SG and DJB resulted in significant improvement in glucose tolerance, lower HOMA-IR, up-regulated hepatic and muscular insulin signaling, higher levels of oral glucose-stimulated insulin secretion, bigger beta-cell mass, higher immunofluorescence intensity of insulin, fewer transferase-mediated dUTP-biotin 3' nick end-labeling (TUNEL)-positive beta cells and higher postprandial GLP-1 and PYY levels than in the Sham group. The improvement in glucose tolerance was reversed at 12 wk postoperatively. Compared with the SG-LFD and DJB-LFD groups, the SG-HFD and DJB-HFD groups showed higher HOMA-IR, down-regulated hepatic and muscular insulin signaling, and more TUNEL-positive beta cells. No significant difference was detected between HFD and LFD groups for body weight, glucose-stimulated insulin secretion, beta-cell mass, immunofluorescence intensity of insulin, and postprandial GLP-1 and PYY levels. Fasting serum ghrelin decreased in SG groups, and there was no difference between HFD-SG and LFD-SG groups.. HFD reverses the improvement in glucose homeostasis after SG and DJB. Diabetes recurrence may correlate with re-impaired insulin sensitivity, but not with alterations of beta-cell function and body weight.

Topics: Animals; Apoptosis; Bariatric Surgery; Body Weight; Diabetes Mellitus, Experimental; Diet, High-Fat; Duodenum; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Homeostasis; Insulin; Insulin Resistance; Insulin-Secreting Cells; Jejunum; Liver; Muscles; Peptide YY; Rats; Recurrence; Remission Induction; Signal Transduction; Streptozocin

Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated.. Atherosclerosis development was evaluated in Apoe. Treatment of Apoe. Lixisenatide decreases atheroma plaque size and instability in Apoe

Topics: Animals; Atherosclerosis; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Inflammation; Insulin Resistance; Macrophages; Mice; Peptides; STAT3 Transcription Factor

Impaired glucose regulation (IGR) patients have increased risk of type 2 diabetes mellitus (T2DM). Identifying relevant risk factors in IGR subjects could facilitate early detection and prevention of IGR progression to diabetes. This study investigated the association between Traditional Chinese Medicine (TCM) body constitution and serum cytokines, and whether body constitution could independently predict diabetes in IGR subjects.. Patients with IGR (n = 306) received a blood test and their body constitution type was assessed using a body constitution questionnaire (BCQ). Serum levels of cytokines were measured by ELISA. Patients were followed up for at least three years, and their status of diabetes were recorded. Multivariate logistic regression was used to estimate odds ratios (ORs) of diabetes for body constitution.. Phlegm-damp, Damp-heat and Qi-deficiency were three most common unbanlenced constitutions among IGR subjects. Phlegm-damp and Damp-heat constitution subjects showed higher serum levels of interleukin 6 (IL-6), tumour necrosis factor-α (TNF-α), leptin and lower serum levels of adiponectin (P<0.05). Qi-deficiency constitution subjects showed higher serum levels of leptin and lower serum levels of adiponectin, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) (P<0.05). Subjects with Phlegm-damp or Damp-heat constitution demonstrated a significantly higher risk of diabetes (P<0.05).. Phlegm-damp and Damp-heat TCM body constitution are strongly associated with abnormal serum cytokines, and could potentially serve as a predictor of diabetes in IGR subjects. Body constitution can help to identify IGR subjects who are at a high risk of progression to diabetes.

Topics: Adiponectin; Cytokines; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Leptin; Male; Medicine, Chinese Traditional; Middle Aged; Prospective Studies; Surveys and Questionnaires

Emerging evidence supports a key role for the gut microbiota in metabolic diseases, including type 2 diabetes (T2D) and obesity. The dipeptidyl peptidase-4 inhibitor vildagliptin is highly efficacious in treating T2D. However, whether vildagliptin can alter the gut microbiome is still unclear. This study aimed to identify whether vildagliptin modifies the gut microbiota structure during T2D treatment. Diabetic Sprague-Dawley (SD) rats were induced by a high-fat diet and streptozotocin injection (HFD/STZ). Diabetic rats were orally administered a low dose of vildagliptin (LV, 0.01 g/kg/d vildagliptin), high dose of vildagliptin (HV, 0.02 g/kg/d vildagliptin), or normal saline for 12 weeks. Fasting blood glucose, blood glucose after glucose loading, and serum insulin levels were significantly reduced in the LV and HV groups compared with those in the T2D group. The serum GLP-1 level increased more in the vildagliptin-treated group than in the T2D group. Pyrosequencing of the V3-V4 regions of 16S rRNA genes revealed that vildagliptin significantly altered the gut microbiota. The operational taxonomic units (OTUs) and community richness (Chao1) index were significantly reduced in the vildagliptin and diabetic groups compared with those in the control group. At the phylum level, a higher relative abundance of Bacteroidetes, lower abundance of Firmicutes, and reduced ratio of Fimicutes/Bacteroidetes were observed in the vildagliptin-treated group. Moreover, vildagliptin treatment increased butyrate-producing bacteria, including Baceroides and Erysipelotrichaeae, in the diabetic rats. Moreover, Lachnospira abundance was significantly negatively correlated with fasting blood glucose levels. In conclusion, vildagliptin treatment could benefit the communities of the gut microbiota.

Topics: Adamantane; Administration, Oral; Animals; Blood Glucose; Butyrates; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Insulin Resistance; Interleukin-6; Male; Nitriles; Pyrrolidines; Random Allocation; Rats, Sprague-Dawley; RNA, Ribosomal, 16S; Vildagliptin

The precise mechanism linking systemic inflammation with insulin resistance (IR) in rheumatoid arthritis (RA) remains elusive. In the present study, we determined whether the incretin-insulin axis and incretin effect are disrupted in patients with RA and if they are related to the IR found in these patients.. We conducted a cross-sectional study that encompassed 361 subjects without diabetes, 151 patients with RA, and 210 sex-matched control subjects. Insulin, C-peptide, glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), dipeptidyl peptidase 4 (DPP-4) soluble form, and IR indexes by homeostatic model assessment (HOMA2) were assessed. A multivariable analysis adjusted for IR-related factors was performed. Additionally, ten patients and ten control subjects underwent a 566-kcal meal test so that we could further study the postprandial differences of these molecules between patients and control subjects.. Insulin, C-peptide, and HOMA2-IR indexes were higher in patients than in control subjects. This was also the case for GLP-1 (0.49 ± 1.28 vs. 0.71 ± 0.22 ng/ml, p = 0.000) and GIP (0.37 ± 0.40 vs. 1.78 ± 0.51 ng/ml, p = 0.000). These differences remained significant after multivariable adjustment including glucocorticoid intake. Disease Activity Score in 28 joints with erythrocyte sedimentation rate (β coefficient 46, 95% CI 6-87, p = 0.026) and Clinical Disease Activity Index (β coefficient 7.74, 95% CI 1.29-14.20, p = 0.019) were associated with DPP-4 serum levels. GLP-1 positively correlated with β-cell function (HOMA2 of β-cell production calculated with C-peptide) in patients but not in control subjects (interaction p = 0.003). The meal test in patients with RA revealed a higher total and late response AUC for glucose response, a later maximal response of C-peptide, and a flatter curve in GIP response.. The incretin-insulin axis, both during fasting and postprandial, is impaired in patients with RA.

Topics: Adult; Aged; Arthritis, Rheumatoid; Cross-Sectional Studies; Dipeptidyl Peptidase 4; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Middle Aged

Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance.. By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a high-fat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes.. Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.

Topics: Animals; Biomarkers; Blood Glucose; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Exenatide; Fatty Acid Synthase, Type I; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide 1; Hepatocytes; Hyperlipidemias; Incretins; Insulin; Insulin Resistance; Intestinal Mucosa; Intestines; Lipoproteins, VLDL; Liver; Male; Mice, Inbred C57BL; Obesity; Peptides; RNA, Messenger; Signal Transduction; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Time Factors; Triglycerides; Up-Regulation; Vagotomy; Vagus Nerve; Venoms

Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo.. We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp.. We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neurons. We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity.

Topics: Animals; Blood Glucose; Energy Metabolism; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Homeostasis; Insulin; Insulin Resistance; Mice; Mice, Transgenic; Neurons; Proglucagon; Receptors, Glucagon

This study aimed to investigate the influence of new biliopancreatic diversion (NBPD) and duodenal-jejunal bypass (DJB) surgery on blood glucose, lipids, gastrointestinal hormones, and insulin in Goto-Kakizaki (GK) rats, an animal model for type 2 diabetes, in order to elucidate the mechanisms underlying the therapeutic effect of these types of surgery on this clinical condition.. Thirty 30 male GK rats (SPF) aged 12 weeks were randomly assigned into three groups (n = 10 per group): sham group, NBPD group, and DJB group. Body weight, random plasma glucose, fasting plasma glucose (FPG), oral glucose tolerance (OGT), blood lipids, plasma insulin, glucagon like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) were measured before and after surgery.. NBPD surgery improved glucose tolerance, decreased fasting free fatty acids, triglycerides, and cholesterol. It also increased fasting and postprandial GIP, but caused no change in GLP-1. DJB surgery produced results similar to NBPD surgery except for causing a decrease in postprandial GLP-1 and insulin, and a larger increase in fasting GIP.. Moving the biliopancreatic duct outlet to the mid-jejunum (NBPD surgery) improves glucose tolerance and increases GIP, but does not change GLP-1. Adding duodenal bypass (DJB surgery) increases fasting GIP and decreases postprandial GLP-1.

Topics: Animals; Biliopancreatic Diversion; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenum; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Insulin Resistance; Jejunum; Lipid Metabolism; Lipids; Male; Rats

To explore the relationships between postmenstrual age (PMA), insulin, C-peptide, glucagon and blood glucose concentrations (BGCs) in preterm and term neonates. To compare glucagon-like peptide-1 (GLP-1) concentrations in fed versus never-fed neonates.. Observational.. Dunedin Hospital Neonatal Intensive Care Unit, New Zealand.. Term or preterm euglycaemic neonates (102) receiving routine blood tests (343 samples).. None: plasma was obtained from surplus samples from routine clinical care.. Insulin, C-peptide, GLP-1 and glucagon concentrations were measured in temporal association with BGC.. Insulin and C-peptide concentrations were elevated in very preterm infants (PMA≤32 weeks) and decreased to term; this relationship persisted when BGCs were accounted for. Generalised linear mixed models showed that insulin:C-peptide ratio and insulin:BGC ratio decreased significantly with increasing PMA (p<0.001). GLP-1 increased following initial oral feeds regardless of PMA (p<0.001).. Preterm neonates exhibit insulin resistance in the absence of hyperglycaemia. Enteral feeds result in an increase in GLP-1. These factors are likely to contribute to the increased risk of hyperglycaemia in premature neonates (PMA<32 weeks).

Topics: Blood Glucose; C-Peptide; Female; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Humans; Infant, Newborn; Infant, Premature; Insulin; Insulin Resistance; Intensive Care Units, Neonatal; Male; New Zealand

Resistant starch (RS) has been well characterized for its glycemic control properties; however, there is little consensus regarding the influence of RS on blood lipid concentrations and lipoprotein distribution and size. Therefore, this study aimed to characterize the effect of daily RS supplementation in a controlled capsule delivery on biomarkers of cardiovascular (blood lipids, lipoproteins) and diabetes (glucose, insulin) risk in a pig model. Twelve 8-week-old male Yorkshire pigs were placed on a synthetic Western diet and randomly divided into two groups (n = 6/group) for 30 days: (1) a placebo group supplemented with capsules containing unmodified pre-gelatinized potato starch (0 g/RS/day); and (2) an RS group supplemented with capsules containing resistant potato starch (10 g/RS/day). Serum lipids including total-cholesterol (C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides did not differ (p > 0.05) between the RS and placebo groups. Although the total numbers of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles were similar (p > 0.05) between the two groups, total high-density lipoprotein (HDL) particles were higher (+28%, p < 0.05) in the RS group compared with placebo, resulting from an increase (p < 0.05) in the small HDL subclass particles (+32%). Compared with the placebo group, RS supplementation lowered (p < 0.05) fasting serum glucose (-20%) and improved (p < 0.05) insulin resistance as estimated by Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) without a change in insulin. Additionally, total serum glucagon-like-peptide 1 (GLP-1) was higher (+141%, p < 0.05) following RS supplementation compared with placebo. This data suggests that in addition to the more well-characterized effect of RS intake in lowering blood glucose and improving insulin sensitivity, the consumption of RS may be beneficial in lipid management strategies by enhancing total HDL particle number.

Topics: Animals; Biomarkers; Blood Glucose; Diet, Western; Dietary Supplements; Fasting; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Male; Random Allocation; Starch; Swine; Triglycerides

Diabesity-obesity resulting in diabetes-is a major health problem globally because of the obesity epidemic. Several anti-diabetic medications cause weight gain and may worsen obesity, and possibly diabeisty. Two recent small retrospective cohort studies showed weight loss and diabetes improvement with combination of glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose co-transporter type-2 (SGLT-2) inhibitors in obese subjects. We assessed the effect of combination therapy with GLP-1 agonists and SGLT-2 inhibitors in the management of diabesity in a retrospective study at the Wolverhampton Diabetes Centre. Out of 79 patients on this combination regimen with other anti-diabetic medications, 37 cases who had follow up at 3-6 months were studied. Mean age and duration of follow up were 57.4 (+/-7.8) and 139 (+/-32.6) days, respectively. Twenty-two patients (59.5 %) were Asians. Statistically significant improvements in clinical parameters such as body weight reduction (3.07 kg), glycated haemoglobin (HbA1c) reduction (1.05 %), lower BMI (-1.13 kg/M

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Retrospective Studies; Sodium-Glucose Transporter 2; Treatment Outcome; Weight Loss

Enteroendocrine cells sense nutrients through taste receptors similar to those on the tongue. Sweet and fatty acid taste receptors (FFAR) coupled to the gustatory G-protein, gustducin, on enteroendocrine cells play a role in gut hormone release. We studied if supplementation of artificial (sucralose) or prebiotic (oligofructose; OFS) sweeteners target gustducin-mediated signaling pathways to alter gut hormone release and reduce obesity-associated disorders.. Wild-type (WT) and α-gustducin knockout (α-gust

Topics: Animals; Diet, High-Fat; Dietary Supplements; Enteroendocrine Cells; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Insulin Resistance; Male; Mice, Inbred C57BL; Mice, Knockout; Oligosaccharides; Peptide YY; Receptors, G-Protein-Coupled; Sucrose; Sweetening Agents; Transducin; Weight Gain

Pharmacological inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme potentiates incretin action and is widely used to treat type 2 diabetes. Nevertheless, the precise cells and tissues critical for incretin degradation and glucose homeostasis remain unknown. Here, we use mouse genetics and pharmacologic DPP4 inhibition to identify DPP4

Topics: Animals; Bone Marrow Transplantation; Diet, High-Fat; Dipeptidyl Peptidase 4; Enteral Nutrition; Feeding Behavior; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Homeostasis; Incretins; Insulin Resistance; Intestinal Mucosa; Intestines; Male; Mice; Models, Biological; Sitagliptin Phosphate

Topics: Adaptive Immunity; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Postprandial Period; Risk Factors

As a new hormone, betatrophin has gained attention as a potential new target to combat insulin resistance (IR) and diabetes. Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among women of the reproductive age with long term sequelae which include IR and metabolic syndrome. The aim of this study is to evaluate the circulating plasma betatrophin levels in overweight/obese or lean women with or without PCOS and also to elucidate possible correlations with anthropometric and metabolic parameters. Thirty-two patients with PCOS as well as fifty-three control subjects were enrolled after obtaining informed written consent. Clinical and biochemical parameters of all subjects were determined. Plasma adiponectin, GLP-1 and betatrophin levels were measured by ELISA. Plasma betatrophin levels were significantly increased in lean patients with PCOS compared with lean and obese controls. Moreover, in PCOS group, betatrophin levels were significantly negatively correlated with waist hip ratio (WHR), fasting insulin level (FINS) and HOMA-IR, whereas, significantly positively correlated with adiponectin level. Multiple regression analysis showed that HOMA-IR was an independent factor influencing serum betatrophin levels. Further follow-up studies are needed to highlight whether and how increased betatrophin secretion play an important role in IR and carbohydrates metabolism in patients with PCOS.

Topics: Adiponectin; Adolescent; Adult; Angiopoietin-Like Protein 8; Angiopoietin-like Proteins; Biomarkers; Body Mass Index; China; Cross-Sectional Studies; Female; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Middle Aged; Obesity; Overweight; Peptide Hormones; Polycystic Ovary Syndrome; Premenopause; Thinness; Waist-Hip Ratio; Young Adult

The superior effect of Roux-en-Y gastric bypass (RYGB) on glucose control compared with laparoscopic adjustable gastric banding (LAGB) is confounded by the greater weight loss after RYGB. We therefore examined the effect of these two surgeries on metabolic parameters matched on small and large amounts of weight loss.. Severely obese individuals with type 2 diabetes were tested for glucose metabolism, β-cell function, and insulin sensitivity after oral and intravenous glucose stimuli, before and 1 year after RYGB and LAGB, and at 10% and 20% weight loss after each surgery.. RYGB resulted in greater glucagon-like peptide 1 release and incretin effect, compared with LAGB, at any level of weight loss. RYGB decreased glucose levels (120 min and area under the curve for glucose) more than LAGB at 10% weight loss. However, the improvement in glucose metabolism, the rate of diabetes remission and use of diabetes medications, insulin sensitivity, and β-cell function were similar after the two types of surgery after 20% equivalent weight loss.. Although RYGB retained its unique effect on incretins, the superiority of the effect of RYGB over that of LAGB on glucose metabolism, which is apparent after 10% weight loss, was attenuated after larger weight loss.

Topics: Adult; Bariatric Surgery; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin Resistance; Longitudinal Studies; Male; Middle Aged; Obesity; Postoperative Period; Prospective Studies; Sweetening Agents; Weight Loss

Topics: Adaptive Immunity; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Postprandial Period; Risk Factors

Lipodystrophic syndromes are uncommon medical conditions which are normally associated with metabolic disorders, such as diabetes mellitus, dyslipidemia, and fatty liver disease. These complications are generally difficult to treat, particularly diabetes, due to severe insulin resistance. We present two case reports of successful treatment of diabetes with glucagon-like peptide-1 analogues in patients with clinical features of lipodystrophic syndromes.. Two white women aged 49 and 60 years manifested marked central body fat deposition with severe lipoatrophy of their limbs and buttocks and pronounced acanthosis nigricans. They had hypertension, dyslipidemia, fatty liver disease, and poorly controlled diabetes (glycated hemoglobin 8.3% and 10.2%, respectively) despite the use of three classes of oral antidiabetic drugs taken in combination in the first case, and high doses of insulin in the second case. Four months after the addition of glucagon-like peptide-1 analogue to their previous treatment they both showed a pronounced improvement in metabolic control (glycated hemoglobin 5.6% and 6.2%, respectively). In the first case, a weight loss of nearly 30 kg was recorded.. We intend to demonstrate that glucagon-like peptide-1 analogues could be a valuable tool for patients with lipodystrophic disorders, probably by improving body fat distribution, with favorable results in insulin-sensitivity and glycemic control.

Topics: Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Lipodystrophy; Middle Aged; Obesity; Treatment Outcome; Weight Loss

Hepatogenous diabetes is a complex disease that is typified by the simultaneous presence of type 2 diabetes and many forms of liver disease. The chief pathogenic determinant in this pathophysiological network is insulin resistance (IR), an asymptomatic disease state in which impaired insulin signaling in target tissues initiates a variety of organ dysfunctions. However, pharmacotherapies targeting IR remain limited and are generally inapplicable for liver disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment in many liver disorders. Here, we utilized the congruent pharmacological activities of OA and glucagon-like-peptide 1 (GLP-1) in relieving IR and improving liver and pancreas functions and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs. In particular, OA-triggered short human GLP-1 (shGLP-1) expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, whereas OA or shGLP-1 monotherapy failed to achieve corresponding therapeutic effects. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficacies of single therapeutics.

Topics: Animals; Cell Engineering; Cell Line; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Design; Gene Expression Regulation; Gene Regulatory Networks; Genetic Engineering; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Liver Diseases; Male; Mice; Mice, Transgenic; Oleanolic Acid; Synthetic Biology

Trehalose is hydrolyzed by a specific intestinal brush-border disaccharidase (trehalase) into two glucose molecules. In animal studies, trehalose has been shown to prevent adipocyte hypertrophy and mitigate insulin resistance in mice fed a high-fat diet. Recently, we found that trehalose improved glucose tolerance in human subjects. However, the underlying metabolic responses after trehalose ingestion in humans are not well understood. Therefore, we examined the glycemic, insulinemic and incretin responses after trehalose ingestion in healthy Japanese volunteers.. In a crossover study, 20 fasted healthy volunteers consumed 25 g trehalose or glucose in 100 mL water. Blood samples were taken frequently over the following 3 h, and blood glucose, insulin, active gastric inhibitory polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) levels were measured.. Trehalose ingestion did not evoke rapid increases in blood glucose levels, and had a lower stimulatory potency of insulin and active GIP secretion compared with glucose ingestion. Conversely, active GLP-1 showed higher levels from 45 to 180 min after trehalose ingestion as compared with glucose ingestion. Specifically, active GIP secretion, which induces fat accumulation, was markedly lower after trehalose ingestion.. Our findings indicate that trehalose may be a useful saccharide for good health because of properties that do not stimulate rapid increases in blood glucose and excessive secretion of insulin and GIP promoting fat accumulation.

Topics: Adult; Asian People; Blood Glucose; Body Mass Index; Cross-Over Studies; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Healthy Volunteers; Humans; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Trehalose; Young Adult

The current study aimed to investigate the effects of duodenal-jejunal bypass (DJB), new bilio-pancreatic diversion (NBPD), and duodenal-jejunal exclusion (DJE) on blood glucose in rats with type 2 diabetes mellitus (T2DM).. Male Sprague Dawley rats were fed with high glucose, high fat food, and intraperitoneally injected with streptozotocin to establish a T2DM animal model. T2DM rats were randomly assigned into 4 groups: a sham group (n = 8), DJB group (n = 9), NBPD group (n = 10), and DJE group (n = 10). Body weight, 2-h postprandial glucose, oral glucose tolerance, fasting serum bile acid, 2-h postprandial serum bile acid, fasting insulin, 2-h postprandial insulin (INS), fasting glucagon-like peptide-1 (GLP-1), and 2-h postprandial GLP-1 were measured before and after surgery.. Six weeks after surgery, the 2-h postprandial glucose in the DJB (16.1 ± 6.7 mmol/L) and NBPD (19.5 ± 5.7 mmol/L) groups decreased significantly compared to the sham group (25.8 ± 4.9 mmol/L) (P < 0.05). There was no significant difference between the DJE (25.0 ± 5.0 mmol/L) and sham groups (P > 0.05). Four weeks after surgery, fasting serum bile acid in the DJB group (60.6 ± 11.4 μmol/L) and NBPD group (54.4 ± 7.64 μmol/L) was significantly higher than that in the sham group (34.3 ± 6.98 μmol/L; P < 0.05). However, fasting GLP-1, 2-h postprandial GLP-1, and insulin remained unchanged at different time points after surgery (P > 0.05). Body weight remained stable after surgery in all 4 groups (P > 0.05).. NBPD plays a major role in the therapy of T2DM with DJB. NBPD may significantly increase fasting serum bile acid in T2DM rats, an action that may be one of the mechanisms underlying the therapeutic effects of DJB on T2DM.

Topics: Animals; Biliopancreatic Diversion; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Duodenum; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Insulin Resistance; Jejunum; Male; Rats; Rats, Sprague-Dawley; Streptozocin

Gastric bypass surgery results in remission of type 2 diabetes in the majority of patients. The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been implicated in the observed remission. Most knowledge so far has been generated in obese subjects. To isolate the surgical effects of gastric bypass on metabolism and hormone responses from the confounding influence of obesity, T2D, or food intake, we performed gastric bypass in lean pigs, using sham-operated and pair-fed pigs as controls. Thus, pigs were subjected to Roux-en-Y gastric bypass (RYGB) or sham surgery and oral glucose tolerance tests (OGTT). RYGB pigs and sham pigs exhibited similar basal and 120-min glucose levels in response to the OGTT. However, RYGB pigs had approximately 1.6-fold higher 30-min glucose (p<0.01). Early insulin release (EIR) was enhanced approximately 3.5-fold in the RYGB pigs (p<0.01). Furthermore, GIP release, both acute and sustained release (p<0.001 and p<0.01, respectively), was increased approximately 2.5-fold and 1.4-fold, respectively, in RYGB pigs. Although total GLP-1 release increased approximately 2.1-fold after RYGB (p<0.001), active GLP-1 was 33% lower (p<0.01). Interestingly basal DPP4-activity was approximately 3.2-fold higher in RYGB pigs (p<0.001). In conclusion, RYGB in lean pigs increases the response of GIP, total GLP-1, and insulin, but reduces levels of active GLP-1 in response to an oral glucose load. These data challenge the role of active GLP-1 as a contributor to remission from diabetes after RYGB.

Topics: Animals; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Obesity; Sus scrofa

GPR119 was originally identified as an orphan β-cell receptor; however, subsequent studies demonstrated that GPR119 also regulates β-cell function indirectly through incretin hormone secretion. We assessed the importance of GPR119 for β-cell function in

Topics: Adipokines; Animals; Apoptosis; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Gene Expression Profiling; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice, Knockout; Oxadiazoles; Pyrimidines; Receptors, G-Protein-Coupled

Non-alcoholic fatty liver disease (NAFLD) is the commonest hepatic disease in many parts of the World, with particularly high prevalence in patients with type 2 diabetes (T2DM). However, a good screening test for NAFLD in T2DM has not been established. Insulin resistance (IR) has been associated with NAFLD, and homeostatic model assessment of insulin resistance (HOMA-IR), a good proxy for IR, may represent an affordable predictive test which could be easily applied in routine clinical practice. We aimed to evaluate the diagnostic accuracy of HOMA-IR for NAFLD in T2DM and sought to estimate an optimal cut-off value for discriminating NAFLD from non-NAFLD cases.. We conducted a retrospective analysis of 56 well-controlled patients with T2DM (HbAc1<7%, on oral anti-diabetic and/or glucagon-like peptide-1 agonist treatment), who had at least one glucose and insulin level determined, and at least one hepatic imaging test (ultrasonography or computed tomography scanning).. The prevalence of NAFLD was 73.2% (95% CI: 59.7-84.2) in our population. An association between HOMA-IR and NAFLD was found (OR 1.5; 95% CI: 1.03-2.1; p=0.033), independently of transaminases, fat percentage, BMI and triglyceride levels. The AUROC curve of HOMA-IR for identifying NAFLD was 80.7% (95% CI: 68.9-92.5). A value of HOMA-IR of 4.5 was estimated to be an optimal threshold for discriminating NAFLD from non-NAFLD cases.. HOMA-IR is independently associated with the presence of NAFLD in adults with T2DM, and might potentially be applied in clinical practice as a screen for this condition.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Liver; Logistic Models; Male; Mass Screening; Middle Aged; Non-alcoholic Fatty Liver Disease; Retrospective Studies; ROC Curve; Spain; Tomography, X-Ray Computed; Ultrasonography

Soluble DPP4 (sDPP4) is a novel adipokine that degrades glucagon-like peptide (GLP-1). We evaluated the fasting serum levels of active GLP-1 and sDPP4 in obese, overweight and normal weight subjects to assess the association between sDPP4 levels, active GLP-1 levels and insulin resistance in obese subjects.. The study involved 235 Malaysian subjects who were randomly selected (66 normal weight subjects, 97 overweight, 59 obese subjects, and 13 subjects who were underweight). Serum sDPP4 and active GLP-1 levels were examined by enzyme-linked immunosorbent assay (ELISA). Also, body mass index kg/m. Serum sDPP4 levels were significantly higher in obese subjects compared to normal weight subjects (p=0.034), whereas serum levels of active GLP-1 were lower (p=0.021). In obese subjects, sDPP4 levels correlated negatively with active GLP-1 levels (r. Elevated serum sDPP4 levels and reduced GLP-1 levels were observed in obese subjects. In addition, sDPP4 levels correlated negatively with active GLP-1 levels but was positively associated with insulin resistance. This finding provides evidence that sDPP4 and GLP-1 may play an important role in the pathogenesis of obesity, suggesting that sDPP4 may be valuable as an early marker for the augmented risk of obesity and insulin resistance.

Topics: Adult; Aged; Biomarkers; Body Mass Index; Dipeptidyl Peptidase 4; Down-Regulation; Female; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Linear Models; Malaysia; Male; Middle Aged; Obesity; Overweight; Risk; Solubility; Thinness; Up-Regulation

The role of incretins in type 2 diabetes is controversial. This study investigated the association between incretin levels in obese Korean children and adolescents newly diagnosed with type 2 diabetes.. We performed a 2-hr oral glucose tolerance test (OGTT) in obese children and adolescents with type 2 diabetes and with normal glucose tolerance.. Twelve obese children and adolescents with newly diagnosed type 2 diabetes (DM group) and 12 obese age-matched subjects without type 2 diabetes (NDM group) were included.. An OGTT was conducted and insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were measured during the OGTT.. The mean age of the patients was 13·8 ± 2·0 years, and the mean body mass index (BMI) Z-score was 2·1 ± 0·5. The groups were comparable in age, sex, BMI Z-score and waist:hip ratio. The DM group had significantly lower homeostasis model assessment of β and insulinogenic index values (P < 0·001). The homeostasis model assessment of insulin resistance index was not different between the two groups. Insulin and C-peptide secretions were significantly lower in the DM group than in the NDM group (P < 0·001). Total GLP-1 secretion was significantly higher in the DM group while intact GLP-1 and GIP secretion values were not significantly different between the two groups.. Impaired insulin secretion might be important in the pathogenesis of type 2 diabetes in obese Korean children and adolescents, however, which may not be attributed to incretin secretion.

Topics: Adolescent; Analysis of Variance; Asian People; Blood Glucose; Body Mass Index; C-Peptide; Case-Control Studies; Child; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Male; Obesity; Republic of Korea

Chronic exposure to lipopolysaccharide (LPS) contributes to metabolic abnormalities, but there has been no study to evaluate plasma LPS levels after ileal transposition (IT). We examined the effect of IT on gut hormone secretion and plasma LPS levels and their correlation with metabolic parameters.. Sprague-Dawley rats underwent either IT or sham operation. After 4 weeks, oral glucose tolerance tests (OGTT) were performed and fasting plasma LPS and gut histology were analyzed.. Compared with the sham group, food intake and body weight decreased, and insulin sensitivity increased in the IT group. During the OGTTs, glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and peptide YY (PYY) were significantly higher in the IT group than the sham group. The villi length, muscle thickness, and the density of GLP-1 and glucose-dependent insulinotropic polypeptide co-expressing cells (K/L-cells) increased in the transposed ileum compared with the ileum of the sham group. Fasting plasma LPS levels were lower in the IT group than the sham group (5.6 ± 0.2 vs. 6.8 ± 0.1 EU/ml, P = 0.002) and significantly correlated with insulin resistance (r = 0.755, P < 0.001). Plasma LPS levels were negatively correlated with PYY secretion (r = -0.710, P = 0.001), and GLP-2 secretion (r = -0.561, P = 0.019).. IT surgery decreased plasma LPS levels in a non-obese non-diabetic rat model, which was associated with improved insulin sensitivity and increased L-cell secretion.

Topics: Animals; Blood Glucose; Body Weight; Drinking; Eating; Enteroendocrine Cells; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Tolerance Test; Ileum; Insulin Resistance; Lipopolysaccharides; Male; Obesity, Morbid; Peptide YY; Rats, Sprague-Dawley

Hymenochirin-1b (Hym-1B; IKLSPETKDNLKKVLKGAIKGAIAVAKMV.NH2) is a cationic, α-helical amphibian host-defense peptide with antimicrobial, anticancer, and immunomodulatory properties. This study investigates the abilities of the peptide and nine analogues containing substitutions of Pro(5), Glu(6), and Asp(9) by either L-lysine or D-lysine to stimulate insulin release in vitro using BRIN-BD11 clonal β cells or isolated mouse islets and in vivo using mice fed a high-fat diet to produce obesity and insulin resistance. Hym-1B produced a significant and concentration-dependent increase in the rate of insulin release from BRIN-BD11 cells without cytotoxicity at concentrations up to 1 µM with a threshold concentration of 1 nM. The threshold concentrations for the analogues were: [P5K], [E6K], [D9K], [P5K, E6K] and [E6K, D9k] 0.003 nM, [E6K, D9K] and [D9k] 0.01 nM, [P5K, D9K] 0.1 nM and [E6k] 0.3 nM. All peptides displayed cytotoxicity at concentrations ≥1 µM except the [P5K] and [D9k] analogues which were non-toxic at 3 µM. The potency and maximum rate of insulin release from mouse islets produced by the [P5K] peptide were significantly greater than produced by Hym-1B. Neither Hym-1B nor the [P5K] analogue at 1 µM concentration had an effect on membrane depolarization or intracellular Ca(2+). The [P5K] analogue (1 µM) produced a significant increase in cAMP concentration in BRIN-BD11 cells and stimulated GLP-1 secretion from GLUTag cells. Down-regulation of the protein kinase A pathway by overnight incubation with forskolin completely abolished the insulin-releasing effects of [P5K]hym-1B. Intraperitoneal administration of the [P5K] and [D9k] analogues (75 nmol/kg body weight) to high-fat-fed mice with insulin resistance significantly enhanced glucose tolerance with a concomitant increase in insulin secretion. We conclude that [P5K]hym-1B and [D9k]hym-1B show potential for development into anti-diabetic agents.

Topics: Amphibian Proteins; Animals; Antimicrobial Cationic Peptides; Anura; Calcium; Cell Line; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; L-Lactate Dehydrogenase; Membrane Potentials; Mice; Mice, Inbred C57BL; Organ Culture Techniques; Protein Kinase C; Rats; Structure-Activity Relationship

This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function.. Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified using in-phase, out-of-phase MRI. Also measured were the first-phase insulin response to a stepped intravenous glucose infusion, hepatic insulin sensitivity, and glycemic and incretin responses to a semisolid test meal.. Weight loss after surgery was similar (NGT: 12.8 ± 0.8% and T2DM: 13.6 ± 0.7%) as was the change in fat mass (56.7 ± 3.3 to 45.4 ± 2.3 vs. 56.6 ± 2.4 to 43.0 ± 2.4 kg). Pancreatic triacylglycerol did not change in NGT (5.1 ± 0.2 to 5.5 ± 0.4%) but decreased in the group with T2DM (6.6 ± 0.5 to 5.4 ± 0.4%; P = 0.007). First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT (0.24 [0.13-0.46] to 0.23 [0.19-0.37] nmol ⋅ min(-1) ⋅ m(-2)) but normalized in T2DM (0.08 [-0.01 to -0.10] to 0.22 [0.07-0.30]) nmol ⋅ min(-1) ⋅ m(-2) at week 8 (P = 0.005). No differential effect of incretin secretion was observed after gastric bypass, with more rapid glucose absorption bringing about equivalently enhanced glucagon-like peptide 1 secretion in the two groups.. The fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Middle Aged; Pancreas; Randomized Controlled Trials as Topic; Triglycerides; Weight Loss

In a recent study, we showed a jejuno-ileal circuit (JIC) procedure that effectively improved glucose homeostasis, but the intrinsic mechanism requires further studies. Furthermore, the role of JIC in lipid metabolism is also unknown. Given that adiposity aggravates insulin sensitivity, we hypothesize that the JIC procedure improves fat metabolism and thus further contributes to diabetic remission. The aim of this study was to investigate the effects of JIC surgery on lipid metabolism and glucose homeostasis in a non-obese diabetic rat model.. Fourteen high-fat diet and low-dose streptozotocin-induced diabetic rats were randomly divided into JIC and sham-JIC groups. Body weight, food intake, glucose tolerance, insulin resistance, serum lipid parameters, glucagon-like peptide 1 (GLP-1), and adipose-derived hormones were measured. At 12 weeks postoperatively, the expressions of hepatic fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) were measured by Western blot. The lipid content of liver was assessed by hematoxylin-eosin staining and Oil Red O staining. The enteroendocrine cells in the distal ileum were examined by immunohistochemical staining.. Relative to the sham group, the JIC rats exhibited significant improvements in glucose tolerance, insulin resistance, and dyslipidemia without weight loss, showing increased GLP-1 and adiponectin and decreased leptin. JIC also reduced the expression of FAS and ACC in the liver, exhibited improved hepatic fat content, and raised the levels of GLP-1 and chromogranin A in the distal gut.. JIC alleviated lipometabolic disorders in hyperglycemic rats, which may contribute to the amelioration of insulin sensitivity and glycemic control.

Topics: Animals; Blood Glucose; Cholesterol; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin Resistance; Jejunoileal Bypass; Lipid Metabolism; Male; Random Allocation; Rats; Rats, Wistar; Triglycerides

To assess glucagon-like peptide 1 (GLP-1) secretion after oral glucose tolerance tests (OGTTs) in subjects with newly diagnosed type 2 diabetes mellitus (T2DM), impaired glucose tolerance (IGT), and normal glucose tolerance (NGT) to clarify changes in GLP-1 secretion during the course of T2DM. . In this cross sectional study, 80 subjects were divided into the NGT, IGT, and T2DM groups after undergoing a 75 g OGTT from March to December 2014 at the School of Medicine, First Affiliated Hospital, Shihezi University, Xinjiang, China. Plasma total GLP-1 was measured at 0, 30, 60, 120, and 180 minutes. Homeostasis model assessment of insulin resistance (HOMA-IR), islet β-cell function (HOMA-β), Gutt index, Matsuda index, incremental GLP-1 (ΔGLP-1), and areas under the curves of GLP-1 (AUCglp-1), glucose (AUCg), and insulin (AUCins) were calculated.. Plasma total GLP-1 at 30-120 minutes and ΔGLP-1 at 30-120 minutes were lower in the T2DM group than in the IGT and NGT groups (p less than 0.05). Peak GLP-1 levels were 35% lower in the T2DM group than in the NGT group. Plasma total GLP-1, ΔGLP-1, and AUCglp-1 correlated negatively with HOMA-IR and AUCg, and positively with HOMA-β, Gutt index, Matsuda index, and AUCins (p less than 0.05). . The GLP-1 secretion after 75 g OGTT was impaired in newly diagnosed T2DM patients, inversely proportional to IR and hyperglycemia, and positively correlated with β-cell function and insulin sensitivity.

Topics: Adult; Area Under Curve; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged

The physiological role of the TGR5 receptor in the pancreas is not fully understood. We previously showed that activation of TGR5 in pancreatic β cells by bile acids induces insulin secretion. Glucagon released from pancreatic α cells and glucagon-like peptide 1 (GLP-1) released from intestinal L cells regulate insulin secretion. Both glucagon and GLP-1 are derived from alternate splicing of a common precursor, proglucagon by PC2 and PC1, respectively. We investigated whether TGR5 activation in pancreatic α cells enhances hyperglycemia-induced PC1 expression thereby releasing GLP-1, which in turn increases β cell mass and function in a paracrine manner. TGR5 activation augmented a hyperglycemia-induced switch from glucagon to GLP-1 synthesis in human and mouse islet α cells by GS/cAMP/PKA/cAMP-response element-binding protein-dependent activation of PC1. Furthermore, TGR5-induced GLP-1 release from α cells was via an Epac-mediated PKA-independent mechanism. Administration of the TGR5 agonist, INT-777, to db/db mice attenuated the increase in body weight and improved glucose tolerance and insulin sensitivity. INT-777 augmented PC1 expression in α cells and stimulated GLP-1 release from islets of db/db mice compared with control. INT-777 also increased pancreatic β cell proliferation and insulin synthesis. The effect of TGR5-mediated GLP-1 from α cells on insulin release from islets could be blocked by GLP-1 receptor antagonist. These results suggest that TGR5 activation mediates cross-talk between α and β cells by switching from glucagon to GLP-1 to restore β cell mass and function under hyperglycemic conditions. Thus, INT-777-mediated TGR5 activation could be leveraged as a novel way to treat type 2 diabetes mellitus.

Topics: Animals; Benzene Derivatives; Benzenesulfonates; Cell Line; Cholic Acids; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Estrenes; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Homeostasis; Humans; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Paracrine Communication; Proprotein Convertase 1; Proprotein Convertase 2; Pyrrolidinones; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones

The small intestine may be involved in the improvement of glucose and lipid metabolism after bariatric surgery; however, the role of the foregut in metabolic changes remains unclear. This study used normal rats fed a high-fat diet (HFD) after bariatric surgery to determine the role of the foregut in glucose and lipid metabolism.. Duodenum-jejunum bypass (DJB), gastrojejunostomy (GJ) and sham-operations were performed on Sprague-Dawley (SD) rats. Oral glucose tolerance, insulin sensitivity, β-cell function, lipid profile, glucose-stimulated glucose-dependent insulinotropic polypeptide (GIP) levels and glucagon-like peptide-1 (GLP-1) levels were measured. The rats were observed for 24 weeks post-surgery.. Food intake and body weight were similar between the groups during the study period (P>0.05). The DJB group exhibited better glucose and lipid metabolism than the other groups (P<0.05). Compared with the GJ group, the DJB group demonstrated superior oral glucose tolerance, insulin sensitivity and lipid profiles (P<0.05); β-cell function in the two groups was similar (P>0.05). The GIP levels were decreased in the DJB group and increased in the GJ group (P<0.05), and the GLP-1 levels were increased in the DJB and GJ groups (P>0.05).. We found that foregut exclusion can prevent disordered glucose and lipid metabolism. Additionally, decreased GIP secretion was associated with improvements in glucose tolerance and insulin sensitivity, particularly related to lipid metabolism. Increased GLP-1 benefited β-cell function; however, it could not reverse the disordered glucose and lipid metabolism induced by a HFD.

Topics: Animals; Blood Glucose; Body Weight; Diet, High-Fat; Duodenum; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin Resistance; Jejunum; Lipid Metabolism; Male; Rats; Rats, Sprague-Dawley

Oxidative stress plays an important role in the development of beta-cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. Expression levels of antioxidant enzymes in beta cells are very low, rendering them more susceptible to damage caused by reactive oxygen species (ROS). Although the antioxidant effects of glucagon-like peptide-1 (GLP-1) and its analogs have been previously reported, the exact mechanisms involved are still unclear. In this study, we demonstrated that GLP-1 was able to effectively inhibit oxidative stress and cell death of INS-1E beta cells induced by the pro-oxidant tert-butyl hydroperoxide (tert-BOOH). Incubation with GLP-1 enhanced cellular levels of glutathione and the activity of its related enzymes, glutathione-peroxidase (GPx) and -reductase (GR) in beta cells. However, inhibition of ERK, but not of the PI3K/AKT pathway abolished, at least in part, the antioxidant effect of GLP-1. Moreover, ERK activation seems to be protein kinase A (PKA)-dependent because inhibition of PKA with H-89 was sufficient to block the GLP-1-derived protective effect on beta cells. GLP-1 likewise increased the synthesis of GR and favored the translocation of the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Glucose-stimulated insulin secretion was also preserved in beta-cells challenged with tert-BOOH but pre-treated with GLP-1, probably through the down-regulation of the mitochondrial uncoupling-protein2 (UCP2). Thus, our results provide additional mechanisms of action of GLP-1 to prevent oxidative damage in beta cells through the modulation of signaling pathways involved in antioxidant enzyme regulation.

Topics: Animals; Antioxidants; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus, Type 2; Extracellular Signal-Regulated MAP Kinases; Glucagon-Like Peptide 1; Glucose; Glutathione; Glutathione Reductase; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Isoquinolines; NF-E2-Related Factor 2; Oxidative Stress; Rats; Reactive Oxygen Species; Sulfonamides; tert-Butylhydroperoxide; Uncoupling Protein 2

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85α regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome - a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism.

Topics: Amino Acid Substitution; Animals; Glucagon-Like Peptide 1; Growth Hormone; Insulin; Insulin Resistance; Insulin Secretion; Lipodystrophy; Liver; Mice; Mice, Mutant Strains; Mutation, Missense; Phosphatidylinositol 3-Kinases

Obesity and type 2 diabetes mellitus are increasing worldwide, reaching pandemic proportions. The understanding of the role of functional restriction and gut hormones can be a beneficial tool in treating obesity and diabetes. However, the exact hormonal profiles in different metabolic states and surgical models are not known.. The HIPER-1 Study is a single-centre cross-sectional study in which 240 patients (in different metabolic states and surgical models) will receive an oral mixed-meal tolerance test (OMTT). At baseline and after 30, 60 and 120 min, peptide YY and glucagon-like peptide 1 levels and glucose and insulin sensitivity will be measured. The primary end point of the study will be the area under the glucagon-like peptide 1 and peptide YY curves after the OMTT. Secondary study end points will include examination of the difference in plasma levels of the distal ileal hormones in subjects with various health statuses and in patients who have been treated with different surgical techniques.. An independent ethics committee, the Institutional Review Board of Istanbul Sisli Kolan International Hospital, Turkey, has approved the study protocol. Dissemination will occur via publication, national and international conference presentations, and exchanges with regional, provincial and national stakeholders.. NCT02532829; Pre-results.

Topics: Adult; Blood Glucose; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Female; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Models, Anatomic; Obesity; Peptide YY; Prospective Studies; Research Design; Turkey

Roux-en-Y gastric bypass (RYGB) causes profound weight loss and remission of diabetes by influencing metabolic physiology, yet the mechanisms behind these clinical improvements remain undefined. After RYGB, levels of glucagon-like peptide-1 (GLP-1), a hormone that enhances insulin secretion and promotes satiation, are substantially elevated. Because GLP-1 signals in both the periphery and the brain to influence energy balance and glucose regulation, we aimed to determine the relative requirements of these systems to weight loss and improved glucose tolerance following RYGB surgery in mice. By pharmacologically blocking peripheral or central GLP-1R signaling, we examined whether GLP-1 action is necessary for the metabolic improvements observed after RYGB. Diet-induced obese mice underwent RYGB or sham operation and were implanted with osmotic pumps delivering the GLP-1R antagonist exendin-(9-39) (2 pmol·kg(-1)·min(-1) peripherally; 0.5 pmol·kg(-1)·min(-1) centrally) for up to 10 wk. Blockade of peripheral GLP-1R signaling partially reversed the improvement in glucose tolerance after RYGB. In contrast, fasting glucose and insulin sensitivity, as well as body weight, were unaffected by GLP-1R antagonism. Central GLP-1R signaling did not appear to be required for any of the metabolic improvements seen after this operation. Collectively, these results suggest a detectable but only modest role for GLP-1 in mediating the effects of RYGB and that this role is limited to its well-described action on glucose regulation.

Topics: Animals; Blood Glucose; Body Weight; Diet, High-Fat; Energy Metabolism; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Insulin; Insulin Resistance; Male; Mice; Obesity; Peptide Fragments; Signal Transduction

According to some authors, in type 2 diabetes there is a reduced postprandial action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, little is known about the role of fasting incretins in glucose homeostasis. Our aim was to evaluate, through a two-step cluster analysis, the possibility of phenotyping patients with type 2 diabetes at onset on the basis of fasting GLP-1, GIP and ghrelin.. A total of 96 patients with type 2 diabetes within 6 months of onset (mean age 62.40 ± 6.36 years) were cross-sectionally studied. Clinical, anthropometric and metabolic parameters were evaluated. At fasting the following were carried out: assay of GLP-1, GIP, ghrelin, insulin, C-peptide, glucagon and a panel of adipocytokines (visfatin, resistin, leptin, soluble leptin receptor and adiponectin).. The analysis resulted in two clusters: cluster 1 (63 patients) had significantly lower levels of GLP-1 (4.93 ± 0.98 vs 7.81 ± 1.98 pmol/L; P < 0.001), GIP (12.73 ± 9.44 vs 23.88 ± 28.56 pmol/L; P < 0.001) and ghrelin (26.54 ± 2.94 vs 39.47 ± 9.84 pmol/L; P < 0.001) compared with cluster 2 (33 patients). Between the two clusters, no differences in age, duration of disease, sex, clinical-anthropometric parameters, insulin sensitivity and adipocytokines were highlighted. However, cluster 1 was associated with significantly higher levels of glycated hemoglobin (7.4 ± 0.61 vs 6.68 ± 0.57%, P = 0.007), glucagon (232.02 ± 37.27 vs 183.33 ± 97.29 ng/L; P = 0.001), fasting glucose (7.85 ± 1.60 vs 6.93 ± 1.01 mmol/L; P = 0.003) and significantly lower levels of C-peptide (0.12 ± 0.11 vs 0.20 ± 0.20 nmol/L; P = 0.017).. The present study suggests that fasting incretins play an important role in the pathophysiology of type 2 diabetes, which requires to further investigation.

Topics: Aged; Blood Glucose; Cluster Analysis; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Incretins; Insulin Resistance; Male; Middle Aged; Phenotype

Several biomarkers within the iron metabolism pathway have been related to the occurrence of diabetes mellitus, but underlying mechanisms are unknown. The aim of our study was to investigate the differential relationships of iron metabolism with a broad range of diabetes markers in young and healthy adults.. 2160 participants aged 25 to 41years were enrolled in a population-based study. Established cardiovascular disease, diabetes or a body mass index >35kg/m(2) were exclusion criteria. Multivariable linear regression models were built to assess the associations of ferritin and transferrin saturation (TSAT) with blood levels of glucagon-like peptide-1 (GLP-1), insulin, homeostatic model assessment-insulin resistance (HOMA-IR), fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c).. Median (interquartile range) age was 37 (31, 40) years. In multivariable linear regression analyses, β-coefficients (95% confidence intervals) per 1-SD increase in ferritin were 0.04 (0.02; 0.07, p=0.0008) for GLP-1, 0.06 (0.04; 0.08, p<0.0001) for insulin, 0.07 (0.04; 0.09, p<0.0001) for HOMA-IR, 0.004 (-0.00; 0.01, p=0.07) for FPG and -0.003 (-0.01; -0.00, p=0.07) for HbA1c. β-coefficients (95% CI) per 1-SD increase in TSAT were -0.07 (-0.09; -0.05, p<0.0001) for GLP-1, -0.06 (-0.08; -0.04, p<0.0001) for insulin, -0.07(-0.09; -0.05, p<0.0001) for HOMA-IR, -0.01 (-0.01; -0.00, p<0.0001) for FPG and -0.01 (-0.01; -0.00, p=0.0004) for HbA1c.. Markers of insulin resistance are strongly related with markers of iron metabolism in healthy subjects. These relationships were inconsistent and weaker for short-term and long-term glucose levels. These results may provide insights in the relationships between iron metabolism and diabetes occurrence.

Topics: Adult; Blood Glucose; C-Reactive Protein; Female; Ferritins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Inflammation; Insulin; Insulin Resistance; Iron; Linear Models; Male; Multivariate Analysis; Transferrin

Muscle microvasculature critically regulates endothelial exchange surface area to facilitate transendothelial delivery of insulin, nutrients, and oxygen to myocytes. Insulin resistance blunts insulin-mediated microvascular recruitment and decreases muscle capillary density; both contribute to lower microvascular blood volume. Glucagon-like peptide 1 (GLP-1) and its analogs are able to dilate blood vessels and stimulate endothelial cell proliferation. In this study, we aim to determine the effects of sustained stimulation of the GLP-1 receptors on insulin-mediated capillary recruitment and metabolic insulin responses, small arterial endothelial function, and muscle capillary density. Rats were fed a high-fat diet (HFD) for 4 wk with or without simultaneous administration of liraglutide and subjected to a euglycemic hyperinsulinemic clamp for 120 min after an overnight fast. Insulin-mediated muscle microvascular recruitment and muscle oxygenation were determined before and during insulin infusion. Muscle capillary density was determined and distal saphenous artery used for determination of endothelial function and insulin-mediated vasodilation. HFD induced muscle microvascular insulin resistance and small arterial vessel endothelial dysfunction and decreased muscle capillary density. Simultaneous treatment of HFD-fed rats with liraglutide prevented all of these changes and improved insulin-stimulated glucose disposal. These were associated with a significantly increased AMPK phosphorylation and the expressions of VEGF and its receptors. We conclude that GLP-1 receptor agonists may exert their salutary glycemic effect via improving microvascular insulin sensitivity and muscle capillary density during the development of insulin resistance, and early use of GLP-1 receptor agonists may attenuate metabolic insulin resistance as well as prevent cardiovascular complications of diabetes.

Topics: Animals; Capillaries; Diet, High-Fat; Endothelium, Vascular; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Insulin; Insulin Resistance; Liraglutide; Male; Microvessels; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Vasodilation

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the incretin hormones secreted from the intestine in response to enteral feeding to stimulate insulin secretion. We investigated the relationship serum GIP and GLP-1 levels with gestational age, and insulin secretion in preterm infants. Serum GIP and GLP-1 levels were measured at birth and at 1, 2 and 4 weeks after birth in 30 infants, including 12 born before 30th week of gestation (early group) and 18 born after 30th week of gestation (late group). Blood glucose and serum insulin levels were measured, and the quantitative insulin sensitivity check index (QUICKI) was also calculated. The levels of GLP-1 at 2 and 4 weeks were significantly higher in the early group than those in the late group. The levels of GIP were not significantly different between two groups. At 4 weeks, serum insulin level was significantly higher and QUICKI was significantly lower in the early group. Furthermore, GLP-1 levels were significantly correlated with QUICKI and the serum insulin levels in all infants at 4 weeks. In preterm infants, enteral feeding to premature intestine may be associated with GLP-1 secretion. GLP-1 is also related to stimulated insulin secretion in early postnatal period.

Topics: Adult; Blood Glucose; Female; Gastric Inhibitory Polypeptide; Gestational Age; Glucagon-Like Peptide 1; Humans; Incretins; Infant, Newborn; Infant, Premature; Insulin; Insulin Resistance; Male; Pilot Projects

The correlation between resected gastric volume (RGV) and neuro-humoral changes (ghrelin and GLP-1) after laparoscopic sleeve gastrectomy (LSG) and their effects on type 2 diabetes mellitus (T2DM) has been evaluated.. Ninety-eight patients were divided in two groups: RGV <1200 mL (group A: 53 pts) and RGV >1200 mL (group B: 45 pts). Insulin secretion (insulin area under the curve (AUC)), insulinogenic index (IGI) and insulin-resistance (homeostasis model assessment, HOMA. A significant difference in T2DM resolution rate was observed after 6, 12 and 24 months in favour of RGV >1200 mL. Group B performed better than group A at the 3rd day and at the 6th, 12th and 24th months with regard to AUC, IGI and HOMA. Ghrelin and GLP-1 changes play a role in the regulation of glucose metabolism during the 1st year after LSG. RGV influences ghrelin and GLP-1 plasma levels after LSG, with a significant improvement in the T2DM control.

Topics: Adult; Bariatric Surgery; Diabetes Mellitus, Type 2; Female; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Laparoscopy; Male; Middle Aged; Obesity, Morbid; Organ Size; Postoperative Period; Preoperative Period; Prospective Studies; Stomach

Glucagon-like peptide 1 (GLP-1), a kind of gut hormone, is used in the treatment of type 2 diabetes (T2D). Emerging evidence indicates that GLP-1 has anti-inflammatory activity. Chronic inflammation in the adipose tissue of obese individuals is a cause of insulin resistance and T2D. We hypothesized that GLP-1 analogue therapy in patients with T2D could suppress the inflammatory response of macrophages, and therefore inhibit insulin resistance. Our results showed that GLP-1 agonist (exendin-4) not only attenuated macrophage infiltration, but also inhibited the macrophage secretion of inflammatory cytokines including TNF-β, IL-6, and IL-1β. Furthermore, we observed that lipopolysaccharide (LPS)-induced macrophage conditioned media could impair insulin-stimulated glucose uptake. This effect was compensated by treatment with the conditioned media from macrophages treated with the combination of LPS and exendin-4. It was also observed that exendin-4 directly inhibited the activation of NF-κB in macrophages. In conclusion, our results indicated that GLP-1 improved inflammatory macrophage-derived insulin resistance by inhibiting NF-κB pathway and secretion of inflammatory cytokines in macrophages. Furthermore, our observations suggested that the anti-inflammatory effect of GLP-1 on macrophages can contribute to GLP-1 analogue therapy of T2D.

Topics: Adipose Tissue; Animals; Cell Migration Assays; Exenatide; Glucagon-Like Peptide 1; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Macrophages; Mice; Peptides; Venoms

To investigate whether or not berberine could improve metabolic status of high-fat-fed rats through modulation of microbiota-gut-brain axis.. Berberine was administered on high-fat-fed Sprague-Dawley rats. Brain-gut hormones were detected, and changes of gut microbiota were analyzed by 16S rRNA gene sequencing.. Berberine could reduce weight gain and lipolysis in the high-fat diet-fed group. Moreover, trends of ameliorated insulin resistance and decreased endogenous glucose production were observed. In addition, the microbiota-gut-brain axis was found to be modulated, including structural and diversity changes of microbiota, elevated serum glucagon-like peptide-1 and neuropeptide Y level, decreased orexin A level, up-regulated glucagon-like peptide-1 receptor mRNA level as well as ultra-structural improvement of the hypothalamus.. Taken together, our findings suggest that berberine improved metabolic disorders induced by high-fat diet through modulation of the microbiota-gut-brain axis.

Topics: Animals; Berberine; Brain; Diet, High-Fat; Energy Metabolism; Gastrointestinal Microbiome; Glucagon-Like Peptide 1; Insulin Resistance; Intestines; Male; Rats; Rats, Sprague-Dawley; RNA, Ribosomal, 16S; Signal Transduction; Weight Gain

The fungal product (+)-antroquinonol activates AMP kinase (AMPK) activity in cancer cell lines. The present study was conducted to examine whether chemically synthesized (+)-antroquinonol exhibited beneficial metabolic effects in insulin-resistant states by activating AMPK and inhibiting dipeptidyl peptidase IV (DPP IV) activity.. Effects of (+)-antroquinonol on DPP IV activity were measured with a DPPIV Assay Kit and effects on GLP-1-induced PKA were measured in AR42J cells. Translocation of the glucose transporter 4, GLUT4, induced either by insulin-dependent PI3K/AKT signalling or by insulin-independent AMPK activation, was assayed in differentiated myotubes. Glucose uptake and GLUT4 translocation were assayed in L6 myocytes. Mice with diet-induced obesity were used to assess effects of acute and chronic treatment with (+)-antroquinonol on glycaemic control in vivo.. The results showed that of (+)-antroquinonol (100 μM ) inhibited the DPP IV activity as effectively as the clinically used inhibitor, sitagliptin. The phosphorylation of AMPK Thr(172) in differentiated myotubes was significantly increased by (+)-antroquinonol. In cells simultaneously treated with S961 (insulin receptor antagonist), insulin and (+)-antroquinonol, the combination of (+)-antroquinonol plus insulin still increased both GLUT4 translocation and glucose uptake. Further, (+)-antroquinonol and sitagliptin reduced blood glucose, when given acutely or chronically to DIO mice.. Chemically synthesized (+)-antroquinonol exhibits dual effects to ameliorate insulin resistance, by increasing AMPK activity and GLUT4 translocation, along with inhibiting DPP IV activity.

Topics: AMP-Activated Protein Kinases; Animals; Caco-2 Cells; Cell Line; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Glucose Transporter Type 4; Humans; Insulin Resistance; Mice; Obesity; Rats; Ubiquinone

The decrease in lipotoxicity is one of the crucial mechanisms by which Roux-en-Y gastric bypass (RYGB) improves insulin sensitivity. Little work, however, has been performed to elucidate the exact mechanism of RYGB reducing hepatic lipid overaccumulation in response to heavy lipid and glucose challenge. Here, we explored the effects of RYGB on hepatic autophagy in obese diabetic rats.. Sprague-Dawley rats were divided into five groups: diabetic RYGB, diabetic RYGB sham, diabetic food restriction (FR), diabetic rats, and non-diabetic controls (n = 12/group). At 4-week post-operation, genetic and protein expressions of autophagy markers including Atg7 and Beclin 1 and the conversion of LC3 were examined with quantitative RT-PCR and Western blotting. Plasma glucagon-like peptide-1 (GLP-1) and triglyceride and total cholesterol levels in liver tissue were tested.. In both genetic and protein levels, we observed a significant upregulated autophagy in liver at 4 weeks after RYGB. Restored autophagy in liver played a key role in reducing the hepatic lipid burden in obese diabetic rats. The marked increase of autophagy in liver after RYGB correlated well with the plasma GLP-1 level.. Our data demonstrate that RYGB significantly upregulated hepatic autophagy. We suggest that the effects of RYGB on autophagy in liver may be due to the increased GLP-1 level after surgery. Moreover, the activated autophagy in liver might play a key role in reducing the hepatic lipid overaccumulation after RYGB.

Topics: Animals; Autophagy; Blood Glucose; Diabetes Mellitus, Experimental; Gastric Bypass; Glucagon-Like Peptide 1; Insulin Resistance; Lipid Metabolism; Liver; Male; Obesity; Rats; Rats, Sprague-Dawley; Triglycerides; Up-Regulation

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin(9-39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.

Topics: Adult; Blood Glucose; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Life Style; Male; Middle Aged; Obesity

Teneligliptin is a novel peptidomimetic-chemotype prolylthiazolidine-based inhibitor of dipeptidyl peptidase-4 (DPP-4). The aim of this study was to evaluate the effects of teneligliptin on 24 h blood glucose control and gastrointestinal hormone responses to a meal tolerance test, and to investigate the glucose-lowering mechanisms of teneligliptin. Ten patients with type 2 diabetes mellitus (T2DM) were treated for 3 days with teneligliptin (20 mg/day). Postprandial profiles for glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), active glucose-dependent insulinotropic polypeptide (GIP), ghrelin, des-acyl ghrelin, and 24 h glycemic fluctuations were measured via continuous glucose monitoring for 4 days. Once daily teneligliptin administration for 3 days significantly lowered postprandial and fasting glucose levels. Significant elevations of fasting and postprandial active GLP-1 and postprandial active GIP levels were observed. Teneligliptin lowered postprandial glucose elevations, 24 h mean blood glucose levels, standard deviation of 24 h glucose levels and mean amplitude of glycemic excursions (MAGE) without hypoglycemia. Serum insulin levels in the fasting state and 30 min after a meal were similar before and after teneligliptin treatment; however significant reductions at 60 to 180 min after treatment were observed. A significant elevation in early-phase insulin secretion estimated by insulinogenic and oral disposition indices, and a significant reduction in postprandial glucagon AUC were observed. Both plasma ghrelin and des-acyl ghrelin levels were unaltered following teneligliptin treatment. Teneligliptin improved 24 h blood glucose levels by increasing active incretin levels and early-phase insulin secretion, reducing the postprandial insulin requirement, and reducing glucagon secretion. Even short-term teneligliptin treatment may offer benefits for patients with T2DM.

Topics: Aged; Blood Glucose; Combined Modality Therapy; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Japan; Middle Aged; Monitoring, Ambulatory; Postprandial Period; Pyrazoles; Thiazolidines

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with metabolic complications. Metabolic biomarkers with roles in obesity, glycaemic control and lipid metabolism are potentially relevant in PCOS. The aim was to investigate metabolic biomarkers in lean and overweight women with and without PCOS and to determine whether any biomarker was able to predict insulin resistance in PCOS.. Cross-sectional study.. Eighty-four women (22 overweight and 22 lean women with PCOS, 18 overweight and 22 lean women without PCOS) were recruited from the community and categorized based on PCOS and BMI status.. Primary outcomes were metabolic biomarkers [ghrelin, resistin, visfatin, glucagon-like peptide-1 (GLP-1), leptin, plasminogen activator inhibitor -1 (PAI-1), glucose-dependent insulinotropic polypeptide (GIP) and C-Peptide] measured using the Bio-Plex Pro Diabetes assay and insulin sensitivity as assessed by glucose infusion rate on euglycaemic-hyperinsulinaemic clamp.. The biomarkers C-peptide, leptin, ghrelin and visfatin were different between overweight and lean women, irrespective of PCOS status. The concentration of circulating biomarkers did not differ between women with PCOS diagnosed by the Rotterdam criteria or National Institute of Health criteria. PAI-1 was the only biomarker that significantly predicted insulin resistance in both control women (P = 0.04) and women with PCOS (P = 0.01).. Biomarkers associated with metabolic diseases appear more strongly associated with obesity rather than PCOS status. PAI-1 may also be a novel independent biomarker and predictor of insulin resistance in women with and without PCOS.

Topics: Adult; Biomarkers; C-Peptide; Case-Control Studies; Cross-Sectional Studies; Cytokines; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose Clamp Technique; Humans; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Overweight; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome; Predictive Value of Tests; Resistin; Young Adult

Gastric bypass (GBP) results in rapid type 2 diabetes (T2D) remission in most cases. Consequences of GBP reversal are unknown. A GBP-operated T2D patient was given mixed-meal tests before (MMTpre), 2 months (MMT2-M) and 12 months (MMT12-M) after GBP reversal. Glucose, hormones and metabolite profiles were assessed. MMT2-M displayed slightly lower glucose levels; MMT12-M displayed higher glucose and insulin levels, indicating deteriorating glycaemia. Homeostasis model assessment (HOMA)-β was higher at MMT2-M, but reduced at MMT12-M. Matsuda index revealed slightly reduced insulin sensitivity at MMT2-M, which deteriorated further at MMT12-M. Markers for metabolic stress and insulin resistance were elevated at MMT12-M. Gastric inhibitory polypeptide (GIP) levels were increased at MMT2-M and decreased at MMT12-M. Glucagon-like peptide-1 (GLP-1) decreased at MMT2-M and further decreased at MMT12-M. In conclusion, in this patient, GBP reversal provoked deteriorating glycaemia and long-term development of insulin resistance.

Topics: Anastomosis, Surgical; Blood Glucose; Diabetes Mellitus, Type 2; Follow-Up Studies; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Meals; Middle Aged; Time Factors

Besides their role in facilitating lipid absorption, bile acids are increasingly being recognized as signaling molecules that activate cell-signaling receptors. Targeted disruption of the sterol 12α-hydroxylase gene (Cyp8b1) results in complete absence of cholic acid (CA) and its derivatives. Here we investigate the effect of Cyp8b1 deletion on glucose homeostasis. Absence of Cyp8b1 results in improved glucose tolerance, insulin sensitivity, and β-cell function, mediated by absence of CA in Cyp8b1(-/-) mice. In addition, we show that reduced intestinal fat absorption in the absence of biliary CA leads to increased free fatty acids reaching the ileal L cells. This correlates with increased secretion of the incretin hormone GLP-1. GLP-1, in turn, increases the biosynthesis and secretion of insulin from β-cells, leading to the improved glucose tolerance observed in the Cyp8b1(-/-) mice. Thus, our data elucidate the importance of Cyp8b1 inhibition on the regulation of glucose metabolism.

Topics: Animals; Cholic Acid; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Homeostasis; Insulin; Insulin Resistance; Insulin-Secreting Cells; Mice; Mice, Knockout; Steroid 12-alpha-Hydroxylase

We determined whether persistent nausea and vomiting (N/V) symptoms following Roux-en-Y gastric bypass surgery is due to elevated systemic glucagon-like peptide-1 (GLP-1) and leptin in female non-diabetic subjects. Subjects with N/V post-Roux-en-Y gastric bypass (RYGB) surgery had significantly elevated fasting GLP-1 levels compared to that with post-operative asymptomatic subjects and to morbidly obese, obese and lean subjects not undergoing surgery. Weight loss, glycaemia, insulin and post-prandial GLP-1 levels were similar in all post-operative subjects. Despite comparable BMI, leptin was significantly lower in symptomatic subjects. Furthermore, leptin secretion from subcutaneous adipose tissue was inhibited by GLP-1 (0.1-1.0 nM; n = 6). Persistent N/V following RYGB surgery is associated with elevated fasting GLP-1, but lower leptin levels. The latter may be a consequence of the direct GLP-1 inhibition of leptin secretion from adipose tissue.

Topics: Adipokines; Adult; Blood Glucose; Case-Control Studies; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Nausea; Obesity, Morbid; Postoperative Nausea and Vomiting; Postprandial Period; Vomiting; Weight Loss

Hypertension and diabetes mellitus are highly correlated, but the underlying mechanisms are only partly understood. Therefore, the aim of our study was to investigate the relationships between plasma levels of glucagon-like peptide-1, a key factor in the regulation of glucose homeostasis, and various blood pressure indices. Healthy adults aged 25 to 41 years were enrolled in a population-based study. Established cardiovascular disease, diabetes mellitus, or a body mass index >35 kg/m(2) were exclusion criteria. Fasting plasma glucagon-like peptide-1 levels as determined with a novel high-sensitive assay and ambulatory blood pressure data were available in 1479 participants not using antihypertensive treatment. Median age of our population was 38 years. Mean systolic and diastolic blood pressure across increasing glucagon-like peptide-1 quartiles were 120.6, 122.8, 123.2, and 124.9 mm Hg and 77.1, 78.7, 78.9, and 79.9 mm Hg, respectively. We found a linear relationship of glucagon-like peptide-1 with 24-hour ambulatory blood pressure after multivariable adjustment (β per 1 log-unit increase 2.01; 95% confidence interval, 1.02-3.00; P<0.0001 for systolic and 1.22; 0.47-1.97; P=0.002 for diastolic blood pressure). In separate analyses, glucagon-like peptide-1 was significantly related to both awake (β per 1 log-unit increase 2.05; 1.02-3.09; P=0.0001 for systolic and 1.15; 0.35-1.96; P=0.005 for diastolic blood pressure) and asleep blood pressure (β per 1 log-unit increase 1.34; 0.26-2.42; P=0.01 for systolic and 1.05; 0.26-1.84; P=0.009 for diastolic blood pressure). In conclusion, plasma levels of glucagon-like peptide-1 are significantly associated with both systolic and diastolic blood pressure levels.

Topics: Adult; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Mass Index; Circadian Rhythm; Diet; Fasting; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Resistance; Life Style; Lipids; Male; Middle Aged; Prospective Studies; Sleep; Smoking; Surveys and Questionnaires; Wakefulness; Young Adult

Gut peptides regulate appetite and adipogenesis. Early weaning (EW) leads to later development of obesity that can be prevented by calcium supplementation. We evaluated gut peptides that may have a role in the establishment of this dysfunction.. At birth, lactating Wistar rats were separated in: EW, lactating rats involved with a bandage interrupting the lactation during the last 4 days of standard lactation, and C (control) dams whose pups had free access to milk during throughout lactation. At 120 days old, half of EW group received calcium supplementation (EWCa); EW and C received standard diet. At 21 days old, EW presented higher glucagon-like peptide 1 (GLP-1) in plasma and glucagon-like peptide 1 receptor (GLP1-R) in adipose tissue and hypothalamus, but lower GLP-1 and GLP1-R in the gut. At 180 days old, GLP-1 response to food intake was blunted in EW and restored by calcium. GLP-1 in the gut was lower in EW and its receptor was lower in adipose tissue, and GLP1-R was higher in the gut of calcium EW group.. Thus, EW had short- and long-term effects upon GLP-1 profile, which may have contributed to obesity development, hyperphagia, and insulin resistance due to its adipogenic and appetite control roles. Calcium supplementation was able to prevent most of the changes in GLP-1 caused by EW.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Composition; Body Mass Index; Calcium Carbonate; Calcium, Dietary; Female; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hyperphagia; Hypothalamus; Insulin Resistance; Lactation; Male; Nutritional Status; Obesity; Rats; Rats, Wistar; Weaning

Consumption of high fat diet and insulin resistance induce significant changes in pancreatic islet morphology and function essential for maintenance of normal glucose homeostasis. We have used incretin receptor null mice to evaluate the role of gastric inhibitory polypeptide (GIP) in this adaptive response.. C57BL/6 and GIPRKO mice were fed high fat diet for 45 weeks from weaning. Changes of pancreatic islet morphology were assessed by immunohistochemistry. Body fat, glucose, insulin, glucagon, glucagon-like peptide 1 (GLP-1) and GIP were assessed by routine assays.. Compared with normal diet controls, high fat fed C57BL/6 mice exhibited increased body fat, hyperinsulinaemia and insulin resistance, associated with decreased pancreatic glucagon, unchanged pancreatic GLP-1 and marked increases of insulin, islet number, islet size and both beta- and alpha-cell areas. Beta cell proliferation and apoptosis were increased under high fat feeding, but the overall effect favoured enhanced beta cell mass. A broadly similar pattern of change was observed in high fat fed GIPRKO mice but islet compensation was severely impaired in every respect. The inability to enhance beta cell proliferation was associated with the depletion of pancreatic GLP-1 and lack of hyperinsulinaemic response, resulting in non-fasting hyperglycaemia. GIP and GLP-1 were expressed in islets of all groups of mice but high fat fed GIPRKO mice displayed decreased numbers of GLP-1 containing alpha cells plus non-functional enhancement of pancreatic GIP content.. These data suggest that GIP released from islet alpha-cells and intestinal K-cells plays an important role in islet adaptations to high fat feeding.

Topics: Adaptation, Physiological; Adiposity; Animals; Apoptosis; Blood Glucose; Cell Proliferation; Diet, High-Fat; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Intestinal Mucosa; Islets of Langerhans; Male; Mice, Inbred C57BL; Mice, Knockout; Receptors, Gastrointestinal Hormone; Time Factors

Acute glucagon-like peptide-1 (GLP-1) infusion reversed the high fat diet-induced microvascular insulin resistance that occurred after both 5 days and 8 weeks of a high fat diet intervention. When GLP-1 was co-infused with insulin it had overt effects on whole body insulin sensitivity as well as insulin-mediated skeletal muscle glucose uptake after 5 days of a high fat diet, but not after 8 weeks of high fat diet intervention. Acute GLP-1 infusion did not have an additive effect to that of insulin on microvascular recruitment or skeletal muscle glucose uptake in the control group. Here we demonstrate that GLP-1 potently increases the microvascular recruitment in rat skeletal muscle but does not increase glucose uptake in the fasting state. Thus, like insulin, GLP-1 increased the microvascular recruitment but unlike insulin, GLP-1 had no direct effect on skeletal muscle glucose uptake.. Acute infusion of glucagon-like peptide-1 (GLP-1) has potent effects on blood flow distribution through the microcirculation in healthy humans and rats. A high fat diet induces impairments in insulin-mediated microvascular recruitment (MVR) and muscle glucose uptake, and here we examined whether this could be reversed by GLP-1. Using contrast-enhanced ultrasound, microvascular recruitment was assessed by continuous real-time imaging of gas-filled microbubbles in the microcirculation after acute (5 days) and prolonged (8 weeks) high fat diet (HF)-induced insulin resistance in rats. A euglycaemic hyperinsulinaemic clamp (3 mU min(-1)  kg(-1) ), with or without a co-infusion of GLP-1 (100 pmol l(-1) ), was performed in anaesthetized rats. Consumption of HF attenuated the insulin-mediated MVR in both 5 day and 8 week HF interventions which was associated with a 50% reduction in insulin-mediated glucose uptake compared to controls. Acute administration of GLP-1 restored the normal microvascular response by increasing the MVR after both 5 days and 8 weeks of HF intervention (P < 0.05). This effect of GLP-1 was associated with a restoration of both whole body insulin sensitivity and increased insulin-mediated glucose uptake in skeletal muscle by 90% (P < 0.05) after 5 days of HF but not after 8 weeks of HF. The present study demonstrates that GLP-1 increases MVR in rat skeletal muscle and can reverse early stages of high fat diet-induced insulin resistance in vivo.

Topics: Animals; Capillaries; Glucagon-Like Peptide 1; Glucose; Insulin; Insulin Resistance; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Regional Blood Flow

Diminished insulin sensitivity in the peripheral tissues and failure of pancreatic beta cells to secrete insulin are known major determinants of type 2 diabetes mellitus. JTT-130, an intestine-specific microsomal transfer protein inhibitor, has been shown to suppress high fat-induced obesity and ameliorate impaired glucose tolerance while enhancing glucagon-like peptide-1 (GLP-1) secretion. We investigated the effects of JTT-130 on glucose metabolism and elucidated the mechanism of action, direct effects on insulin sensitivity and glucose-stimulated insulin secretion in a high fat diet-induced obesity rat model. Male Sprague Dawley rats fed a high-fat diet were treated with a single administration of JTT-130. Glucose tolerance, hyperglycemic clamp and hyperinsulinemic-euglycemic testing were performed to assess effects on insulin sensitivity and glucose-stimulated insulin secretion, respectively. Plasma GLP-1 and tissue triglyceride content were also determined under the same conditions. A single administration of JTT-130 suppressed plasma glucose elevations after oral glucose loading and increased the disposition index while elevating GLP-1. JTT-130 also enhanced glucose-stimulated insulin secretion in hyperglycemic clamp tests, whereas increased insulin sensitivity was observed in hyperinsulinemic-euglycemic clamp tests. Single-dose administration of JTT-130 decreased lipid content in the liver and skeletal muscle. JTT-130 demonstrated acute and direct hypoglycemic effects by enhancing insulin secretion and/or insulin sensitivity.

Topics: Animals; Benzamides; Blood Glucose; Carrier Proteins; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Malonates; Muscle, Skeletal; Obesity; Rats; Triglycerides

Firmicutes and Bacteroidetes, 2 major phyla of gut microbiota, are involved in lipid and bile acid metabolism to maintain systemic energy homeostasis in host. Recently, accumulating evidence has suggested that dietary changes promptly induce the alteration of abundance of both Firmicutes and Bacteroidetes in obesity and its related metabolic diseases. Nevertheless, the metabolic roles of Firmicutes and Bacteroidetes on such disease states remain unclear. The aim of this study was to determine the effects of antibiotic-induced depletion of Firmicutes and Bacteroidetes on dysregulation of energy homeostasis in obesity. Treatment of C57BL/6J mice with the antibiotics (vancomycin [V] and bacitracin [B]), in the drinking water, before diet-induced obesity (DIO) greatly decreased both Firmicutes and Bacteroidetes in the gut as revealed by pyrosequencing of the microbial 16S rRNA gene. Concomitantly, systemic glucose intolerance, hyperinsulinemia, and insulin resistance in DIO were ameliorated via augmentation of GLP-1 secretion (active form; 2.03-fold, total form; 5.09-fold) independently of obesity as compared with untreated DIO controls. Furthermore, there were increases in metabolically beneficial metabolites derived from the gut. Together, our data suggest that Firmicutes and Bacteroidetes potentially mediate insulin resistance through modulation of GLP-1 secretion in obesity.

Topics: Animals; Anti-Bacterial Agents; Bacitracin; Bacteroidetes; Blood Glucose; Blotting, Western; Cell Line, Tumor; Diet, High-Fat; Gastrointestinal Tract; Glucagon-Like Peptide 1; Gram-Positive Bacteria; Humans; Insulin; Insulin Resistance; Metabolomics; Mice, Inbred C57BL; Microbiota; Obesity; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Vancomycin

Serum bile acids (BAs) are elevated after metabolic surgeries including Roux-en-Y gastric bypass (RYGB), ileal transposition (IT), and duodenal-jejunal bypass (DJB). Recently, BAs have emerged as a kind of signaling molecules, which can not only promote glucagon-like peptide-1 (GLP-1) secretion but can also regulate multiple enzymes involved in glucose metabolism. The aim of this study was to investigate whether expedited biliopancreatic juice flow to the distal gut contributes to the increased serum GLP-1 and BAs and benefits the diabetes control after DJB.. DJB, long alimentary limb DJB (LDJB), duodenal-jejunal anastomosis (DJA), and sham operation were performed in diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ). Body weight, food intake, oral glucose tolerance, insulin tolerance, glucose-stimulated insulin and GLP-1 secretion, fasting serum total bile acids (TBAs), and lipid profiles were measured at indicated time points.. Compared with sham operation, DJA, DJB, and LDJB all achieved rapid and dramatic improvements in glucose tolerance and insulin sensitivity independently of food restriction and weight loss. DJB and LDJB-operated rats exhibited even better glucose tolerance, higher fasting serum TBAs, and higher glucose-stimulated GLP-1 secretion than the DJA group postoperatively. No difference was detected in insulin sensitivity and glucose-stimulated insulin secretion between DJA, DJB, and LDJB groups.. Expedited biliopancreatic juice flow to the distal gut was associated with augmented GLP-1 secretion and increased fasting serum TBA concentration, which may partly explain the metabolic benefits of DJB.

Topics: Animals; Bile; Bile Acids and Salts; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Duodenum; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin; Insulin Resistance; Jejunum; Male; Pancreatic Juice; Rats; Rats, Wistar

We evaluated the insulinotropic properties of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in healthy individuals at risk of developing type 2 diabetes before and after glucocorticoid-induced insulin resistance.. Nineteen healthy, glucose tolerant, first-degree relatives of type 2 diabetic patients underwent OGTT and 7 mmol/l and 15 mmol/l glucose clamps with concomitant infusions of GLP-1, GIP or NaCl and a final infusion of arginine for determination of maximum beta cell capacity before and after treatment with dexamethasone. In addition, first-phase insulin responses were determined at 7 mmol/l and 15 mmol/l and second-phase insulin responses at 7 mmol/l.. After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2 h plasma glucose concentrations, while beta cell function indices generally increased according to the increased resistance. First-phase insulin responses induced by GLP-1 and GIP at 7 mmol/l and maximal beta cell secretory capacity did not differ before and after dexamethasone, while second-phase responses to 7 mmol/l and first-phase responses to 15 mmol/l glucose were reduced equally for both hormones.. Glucocorticoid-induced insulin resistance in individuals at risk of type 2 diabetes leads to a reduced insulinotropic effect of the incretin hormones. This reduction was not associated with a decrease in the maximal beta cell secretory capacity, indicating that the reduced incretin effect in the developing dysglycaemia of the present experimental model is due to a specific early reduction of the insulinotropic effects of the incretin hormones.. Clinicaltrials.gov NCT02235584.

Topics: Adult; Blood Glucose; Dexamethasone; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucocorticoids; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Risk Factors

Topics: Animals; Anti-Bacterial Agents; Gastrointestinal Tract; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Microbiota; Obesity

Pulses, including dried peas, are nutrient- and fibre-rich foods that improve glucose control in diabetic subjects compared with other fibre sources. We hypothesized feeding cooked pea seed coats to insulin-resistant rats would improve glucose tolerance by modifying gut responses to glucose and reducing stress on pancreatic islets. Glucose intolerance induced in male Sprague-Dawley rats with high-fat diet (HFD; 10% cellulose as fibre) was followed by 3 weeks of HFD with fibre (10%) provided by cellulose, raw-pea seed coat (RP), or cooked-pea seed coat (CP). A fourth group consumed low-fat diet with 10% cellulose. Oral and intraperitoneal glucose tolerance tests (oGTT, ipGTT) were done. CP rats had 30% and 50% lower glucose and insulin responses in oGTT, respectively, compared with the HFD group (P < 0.05) but ipGTT was not different. Plasma islet and incretin hormone concentrations were measured. α- and β-cell areas in the pancreas and density of K- and L-cells in jejunum and ileum were quantified. Jejunal expression of hexose transporters was measured. CP feeding increased fasting glucagon-like peptide 1 and glucose-stimulated gastric inhibitory polypeptide responses (P < 0.05), but K- and L-cells densities were comparable to HFD, as was abundance of SGLT1 and GLUT2 mRNA. No significant difference in β-cell area between diet groups was observed. α-cell area was significantly smaller in CP compared with RP rats (P < 0.05). Overall, our results demonstrate that CP feeding can reverse adverse effects of HFD on glucose homeostasis and is associated with enhanced incretin secretion and reduced α-cell abundance.

Topics: Animals; Blood Glucose; Cooking; Diet, High-Fat; Dietary Fiber; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Glucose Transporter Type 2; Glucose Transporter Type 5; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Pancreatic Hormones; Pisum sativum; Rats; Rats, Sprague-Dawley; Seeds; Sodium-Glucose Transporter 1

Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity.

Topics: Animals; Blood Glucose; Body Composition; Body Fat Distribution; Cholecystokinin; Diet; Diet, High-Fat; Gastric Emptying; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Obesity; Postprandial Period; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sucrose

This study was initiated to evaluate the effects of Roux-en-Y gastric bypass surgery on renal gluconeogenesis in type 2 diabetic rats and its relationship with hormonal parameters.. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ; 35 mg/kg) combined with a high-fat diet. They were then randomly divided into three groups: diabetes model group (DM group, n = 8), sham Roux-en-Y gastric bypass group (SRYGB group, n = 8), and Roux-en-Y gastric bypass group (RYGB group, n = 14). Another 8 normal rats comprised the normal control group (NC group, n = 8). Body weight, glucose, serum lipid, insulin, glucagon-like peptide-1 (GLP-1), leptin, and adiponectin were measured pre- and postoperatively. Glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor-α (IR-α), insulin receptor-β (IR-β), and glycogen synthase kinase 3 beta (Gsk3b) were measured in renal cortex by using RT-PCR and Western immune-blot analyses on the 4th week after operation.. Following RYGB surgery, surgery-treated rats showed significantly improved oral glucose tolerance, dyslipidemia and insulin resistance as well as increased post-gavage insulin levels and serum circulating levels of GLP-1 and adiponectin. RT-PCR and Western immune-blot analyses showed PEPCK and G6Pase protein and mRNA to be significantly decreased in the renal cortex in the RYGB group (p < 0.05 vs. DM or SRYGB group); in addition, IR-α and Gsk3b phosphorylation levels increased in the RYGB group (p < 0.05 vs. DM or SRYGB group).. Down-regulation of renal gluconeogenic enzymes might be a potential mechanism in hypoglycemia. An improved insulin signal pathway in the renal cortex and increased circulating adiponectin concentrations may contribute to the decline of renal gluconeogenesis following RYGB surgery.

Topics: Adiponectin; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diet, High-Fat; Down-Regulation; Gastric Bypass; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Kidney; Male; Rats, Sprague-Dawley; Receptor, Insulin; RNA, Messenger

Evidence indicates that subtle abnormalities in GC (glucocorticoid) plasma concentrations and/or in tissue sensitivity to GCs are important in the metabolic syndrome, and it is generally agreed that GCs induce insulin resistance. In addition, it was recently reported that short-term exposure to GCs reduced the insulinotropic effects of the incretin GLP-1 (glucagon-like peptide 1). However, although defective GLP-1 secretion has been correlated with insulin resistance, potential direct effects of GCs on GLP-1-producing L-cell function in terms of GLP-1 secretion and apoptosis have not been studied in any greater detail. In the present study, we sought to determine whether GCs could exert direct effects on GLP-1-producing L-cells in terms of GLP-1 secretion and cell viability. We demonstrate that the GR (glucocorticoid receptor) is expressed in GLP-1-producing cells, where GR activation in response to dexamethasone induces SGK1 (serum- and glucocorticoid-inducible kinase 1) expression, but did not influence preproglucagon expression or cell viability. In addition, dexamethasone treatment of enteroendocrine GLUTag cells reduced GLP-1 secretion induced by glucose, 2-deoxy-D-glucose, fructose and potassium, whereas the secretory response to a phorbol ester was unaltered. Furthermore, in vivo administration of dexamethasone to rats reduced the circulating levels of GLP-1 concurrent with induction of insulin resistance and glucose intolerance. We can conclude that GR activation in GLP-1-producing cells will diminish the secretory responsiveness of these cells to subsequent carbohydrate stimulation. These effects may not only elucidate the pathogenesis of steroid diabetes, but could ultimately contribute to the identification of novel molecular targets for controlling incretin secretion.

Topics: Animals; Blood Glucose; Cell Line; Dexamethasone; Diabetes Mellitus; Down-Regulation; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucocorticoids; Insulin; Insulin Resistance; Male; Mice; Rats, Wistar; Receptors, Glucocorticoid; Signal Transduction; Time Factors

The impaired glucose tolerance in cirrhosis is poorly understood. We evaluated the influence of gastrointestinal-mediated glucose disposal and incretin effect in patients with cirrhosis.. Non-diabetic patients with Child-Pugh A or B cirrhosis (n = 10) and matched healthy controls (n = 10) underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion. We presented data as median ± interquartile range and compared groups using non-parametric analysis of variance.. Patients with cirrhosis were glucose intolerant compared with healthy controls (4-h OGTTAUC : 609 ± 458 vs 180 ± 155 min × mmol/L; P = 0.005), insulin resistant (homeostatic model assessment for insulin resistance: 3.7 ± 4.9 vs 2.6 ± 1.4; P = 0.014) and had fasting hyperglucagonemia (8 ± 3 vs 3 ± 4 pmol/L; P = 0.027). Isoglycemia was achieved using 35 ± 12 g of intravenous glucose in patients with cirrhosis compared with 24 ± 10 g in healthy controls (P = 0.003). The gastrointestinal-mediated glucose disposal was markedly lower in patients with cirrhosis (30 ± 23 vs 52 ± 20%; P = 0.003). Despite higher levels of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide patients with cirrhosis had reduced incretin effect (35 ± 44 vs 55 ± 30%; P = 0.008).. Impaired gastrointestinal-mediated glucose disposal and reduced incretin effect may contribute to the glucose intolerance seen in patients with cirrhosis.

Topics: Adult; Aged; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Incretins; Insulin Resistance; Liver Cirrhosis; Male; Middle Aged

Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been demonstrated to reduce hepatic steatosis. However, the mechanism of the lipid-lowering effect of liraglutide in the liver remains unclear. The aim of the present study was to investigate the beneficial effect of liraglutide on diet-induced non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism in rats. NAFLD was induced in Sprague-Dawley rats by feeding a high fat and high cholesterol (HFHC) diet. Liraglutide (0.6 mg/kg body weight/d) was injected intraperitoneally to the rats subjected to HFHC diet four weeks before sacrificing the animals. Body and liver weight, fasting blood glucose (FBG), fasting insulin, serum aminotransferase (ALT) and lipid accumulation in the liver were determined. Markers of oxidative stress, such as malondialdehyde (MDA), free fatty acid (FFAs), superoxide dismutase (SOD), and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) were detected by colorimetric detection or enzyme-linked immunosorbent assay (ELISA). Serum and hepatic adiponectin were measured by ELISA. The expression of c-Jun N-terminal kinase-1 (JNK-1) and phosphorylated JNK-1 were examined by Western blotting. Liraglutide improved insulin resistance, decreased hepatic steatosis and reversed liver dysfunction. The hepatic levels of MDA, FFAs, and TNF-α were significantly decreased versus controls. Meanwhile, administration of liraglutide significantly increased SOD and adiponectin levels in the liver and inhibited the expression of JNK-1 and phosphorylated JNK-1 versus control rats. Liraglutide exerted anti-oxidative and anti-inflammatory effects in the liver and consequently reversed hepatic steatosis and insulin resistance. Such effects might be mediated by the elevation of adiponectin levels and the inactivation of JNK-1.

Topics: Adiponectin; Alanine Transaminase; Animals; Anti-Inflammatory Agents; Antioxidants; Diet, High-Fat; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Liraglutide; Liver; Male; Malondialdehyde; Mitogen-Activated Protein Kinase 8; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha

The female estrogen 17β-estradiol (E2) enhances pancreatic β-cell function via estrogen receptors (ERs). However, the risk of hormone dependent cancer precludes the use of general estrogen therapy as a chronic treatment for diabetes. To target E2 to β-cells without the undesirable effects of general estrogen therapy, we created fusion peptides combining active or inactive glucagon-like peptide-1 (GLP-1) and E2 in a single molecule (aGLP1-E2 and iGLP1-E2 respectively). By combining the activities of GLP-1 and E2, we envisioned synergistic insulinotropic activities of these molecules on β-cells. In cultured human islets and in C57BL/6 mice, both aGLP1 and aGLP1-E2 enhanced glucose-stimulated insulin secretion (GSIS) compared to vehicle and iGLP1-E2 without superior efficacy of aGLP1-E2 compared to GLP-1 alone. However, aGLP1-E2 decreased fasting and fed blood glucose to a greater extent than aGLP1 and iGLP1-E2 alone. Further, aGLP1-E2 exhibited improved insulin sensitivity compared to aGLP1 and iGLP1-E2 alone (HOMA-IR and insulin tolerance test). In conclusion, targeted estrogen delivery to non-diabetic islets in the presence of GLP-1 does not enhance GSIS. However, combining GLP-1 to estrogen delivers additional efficacy relative to GLP-1 alone on insulin sensitivity and glucose homeostasis in non-diabetic mice.

Topics: Animals; Body Composition; Cell Culture Techniques; Drug Carriers; Drug Delivery Systems; Estrogens; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Mice; Middle Aged

KBP-042 is a synthetic peptide dual amylin- and calcitonin-receptor agonist (DACRA) developed to treat type 2 diabetes by inducing a significant weight loss while improving glucose homeostasis. In this study the aim was to compare two different formulations: An oral formulation (1mg/kg) to subcutaneous formulations of KBP-042 (2.5μg/kg, 5.0μg/kg and 7.5μg/kg) with comparable pharmacokinetic profiles. Furthermore to examine if differences in mode of action between the two different routes of administration in high-fat fed Sprague-Dawley rats were present. It was established that the subcutaneous administrations of KBP-042 were able to dose-dependently cause a significant weight-loss, reduce food intake, and improve glucose homeostasis without increasing insulin secretion, effects comparable to those observed with oral administration. At the same time, s.c. KBP-042 suppressed the inappropriate glucagon response better than the oral formulation. Furthermore, KBP-042 was found to reduce incretins GLP-1 and GIP and considerably, improve gastric emptying, and to alleviate leptin resistance, as well as insulin resistance. In conclusion, the subcutaneous route of administration was found to have the same beneficial effects on blood glucose homeostasis and weight loss as well as resistance towards important insulin and leptin, albeit with a markedly lower variation in both exposure and biological responses. These data support the application of subcutaneously delivered peptide for mechanistic studies, and highlight the potential of developing s.c. KBP-042 as a therapy for T2D.

Topics: Adiposity; Animals; Blood Glucose; Body Weight; Calcitonin; Diet, High-Fat; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Homeostasis; Insulin Resistance; Intra-Abdominal Fat; Islet Amyloid Polypeptide; Leptin; Male; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Calcitonin

Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti-inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor κB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; Cell Line, Transformed; Cell Line, Tumor; Cells, Cultured; Diet, High-Fat; Docosahexaenoic Acids; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liver; Macrophages; Mice, Inbred C57BL; Obesity; Prediabetic State; Prodrugs; Salicylates; Signal Transduction

Bariatric operations in obese patients with type 2 diabetes often improve diabetes before weight loss is observed. In patients mainly Roux-en-Y-gastric bypass with partial stomach resection is performed. Duodenojejunal bypass (DJB) and ileal interposition (IIP) are employed in animal experiments. Due to increased glucose exposition of L-cells located in distal ileum, all bariatric surgery procedures lead to higher secretion of antidiabetic glucagon like peptide-1 (GLP-1) after glucose gavage. After DJB also downregulation of Na(+)-d-glucose cotransporter SGLT1 was observed. This suggested a direct contribution of decreased glucose absorption to the antidiabetic effect of bariatric surgery. To investigate whether glucose absorption is also decreased after IIP, we induced diabetes with decreased glucose tolerance and insulin sensitivity in male rats and investigated effects of IIP on diabetes and SGLT1. After IIP, we observed weight-independent improvement of glucose tolerance, increased insulin sensitivity, and increased plasma GLP-1 after glucose gavage. The interposed ileum was increased in diameter and showed increased length of villi, hyperplasia of the epithelial layer, and increased number of L-cells. The amount of SGLT1-mediated glucose uptake in interposed ileum was increased 2-fold reaching the same level as in jejunum. Thus, improvement of glycemic control by bariatric surgery does not require decreased glucose absorption.

Topics: Animals; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Enteroendocrine Cells; Glucagon-Like Peptide 1; Glucose; Hyperglycemia; Hyperplasia; Hypoglycemia; Ileum; Insulin Resistance; Intestinal Absorption; Male; Microvilli; Obesity; Rats, Inbred Lew; Sodium-Glucose Transporter 1; Specific Pathogen-Free Organisms

The relation between hunger, satiation, and integrated gastrointestinal motility and hormonal responses in morbidly obese patients after sleeve gastrectomy has not been determined.. The objective was to assess the effects of sleeve gastrectomy on hunger, satiation, gastric and gallbladder motility, and gastrointestinal hormone response after a liquid meal test.. Three groups were studied: morbidly obese patients (n = 16), morbidly obese patients who had had sleeve gastrectomy (n = 8), and nonobese patients (n = 16). The participants fasted for 10 h and then consumed a 200-mL liquid meal (400 kcal + 1.5 g paracetamol). Fasting and postprandial hunger, satiation, hormone concentrations, and gastric and gallbladder emptying were measured several times over 4 h.. No differences were observed in hunger and satiation curves between morbidly obese and nonobese groups; however, sleeve gastrectomy patients were less hungry and more satiated than the other groups. Antrum area during fasting in morbidly obese patients was statistically significant larger than in the nonobese and sleeve gastrectomy groups. Gastric emptying was accelerated in the sleeve gastrectomy group compared with the other 2 groups (which had very similar results). Gallbladder emptying was similar in the 3 groups. Sleeve gastrectomy patients showed the lowest ghrelin concentrations and higher early postprandial cholecystokinin and glucagon-like peptide 1 peaks than did the other participants. This group also showed an improved insulin resistance pattern compared with morbidly obese patients.. Sleeve gastrectomy seems to be associated with profound changes in gastrointestinal physiology that contribute to reducing hunger and increasing sensations of satiation. These changes include accelerated gastric emptying, enhanced postprandial cholecystokinin and glucagon-like peptide 1 concentrations, and reduced ghrelin release, which together may help patients lose weight and improve their glucose metabolism after surgery. This trial was registered at clinicaltrials.gov as NCT02414893.

Topics: Adult; Body Mass Index; C-Reactive Protein; Case-Control Studies; Cholecystokinin; Fasting; Female; Gastrectomy; Gastric Emptying; Gastrointestinal Hormones; Gastrointestinal Motility; Ghrelin; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Hunger; Insulin Resistance; Male; Meals; Middle Aged; Obesity, Morbid; Postprandial Period; Satiation

We compared the therapeutic effects of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and duodenal-jejunal bypass (DJB) on type-2 diabetes mellitus (T2DM) in non-obese rats using clamp testing.. Goto-Kakizaki rats (non-obese rats with T2DM) underwent surgery: RYGB, SG, or DJB. Rats were observed for 8 weeks after surgery to evaluate weight changes. Levels of glucose, insulin, and glucagon-like peptide (GLP)-1 were determined 2, 4, 6, and 8 weeks after surgery. An oral glucose tolerance test (OGTT) and clamp test was used to evaluate glucose tolerance and insulin resistance.. Rats in RYGB, SG, and DJB groups weighed significantly less than sham-group rats 6 and 8 weeks after surgery. Fasting blood glucose levels of RYGB, SG, and DJB rats were significantly lower than preoperative levels. One month after surgery, the area under the curve of the OGTT (in mmol•h/L) for RYGB, SG, DJB, and sham surgery groups was 38.9 ± 5.9, 50.9 ± 2.9, 46.8 ± 3.3, and 67.4 ± 6.0, respectively; there was no significant difference in glucose levels of SG and DJB groups. Glucose infusion rates (in mg/(kg•min)) were 18.3 ± 2.7, 17.2 ± 2.1, and 16.8 ± 1.9 in hyperinsulinemic-euglycemic-clamped RYGB, DJB, and SG rats, respectively, 8 weeks after surgery. The rate in the sham surgery group was 6.3 ± 0.9. Area under plasma insulin curves 8 weeks after surgery in hyperglycemic-clamped RYGB, DJB, SG, and sham surgery rats (in mU•h/L) were 98.8 ± 7.0, 84.4 ± 6.1, 89.0 ± 7.1, and 22.6 ± 2.6, respectively.. The three surgical methods described alleviated T2DM and reduced insulin resistance in non-obese rats with T2DM.

Topics: Animals; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Duodenum; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Clamp Technique; Insulin; Insulin Resistance; Jejunum; Male; Rats; Rats, Inbred Strains

Inflammation, insulin resistance, dyslipidemia, and glucagon-like peptide-1 (GLP-1) are risk factors for osteoporosis. Dipeptidyl peptidase-4 (DPP4) is a newly identified adipokine related to these risk factors.. To investigate the association between plasma DPP4 activities and osteoporosis.. This was a cross-sectional study conducted in Guilin, China. A total of 744 postmenopausal women with normal glucose tolerance were studied.. Plasma DPP4 activity, inflammatory markers, blood lipids, homeostatic model assessment of insulin resistance (HOMA-IR), active GLP-1, bone turnover markers, and bone mineral density (BMD) were measured in all participants.. Participants in the highest quartile of DPP4 activity had higher triglyceride, total cholesterol, HOMA-IR, IL-6, high-sensitivity C-reactive protein (hs-CRP), C-terminal telopeptide of type I collagen, and osteocalcin and lower BMD (lumbar spine and femoral neck) and active GLP-1 compared with participants in the lowest quartile (P < .05). DPP4 activities were associated positively with triglyceride, total cholesterol, HOMA-IR, IL-6, hs-CRP, C-terminal telopeptide of type I collagen, and osteocalcin and negatively with active GLP-1 and BMD (P < .05). In the highest DPP4 quartile, osteoporosis risk was significantly higher (odds ratio, 3.01; 95% confidence interval, 1.66-5.43) than in the lowest quartile after adjustment for potential confounders. The risk for osteoporosis increased more with higher levels of DPP4 activity, HOMA-IR, IL-6, and hs-CRP (P < .05), but not with higher levels of triglyceride and total cholesterol or lower levels of active GLP-1.. This study shows that increased DPP4 activities are independently associated with osteoporosis. The mechanisms may be partly explained by the effect of DPP4 on inflammation and insulin resistance.

Topics: Aged; Biomarkers; Bone Density; Cross-Sectional Studies; Dipeptidyl Peptidase 4; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin Resistance; Lipids; Middle Aged; Osteoporosis; Postmenopause; Prevalence

The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

Topics: AMP-Activated Protein Kinases; Animals; Blood Glucose; Calorimetry, Indirect; Cecum; Dietary Fiber; Fatty Acids, Volatile; Galactans; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin Resistance; Male; Mannans; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Plant Gums; PPAR gamma

Homozygous glucagon-GFP knock-in mice (Gcggfp/gfp) lack proglucagon derived-peptides including glucagon and GLP-1, and are normoglycemic. We have previously shown that Gcggfp/gfp show improved glucose tolerance with enhanced insulin secretion. Here, we studied glucose and energy metabolism in Gcggfp/gfp mice fed a high-fat diet (HFD). Male Gcggfp/gfp and Gcggfp/+ mice were fed either a normal chow diet (NCD) or an HFD for 15-20 weeks. Regardless of the genotype, mice on an HFD showed glucose intolerance, and Gcggfp/gfp mice on HFD exhibited impaired insulin secretion whereas Gcggfp/+ mice on HFD exhibited increased insulin secretion. A compensatory increase in β-cell mass was observed in Gcggfp/+mice on HFD, but not in Gcggfp/gfp mice on the same diet. Weight gain was significantly lower in Gcggfp/gfp mice than in Gcggfp/+mice. Oxygen consumption was enhanced in Gcggfp/gfp mice compared to Gcggfp/+ mice on an HFD. HFD feeding significantly increased uncoupling protein 1 mRNA expression in brown adipose and inguinal white adipose tissues of Gcggfp/gfp mice, but not of Gcggfp/+mice. Treatment with the glucagon-like peptide-1 receptor agonist liraglutide (200 mg/kg) improved glucose tolerance in Gcggfp/gfp mice and insulin content in Gcggfp/gfp and Gcggfp/+ mice was similar after liraglutide treatment. Our findings demonstrate that Gcggfp/gfp mice develop diabetes upon HFD-feeding in the absence of proglucagon-derived peptides, although they are resistant to diet-induced obesity.

Topics: Animals; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Obesity; Peptides; Proglucagon; Weight Gain

The enteroinsular axis is a complex system that includes the release of incretin hormones from the gut to promote the absorption and utilization of glucose after a meal. The insulinogenic effect of incretin hormones such as glucagon-like peptide-1 (GLP-1) remains poorly characterized in the horse. The aim of this study was to compare postprandial glucose, insulin, and GLP-1 responses of different equine breeds adapted to twice-daily meals containing micronized maize. Four Standardbred horses, 4 mixed-breed ponies, and 4 Andalusian cross horses in moderate BCS (5.5 ± 0.2 out of 9) were fed meals at 0800 and 1600 h each day. The meals contained micronized maize (mixed with soaked soybean hulls and lucerne chaff), with the amount of maize gradually increased over 12 wk to reach a final quantity of 1.7 g/kg BW (1.1 g/kg BW starch) in each meal. Animals had ad libitum access to the same hay throughout. After 12 wk of acclimation, serial blood samples were collected from all animals over a 14-h period to measure concentrations of glucose, insulin, and GLP-1, with meals fed immediately after the 0 and 8 h samples. Glucose area under the curve (AUC) values were similar between breed groups (P = 0.41); however, ponies and Andalusian horses exhibited significantly higher insulin AUC values after both meals compared with Standardbred horses (both P < 0.005). Postprandial GLP-1 AUC values were also significantly higher in ponies and Andalusian horses compared with Standardbred horses (breed × time interaction; P < 0.001). Correlation analysis demonstrated a strong positive association between concentrations of insulin and GLP-1 over time (rs = 0.752; P < 0.001). The increased insulin concentrations in ponies and Andalusian horses may partly reflect lower insulin sensitivity but could also be attributed to increased GLP-1 release. Given that hyperinsulinemia is a recognized risk factor for the development of laminitis in domestic equids, this study provides evidence that the enteroinsular axis warrants further investigation.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Breeding; Diet; Food Handling; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Horses; Insulin; Insulin Resistance; Postprandial Period; Zea mays

Nowadays no researches has been performed on fatty acid profile (FA) and desaturase activity in metabolically healthy obesity (MHO). The aim of this study was to assessed gender and BMI-related difference in FA, estimated desaturase activities and the efficacy on metabolic changes produced by 2-months well-balance diet in MHO subjects.. In 103 MHO subjects (30/73 M/F; age:42.2 ± 9.5) FA, estimated desaturase activity, body composition (by DXA), Body Mass Index (BMI), lipid profile, adipokines (leptin, adiponectin, grelin, glucagon-like peptide-1), insulin resistence (by Homestasis metabolic assessment), C-reactive proteine, Atherogenic index of plasma (AIP) and Body Shape Index (ABSI) have been assessed. Gender and BMI related difference have been evaluated and the efficacy produced by 2-months well-balance diet has been considered.. At baseline, obese subjects, compared to overweight, show a significantly higher oleic (p <0.050), monounsaturated fatty acids (p <0.040), C18:0 delta-9 desaturase activity (D9D) (p <0.040) and lower linoleic acid (p <0.020), polyunsaturated fatty acids (p <0.020) and n-6 LCPUFA (p <0.010). Concerning gender-related difference, women show a significantly higher arachidonic acid (p <0.001), polyunsaturated fatty acids (p <0.001), n-6 LCPUFA (p <0.002), and lower monounsaturated fatty acids (p <0.001), D6D activity (p <0.030), C18:0 D9D (0.000) and C16:0 D9D (p <0.030). The 2-months diet was associated with a significantly increase in arachidonic acid (p = 0.007), eicosapentaenoic acid (p = 0.030), docosahexaenoic acid (p <0.001), long chain omega 3 polyunsaturated fatty acids (n-3 LCPUFA) (p <0.001), delta-5 desaturase activity (D5D) (p = 0.002), glucagon like peptide-1 (p <0.001) and a significant decrease in palmitoleic acid (p = <0.030), n-6/n-3 LCPUFA (p <0.001), insulin resistance (p = 0.006), leptin (p = 0.006), adiponectin (p <0.001), grelin (p = 0.030), CRP (p = 0.004), BMI (p <0.001) and android fat mass (p <0.001).. The balanced diet intervention was effective in improving metabolic indices.

Topics: Adiponectin; Adult; Arachidonic Acid; Body Composition; Body Mass Index; C-Reactive Protein; Delta-5 Fatty Acid Desaturase; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Fatty Acid Desaturases; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Leptin; Linoleic Acid; Male; Middle Aged; Obesity, Metabolically Benign; Sex Factors; Triglycerides

Patients admitted to the intensive care unit often develop hyperglycaemia, but the underlying mechanisms have not been fully described. The incretin effect is reduced in patients with type 2 diabetes. Type 2 diabetes and critical illness have phenotypical similarities, such as hyperglycaemia, insulin resistance and systemic inflammation. Previous studies have shown beneficial effects of exogenous glucagon-like peptide (GLP)-1 on glycaemia in critically ill patients, a phenomenon also seen in patients with type 2 diabetes. In this study, we hypothesised that the incretin effect, which is mediated by the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP), is impaired in critically ill patients.. The incretin effect (i.e., the relative difference between the insulin response to oral and intravenous glucose administration) was investigated in a cross-sectional case-control study. Eight critically ill patients without diabetes admitted to a mixed intensive care unit and eight healthy control subjects without diabetes, matched at group level by age, sex and body mass index, were included in the study. All subjects underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the next day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide and plasma levels of GLP-1, GIP, glucagon and proinflammatory cytokines were measured intermittently. The incretin effect was calculated as the increase in insulin secretion during oral versus intravenous glucose administration in six patients. The groups were compared using either Student's t test or a mixed model of repeated measurements.. Blood glucose levels were matched between the OGTT and the IVGI in both groups. Compared with control subjects, proinflammatory cytokines, tumour necrosis factor α and interleukin 6, were higher in patients than in control subjects. The endogenous response of GIP and glucagon, but not GLP-1, to the OGTT was greater in patients. The insulin response to the OGTT did not differ between groups, whereas the insulin response to the IVGI was higher in patients. Consequently, the calculated incretin effect was lower in patients (23 vs. 57%, p=0.003).. In critically ill patients, the incretin effect was reduced. This resembles previous findings in patients with type 2 diabetes.. ClinicalTrials.gov identifier: NCT01347801 . Registered on 2 May 2011.

Topics: Administration, Intravenous; Aged; Blood Glucose; Case-Control Studies; Critical Illness; Cross-Sectional Studies; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Male; Middle Aged

Both glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are gut hormones involved in energy homoeostasis. Obesity, insulin resistance and hyperglycaemia are significant confounders when GLP-1 and PYY secretion is assessed. Thus, we evaluated GLP-1 and PYY response after fat load in morbidly obese patients with different degrees of insulin resistance and glycemic status.. We studied 40 morbidly obese subjects (mean age, 40·6 ± 1·3 years; mean BMI, 53·1 ± 1·2 kg/m(2) ) divided into groups according to their glycemic status: normal fasting glucose (NFG) group, impaired fasting glucose (IFG) group and type 2 diabetes mellitus (T2D) group. NFG patients were additionally subclassified, according to the homoeostasis model assessment of insulin resistance (HOMAIR ), into a low insulin-resistance (LIR) group (HOMAIR <3·9) or a high insulin-resistance (HIR) group (HOMAIR ≥3·9).. Lipid emulsion was administered orally and measurements made at baseline and 180 min postprandially of levels of GLP-1, PYY, insulin, glucose, free fatty acids, triglycerides and leptin.. At the 180-minute postprandial reading, GLP-1 and PYY had increased in LIR-NFG subjects (41·84%, P = 0·01; 35·7%, P = 0·05; respectively), whereas no changes were observed in HIR-NFG, IFG or T2D subjects.. These results suggest that in morbidly obese subjects, both insulin resistance and abnormal glucose metabolism (IFG or T2D) impair the GLP-1 and PYY response to fat load. The implications of this attenuated enteroendocrine response should be elucidated by further studies.

Topics: Adult; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin Resistance; Lipids; Male; Middle Aged; Obesity, Morbid; Peptide YY

The aim was to investigate both individual and synergistic effects of quercetin-3-O-β-glucoside (Q3G) and fructooligosaccharide (FOS) on indices of metabolic syndrome and plasma total cholesterol level with potential mechanisms of action.. Five groups of rats were fed a dextrin-based diet as the normal reference group, or sucrose-based (S) diets with 0.3% Q3G, 5% FOS, or 0.3% Q3G + 5% FOS (Q3G + FOS) for 48 days. Oral glucose tolerance tests (OGTTs) were conducted on days 0, 14, 28, and 45, and adipose tissue and aortic blood were collected on day 48. Effects of Q3G and FOS on portal GLP-1 secretion were separately examined using rats after ileal administration.. Abdominal fat weight reduced in FOS-fed groups. Blood glucose levels of the Q3G + FOS group at 60 min in OGTT and HOMA-IR (0.25 ± 0.03 vs 0.83 ± 0.12 on day 45) were clearly lower in the Q3G + FOS group than in S group throughout the experimental period. Muscle Akt phosphorylation was enhanced only in the Q3G group. The plasma quercetin was largely increased by FOS feeding on day 48 (18.37 ± 1.20 with FOS, 2.02 ± 0.30 without FOS). Plasma total cholesterol levels in the Q3G + FOS group (3.10 ± 0.12, P < 0.05 on day 45) were clearly suppressed compared to the S group (4.03 ± 0.18). GLP-1 secretion was enhanced in Q3G + FOS group than in Q3G or FOS group.. Q3G + FOS diet improved glucose tolerance, insulin sensitivity, and total cholesterol level with increasing GLP-1 secretion and a higher level of blood quercetin. Q3G + FOS may reduce the risk of T2DM.

Topics: Absorption; Animals; Blood Glucose; Body Weight; Cecum; Cholesterol; Diabetes Mellitus, Type 2; Diet; Flavonoids; Fructose; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hydrogen-Ion Concentration; Insulin Resistance; Male; Oligosaccharides; Phosphorylation; Proto-Oncogene Proteins c-akt; Quercetin; Rats; Rats, Wistar; Sucrose

We assessed the acute impact of laparoscopic Roux-en-Y gastric bypass (GBP) or sleeve gastrectomy (SG) compared to caloric-matched control group without surgery on glucose excursion in obese patients with type 2 diabetes, and examined if this was mediated by changes in insulin resistance, early insulin response or glucagon-like peptide (GLP)-1 levels.. Six-day subcutaneous continuous glucose monitoring (CGM) recordings were obtained from patients beginning 3 days before GBP (n = 11), SG (n = 10) or fasting in control group (n = 10). GLP-1, insulin and glucose were measured during 75 g oral glucose tolerance testing at the start and end of each CGM.. Post-operative hyperglycaemia occurred after both surgeries in the first 6 h, with a more rapid decline in glycaemia after GBP (p < 0.001). Beyond 24 h post-operatively, continuous overlapping of net glycaemia action reduced from baseline after GBP (median [interquartile range]) 1.6 [1.2-2.4] to 1.0 [0.7-1.3] and after SG 1.4 [0.9-1.8] to 0.7 [0.7-1.0]; p < 0.05), similar to controls (2.2 [1.7-2.5] to 1.3 [0.8-2.8] p < 0.05). Higher log GLP-1 increment post-oral glucose occurred after GBP (mean ± SE, 0.80 ± 0.12 vs. 0.37 ± 0.09, p < 0.05), but not after SG or control intervention. Among subgroup with baseline hyperglycaemia, a reduction in HOMA-IR followed GBP. Reduction in time and level of peak glucose and 2-h glucose occurred after both surgeries but not in controls.. GBP and SG have a similar acute impact on reducing glycaemia to caloric restriction; however, with a superior impact on glucose tolerance.

Topics: Adult; Bariatric Surgery; Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Female; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Laparoscopy; Male; Middle Aged; Obesity, Morbid

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults.

Topics: Adult; Blood Glucose; Body Weight; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Male; Obesity; Peptide Fragments

This study aims to investigate the relationship between gastric emptying, postprandial GLP-1 and insulin sensitivity after pancreaticoduodenectomy (PD).. Abnormal glucose regulation is highly prevalent in patients with pancreatic neoplasm and resolves in some after PD, the cause of which is unclear. The procedure is carried out with pylorus preservation (PPPD) or with distal gastrectomy (Whipple procedure). Accelerated gastric emptying and ensuing enhanced release of glucagon-like peptide-1 (GLP-1) conceivably play a role in glucose metabolism after PD. It was the purpose of this study to shed light on the relationship between gastric emptying, GLP-1 and glycemic control after PPPD and the Whipple procedure.. A 75-g oral glucose tolerance test was carried out in 13 patients having undergone PPPD and in 13 after the Whipple procedure, median age 61 (range, 32-70) years, following an interval of 23 (range, 5-199) months. Gastric emptying was measured by the paracetamol absorption method. Plasma concentrations of glucose, insulin, GLP-1 and paracetamol were measured at baseline, 10, 20, 30 60, 90, 120, 150 and 180 min. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) and oral glucose insulin sensitivity were calculated from glucose and insulin concentrations.. Patients with Whipple procedure as compared to PPPD had accelerated gastric emptying (p = 0.01) which correlated with early (0-30 min) integrated GLP-1 (AUC30; r (2) = 0.61; p = 0.02) and insulin sensitivity (r (2) = 0.41; p = 0.026) and inversely with HOMA-IR (r (2) = 0.17; p = 0.033). Two of 13 Whipple patients (15 %) as compared to seven of 13 after PPPD (54 %) had postload glucose concentrations (i.e. 120 min postmeal) ≥200 mg/dl (p < 0.05). None of 13 (0 %) after Whipple procedure but four of 13 patients (31 %) after PPPD had fasting glucose concentrations ≥126 mg/dl (p < 0.05) CONCLUSIONS: Gastric emptying was accelerated after Whipple procedure as compared to patients who have undergone PPPD, resulting in higher postprandial GLP-1 concentrations and insulin sensitivity and improved glycemic control.

Topics: Acetaminophen; Adult; Aged; Blood Glucose; Female; Follow-Up Studies; Gastrectomy; Gastric Emptying; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Organ Sparing Treatments; Pancreaticoduodenectomy; Postprandial Period; Pylorus

Cancer cachexia is the syndrome of weight loss, loss of appetite, and wasting of skeletal muscle and adipose tissue experienced by many individuals with cancer. Currently, few effective treatment and prevention strategies are available for these patients, due in part to a poor understanding of the mechanisms contributing to cachexia. Insulin resistance has been associated with cancer cachexia in epidemiological, human, and animal research. The present experiment was designed to examine the ability of Exendin-4, a GLP-1 agonist and insulin sensitizing agent, to prevent the development of cachexia symptoms in male Sprague Dawley rats bearing the Yoshida sarcoma. Following tumor implantation or sham surgery, rats were treated daily with saline or Exendin-4 (3 μg/kg body weight/day) and were monitored for tumor growth and cachexia symptoms for 21-23 days. As a result of large variability in treatment effects, data were analyzed separately for animals with large and small tumors. Exendin-4 treatment reduced tumor growth and prevented the development of cancer cachexia symptoms in animals with small, but not large, tumors. In addition, insulin levels were preserved in Exendin-4-treated tumor-bearing animals. The results of this experiment demonstrate a novel preventative therapy for cancer cachexia and a novel use of Exendin-4. Further research is necessary to determine the mechanisms through which Exendin-4 exerts these potent effects.

Topics: Animals; Cachexia; Carcinogenesis; Exenatide; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Male; Neoplasm Transplantation; Peptides; Rats; Rats, Sprague-Dawley; Sarcoma, Yoshida; Tumor Burden; Venoms

To stop smoking is commonly associated with significant weight gain, but the mechanisms for this are poorly understood. We assessed the effects of smoking cessation on body weight, insulin sensitivity, β-cell function, and appetite.. Twenty-seven long-term smokers (n=27; nine females/18 males, 28±1 years, 22.9±0.6 kg/m(2)) attending an ambulatory smoking cessation program in a community hospital in Vienna, Austria were examined at baseline (Visit A; still smoking) and after a minimum of 3 months of smoking abstinence (Visit B; n=14); relapsed smokers were not followed up. Participants underwent 3-h oral glucose tolerance tests and body composition measurements at each study visit. Fasting (QUICKI) and dynamic (oral glucose insulin sensitivity (OGIS)) insulin sensitivity and β-cell secretion (insulinogenic index 140 (IGI40)) were calculated. Food intake was quantified with a free choice buffet. Fasting plasma concentrations of neuropeptide-Y (NPY), peptide-YY (PYY), glucagon-like peptide 1 (GLP1), leptin, ghrelin, and visfatin were measured.. AFTER 3 MONTHS' SMOKING ABSTINENCE, BODY WEIGHT, AND FAT MASS WERE INCREASED (+4 AND +22% RESPECTIVELY, P0.05) AND FASTING INSULIN SENSITIVITY DETERIORATED (QUICKI: post, 0.37±0.02 vs baseline, 0.41±0.2; P<0.05), while OGIS remained unchanged throughout. IGI40 increased by 31% after >3 months' smoking abstinence (P<0.01). Carbohydrate ingestion increased after stopping smoking (P<0.05). NPY fasting levels were increased after >3 months (P<0.05), PYY, GLP1, leptin, ghrelin, and visfatin were unchanged.. Smoking cessation is associated with transient metabolic changes including increased β-cell secretion in response to glucose and fasting insulin resistance. These alterations may be associated with or contribute to the body weight gain after smoking cessation.

Topics: Adult; Appetite; Body Weight; Eating; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Leptin; Male; Neuropeptide Y; Peptide YY; Smoking Cessation

In order to understand the underlying mechanisms by which weight loss surgeries improve metabolic profiles in type 2 diabetes mellitus (T2DM) patients and to evaluate the relevance of the length of the common limb in modulating various aspects of metabolism, we performed regular duodenal-jejunal bypass (DJB) and long-limb DJB (LL-DJB) surgeries in Goto-Kakizaki (GK) rats and compared their effects on glycemic control.. Male GK rats at 12 weeks of age were used for this study. Body weight, food intake, fasting glucose, glucagon-like peptide-1 (GLP-1) level, glucose tolerance, insulin sensitivity, cholesterol and triglycerides levels, and fecal energy content were monitored for 26 weeks after the two types of surgeries.. We performed systematic analyses on GK rats after DJB or long-limb surgeries. Both procedures prevented body weight gain, reduced blood glucose and lipid levels, increased GLP-1 levels, and led to better insulin sensitivity. In general, LL-DJB displayed better effects than DJB, except that both surgeries caused similar increase in GLP-1 levels.. Both DJB and LL-DJB surgeries triggered beneficial effects in GK rats. LL-DJB showed better outcomes than DJB, which may be due to reduced food intake and higher fecal energy content. This indicates that the length of the common limb could influence metabolic profiles of surgery recipients.

Topics: Animals; Bariatric Surgery; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Duodenum; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Insulin Resistance; Jejunum; Male; Rats

Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell-to-α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from duct cells and transdifferentiation of α-cells are potential contributors to the β-cell compensatory response to insulin resistance in the absence of overt diabetes.

Topics: Adult; Aged; Female; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Humans; Hyperplasia; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Male; Middle Aged; Pancreatectomy

Gastric bypass surgery can dramatically improve type 2 diabetes. It has been hypothesized that by excluding duodenum and jejunum from nutrient transit, this procedure may reduce putative signals from the proximal intestine that negatively influence insulin sensitivity (SI). To test this hypothesis, resection or bypass of different intestinal segments were performed in diabetic Goto-Kakizaki and Wistar rats. Rats were randomly assigned to five groups: duodenal-jejunal bypass (DJB), jejunal resection (jejunectomy), ileal resection (ileectomy), pair-fed sham-operated, and nonoperated controls. Oral glucose tolerance test was performed within 2 weeks after surgery. Baseline and poststimulation levels of glucose, insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured. Minimal model analysis was used to assess SI. SI improved after DJB (SI = 1.14 ± 0.32 × 10(-4) min(-1) ⋅ pM(-1)) and jejunectomy (SI = 0.80 ± 0.14 × 10(-4) min(-1) ⋅ pM(-1)), but not after ileectomy or sham operation/pair feeding in diabetic rats. Both DJB and jejunal resection normalized SI in diabetic rats as shown by SI levels equivalent to those of Wistar rats (SI = 1.01 ± 0.06 × 10(-4) min(-1) ⋅ pM(-1); P = NS). Glucose effectiveness did not change after operations in any group. While ileectomy increased plasma GIP levels, no changes in GIP or GLP-1 were observed after DJB and jejunectomy. These findings support the hypothesis that anatomic alterations of the proximal small bowel may reduce factors associated with negative influence on SI, therefore contributing to the control of diabetes after gastric bypass surgery.

Topics: Animals; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Duodenum; Gastric Bypass; Glucagon-Like Peptide 1; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Jejunum; Male; Rats; Rats, Wistar

Higher insulin levels during an oral glucose test (OGTT) have been shown in South Asians. We aimed to investigate if this increased insulin response causes reactive hypoglycemia later on, and if an increased glucagon-like-peptide-1 (GLP-1) response, which could contribute to the hyperinsulinemia, is present in this ethnic group.. A prolonged, 6-h, 75-g OGTT was performed in healthy, young Caucasian (n=10) and South Asian (n=8) men. The glucose, insulin and GLP-1 response was measured and indices of insulin sensitivity and beta-cell activity were calculated.. Age (Caucasians (CAU) 21.5±0.7 years vs South Asians (SA) 21.4±0.7 years (mean±SEM)) and body mass index (CAU 22.7±0.7 kg/m(2) vs SA 22.1±0.8 kg/m(2)) were comparable between the two groups. South Asian men were more insulin resistant, as indicated by a comparable glucose but significantly higher insulin response, and a significantly lower Matsuda index (CAU 8.7(8.6) vs SA 3.2(19.2), median(IQR)). South Asians showed a higher GLP-1 response, as reflected by a higher area under the curve for GLP-1 (CAU 851±99.8 mmol/l vs SA 1235±155.0 mmol/L). During the whole 6-h period, no reactive hypoglycemia was observed.. Healthy, young South Asian men have higher insulin levels during an OGTT as compared to Caucasians. This does not, however, lead to reactive hypoglycemia. The hyperinsulinemia is accompanied by increased levels of GLP-1. Whether this is an adaptive response to facilitate hyperinsulinemia to overcome insulin resistance or reflects a GLP-1 resistant state has yet to be elucidated.

Topics: Adult; Area Under Curve; Asian People; Blood Glucose; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Reference Values; Suriname; White People

Low GLP-1 has been implicated in obesity and type 2 diabetes. Some studies reported reduced post-prandial GLP-1 levels in type 2 diabetics, whereas others reported GLP-1 levels not reduced in patients with impaired glucose tolerance (IGT) or type 2 diabetes. We undertook this study to evaluate the effect of obesity and pre-diabetes on GLP-1 levels in response to 75 g oral glucose.. Eighty subjects comprised four groups: 20 control subjects (normal weight and normal glucose tolerance (NGT)), 20 obese with NGT, 20 obese with impaired fasting glucose (IFG) and 20 obese with both IFG and impaired glucose tolerance (IGT). Laboratory tests included fasting blood glucose (FBG), 75 g glucose OGTT, fasting insulin and glucose-stimulated GLP-1 (30 min after 75 g glucose). Insulin resistance was quantified using HOMA-IR.. GLP-1 levels were significantly decreased in obese subjects compared to controls (571.17 ± 170.37 vs. 908.50 ± 169.90 pg/mL, p <0.001) and it was negatively correlated with body mass index (BMI) and waist circumference in all studied groups. Levels of GLP-1 were negatively correlated with HOMA-IR in all obese groups (r = -0.75, p <0.001). No significant difference was found in GLP-1 levels between all obese subjects (611.50 ± 187.96, 577.50 ± 150.85, 524.50 ± 167.35 pg/mL respectively, p >0.05). Morbidly obese cases (n = 15) had a significantly higher fasting insulin (25.20 ± 2.49 vs. 14 ± 3.81 μIU/ml), higher HOMA-IR (6.69 ± 1.2 vs. 3.48 ± 1.20), and lower GLP- 1 (212.0 ± 35.64 vs. 603.82 ± 136.35 pg/mL) (p <0.001) compared to non-morbid obese cases (n = 45).. Obesity reduces the GLP-1 levels. In insulin resistance, GLP-1 levels were reduced and it was related to the degree of insulin resistance.

Topics: Adult; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Fasting; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Prediabetic State

A polymorphism (1359 G/A) of the cannabinoid receptor 1 (CNR1) gene was reported as a common polymorphism (rs1049353) with potential implications in weight loss. We decide to investigate the role of this polymorphism on metabolic changes and weight loss secondary to treatment with liraglutide.. A population of 86 patients with diabetes mellitus type 2 and obesity, unable to achieve glycemic control (hemoglobine glycate A1c >7%) with metformin alone or associated to sulfonylurea, who require initiation of liraglutide treatment in progressive dose to 1.8 mg/d subcutaneously, was analyzed.. Fifty-one patients (59.3%) had the genotype G1359G, and 35 patients (40.7%) had G1359A (28 patients, 32.6%) or A1359A (7 patients, 8.1%) (A allele carriers). In patients with both genotypes, basal glucose, HbA1c, body mass index, weight, fat mass, waist circumference, and systolic blood pressures decreased. In patients with G1359G genotype, total cholesterol and low-density lipoprotein cholesterol decreased, and in patients with A allele, homeostasis model assessment for insulin resistance decreased, too.. There is an association of the A allele with an improvement of insulin resistance secondary to weight loss after liraglutide treatment in obese patients with diabetes mellitus type 2. Noncarriers of A allele showed an improvement in cholesterol levels after weight loss.

Topics: Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Genetic Variation; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Male; Middle Aged; Obesity; Prospective Studies; Receptor, Cannabinoid, CB1; Risk Factors; Treatment Outcome; Weight Loss

The portal neural system may have an important role on the regulation of glucose homeostasis since activation of the gut-brain-liver neurocircuit by nutrient sensing in the proximal intestine reduces hepatic glucose production through enhanced liver insulin sensitivity. Although there have been many studies investigating the role of portal neural system, surgical denervation of the sole portal vein has not been reported to date. The aim of this study was to clarify the role of the portal neural system on the regulation of glucose homeostasis and food intake in the physiological condition. Surgical denervation of portal vein (DV) was performed in 10 male 12 week-old Wistar rats. The control was a sham operation (SO). One week after surgery, food intake and body weight were monitored; an oral glucose tolerance test (OGTT) was performed; and glucagon-like peptide-1 (GLP-1) and insulin levels during OGTT were assayed. In addition, insulinogenic index, homeostatic model assessment, and Matsuda index were calculated. All rats regained the preoperative body weight at one week after surgery. There was no significant difference in food intake between DV and SO rats. DV rats exhibited increased blood glucose levels associated with decreased insulin sensitivity but increased GLP-1 and insulin secretion during OGTT. In summary, in the physiological state, loss of the portal neural system leads to decreased insulin sensitivity and increased blood glucose levels but does not affect food intake. These data indicate that an intact portal neural system is important for maintaining normal glucose metabolism.

Topics: Animals; Blood Glucose; Eating; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Portal Vein; Rats; Rats, Wistar

Bariatric surgery (BS) is able to positively influence fasting lipid profile in obese type 2 diabetic patients (T2DM), but no data is available on the impact of BS on postprandial lipid metabolism neither on its relation with incretin hormones. We evaluated the short-term (2 weeks) effects of BS on fasting and postprandial lipid metabolism in obese T2DM patients and the contribution of changes in active GLP-1.. We studied 25 obese T2DM patients (age = 46 ± 8 years, BMI = 44 ± 7 kg/m2), of which 15 underwent sleeve gastrectomy and 10 underwent gastric bypass. Lipid and incretin hormone concentrations were evaluated for 3 h after ingestion of a liquid meal before and 2 weeks after BS.. After BS, there was a significant reduction in body weight (p < 0.001), fasting plasma glucose (p < 0.001), fasting plasma insulin (p < 0.05), HOMA-IR (p < 0.001), and fasting plasma lipids (p < 0.05). The meal response of plasma triglycerides, total cholesterol, and HDL cholesterol was significantly lower compared to pre-intervention (p < 0.05, p < 0.001). In particular, the incremental area under the curve (IAUC) of plasma triglycerides decreased by 60% (p < 0.005). The meal-stimulated response of active GLP-1 increased, reaching a statistical significance (p < 0.001).. BS leads to an early improvement of fasting and postprandial lipemia. The fall in fasting triglycerides is associated with an improvement of insulin resistance, while the reduction of postprandial lipemia is likely related to reduced intestinal lipid absorption consequent to bariatric surgery.

Topics: Adult; Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Homeostasis; Humans; Hyperlipidemias; Incretins; Insulin Resistance; Lipids; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Treatment Outcome; Triglycerides

Grape-seed procyanidin extract (GSPE) has been reported to improve insulin resistance in cafeteria rats. Because glucagon-like peptide-1 (GLP-1) is involved in glucose homeostasis, the preventive effects of GSPE on GLP-1 production, secretion, and elimination were evaluated in a model of diet-induced insulin resistance. Rats were fed a cafeteria diet for 12 weeks, and 25 mg of GSPE/kg of body weight was administered concomitantly. Vehicle-treated cafeteria-fed rats and chow-fed rats were used as controls. The cafeteria diet decreased active GLP-1 plasma levels, which is attributed to a decreased intestinal GLP-1 production, linked to reduced colonic enteroendocrine cell populations. Such effects were prevented by GSPE. In the same context, GSPE avoided the decrease on intestinal dipeptidyl-peptidase 4 (DPP4) activity and modulated the gene expression of GLP-1 and its receptor in the hypothalamus. In conclusion, the preventive treatment with GSPE abrogates the effects of the cafeteria diet on intestinal GLP-1 production and DPP4 activity.

Topics: Animals; Biflavonoids; Catechin; Diet; Down-Regulation; Female; Glucagon-Like Peptide 1; Glucose; Grape Seed Extract; Humans; Insulin Resistance; Proanthocyanidins; Rats; Rats, Wistar; Vitis

The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.. N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH) patients) and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.. Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.. Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.

Topics: Case-Control Studies; Fatty Liver; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Non-alcoholic Fatty Liver Disease

Topics: Acanthosis Nigricans; Adult; Diabetes Mellitus, Type 2; Epidermis; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide

To evaluate the effects of liraglutide after 14 weeks of treatment on serum adipokines, insulin resistance index and cardiovascular risk biomarkers in overweight or obese T2DM patients unable to achieve glycemic control with metformin alone or in association with a sulfonylurea in daily clinical practice.. Prospective study in 59 consecutive overweight or obese (BMI≥25kg/m(2)) T2DM patients unable to achieve glycemic control (HbA1c>7%, 53mmol/mol) with metformin alone or in association with sulfonylurea that require initiation of liraglutide in progressive dose increase up to 1.8mg/day subcutaneously. Weight, body composition, blood pressure, glucose, HbA1c, C-peptide, insulin, plasma lipids, adipokines (leptin, adiponectin, resistin and visfatin) as well as cardiovascular biomarkers (IL-6 and TNF-a) levels were measured fasting at baseline and 14 weeks after liraglutide initiation.. 14 weeks of liraglutide treatment significantly reduced HbA1c, BMI and total body fat mass by 0.9%, 1.4kg/m(2) and 0.5% respectively. Statistically significant lower insulin resistance and higher insulin secretion was found by HOMA-IR 8.4 (1.6) vs 4.6 (0.9)molmIU/L(2) and HOMA-B 48.2 (9.0) vs 87.6 (16.3)μIU/mmol. Statistically significantly higher levels of visfatin 6.3 (2.1) vs 6.8 (2.1)ng/ml and resistin 3.6 (2.0) vs 4.3 (2.3)ng/ml were also observed after treatment. Baseline visfatin was negatively correlated with basal fasting plasma glucose r=-0.360 (p<0.05).. Liraglutide treatment for 14 weeks in daily clinical practice led to reduction of BMI and improvement of glucose control and insulin sensitivity and resistance parameters. Additionally, circulating levels of adipokines and pro-inflammatory factors could play an important role in GLP-1 treatment response.

Topics: Adipokines; Biomarkers; Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Male; Middle Aged; Obesity; Prospective Studies; Risk Factors

Folk medicine stories accredited the aptitude of camel milk (CMK) as a hypoglycemic agent and recent studies have confirmed this in the diabetic patients and experimental animals. However, the mechanism(s) by which CMK influences glucose homeostasis is yet unclear. The current study investigated the changes in the glucose homeostatic parameters, the incretin hormones, and the inflammatory cytokines in the CMK-treated diabetic animals. A model of type 2 diabetes mellitus was induced in rats by intraperitoneal injection of streptozotocin 40 mg/kg/day for 4 repeated doses. Camel milk treatment was administered for 8 weeks. The changes in glucagon like peptide-1 (GLP-1), glucose dependent insulinotropic peptide (GIP), glucose tolerance, fasting and glucose-stimulated insulin secretion, insulin resistance (IR), TNF-α, TGF-β1, lipid profile, atherogenic index (AI), and body weight were investigated. The untreated diabetic animals showed hyperglycemia, increased HOMA-IR, hyperlipidemia, elevated AI, high serum incretins [GLP-1 and GIP], TNF-α, and TGF-β1 levels and weight loss as compared with the control group. Camel milk treatment to the diabetic animals resulted in significant lowered fasting glucose level, hypolipidemia, decreased HOMA-IR, recovery of insulin secretion, weight gain, and no mortality during the study. Additionally, CMK inhibits the diabetes-induced elevation in incretin hormones, TNF-α and TGF-β1 levels. The increase in glucose-stimulated insulin secretion, decreased HOMA-IR, modulation of the secretion and/or the action of incretins, and the anti-inflammatory effect are anticipated mechanisms to the antidiabetic effect of CMK and suggest it as a valuable adjuvant antidiabetic therapy.

Topics: Animals; Atherosclerosis; Blood Glucose; Body Weight; Camelus; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fasting; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypoglycemic Agents; Incretins; Inflammation Mediators; Insulin; Insulin Resistance; Lipids; Male; Milk; Rats, Wistar; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin's metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy.

Topics: Animals; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Insulin; Insulin Resistance; Lipids; Male; Muscle, Skeletal; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley

Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous subgroup of nonautoimmune diabetes, constituting 1-2% of all diabetes. Because little is known about incretin function in patients with MODY, we studied the incretin effect and hormone responses to oral and intravenous glucose loads in patients with glucokinase (GCK)-diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A)-diabetes (MODY3), respectively, and in matched healthy control subjects. Both MODY groups exhibited glucose intolerance after oral glucose (most pronounced in patients with HNF1A-diabetes), but only patients with HNF1A-diabetes had impaired incretin effect and inappropriate glucagon responses to OGTT. Both groups of patients with diabetes showed normal suppression of glucagon in response to intravenous glucose. Thus, HNF1A-diabetes, similar to type 2 diabetes, is characterized by an impaired incretin effect and inappropriate glucagon responses, whereas incretin effect and glucagon response to oral glucose remain unaffected in GCK-diabetes, reflecting important pathogenetic differences between the two MODY forms.

Topics: Administration, Intravenous; Administration, Oral; Adult; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucokinase; Glucose; Hepatocyte Nuclear Factor 1-alpha; Humans; Incretins; Insulin Resistance; Male; Middle Aged

There is accumulating evidence that obesity leads to a proinflammatory state, which plays crucial roles in insulin resistance and development of type 2 diabetes mellitus (T2DM). Previous studies demonstrated that weight loss after bariatric surgery was accompanied by a suppression of the proinflammatory state. However, the effect of bariatric surgery on the proinflammatory state and associated signaling beyond weight loss is still elusive. The objective of this study was to investigate the effect of duodenal-jejunal bypass (DJB) on glucose homeostasis, the proinflammatory state and the involving signaling independently of weight loss.. A high-fat diet and low-dose streptozotocin administration were used to induce T2DM in male Sprague-Dawley rats. The diabetic rats underwent DJB or sham surgery. The blood glucose, glucose tolerance and insulin resistance were determined to evaluate the glucose homeostasis. Serum insulin, GLP-1 and hsCRP were detected by ELISA. The gene expression of TNF-α, IL-6, IL-1β and MCP-1 in liver and fat was determined by quantitative real-time RT-PCR. The JNK activity and serine phosphorylation of IRS-1 in liver and adipose tissue were determined by Western blotting.. Compared to the S-DJB group, DJB induced significant and sustained glycemic control with improved insulin sensitivity and glucose tolerance independently of weight loss. DJB improved the proinflammatory state indicated by decreased circulating hsCRP and proinflammatory gene expression in the liver and adipose tissue. The JNK activity and serine phosphorylation of IRS-1 in liver and adipose tissue were significantly reduced after DJB.. DJB achieved a rapid and sustainable glycemic control independently of weight loss. The data indicated that the improved proinflammatory state and decreased JNK activity after DJB may contribute to the improved glucose homeostasis.

Topics: Adipose Tissue; Animals; Blood Glucose; Chemokine CCL2; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Duodenum; Gastric Bypass; Glucagon-Like Peptide 1; Insulin Receptor Substrate Proteins; Insulin Resistance; Interleukins; Jejunum; Liver; Male; MAP Kinase Signaling System; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Weight Loss

To assess the rapid improvement of insulin sensitivity and β-cell function following biliopancreatic diversion with duodenal switch (BPD-DS) and determine the role played by caloric restriction in these changes.. Standard meals were administrated before and on day 3, 4, and 5 after BPD-DS to measure total caloric intake, glucose excursion, insulin sensitivity, and secretion in matched type 2 diabetes and normoglycemic (NG) subjects. In a second set of study, other subjects with type 2 diabetes had the same meal tests prior to and after a 3-day caloric restriction identical to that observed after BPD-DS and then 3 days after actually undergoing BPD-DS.. Improvement of HOMA-IR occurred at day 3 after BPD-DS in diabetes and after 3 days of caloric restriction. The disposition index (DI) improved rapidly in diabetes after BPD-DS and to a similar extent after caloric restriction. DI was higher and did not change after BPD-DS in NG. Changes in glucagon-like peptide-1, gastric inhibitory peptide, peptide tyrosine tyrosine, ghrelin, and pancreatic polypeptide levels were not associated with modulation of DI in the participants.. Caloric restriction is the major mechanism underlying the early improvement of insulin sensitivity and β-cell function after BPD-DS in type 2 diabetes.

Topics: Adult; Biliopancreatic Diversion; Blood Glucose; Caloric Restriction; Diabetes Mellitus, Type 2; Duodenum; Female; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Obesity, Morbid; Peptide YY; Pilot Projects

The rising prevalence of type-2 diabetes is becoming a pressing issue based on emerging reports that T2DM can also adversely impact mental health. We have utilized the UCD-T2DM rat model in which the onset of T2DM develops spontaneously across time and can serve to understand the pathophysiology of diabetes in humans. An increased insulin resistance index and plasma glucose levels manifested the onset of T2DM. There was a decrease in hippocampal insulin receptor signaling in the hippocampus, which correlated with peripheral insulin resistance index along the course of diabetes onset (r=-0.56, p<0.01). T2DM increased the hippocampal levels of 4-hydroxynonenal (4-HNE; a marker of lipid peroxidation) in inverse proportion to the changes in the mitochondrial regulator PGC-1α. Disrupted energy homeostasis was further manifested by a concurrent reduction in energy metabolic markers, including TFAM, SIRT1, and AMPK phosphorylation. In addition, T2DM influenced brain plasticity as evidenced by a significant reduction of BDNF-TrkB signaling. These results suggest that the pathology of T2DM in the brain involves a progressive and coordinated disruption of insulin signaling, and energy homeostasis, with profound consequences for brain function and plasticity. All the described consequences of T2DM were attenuated by treatment with the glucagon-like peptide-1 receptor agonist, liraglutide. Similar results to those of liraglutide were obtained by exposing T2DM rats to a food energy restricted diet, which suggest that normalization of brain energy metabolism is a crucial factor to counteract central insulin sensitivity and synaptic plasticity associated with T2DM.

Topics: Aldehydes; Animals; Biomarkers; Blood Glucose; Brain; Crosses, Genetic; Diabetes Mellitus, Type 2; Disease Models, Animal; Energy Metabolism; Glucagon-Like Peptide 1; Hippocampus; Homeostasis; Hypoglycemic Agents; Immunoblotting; Insulin Resistance; Liraglutide; Male; Neuronal Plasticity; Obesity; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor, Insulin

Type 2 diabetes is caused by interactions between genetic and environmental factors. Our previous studies reported that paired box 6 mutation heterozygosity (Pax6(m/+)) led to defective proinsulin processing and subsequent abnormal glucose metabolism in mice at 6  months of age. However, high-fat diet exposure could be an important incentive for diabetes development. In this study, we aimed to develop a novel diabetic model imitating human type 2 diabetes by exposing Pax6(m/+) mice to high-fat diet and to explore the underlying mechanism of diabetes in this model.. Over 300 Pax6(m/+) and wild-type male weanling mice were randomly divided into two groups and were fed an high-fat diet or chow diet for 6-10  weeks. Blood glucose and glucose tolerance levels were monitored during this period. Body weights, visceral adipose weights, blood lipid profiles and insulin sensitivity (determined with an insulin tolerance test) were used to evaluate obesity and insulin resistance. Proinsulin processing and insulin secretion levels were used to evaluate pancreatic β cell function.. After 6  weeks of high-fat diet exposure, only the Pax6(m/+) mice showed dramatic postloading hyperglycaemia. These mice exhibited significant high-fat diet-induced visceral obesity and insulin resistance and displayed defective prohormone convertase 1/3 production, an increased proinsulin:total insulin ratio and impaired early-phase insulin secretion, because of the Pax6 mutation. Hyperglycaemia worsened progressively over time with the high-fat diet, and most Pax6(m/+) mice on high-fat diet developed diabetes or impaired glucose tolerance after 10  weeks. Furthermore, high-fat diet withdrawal partly improved blood glucose levels in the diabetic mice.. By combining the Pax6(m/+) genetic background with an high-fat diet environment, we developed a novel diabetic model to mimic human type 2 diabetes. This model is characterized by impaired insulin secretion, caused by the Pax6 mutation, and high-fat diet-induced insulin resistance and therefore provides an ideal tool for research on type 2 diabetes pathogenesis and therapies.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Eye Proteins; Glucagon-Like Peptide 1; Heterozygote; Homeodomain Proteins; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Obesity, Abdominal; Paired Box Transcription Factors; PAX6 Transcription Factor; Prediabetic State; Proinsulin; Proprotein Convertase 1; Random Allocation; Repressor Proteins; Weaning; Weight Gain

We investigated the effects of liraglutide on insulin sensitivity and glucose metabolism in male Wistar rats. The rats were fed a normal chow diet (NCD) or a 60% high-fat diet (HFD) for a total of 4 weeks. After 3 weeks of feeding, they were injected with liraglutide once a day for 7 days. Subsequently, euglycemic-hyperinsulinemic clamp studies were performed after fasting the animals for 8 hours. During the clamp studies on the NCD-fed rats, the glucose infusion rate required for euglycemia was significantly higher in the liraglutide group than in the control group. The clamp hepatic glucose output was significantly lower in the liraglutide group than in the control group, but the insulin-stimulated glucose disposal rate did not change significantly in the liraglutide groups. The clamp studies on the HFD-fed rats revealed that the glucose infusion rate required to achieve euglycemia was significantly higher in the liraglutide group than in the control HFD group, and the insulin-stimulated glucose disposal rate increased significantly in the liraglutide groups. The clamp hepatic glucose output decreased significantly in the liraglutide groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt and AMP-activated protein kinase was enhanced in the livers of the NCD- and HFD-fed rats and in the skeletal muscles of the HFD-fed rats. Oil red O staining indicated that liraglutide also improved hepatic steatosis. In summary, our studies suggest that in normal glucose tolerance states, liraglutide enhances insulin sensitivity in the liver but not in skeletal muscles. However, in insulin-resistant states, liraglutide improves insulin resistance in the liver and muscles and improves fatty liver.

Topics: AMP-Activated Protein Kinases; Animals; Enzyme Activation; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Liraglutide; Liver; Male; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar

Rerouting of nutrients and/or increasing nutrient delivery to the small intestine after Roux-en-Y gastric bypass may have important potential as a diabetes treatment modality. However, it is still important question which part of the gastrointestinal tract is the most important for control of glycemia. The aim of this study was to investigate the role of different segments of the gastrointestinal tract on glucose metabolism in the physiological state.. Forty 12-week-old male Wistar rats were divided into the following four groups of 10 animals each: the gastrostomy group, the duodenostomy group, the jejunostomy group, and the ileostomy group. All rats were subjected to a glucose tolerance test by infusion of glucose via the surgically inserted tubes in the stomach (gastrostomy), in the duodenum (duodenostomy), in the jejunum (jejunostomy), or in the ileum (ileostomy). Plasma glucagon-like peptide-17-36 (GLP-17-36) and insulin levels during the glucose tolerance test were assayed and Matsuda index was calculated.. Ileostomy rats exhibited significantly lower glycemic excursions compared with gastrostomy, duodenostomy, and jejunostomy rats. Insulin and GLP-1 levels during the glucose tolerance test were significantly higher in duodenostomy and jejunostomy rats than in gastrostomy and ileostomy rats. Matsuda index was significantly higher in ileostomy rats than in duodenostomy and jejunostomy rats.. Ileal glucose infusion leads to increased insulin sensitivity, further decreasing blood glucose levels.

Topics: Animals; Blood Glucose; Duodenostomy; Gastrostomy; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Ileostomy; Ileum; Infusions, Parenteral; Insulin; Insulin Resistance; Jejunostomy; Male; Models, Animal; Rats; Rats, Wistar

Role of GLP-1 and GIP in beta cell compensatory responses to beta cell attack and insulin resistance were examined in C57BL/6 mice lacking functional receptors for GLP-1 and GIP. Mice were treated with multiple low dose streptozotocin or hydrocortisone. Islet parameters were assessed by immunohistochemistry and hormone measurements were determined by specific enzyme linked immunoassays. Wild-type streptozotocin controls exhibited severe diabetes, irregularly shaped islets with lymphocytic infiltration, decreased Ki67/TUNEL ratio with decreased beta cell and increased alpha cell areas. GLP-1 and GIP were co-expressed with glucagon and numbers of alpha cells mainly expressing GLP-1 were increased. In contrast, hydrocortisone treatment and induction of insulin resistance increased islet numbers and area, with enhanced beta cell replication, elevated mass of beta and alpha cells, together with co-expression of GLP-1 and GIP with glucagon in islets. The metabolic responses to streptozotocin in GLP-1RKO and GIPRKO mice were broadly similar to C57BL/6 controls, although decreases in islet numbers and size were more severe. In contrast, both groups of mice lacking functional incretin receptors displayed substantially impaired islet adaptations to insulin resistance induced by hydrocortisone, including marked curtailment of expansion of islet area, beta cell mass and islet number. Our observations cannot be explained by simple changes in circulating incretin concentrations, suggesting that intra-islet GLP-1 and GIP make a significant contribution to islet adaptation, particularly expansion of beta cell mass and compensatory islet compensation to hydrocortisone and insulin resistance.

Topics: Animals; Apoptosis; Cell Proliferation; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Hormones; Hydrocortisone; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Lymphocytes; Male; Mice; Mice, Knockout; Pancreas; Protein Transport; Streptozocin

The significance of associations between prediabetes, type 2 diabetes, and dipeptidyl peptidase-4 (DPP4) activity in a Chinese population is not clear.. The objective of the study was to determine whether DPP4 activity and active glucagon-like peptide-1 (GLP-1) were predictive of the onset of prediabetes and type 2 diabetes.. This was a 4-year follow-up study conducted in Sichuan, China. A total of 474 Chinese women and men aged 18-70 years were studied.. All subjects were divided into 3 groups (normal glucose tolerance, prediabetes, and type 2 diabetes) on the basis of their glucose metabolism status after 4 years. The DPP4 activity, active GLP-1, and glucagon were measured at baseline and 4 years later.. The baseline DPP4 activity was significantly higher in subjects who had progressed to prediabetes or type 2 diabetes compared with subjects who remained normoglycemic (P < .01). In a multiple linear regression analysis, baseline DPP4 activity and active GLP-1 were independent predictors of an increase in insulin resistance over a 4-year period (P < .05). Cox proportional hazards models revealed that DPP4 activity independently predicted the risk of developing prediabetes [relative risk 2.77 (95% confidence interval 1.38-5.55), P < .01] and type 2 diabetes [5.10 (95% confidence interval 1.48-17.61), P < .05] after adjustment for confounding risk factors.. DPP4 activity is an important predictor of the onset of insulin resistance, prediabetes, and type 2 diabetes in apparently healthy Chinese individuals. This finding may have important implications for understanding the etiology of diabetes.

Topics: Adolescent; Adult; Aged; Blood Glucose; China; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glucose Tolerance Test; Health Surveys; Humans; Insulin Resistance; Longitudinal Studies; Male; Middle Aged; Prediabetic State; Risk; Young Adult

Ginsenosides, major bioactive constituents in Panax ginseng, have been shown to exert anti-hyperlipidemia effects. However, the underlying mechanism was not well-elucidated due to the low bioavailability of ginsenosides. Glucagon-like peptide-1 (GLP-1) was considered to be a critical regulator of energy homeostasis. Our previous studies have showed that ginseng total saponins (GTS) exhibited antidiabetic effects partly via modulating GLP-1 release. The aim of this study was to investigate the potential role of GLP-1 in anti-hyperlipidemia effect of GTS in rats fed with high-fat diet.. Male Sprague-Dawley rats were fed with normal diet (CON) or high-fat diet (HFD) for 4 weeks. Then, the HFD rats orally received vehicle (HFD), 150 mg/kg/day (HFD-GL) and 300 mg/kg/day of GTS (HFD-GH) for another 4 weeks, respectively.. Four-week GTS treatment significantly ameliorated hyperlipidemia, decreased body fat, liver weight and improved insulin resistance. It was found that high-dose GTS treatment increased portal GLP-1 level induced by glucose loading, accompanied by increased intestinal GLP-1 content, L-cell number and prohormone convertase 3 mRNA expression. Data from NCI-H716 cells showed that both GTS and ginsenoside Rb1 significantly increased GLP-1 secretion as well as proglucagon mRNA level in NCI-H716 cells supplemented with 10% HFD-rat serum.. Hyperlipidemia and insulin resistance were attenuated effectively in response to GTS treatment. These improvements may be associated with the increased secretion of GLP-1.

Topics: Animals; Blood Glucose; Body Weight; Cell Line; Diet, High-Fat; Energy Intake; Ginsenosides; Glucagon-Like Peptide 1; Glucose; Humans; Hyperlipidemias; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Rats; Rats, Sprague-Dawley

We previously demonstrated that older beagles have impaired whole body and myocardial insulin responsiveness (MIR), and that glucagon-like peptide-1 (GLP-1 [7-36] amide) improves MIR in young beagles with dilated cardiomyopathy (DCM). Here, we sought to determine if aging alone predisposes to an accelerated course of DCM, and if GLP-1 [7-36] amide would restore MIR and impact the course of DCM in older beagles.. Eight young beagles (Young-Control) and sixteen old beagles underwent chronic left ventricle (LV) instrumentation. Seven old beagles were treated with GLP-1 (7-36) amide (2.5 pmol/kg/min) for 2 weeks prior to instrumentation and for 35 days thereafter (Old + GLP-1), while other 9 served as control (Old-Control). All dogs underwent baseline metabolic determinations and LV biopsy for mitochondria isolation prior to the development of DCM induced by rapid pacing (240 min-1). Hemodynamic measurements were performed routinely as heart failure progressed.. At baseline, all old beagles had elevated non-esterifed fatty acids (NEFA), and impaired MIR. GLP-1 reduced plasma NEFA (Old-Control: 853 ± 34; Old + GLP-1: 531 ± 33 μmol/L, p < 0.02), improved MIR (Old-Control: 289 ± 54; Old + GLP-1: 512 ± 44 mg/min/100 mg, p < 0.05), and increased uncoupling protein-3 (UCP-3) expression in isolated mitochondria. Compared to the Young-Control, the Old-Controls experienced an accelerated course of DCM (7 days versus 29 days, p < 0.005) and excess mortality, while the Old + GLP-1 experienced increased latency to the onset of DCM (7 days versus 23 days, p < 0.005) and reduced mortality.. Aging is associated with myocardial insulin resistance, which predispose to an accelerated course of DCM. GLP-1 treatment is associated with increased MIR and protection against an accelerated course of DCM in older beagles.

Topics: Aging; Animals; Cardiotonic Agents; Disease Progression; Dogs; Glucagon-Like Peptide 1; Heart Failure; Infusions, Intravenous; Insulin Resistance; Myocardium; Peptide Fragments; Random Allocation

Maternal protein restriction (PR) during pregnancy is known to have numerous adverse effects on offspring, including increased adiposity and impaired glucose tolerance later in life. A few studies have shown that this adverse programming can be reversed by dietary or hormonal therapies early in postnatal life. The objective of this study was to determine if a weaning diet high in prebiotic fiber could mitigate some of the negative effects of maternal PR, such as increased adiposity and impaired glucose tolerance. Wistar rats were fed a low- (8%) or normal- (20%) protein diet during pregnancy. Male and female pups were weaned onto control (C; 5% fiber, 20% protein) or high (prebiotic) fiber (HF; 21% wt:wt, 1:1 ratio oligofructose and inulin at 4-10 wk; 10% wt:wt, 1:1 ratio oligofructose and inulin at 10-24 wk; 17.3% protein) diets. At 24 wk of age, glucose tolerance, body composition, satiety hormones, gut microbiota, and markers of intestinal permeability were measured in the offspring. Maternal PR reduced offspring birth weight by 5% and lean mass by 9% compared with the C offspring (P < 0.007). HF-fed offspring had lower body weights and percentage body fat (∼23% in males, ∼19% in females) at 24 wk than did C offspring (P < 0.02). Compared with C pups, pups fed the HF diet had greater cecal Bifidobacterium spp. (>5-fold) and plasma concentrations of the gut trophic hormone glucagon-like peptide 2 (GLP-2) (P < 0.05). In male PR offspring fed the HF diet, insulin resistance measured by the homeostasis model assessment of insulin resistance was reduced by 81% compared with those fed the C diet (P = 0.02). In female PR offspring fed the HF diet, plasma endotoxin was greater and colonic tight junction protein 1 (Tjp1) expression was lower than in those fed the C diet. A high prebiotic fiber weaning diet mitigated increased adiposity and insulin resistance associated with maternal PR, which could improve health and decrease risk of chronic disease in offspring born to malnourished dams. However, the functional importance of sex-specific changes in markers of intestinal barrier function warrants further investigation.

Topics: Adiposity; Animals; Blood Glucose; Body Composition; Body Weight; Diet; Diet, High-Fat; Diet, Protein-Restricted; Dietary Fiber; Female; Gastrointestinal Tract; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Insulin; Insulin Resistance; Male; Maternal Nutritional Physiological Phenomena; Peptide YY; Permeability; Prebiotics; Pregnancy; Rats; Rats, Wistar; Satiation; Sex Factors; Weaning

This study is to explore the possible mechanism of ileal interposition (IT) treatment of glycemic control of the type 2 diabetes mellitus (T2DM) by establishing an IT animal model. Twelve T2DM rats (GK rats) of 8-week old were divided into GK IT surgery group (GK-IT) and GK sham group (GK-Sham). Six Wistar rats were used as the non-T2DM sham group (WS-Sham). Enzyme-linked immunosorbent assay was used to detect plasma insulin concentration and fasting pancreas glucagon-like peptide-1 (GLP-1) concentration changes. Homeostasis model assessment of insulin resistance was used to quantitatively measure insulin resistance. Glucagon-like peptide-1 receptor (GLP-1R) expression was detected by Western blotting. IT significantly decreased fasting blood glucose level and the oral glucose tolerance, and reduced insulin resistance of GK rats by increasing GLP-1 concentration and GLP-1R levels. The postoperative pancreatic β-cell apoptosis rate of GK-Sham group was significantly higher than those in the GK-IT group and the WS-Sham group. IT significantly reduces blood glucose and decreases insulin resistance by up-regulating GLP-1 concentrations and GLP-1R levels, which may contribute to insulin secretion of pancreatic β-cells and decreases apoptosis of pancreatic β-cell.

Topics: Animals; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Ileum; Insulin Resistance; Insulin-Secreting Cells; Jejunoileal Bypass; Male; Rats; Rats, Wistar; Receptors, Glucagon; Up-Regulation

The combination of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) has been proposed as a potential treatment for diabetes and obesity. However, the combined effects of these hormones, PYY(3-36) and GLP-1(7-36 amide), on glucose homeostasis are unknown.. This study sought to investigate the acute effects of PYY(3-36) and GLP-1(7-36) amide, individually and in combination, on insulin secretion and sensitivity.. Using a frequently sampled iv glucose tolerance test (FSIVGTT) and minimal modeling, this study measured the effects of PYY(3-36) alone, GLP-1(7-36) amide alone, and a combination of PYY(3-36) and GLP-1(7-36) amide on acute insulin response to glucose (AIRg) and insulin sensitivity index (SI) in 14 overweight human volunteers, studied in a clinical research facility.. PYY(3-36) alone caused a small but nonsignificant increase in AIRg. GLP-1(7-36) amide alone and the combination of PYY(3-36) and GLP-1(7-36) amide did increase AIRg significantly. No significant differences in SI were observed with any intervention.. PYY(3-36) lacks any significant acute effects on first-phase insulin secretion or SI when tested using an FSIVGTT. Both GLP-1(7-36) amide alone and the combination of PYY3-36 and GLP-1(7-36) amide increase first-phase insulin secretion. There does not seem to be any additive or synergistic effect between PYY(3-36) and GLP-1(7-36) amide on first-phase insulin secretion. Neither hormone alone nor the combination had any significant effects on SI.

Topics: Adult; Blood Glucose; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Overweight; Peptide Fragments; Peptide YY; Young Adult

The purpose of this study is to investigate the impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass (RYGB) on the level of fasting and postprandial serum glucagon-like peptide-1 (GLP-1) in type 2 diabetic mellitus rats.. Randomized block design, factorial experiment. Forty-five type 2 diabetic rats were divided into four groups: sham operation (S, n = 10) and sham operation with the hepatic branch of the vagotomy (SV, n = 11), Roux-en-Y gastric bypass (RYGB, n = 12) and RYGB without preservation of the vagus (RYGBV, n = 12). Levels of fasting and postprandial serum GLP-1 30 min after 50 % glucose solution (2 g/kg) by gavage were determined before surgery and postoperatively at 1, 4, and 8 weeks. Interactions between RYGB and the common hepatic branch were also assessed.. Roux-en-Y gastric bypass surgery significantly increased the concentration of postprandial serum GLP-1 and maintained it at a higher level (P < 0.05). Preservation of vagus hepatic branch only increased the concentration of postprandial serum GLP-1 at the initial stage (P < 0.05), which gradually weakened over time (P > 0.05). Both RYGB and vagotomy of the hepatic branch had no influence on fasting serum GLP-1 (P > 0.05).. During RYGB surgery for the long-term treatment of T2DM, preservation of the hepatic branch of the vagus might have no impact on serum GLP-1 level.

Topics: Analysis of Variance; Anastomosis, Roux-en-Y; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Gastric Bypass; Glucagon-Like Peptide 1; Insulin Resistance; Liver; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Streptozocin; Survival Rate; Treatment Outcome; Vagotomy; Vagus Nerve

Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion and pancreatic β-cell proliferation. We previously showed that the effect of GluOC on insulin secretion is mediated largely by glucagon-like peptide-1 (GLP-1) secreted from the intestine in response to GluOC exposure. We have now examined the effect of oral administration of GluOC on glucose utilization as well as the fate of such administered GluOC in mice. Long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level and improved glucose tolerance in mice without affecting insulin sensitivity. It also increased the fasting serum insulin concentration as well as the β-cell area in the pancreas. A small proportion of orally administered GluOC reached the small intestine and remained there for at least 24h. GluOC also entered the general circulation, and the serum GLP-1 concentration was increased in association with the presence of GluOC in the intestine and systemic circulation. The putative GluOC receptor, GPRC6A was detected in intestinal cells, and was colocalized with GLP-1 in some of these cells. Our results suggest that orally administered GluOC improved glucose handling likely by acting from both the intestinal lumen and the general circulation, with this effect being mediated in part by stimulation of GLP-1 secretion. Oral administration of GluOC warrants further study as a safe and convenient option for the treatment or prevention of metabolic disorders.

Topics: Administration, Oral; Animals; Blood Glucose; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Glucose; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Inbred C57BL; Osteocalcin

Hemorrhagic shock (HS) may contribute to organ failure, by profoundly altering mitochondrial function. Resveratrol (RSV), a naturally occurring polyphenol, has been shown to promote mitochondrial function and regulate glucose homeostasis in diabetes. We hypothesized that RSV during resuscitation would ameliorate HS-induced mitochondrial dysfunction and improve hyperglycemia following acute blood loss.. With the use a decompensated HS model, male Long-Evans rats (n = 6 per group) were resuscitated with lactated Ringer's solution with or without RSV (30 mg/kg) and were killed before hemorrhage (sham), at severe shock, following resuscitation, and 18 hours after resuscitation. At each time point, the liver and kidney mitochondria were isolated to assess individual respiratory complexes (CI, CII, and CIV) and the production of reactive oxygen species (ROS). Blood samples were assayed for glucose, insulin, corticosterone, total glucagon-like peptide (GLP-1), glucagon, and serum cytokine levels. The Homeostatic Model Assessment-Insulin Resistance index was used to quantify insulin resistance.. RSV supplementation following HS significantly improved mitochondrial function and decreased mitochondrial ROS production in both liver and kidney. RSV-treated animals had significantly lower blood glucose levels following resuscitation when compared with sham animals (116.0 ± 20.2 mg/dL vs. 227.7 ± 8.3 mg/dL, p < 0.05) or those resuscitated with lactated Ringer's solution (116.0 ± 20.2 mg/dL vs. 359.0 ± 79.5 mg/dL, p < 0.05). RSV supplementation was associated with significantly decreased plasma insulin levels (1.0 ± 0.4 ng/mL vs. 6.5 ± 3.7 ng/mL, p < 0.05), increased total GLP-1 levels (385.8 ± 56.6 ng/mL vs. 187.3 ± 11.1 ng/mL, p < 0.05), and a lower natural Log Homeostatic Model Assessment-Insulin Resistance index (1.30 ± 0.42 vs. 4.18 ± 0.68, p < 0.05) but had minimal effect on plasma corticosterone, glucagon, or cytokine levels.. Resuscitation with RSV restores mitochondrial function and decreases insulin resistance but may be associated with increased hypoglycemia. The observed antiglycemic effects of RSV may be mediated by decreased mitochondrial ROS and increased GLP-1 secretion.

Topics: Animals; Blood Glucose; Corticosterone; Glucagon; Glucagon-Like Peptide 1; Hypoglycemia; Insulin; Insulin Resistance; Kidney; Male; Mitochondria; Mitochondria, Liver; Rats, Long-Evans; Reactive Oxygen Species; Resuscitation; Resveratrol; Shock, Hemorrhagic; Stilbenes

Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced β-cell area in control offspring of LIRKO mothers shortly after birth. β-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller β-cell mass/area and β-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development.

Topics: Animals; Animals, Newborn; Blood Glucose; Cell Proliferation; Diabetes, Gestational; Disease Models, Animal; Female; Glucagon; Glucagon-Like Peptide 1; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Leptin; Mice; Organ Size; Phenotype; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Weight Gain

Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., palmitic-acid-9-hydroxy-stearic-acid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion. PAHSAs also reduce adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 to enhance insulin-stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with the potential to treat type 2 diabetes.

Topics: Adipose Tissue; Adult; Animals; Diabetes Mellitus, Type 2; Diet; Esters; Fatty Acids; Female; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Humans; Inflammation; Insulin; Insulin Resistance; Lipogenesis; Male; Mass Spectrometry; Mice, Inbred C57BL; Middle Aged; Receptors, G-Protein-Coupled

Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Diet, High-Fat; Drug Synergism; Eating; Exenatide; Glucagon; Glucagon-Like Peptide 1; Insulin Resistance; Male; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptides; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Venoms

Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic β-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive β-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.

Topics: Animals; Chromans; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; In Vitro Techniques; Insulin; Insulin Resistance; Insulin Secretion; Intestines; Islets of Langerhans; KCNQ1 Potassium Channel; Mice; Pancreas; Sulfonamides

The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Models, Animal; Endothelium, Vascular; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin Resistance; Kidney Diseases; Lipid Metabolism; Liver Diseases; Multicenter Studies as Topic; Nervous System Diseases; Neuroprotective Agents; Organ Specificity; Receptors, Glucagon; Recombinant Proteins

Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge-high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

Topics: Age Factors; Animals; Biomarkers; Body Mass Index; Dentate Gyrus; Female; Glucagon-Like Peptide 1; Insulin Resistance; Macaca radiata; Male; Neurogenesis; Neuronal Plasticity; Stress, Psychological

The aim of this study is to investigate the mechanisms of improvement in insulin resistance after duodenal-jejunal bypass (DIB), especially regarding the correlation between bile acids and glucagon-like peptide-1 (GLP-1).. SD rats were divided into two groups: DIB or Sham group. Blood glucose, insulin, GLP-1, bile acids, and the number of L cells in the small intestine were investigated three weeks after the operations. Next, to assess the effect of the bile acids on GLP-1 secretion in ileum, bile diversion model (=inhibition of rapid bile exposure to the ileum; BD group) were performed and postoperative glycemic parameters were measured.. DJB improved insulin resistance and increased GLP-1 compared with sham. Higher bile acids in DJB were found than that in sham. The number of L cells in the common limb of DJB was increased compared with that in the distal segment of sham. In BD group, insulin resistance had not improved. GLP-1, bile acids, and the number of L cells revealed no significant changes compared with sham.. DJB has a potential to improve insulin resistance, which may be related to enhanced GLP-1 secretion through the increase of bile acids in the common limb of the small intestine.

Topics: Anastomosis, Surgical; Animals; Bile Acids and Salts; Blood Glucose; Duodenum; Enteroendocrine Cells; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Jejunum; Male; Rats, Sprague-Dawley; Time Factors; Up-Regulation

Obesity is widely acknowledged as a critical risk factor for metabolic complications. Among obese subjects, there is a phenotype of metabolically healthy but obese (MHO) individuals that shows a favorable cardiometabolic risk profile. We aimed to evaluate the potential mechanisms underlying the metabolic profile of this subset, including alpha and beta cell function and entero-insular axis.. One hundred twenty-nine obese and 24 nonobese subjects were studied. Obese participants were defined as MHO or at-risk obese, according to the homeostasis model of assessment-insulin resistance (HOMA-IR) index (MHO: lower tertile of HOMA-IR, n = 43; at-risk: upper tertile of HOMA-IR index, n = 41). Insulin, glucagon, and incretin responses after a 120' oral glucose tolerance test (75-g OGTT) were investigated.. During OGTT, MHO individuals showed in comparison with at-risk subjects: lower fasting and afterloads plasma levels of glucose, insulin, and C-peptide; higher disposition index; lower fasting (P = 0.004) and at 30' (P = 0.01) plasma glucose-dependent insulinotropic polypeptide (GIP) levels; lower area under the curve (AUC) (0-30) for GIP (P = 0.008); higher glucagon-like peptide-1 (GLP-1) plasma levels at 90' (P = 0.02) and 120' (P = 0.02); lower glucagon plasma levels at baseline (P = 0.04) and at 30' (P = 0.03); and appropriate glucagon suppression after the oral glucose load.. MHO subjects show, as well as normal-weight individuals, a lower diabetogenic profile by virtue of higher disposition index and unaffected entero-insular axis. At-risk obese individuals present increased GIP levels that might play a role in determining increased glucagon secretion and inappropriate glucagon responses after glucose load, thus contributing to impaired glucose homeostasis.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Obesity

We investigated postprandial glucagon-like peptide-1 (GLP-1) responses in pregnant women with and without gestational diabetes mellitus (GDM) and again following delivery when normal glucose tolerance (NGT) was re-established.. Eleven women with GDM [plasma glucose (PG) concentration at 120 min after a 75-g oral glucose tolerance test (OGTT): 10.0 ± 0.9 mM (mean ± SD); age: 31 ± 6 years; body mass index (BMI): 31.6 ± 6.4 kg/m(2) ; haemoglobin A1c (HbA1c): 5.6 ± 0.5%] and eight pregnant women with NGT (PG(120 min), OGTT : 5.7 ± 0.7 mM; age: 28 ± 3 years; BMI: 29.7 ± 5.4 kg/m(2) ; HbA1c: 5.4 ± 0.3%) were investigated with a 4-h liquid meal test during third trimester (TT) and 3-4 months postpartum (PP). All patients with GDM re-established NGT following delivery.. Pregnancy was associated with low postprandial GLP-1 responses. Patients with GDM exhibited reduced postprandial GLP-1 responses compared to their PP levels [area under curve (AUC): 5.5 ± 1.3 vs. 8.4 ± 3.2 nM × min, p=0.005], but the difference among NGT women (7.3 ± 2.8 vs. 8.8 ± 2.0 nM × min, p=0.066) was not statistically significant. Pregnancy did not influence postprandial responses of the other incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in any of the groups, but GDM patients were characterized by greater postprandial GIP responses during both TT and PP compared to NGT subjects.. Pregnancy is associated with reduced postprandial GLP-1 responses (most pronounced in patients with GDM) that normalize after delivery. In contrast, postprandial GIP responses seem unaffected by pregnancy but is increased in GDM patients.

Topics: Adult; Area Under Curve; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Diabetes, Gestational; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Postpartum Period; Postprandial Period; Pregnancy

Liraglutide, a Glucagon-like peptide-1(GLP-1) analogue with 97% sequence identity to human GLP-1, increases insulin secretion and insulin sensitivity. Its effect on non-alcoholic fatty liver disease (NAFLD) remains poorly understood. In this study, we examined whether liraglutide can protect against inflammatory stress by inhibiting activation of c-Jun N-terminal protein kinase (JNK).. ApoE KO and adiponectin (Acrp30) knockdown mice fed a high-fat diet (HFD) were treated with liraglutide (1 mg/kg, twice daily) for 8 weeks. Liver tissue was procured for histological examination, real-time RT-PCR and Western blot analysis.. The results showed that the combination of HFD, Acrp30 knockdown and ApoE deficiency had additive effects on the development of insulin resistance (IR) and NAFLD. Administration of liraglutide prevented the development of HFD and hypoadiponectinaemia-induced IR and NAFLD in this model. Liraglutide also attenuated the expression of proinflammatory cytokines or transcription factor, including TNF-α and NF-κB(65) , and the expression of two lipogenesis-related genes, Acetyl-CoA Carboxylase (ACC) and fatty acid synthase (FAS). These changes were accompanied by elevated plasma of Acrp30, increased Acrp30 mRNA, AMP Kinase phosphorylation, and decreased mitogen-activated protein kinase 4 (MKK4) mRNA expression and JNK phosphorylation.. Our study also showed potent inhibitory effects of liraglutide on MKK4/JNK signalling which may be a mechanism for the observed improved insulin sensitivity and inflammatory stress induced by HFD and hypoadiponectinaemia.

Topics: Adiponectin; Analysis of Variance; Animals; Apolipoproteins E; Blotting, Western; Diet, High-Fat; Enzyme Activation; Fatty Liver; Gene Knockdown Techniques; Glucagon-Like Peptide 1; Histological Techniques; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut in response to nutrient ingestion and that has a range of metabolic effects, including enhancing insulin secretion and decreasing food intake. Postprandial GLP-1 secretion is greatly enhanced in rats and humans after some bariatric procedures, including vertical sleeve gastrectomy (VSG), and has been widely hypothesized to contribute to reduced intake, weight loss, and the improvements in glucose homeostasis after VSG. We tested this hypothesis using two separate models of GLP-1 receptor deficiency. We found that VSG-operated GLP-1 receptor-deficient mice responded similarly to wild-type controls in terms of body weight and body fat loss, improved glucose tolerance, food intake reduction, and altered food selection. These data demonstrate that GLP-1 receptor activity is not necessary for the metabolic improvements induced by VSG surgery.

Topics: Animals; Body Composition; Body Weight; Eating; Exenatide; Gastrectomy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Mice; Mice, Knockout; Obesity; Peptides; Postprandial Period; Receptors, Glucagon; Venoms

The aim of this study was to characterize the conformation and potency of a mutated glucagon-like peptide-1 (mGLP-1), and evaluate its glucose-lowering activity in diabetic mice.. Spectroscopy techniques were employed to characterize the conformation of mGLP-1. Glucose tolerance test was performed to determine the potency of mGLP-1 in vivo. A mouse model in which diabetes was induced by multiple low doses of streptozotocin was established to evaluate the glucose-lowering activity of mGLP-1.. Compared with native GLP-1, mGLP-1 had a similar conformation and an enhanced potency in vivo. In diabetic mice, mGLP-1 displayed a significantly improved glucose-lowering activity as judged by fasting glucose and insulin, oral glucose tolerance test, beta cell function analysis and histochemical analysis.. Collectively, mGLP-1 possesses an improved glucose-lowering activity in vivo and therefore can be recognized as a potential candidate for the future development of anti-diabetic drugs.

Topics: Amino Acid Substitution; Animals; Diabetes Mellitus, Experimental; Drug Design; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Injections, Intraperitoneal; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Kidney; Liver; Male; Mice; Mice, Inbred Strains; Mutant Proteins; Protein Conformation; Recombinant Proteins

Transoral gastroplasty (TOGA) is a safe and less invasive procedure than traditional bariatric surgery. We studied the effects of TOGA on the risk of progression from prediabetes to overt type 2 diabetes mellitus (T2DM) or on regression from diabetes or prediabetes to a lower risk category.. Prospective, observational study (October 2008 to October 2010) performed at Catholic University, Rome, Italy. Fifty consecutive subjects 18-60 years old, 35 ≥ body mass index < 55 kg/m², were enrolled. Glucose tolerance, insulin sensitivity, and secretion were studied at baseline and 1 week and 1, 6, and 12 months after TOGA. Plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and ghrelin levels were measured.. Forty-three patients (86%) completed the 1-year postoperative follow-up. Patients lost 16.90% of baseline weight (P level × factor time <0.001). Body mass index decreased from 42.24 ± 3.43 to 34.65 ± 4.58 kg/m² (P < .001). Twenty-three patients (53.5%) were diagnosed as normal glucose tolerance (NGT) before treatment, 2 (4.6%) were impaired fasting glucose (IFG), 12 (27.9%) were impaired glucose tolerance (IGT), 1 (2.3%) had both IFG and IGT, and 5 (11.6%) had T2DM. At 1-year posttreatment, the percentages changed to 86.0% NGT, 2.3% IFG, 11.6% IGT, 0% IFG plus IGT, and 0% T2DM, respectively. Peripheral insulin resistance and homeostasis model of assessment-insulin resistance improved significantly. Fasting glucose-dependent insulinotropic peptide and ghrelin decreased from 316.9 ± 143.1 to 156.2 ± 68.2 pg/mL (P < .001) and from 630.6 ± 52.1 to 456.7 ± 73.1 pg/mL (P < .001), respectively, whereas GLP-1 increased from 16.2 ± 4.9 to 23.7 ± 9.5 pg/mL (P < .001).. TOGA induced glucose disposal improvement with regression of diabetes to NGT or IGT and regression of IGT and IFG to NGT in half of the cases. Regressors showed a much larger increase of GLP-1 levels than progressors.

Topics: Adolescent; Adult; Body Mass Index; Coronary Disease; Diabetes Mellitus, Type 2; Disease Progression; Follow-Up Studies; Gastric Inhibitory Polypeptide; Gastroplasty; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Middle Aged; Obesity; Obesity, Morbid; Prediabetic State; Prospective Studies; Risk; Rome; Weight Loss; Young Adult

To evaluate the association between glucagon-like peptide 1 (GLP-1) secretion and the long-term (>2 years) outcome of type 2 diabetes mellitus (T2DM) after Roux-en-Y gastric bypass (RYGBP).. Cross-sectional study in 18 T2DM morbidly obese subjects who underwent RYGBP but differed in the long-term outcome of T2DM (remission: G1, n = 6; relapse: G2, n = 6; lack of remission: G3: n = 6). Groups were matched for their sex, age, and body mass index. The GLP-1, glucose, C-peptide, and glucagon responses to a standardized test meal (STM) were evaluated. Insulin secretion and insulin sensitivity were estimated from the STM and by frequently sampling intravenous glucose tolerance test (FSIVGTT). Dual-energy X-ray absorptiometry was used to assess body composition.. Patients in G1 presented a lower area under the curve (AUC0-120) of glucose in response to the STM as compared with G2, and G3 (P < 0.01). In contrast, the AUC0-120 of GLP-1 (P = 0.884) and glucagon (P = 0.630) did not differ significantly among the 3 groups. Indices of insulin secretion adjusted by the prevailing insulin sensitivity derived from STM and FSIVGTT, demonstrated larger β-cell function in subjects in G1 as compared with G2 or G3 (Disposition Index-STM, P = 0.005; DI-FSIVGTT, P = 0.006). Body composition and inflammatory markers did not differ significantly among the 3 study groups.. Our data show that in subjects with T2DM an enhanced GLP-1 response to meal intake is not sufficient to maintain normal glucose tolerance in the long term after RYGBP. Our data suggest that β-cell function is a key determinant of the long-term remission of T2DM after this bariatric surgery technique.

Topics: Absorptiometry, Photon; Aged; Biomarkers; Blood Glucose; Body Composition; C-Peptide; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastric Bypass; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Treatment Outcome

To investigate the relationship between postprandial nutrient balance, satiety and hormone changes induced by two different meals taken after a moderate intensity exercise bout.. Ten prepubertal obese children participated in the study. The experiment was designed as a cross-over study for repeated measures. Each test period lasted five consecutive hours during which the children were under medical supervision. The effects of two isocaloric meals were compared after a moderate intensity exercise (4 multiples of resting metabolic rate, 30 min, cycling): a low-fat/high-carbohydrate meal (meal A) and a high-fat/low-carbohydrate meal (meal B). Pre and postprandial (3 h) substrate oxidation, biochemical parameters, gastrointestinal hormone concentrations and appetite were measured.. The main results were: (i) higher fat balance (5.1±5.0 vs -5.0±6.6 g, P=0.001) and lower carbohydrate balance after meal B than A (-9.7±13.3 vs 11.3±18.3 g, P<0.01); (ii) higher energy balance after meal B than after meal A (5.9±21.5 vs -13.9±20.2 kcal, P<0.05); (iii) higher plasma triglyceride concentrations (area under the curve) after meal B than after meal A (2962.5±2095.8 mg*180 min/dl vs -169.5±1633.7 mg*180 min/dl, P<0.01); (iv) higher serum glucagon-like peptide-1 concentrations after meal B than after meal A (1101.5±873.0 pmol*180 min/l vs 478.8±638.3 pmol*180 min/l, P<0.05).. After a bout of moderate intensity exercise, a meal with a high-fat/low-carbohydrate ratio had a less favorable metabolic impact than an isoenergetic, isoproteic low-fat/high-carbohydrate meal.

Topics: Appetite; Basal Metabolism; Blood Glucose; Child; Cross-Over Studies; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Diet, High-Fat; Dietary Carbohydrates; Energy Intake; Exercise; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Meals; Pediatric Obesity; Postprandial Period; Triglycerides

β-Cell function improves in patients with type 2 diabetes in response to an oral glucose stimulus after Roux-en-Y gastric bypass (RYGB) surgery. This has been linked to the exaggerated secretion of glucagon-like peptide 1 (GLP-1), but causality has not been established. The aim of this study was to investigate the role of GLP-1 in improving β-cell function and glucose tolerance and regulating glucagon release after RYGB using exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R)-specific antagonist. Nine patients with type 2 diabetes were examined before and 1 week and 3 months after surgery. Each visit consisted of two experimental days, allowing a meal test with randomized infusion of saline or Ex-9. After RYGB, glucose tolerance improved, β-cell glucose sensitivity (β-GS) doubled, the GLP-1 response greatly increased, and glucagon secretion was augmented. GLP-1R blockade did not affect β-cell function or meal-induced glucagon release before the operation but did impair glucose tolerance. After RYGB, β-GS decreased to preoperative levels, glucagon secretion increased, and glucose tolerance was impaired by Ex-9 infusion. Thus, the exaggerated effect of GLP-1 after RYGB is of major importance for the improvement in β-cell function, control of glucagon release, and glucose tolerance in patients with type 2 diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Female; Gastric Bypass; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Peptide Fragments; Receptors, Glucagon

Incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)] released by the gut modulate gastrointestinal motility and influence gastric emptying (GE). Abnormal secretion or sensitivity to these hormones could contribute to the pathogenesis of gastroparesis. The aim of this study was to investigate incretin hormone secretion during a prolonged oral glucose load in non-diabetic patients with documented idiopathic gastroparesis.. Fifteen patients referred for digestive postprandial discomfort with delayed GE demonstrated by a (13) C-labeled octanoate breath test were included and compared with 10 healthy controls. A 75 g oral glucose load was performed, with blood samplings every 30 min for 5 h, to determine glucose, insulin, GIP, and GLP-1 blood levels.. Fasting GIP concentration was significantly higher in the patient group (56.1 ± 5.8 pg mL(-1) vs 29.9 ± 7.7 pg mL(-1), P =0.012). Postglucose load GIP concentrations were also significantly elevated in patients with gastroparesis, whereas GLP-1 concentrations during fasting and postglucose load conditions were not different to those of healthy controls. Moreover, glucose tolerance during glucose load was abnormal in patients, combining hyperglycemic insulin resistance and hyperinsulinism patterns, while fasting values for glycemia, insulin sensitivity, and insulin concentrations were normal.. Patients with idiopathic gastroparesis exhibit abnormal GIP levels associated with impaired insulin sensitivity during oral glucose load. Further studies are needed to establish the involvement of these defects in the pathophysiology of gastroparesis.

Topics: Administration, Oral; Adult; Blood Glucose; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastroparesis; Glucagon-Like Peptide 1; Glucose; Humans; Incretins; Insulin Resistance; Male; Middle Aged; Pilot Projects; Postprandial Period

Incretin hormones are secreted in the gut after a meal and stimulate insulin production. Both major incretins, that is, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are eliminated by the kidneys. Little is known about the influence of end-stage renal disease (ESRD) on the incretin axis. The aim of the study was to assess the effect of the commencement of chronic hemodialysis (HD) therapy on serum GLP-1 and GIP, and insulin sensitivity in diabetic and non-diabetic patients.. The study comprised 56 patients (23 F, 33 M; mean age 57 ± 14 years) with ESRD in the course of diabetic nephropathy (n = 23) and non-diabetic renal diseases (n = 34) who started chronic HD. Glucose metabolism, including incretin hormones concentration, was assessed before the first HD session and repeated after the first 6 months of the therapy.. After 6 months of HD, a significant increase in fasting GLP-1 concentration was observed in both diabetic and non-diabetic patients [by 2.27 pmol/l (45 %) and 1.28 pmol/l (22 %), respectively, p = 0.0003]. Serum GIP increased significantly only in diabetic patients [by 30.9 pg/ml (55 %); p = 0.008]. No significant change of fasting glucose was found but HOMA-IR and serum insulin decreased significantly in diabetic patients (p = 0.01 and p = 0.008, respectively). In contrast, HOMA-B was unchanged in both groups. Changes of HOMA-IR did not significantly correlate with serum GLP-1 or GIP concentrations.. Our results indicate that starting the hemodialysis therapy helps to restore the incretin axis in particular in patients with the diabetic kidney disease.

Topics: Adult; Aged; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin Secretion; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Time Factors

Fibroblast growth factor (FGF)-19 and FGF-21 are novel metabolic regulators that improve insulin resistance and obesity in rodents. The aim of the study was to assess the effects of laparoscopic sleeve gastrectomy (LSG) on serum concentrations of FGF-19 and FGF-21 along with circulating bile acids and other relevant hormonal and biochemical parameters.. Seventeen females with obesity undergoing LSG and 15 lean healthy females were included into the study. Anthropometric and biochemical parameters, serum concentrations of FGF-19 and -21, insulin, adiponectin, leptin, C-reactive protein, resistin, amylin (total), ghrelin (active), glucagon-like peptide 1 (GLP-1, active), glucose-dependent insulinotropic peptide (GIP, total), peptide YY (PYY, total), pancreatic polypeptide (PP), and bile acids, and mRNA expression of selected adipokines and inflammatory markers in bioptic samples of subcutaneous fat were assessed at baseline and 6, 12, and 24 months after LSG.. LSG markedly decreased body weight, BMI, waist circumference, and insulin levels and improved systemic inflammation and lipid levels. FGF-19 concentrations increased and FGF-21 concentrations decreased after LSG along with increased adiponectin and decreased leptin, amylin, and ghrelin levels. GLP-1, GIP, PP, and circulating bile acids were not affected by LSG. PYY decreased significantly 24 months after surgery only. mRNA expression analysis in subcutaneous fat showed markedly reduced proinflammatory state.. Our results indicate that increased FGF-19 and decreased ghrelin concentrations could have partially contributed to the improvement of systemic inflammation and some metabolic parameters after LSG, while changes of FGF-21 are rather secondary because of weight loss.

Topics: Adiponectin; Adult; Bile Acids and Salts; Body Mass Index; C-Reactive Protein; Female; Fibroblast Growth Factors; Gastrectomy; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Leptin; Middle Aged; Obesity, Morbid; Pancreatic Polypeptide; Peptide YY; Prospective Studies; Resistin; RNA, Messenger; Subcutaneous Fat; Waist Circumference; Weight Loss

Duodenal-jejunal bypass (DJB), which is not routinely applied in metabolic surgery, is an effective surgical procedure in terms of type 2 diabetes mellitus resolution. However, the underlying mechanisms are still undefined. Our aim was to investigate the diabetic improvement by DJB and to explore the changes in hepatic insulin signaling proteins and regulatory enzymes of gluconeogenesis after DJB in a non-obese diabetic rat model.. Sixteen adult male Goto-Kakizaki rats were randomly divided into DJB and sham-operated groups. The body weight, food intake, hormone levels, and glucose metabolism were measured. The levels of protein expression and phosphorylation of insulin receptor-beta (IR-β) and insulin receptor substrate 2 (IRS-2) were evaluated in the liver. We also detected the expression of key regulatory enzymes of gluconeogenesis [phosphoenoylpyruvate carboxykinase-1 (PCK1), glucose-6-phosphatase-alpha (G6Pase-α)] in small intestine and liver.. DJB induced significant diabetic improvement with higher postprandial glucagons-like peptide 1, peptide YY, and insulin levels, but without weight loss. The DJB group exhibited increased expression and phosphorylation of IR-β and IRS-2 in liver, up-regulated the expression of PCK1 and G6Pase-α in small intestine, and down-regulated the expression of these enzymes in liver.. DJB is effective in up-regulating the expression of the key proteins in the hepatic insulin signaling pathway and the key regulatory enzymes of intestinal gluconeogenesis and down-regulating the expression of the key regulatory enzymes of hepatic gluconeogenesis without weight loss. Our study helps to reveal the potential role of hepatic insulin signaling pathway and intestinal gluconeogenesis in ameliorating insulin resistance after metabolic surgery.

Topics: Animals; Biological Transport; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Down-Regulation; Duodenum; Gastric Bypass; Glucagon-Like Peptide 1; Gluconeogenesis; Glucose-6-Phosphatase; Incretins; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Jejunum; Liver; Male; Phosphoenolpyruvate Carboxykinase (GTP); Rats; Rats, Inbred Strains; Remission Induction; Signal Transduction; Up-Regulation; Weight Loss

A single bout of exercise can improve acute postprandial glucose metabolism aggravated by short-term low-carbohydrate/high-fat diet (HFD). The purpose of this study was to investigate the effect of a single bout of aerobic exercise on short-term HFD-induced postprandial glucose and incretin metabolism during an oral glucose tolerance test (OGTT).. Eleven healthy young men (age [mean±SE] 27±1 years; body mass index, 22±1 kg/m(2)) performed three, 3-day interventions in randomized order: (1) a normal diet (ND: ~22% fat), (2) an HFD (~69% fat) and (3) an HFD with a single bout of aerobic exercise (HFDEx). The exercise (50% peak oxygen consumption; ~200 kcal) was performed on the third day in HFDEx. An OGTT was performed after each 3-day dietary intervention.. The incremental area under the curve (iAUC) of plasma glucose levels during the OGTT was significantly higher in the HFD and HFDEx trials than in the ND trial (P=0.001). In addition, the iAUC of glucagon-like peptide-1 (GLP-1) level was significantly higher in the HFD trial than in the ND and HFDEx trials (P=0.04). The first-phase insulin secretion indexes were significantly lower in the HFD (P=0.01 and 0.002) and HFDEx trials (P=0.05 and 0.008) than in the ND trial.. A single bout of aerobic exercise did not improve the short-term HFD-induced aggravation of postprandial glucose and insulin metabolism during the OGTT. However, it did normalize the increased postprandial GLP-1 level induced by HFD.

Topics: Adipokines; Adult; Area Under Curve; Blood Glucose; Caloric Restriction; Diet, High-Fat; Energy Intake; Exercise; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Hormones; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Male; Postprandial Period

Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in non-diabetic individuals with obesity and cardiovascular disease. However, their effect on beta cell mass in normoglycaemic conditions is not clear. Here, we investigate the effects of the GLP-1RA liraglutide on beta cell mass and function in normoglycaemic mice.. C57BL/6J mice were treated with the GLP-1RA liraglutide or PBS and fed a control or high-fat diet (HFD) for 1 or 6 weeks. Glucose and insulin tolerance tests were performed after 6 weeks. BrdU was given to label proliferating cells 1 week before the animals were killed. The pancreas was taken for either histology or islet isolation followed by a glucose-induced insulin-secretion test.. Treatment with liraglutide for 6 weeks led to increased insulin sensitivity and attenuation of HFD-induced insulin resistance. A reduction in beta cell mass was observed in liraglutide-treated control and HFD-fed mice at 6 weeks, and was associated with a lower beta cell proliferation rate after 1 week of treatment. A similar reduction in alpha cell mass occurred, resulting in an unchanged alpha to beta cell ratio. In contrast, acinar cell proliferation was increased. Finally, islets isolated from liraglutide-treated control mice had enhanced glucose-induced insulin secretion.. Our data show that GLP-1RA treatment in normoglycaemic mice leads to increases in insulin sensitivity and beta cell function that are associated with reduced beta cell mass to maintain normoglycaemia.

Topics: Animals; Cell Proliferation; Diet, High-Fat; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Immunohistochemistry; Insulin Resistance; Insulin-Secreting Cells; Liraglutide; Male; Mice; Mice, Inbred C57BL; Receptors, Glucagon

Type 2 diabetes is a chronic metabolic disorder characterized by hyperglycemia with insulin resistance and impaired insulin secretion. DPP-4 inhibitors have attracted attention as a new class of anti-diabetic agents for the treatment of type 2 diabetes. We investigated the effects of anagliptin, a highly selective DPP-4 inhibitor, on insulin secretion and insulin resistance in high-fat diet-fed mice with haploinsufficiency of glucokinase (GckKO) as animal models of type 2 diabetes.. Wild-type and GckKO mice were administered two doses of anagliptin by dietary admixture (0.05% and 0.3%) for 10weeks.. Both doses of anagliptin significantly inhibited the plasma DPP-4 activity and increased the plasma active GLP-1 levels in both the wild-type and GckKO mice to a similar degree. After 10weeks of treatment with 0.3% anagliptin, body weight gain and food intake were significantly suppressed in both wild-type and GckKO mice. In addition, 0.3% anagliptin ameliorated insulin resistance and glucose intolerance in both genotypes of mice. On the other hand, treatment with 0.05% anagliptin was not associated with any significant change of the body weight, food intake or insulin sensitivity in either genotype of mice, but it did improve the glucose tolerance by enhancing insulin secretion and increasing the β-cell mass in both genotypes of mice.. High-dose anagliptin treatment improved glucose tolerance by suppression of body weight gain and amelioration of insulin resistance, whereas low-dose anagliptin treatment improved glucose tolerance by enhancing insulin secretion.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Energy Intake; Glucagon-Like Peptide 1; Glucokinase; Glucose Intolerance; Haploinsufficiency; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Pyrimidines; Weight Gain

Topics: Animals; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Insulin-Secreting Cells; Liraglutide; Male; Receptors, Glucagon

Obesity and diabetes are associated with excess caloric intake and reduced energy expenditure resulting in a negative energy balance. The incidence of diabetes has reached epidemic proportions, and childhood diabetes and obesity are increasing alarmingly. Therefore, it is important to develop safe, easily deliverable, and economically viable treatment alternatives for these diseases. Here, we provide data supporting the candidacy of probiotics as such a therapeutic modality against obesity and diabetes. Probiotics are live bacteria that colonize the gastrointestinal tract and impart beneficial effects for health. However, their widespread prescription as medical therapies is limited primarily because of the paucity of our understanding of their mechanism of action. Here, we demonstrate that the administration of a probiotic, VSL#3, prevented and treated obesity and diabetes in several mouse models. VSL#3 suppressed body weight gain and insulin resistance via modulation of the gut flora composition. VSL#3 promoted the release of the hormone GLP-1, resulting in reduced food intake and improved glucose tolerance. The VSL#3-induced changes were associated with an increase in the levels of a short chain fatty acid (SCFA), butyrate. Using a cell culture system, we demonstrate that butyrate stimulated the release of GLP-1 from intestinal L-cells, thereby providing a plausible mechanism for VSL#3 action. These findings suggest that probiotics such as VSL#3 can modulate the gut microbiota-SCFA-hormone axis. Moreover, our results indicate that probiotics are of potential therapeutic utility to counter obesity and diabetes.

Topics: Animals; Appetite Regulation; Butyrates; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Insulin Resistance; Intestinal Mucosa; Intestines; Male; Mice; Obesity; Probiotics

Liraglutide, a long-lasting glucagon‑like peptide‑1 analogue, has been used for the treatment of patients with type 2 diabetes mellitus since 2009. In this study, we investigated the anti-diabetic effects and mechanisms of action of liraglutide in a spontaneous diabetic animal model, using KK/Upj-Ay/J (KKAy) mice. The KKAy mice were divided into 2 groups, the liraglutide group (mice were treated with 250 µg/kg/day liraglutide) and the model group (treated with an equivalent amount of normal saline). C57BL/6J mice were used as the controls (treated with an equivalent amount of normal saline). The treatment period lasted 6 weeks. During this treatment period, fasting blood glucose (FBG) levels and the body weight of the mice were measured on a weekly basis. Our results revealed that liraglutide significantly decreased FBG levels, the area under the curve following a oral glucose tolerance test and insulin tolerance test, increased serum insulin levels, reduced homeostasis model assessment of insulin resistance and increased the insulin sensitivity index. Furthermore, liraglutide ameliorated glycometabolism dysfunction by increasing glycolysis via hexokinase and glycogenesis via pyruvate kinase activation. An ultrastructural examination of the pancreas revealed that liraglutide improved the damaged state of islet β cells and increased the number of insulin secretory granules. The real-time PCR results revealed that the gene expression of glucose transporter 4 (GLUT4) increased following treatment with liraglutide. Liraglutide also upregulated the protein expression of GLUT4 in liver tissue and skeletal muscle. Our results suggest that liraglutide ameliorates glycometabolism and insulin resistance in diabetic KKAy mice by stimulating insulin secretion, increasing glycogenesis and glycolysis and upregulating the expression of GLUT4.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glucose Transporter Type 4; Glycolysis; Hypoglycemic Agents; Immunohistochemistry; Insulin; Insulin Resistance; Liraglutide; Liver; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Muscle, Skeletal; Real-Time Polymerase Chain Reaction; Up-Regulation

Topics: Algorithms; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liver; Metformin; Muscles

Eating a "Westernized" diet high in fat and sugar leads to weight gain and numerous health problems, including the development of type 2 diabetes mellitus (T2DM). Rodent studies have shown that resveratrol supplementation reduces blood glucose levels, preserves β-cells in islets of Langerhans, and improves insulin action. Although rodent models are helpful for understanding β-cell biology and certain aspects of T2DM pathology, they fail to reproduce the complexity of the human disease as well as that of nonhuman primates. Rhesus monkeys were fed a standard diet (SD), or a high-fat/high-sugar diet in combination with either placebo (HFS) or resveratrol (HFS+Resv) for 24 months, and pancreata were examined before overt dysglycemia occurred. Increased glucose-stimulated insulin secretion and insulin resistance occurred in both HFS and HFS+Resv diets compared with SD. Although islet size was unaffected, there was a significant decrease in β-cells and an increase in α-cells containing glucagon and glucagon-like peptide 1 with HFS diets. Islets from HFS+Resv monkeys were morphologically similar to SD. HFS diets also resulted in decreased expression of essential β-cell transcription factors forkhead box O1 (FOXO1), NKX6-1, NKX2-2, and PDX1, which did not occur with resveratrol supplementation. Similar changes were observed in human islets where the effects of resveratrol were mediated through Sirtuin 1. These findings have implications for the management of humans with insulin resistance, prediabetes, and diabetes.

Topics: Animals; Blood Glucose; Body Weight; Cell Dedifferentiation; Densitometry; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Fluorescent Antibody Technique; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose Tolerance Test; Glycated Hemoglobin; Homeobox Protein Nkx-2.2; Homeodomain Proteins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans; Macaca mulatta; Nuclear Proteins; Protective Agents; Resveratrol; Sirtuin 1; Stilbenes; Transcription Factors

Exogenous bile acid (BA) administration is associated with beneficial metabolic effects very similar to those seen after Roux-en-Y gastric bypass (RYGB) surgery. Re-routing of bile into a biliopancreatic limb with simultaneous exclusion of food occurs after RYGB, with subsequent increased fasting plasma BAs. The study assessed fasting and post-prandial plasma BA response before and 15 months after RYGB.. The prospective study recruited 63 obese individuals (43 females), aged 43 (36-56) [median (IQR)] years. Blood samples were collected before and every 30 min for 120 min after a standard 400 kcal meal. Fasting and post-prandial plasma BAs, glucagons like peptide-1 (GLP-1), -tyrosine (PYY), fasting C-reactive protein (CRP), glucose and insulin were measured and homeostasis model assessment-insulin resistance (HOMA-IR) was calculated.. Following RYGB, body mass index, CRP, fasting glucose and HOMA-IR decreased; 43.7 (39.3-49.2) kg/m(2) to 29.2 (25.1-35.0) kg/m(2), 7.9 (4.1-11.9) mg/L to 0.4 (0.2-1.0) mg/L, 5.5 (5.0-6.0) mmol/L to 4.6 (4.3-4.9) mmol/L and 5.9 (3.5-9.2) to 1.7 (1.1-2.2), respectively, all P < 0.001. Fasting total BAs, GLP-1 and PYY increased after RYGB; 1.69 (0.70-2.56) µmol/L to 2.43 (1.23-3.82) µmol/L (P = 0.02), 6.8 (1.5-15.3) pmol/L to 17.1 (12.6-23.9) pmol/L (P < 0.001) and 4.0 (1.0-7.1) pmol/L to 15.2 (10.0-28.3) pmol/L (P < 0.001), respectively. The area under the curve for post-prandial total BAs, total glycine-conjugated BAs, GLP-1 and PYY were greater after RYGB; 486 (312-732) µmol/L/min versus 1012 (684-1921) µmol/L/min, 315 (221-466) µmol/L/min versus 686 (424-877) µmol/L/min, 3679 (3162-4537) pmol/L/min versus 5347 (4727-5781) pmol/L/min and 1887 (1423-2092) pmol/L/min versus 3296 (2534-3834) pmol/L/min, respectively, all P < 0.0001.. Weight loss following RYGB is associated with an increase in post-prandial plasma BA response due to larger amounts of glycine-conjugated BAs. This suggests up regulation of BA production and conjugation after RYGB.

Topics: Adult; Bile; Blood Glucose; Body Mass Index; C-Reactive Protein; Cohort Studies; Fasting; Female; Gastric Bypass; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Postprandial Period; Time Factors; Weight Loss

In obese patients with type 2 diabetes (T2DM), Roux-en-Y-gastric-bypass (RYGB) and sleeve gastrectomy (SLG) improve glycemic control.. The objective of this study was to investigate the mechanisms of surgery-induced T2DM improvement and role of gastrointestinal hormones. PATIENTS, SETTING, AND INTERVENTION: In 35 patients with T2DM, we performed a mixed-meal test before and 15 days and 1 year after surgery (23 RYGB and 12 SLG).. Insulin sensitivity, β-cell function, and amylin, ghrelin, PYY, pancreatic polypeptide (PP), glucagon, and glucagon-like peptide-1 (GLP-1) responses to the meal were measured.. T2DM remission occurred in 13 patients undergoing RYGB and in 7 patients undergoing SLG. Similarly in the RYGB and SLG groups, β-cell glucose sensitivity improved both early and long term (P < .005), whereas insulin sensitivity improved long term only (P < .006), in proportion to body mass index changes (P < .001). Early after RYGB, glucagon and GLP-1 responses to the meal increased, whereas the PP response decreased. At 1 year, PYY was increased, and PP, amylin, ghrelin, and GLP-1 were reduced. After SLG, hormonal responses were similar to those with RYGB except that PP was increased, whereas amylin was unchanged. In remitters, fasting GLP-1 was higher (P = .04), but its meal response was flat compared with that of nonremitters; postsurgery, however, the GLP-1 response was higher. Other hormone responses were similar between the 2 groups. In logistic regression, presurgery β-cell glucose sensitivity (positive, P < .0001) and meal-stimulated GLP-1 response (negative, P = .004) were the only predictors of remission.. RYGB and SLG have a similar impact on diabetes remission, of which baseline β-cell glucose sensitivity and a restored GLP-1 response are the chief determinants. Other hormonal responses are the consequences of the altered gastrointestinal anatomy.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Gastrectomy; Gastric Bypass; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glycemic Index; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Male; Middle Aged; Obesity, Morbid; Pancreatic Polypeptide; Peptide YY; Remission Induction

To investigate the effect of glucagon-like peptide-1 (GLP-1) on glycolipid metabolism in 3T3-L1 adipocytes and explore the mechanism.. 3T3-L1 adipocytes were treated with GLP-1, insulin, or both for 24 h, and Western blotting was used to analyze the expression levels of adipose triglyceride lipase (ATGL), glucose transporter type 4 (GLUT4), Akt1, Akt2 and phosphorylated Akt in the cells. Immunofluorescence was used to observe lipid content in 3T3-L1 adipocytes.. Akt1 and Akt2 were not activated by insulin stimulation in 3T3-L1 adipocytes. Akt was phosphorylated by GLP-1 stimulation, which inhibited the expression of ATGL and increased the translocation of GLUT4 from the intracellular membranes to plasma membranes. These changes were more obvious under the synergistic effect of insulin in 3T3-L1 adipocytes.. GLP-1 decreases lipolysis by inhibiting the expression of ATGL and improves insulin resistance by increasing the translocation of GLUT4 in 3T3-L1 adipocytes.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Cell Membrane; Down-Regulation; Drug Synergism; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Insulin; Insulin Resistance; Intracellular Membranes; Lipase; Mice; Phosphorylation; Protein Transport; Proto-Oncogene Proteins c-akt

Combination with suitable pharmacological agents can improve the antiobesity and antidiabetic actions of glucagon like peptide-1 (GLP-1) based therapies. GLP-1 agonist exendin-4 may have insulin-independent effects on amelioration of insulin resistance and hepatic steatosis by virtue of its action on hepatic GLP-1 receptors, and these effects can be improved by combination with proton pump inhibitors. However, it was not assessed whether omeprazole can improve the peripheral actions of exendin-4 in the state of insulin deficiency.. We investigated the effects of combination of omeprazole with GLP-1 agonist exendin-4 in multiple low-dose streptozotocin (STZ)-induced diabetes in C57BL/KsJ mice, a model of type 1 diabetes. Male diabetic mice were treated with exendin-4 and/or omeprazole for a period of 4 weeks.. Omeprazole treatment had no significant effect on lowering the blood glucose levels of diabetic mice, when compared to control, although it improved the antihyperglycemic actions of exendin-4. Similarly, serum triglycerides and total cholesterols levels were significantly lower in the combination treated mice compared to either exendin-4 and omeprazole alone. In addition, the combination treatment significantly ameliorated lipid peroxidation and hepatic triglycerides in diabetic mice compared to either exendin-4 and omeprazole alone. The improvement in hepatic insulin sensitivity, as indicated by insulin tolerance test (ITT) and pyruvate tolerance test (IPPTT), was correlated with the expression of nuclear factor erythroid-related factor 2 (Nrf2) and insulin receptor substrate-1 (IRS-1) and the combination treatment significantly improved the insulin sensitivity in comparison to vehicle control.. We conclude that combination with omeprazole improves the insulin sensitizing actions of GLP-1 therapy and these effects are partially mediated through the decrease in hepatic steatosis and improvement in antioxidant status in the liver.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Male; Mice; NF-E2-Related Factor 2; Omeprazole; Peptides; Proton Pump Inhibitors; Venoms

Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA(2)]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA(2)]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA(2)]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA(2)]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA(2)]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA(2)]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA(2)]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes.

Topics: Amino Acid Sequence; Animals; Blood Glucose; Cyclic AMP; Diet, High-Fat; Dipeptidyl Peptidase 4; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin; Insulin Resistance; Insulin Secretion; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Molecular Sequence Data; Obesity; Receptors, Gastrointestinal Hormone; Receptors, Glucagon; Recombinant Fusion Proteins

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduce body weight without inducing hyperglycemia in rodents. However, the effect of a co-agonist on insulin sensitivity and lipid metabolism has not been thoroughly assessed. Diet-induced obese (DIO) mice received 0.5 mg·kg(-1) of co-agonist or 2.5 mg·kg(-1) of glucagon or 8 μg·kg(-1) of exendin-4 by subcutaneous route, twice daily, for 28 days. A separate group of mice was pair-fed to the co-agonist-treated group for 28 days. Co-agonist treatment reduced food intake and reduced body weight up to 28 days. In addition, it reduced leptin levels and increased fibroblast growth factor 21 (FGF21) levels in plasma, when compared with control and pair-fed groups. Co-agonist treatment decreased triglyceride levels in serum and liver and reduced serum cholesterol, mainly due to reduction in low-density lipoprotein (LDL) cholesterol. These changes were not seen with pair-fed controls. Co-agonist treatment improved glucose tolerance and increased insulin sensitivity, as observed during glucose and insulin-tolerance test, hyperinsulinemic clamp, and reduced gluconeogenesis, as observed in pyruvate-tolerance test. The effects on insulin sensitivity and lipid levels are mostly independent of the food intake or body weight lowering effect of the co-agonist.

Topics: Animals; Appetite; Body Weight; Cholesterol; Cholesterol, LDL; Diet; Eating; Fibroblast Growth Factors; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Gluconeogenesis; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Receptors, Glucagon; Triglycerides

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that decreases postprandial glycemic excursions by enhancing insulin secretion but with short half-life due to rapid inactivation by enzymatic N-terminal truncation. Therefore, efforts are being made to improve the stability of GLP-1 via modifying its structure or inhibiting dipeptidylpeptidase IV (DPP IV), which is responsible for its degradation. GLP-M, consisting of 10 tandem repeated rolGLP-1 (GLP-1 analog), has been expressed in Pichia pastoris by our laboratory. Although it had a long effect of maintaining glucose homeostasis, redundant amino acids and purification tag limited its application. Here, optimized rolGLP-1(GLPO) with no redundant amino acids and purification tag was constructed by molecular cloning and site-directed mutagenesis, which was expressed efficiently in Escherichia coli BL21(DE3) with the production of 81.5 mg/L, and confirmed by the results of SDS-PAGE electrophoresis and Western Blotting. Then GLP-O was purified via ion exchange chromatography and gel filtration chromatography. The purity of GLP-O was close to 100%. GLP-O could be cut into single rolGLP-1 by trypsin in vitro, and rolGLP-1 had anti-trypsin activity. After oral administration of GLP-O for 4 weeks, the level of blood glucose in type 2 diabetic mice was lowered effectively, and the oral glucose tolerance of mice was improved significantly. These results settled the foundation for further clinical application of GLP-O.

Topics: Animals; Blood Glucose; Cloning, Molecular; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Escherichia coli; Glucagon-Like Peptide 1; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Pichia; Protein Engineering; Treatment Outcome

Consumption of high-fat diet exerts adverse effects on learning and memory formation, which is linked to impaired hippocampal function. Activation of glucagon-like peptide-1 (GLP-1) signalling ameliorates detrimental effects of obesity-diabetes on cognitive function; however, mechanisms underlying these beneficial actions remain unclear. This study examined effects of daily subcutaneous treatment with GLP-1 mimetic, Liraglutide, on synaptic plasticity, hippocampal gene expression and metabolic control in adult obese diabetic (ob/ob) mice.. Long-term potentiation (LTP) induced by area CA1 was completely abolished in ob/ob mice compared with lean controls. Deleterious effects on LTP were rescued (P<0.001) with Liraglutide. Indeed, Liraglutide-treated mice exhibited superior LTP profile compared with lean controls (P<0.01). Expression of hippocampal brain-derived neurotropic factor and neurotrophic tyrosine kinase receptor-type 2 were not significantly different, but synaptophysin and Mash1 were decreased in ob/ob mice. Treatment with Liraglutide over 21 days increased expression of Mash1 in ob/ob mice (2.0-fold; P<0.01). These changes were associated with significantly reduced plasma glucose (21% reduction; P<0.05) and markedly improved plasma insulin concentrations (2.1- to 3.3-fold; P<0.05 to P<0.01). Liraglutide also significantly reduced the glycaemic excursion following an intraperitonal glucose load (area under curve (AUC) values: 22%; P<0.05) and markedly enhanced the insulin response to glucose (AUC values: 1.6-fold; P<0.05). O2 consumption, CO2 production, respiratory exchange ratio and energy expenditure were not altered by Liraglutide therapy. On day 21, accumulated food intake (32% reduction; P<0.05) and number of feeding bouts (32% reduction; P<0.05) were significantly reduced but simple energy restriction was not responsible for the beneficial actions of Liraglutide.. Liraglutide elicits beneficial effects on metabolic control and synaptic plasticity in mice with severe obesity and insulin resistance mediated in part through increased expression of Mash1 believed to improve hippocampal neurogenesis and cell survival.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Brain-Derived Neurotrophic Factor; Diet, High-Fat; Glucagon-Like Peptide 1; Glucose; Hippocampus; Hypoglycemic Agents; Infusions, Subcutaneous; Insulin; Insulin Resistance; Liraglutide; Male; Membrane Glycoproteins; Mice; Neuronal Plasticity; Obesity; Protein-Tyrosine Kinases; Signal Transduction

Alzheimer's disease (AD) has been shown to involve desensitised insulin receptor (IR) signalling. Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue that facilitates insulin signalling, is currently approved for use in type 2 diabetes mellitus. In the present study, we show that distinctive alterations in the localisation and distribution of the IR and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS(616)), a key marker of insulin resistance, are associated with amyloid-β plaque pathology in the frontal cortex of a mouse model of AD, APPSWE/PS1dE9. Altered IR status in APPSWE/PS1dE9 is most evident in extracellular deposits with the appearance of dystrophic neurites, with significantly increased IRS-1 pS(616) levels detected within neurons and neurites. The IR and IRS-1 pS(616) changes occur in the vicinity of all plaques in the APPSWE/PS1dE9 brain, and a significant upregulation of astrocytes and microglia surround this pathology. We show that liraglutide treatment for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old mice significantly decreases IR aberrations in conjunction with a concomitant decrease in amyloid plaque load and levels of IRS-1 pS(616). Liraglutide also induces a highly significant reduction in astrocytosis and microglial number associated with both plaques and IR pathology. The amelioration of IR aberrations and attenuation of IRS-1 pS(616) upregulation, plaque and glial activation in APPSWE/PS1dE9 mice treated with liraglutide support the investigation of the therapeutic potential of liraglutide and long-lasting GLP-1 agonists in patients with AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Astrocytes; Disease Models, Animal; Female; Frontal Lobe; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Receptor Substrate Proteins; Insulin Resistance; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Mutation, Missense; Neuroprotective Agents; Phosphorylation; Plaque, Amyloid; Presenilin-1; Protein Processing, Post-Translational; Protein Transport; Receptor, Insulin; Signal Transduction

The glucagon-like peptides (GLP-1 and GLP-2) are processed from the proglucagon polypeptide and secreted in equimolar amounts but have opposite effects on chylomicron (CM) production, with GLP-1 significantly reducing and GLP-2 increasing postprandial chylomicronemia. In the current study, we evaluated the apparent paradoxical roles of GLP-1 and GLP-2 under physiological conditions in the Syrian golden hamster, a model with close similarity to humans in terms of lipoprotein metabolism. A short (30-min) intravenous infusion of GLP-2 resulted in a marked increase in postprandial apolipoprotein B48 (apoB48) and triglyceride (TG) levels in the TG-rich lipoprotein (TRL) fraction, whereas GLP-1 infusion decreased lipid absorption and levels of TRL-TG and apoB48. GLP-1 and GLP-2 coinfusion resulted in net increased lipid absorption and an increase in TRL-TG and apoB48. However, prolonged (120-min) coinfusion of GLP-1 and GLP-2 decreased postprandial lipemia. Blocking dipeptidyl peptidase-4 activity resulted in decreased postprandial lipemia. Interestingly, fructose-fed, insulin-resistant hamsters showed a more pronounced response, including possible hypersensitivity to GLP-2 or reduced sensitivity to GLP-1. In conclusion, under normal physiological conditions, the actions of GLP-2 predominate; however, when GLP-1 activity is sustained, the hypolipidemic action of GLP-1 predominates. Pharmacological inhibition of GLP-1 degradation tips the balance toward an inhibitory effect on intestinal production of atherogenic CM particles.

Topics: Animals; Apolipoprotein B-48; Chylomicrons; Cricetinae; Dipeptidyl-Peptidase IV Inhibitors; Fructose; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Hyperlipidemias; Insulin Resistance; Intestinal Absorption; Intestines; Lipid Metabolism; Lipoproteins; Male; Mesocricetus; Postprandial Period; Triglycerides

This study examined the biological properties of a novel GLP-1 peptide, (Val(8))GLP-1-Glu-PAL, engineered with an Ala(8)→Val(8) substitution and additional incorporation of a C(16) fatty acid moiety at Lys(26) via a glutamic acid linker. GLP-1 underwent 75 % degradation by DPP-IV over 8 h, whereas (Val(8))GLP-1 and (Val(8))GLP-1-Glu-PAL remained intact. All GLP-1 peptides significantly stimulated insulin secretion at 5.6 mM (1.3- to 4.9-fold, p<0.01 to p<0.001) and 16.7 mM glucose (1.5- to 2.3-fold, p<0.001). At higher concentrations (Val(8))GLP-1-Glu-PAL was significantly more potent at stimulating insulin secretion (1.2- to 1.3-fold, p<0.05). In high-fat-fed mice, all GLP-1 peptides significantly lowered plasma glucose concentrations (41-66 % decrease, p<0.05 to p<0.001), with (Val(8))GLP-1-Glu-PAL eliciting protracted glucose-lowering actions (32-59 % decrease, p<0.05 to p<0.01) when administered 8 h prior to a glucose load. Twice-daily administration of (Val(8))GLP-1-Glu-PAL in high-fat-fed mice for 21 days had no effect on bodyweight or food intake, but significantly lowered non-fasting plasma glucose (43-46 % decrease, p<0.05). (Val(8))GLP-1-Glu-PAL markedly decreased glycemic excursion following intraperitoneal glucose (32-48 % decrease, p<0.05), enhanced insulin response to glucose (2- to 2.3-fold, p<0.05 to p<0.01), and improved insulin sensitivity (25-38 % decrease in plasma glucose, p<0.05). O(2) consumption, CO(2) production, RER, and energy expenditure were not altered by (Val(8))GLP-1-Glu-PAL therapy. Treatment with (Val(8))GLP-1-Glu-PAL resulted in a significant increase in BrdU-positive cells (1.3-fold, p<0.05) in the granule cell layer of the dentate gyrus. These data demonstrate that (Val(8))GLP-1-Glu-PAL is a long-acting GLP-1 peptide that significantly improves hippocampal neurogenesis, glucose homeostasis, and insulin secretion in high-fat-fed mice.

Topics: Administration, Oral; Amino Acid Sequence; Animals; Blood Glucose; Cells, Cultured; Diet, High-Fat; Dipeptidyl Peptidase 4; Drug Design; Energy Metabolism; Glucagon-Like Peptide 1; Hippocampus; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Lipopeptides; Male; Mice; Molecular Sequence Data; Neurogenesis

Valproic acid (VPA), as one of the most widely prescribed antiepileptic drugs (AED) for many types of epilepsy in adults and children, is associated with weight gain, alteration of adipocytokine homeostasis, insulin resistance and Non-Alcoholic Fatty Liver Disease (NAFLD). Retinol-binding protein 4 (RBP4) and Glucagon-like peptide-1 (GLP-1) are considered as important new targets in modern type 2 diabetes mellitus therapy linked to insulin resistance, NAFLD and visceral obesity acting via peripheral or central mechanisms. We herein demonstrate the lack of an influence of VPA treatment on RBP4 and GLP-1 in otherwise healthy patients. In summary, the absence of any relationship with RBP4 and GLP-1 concentrations does not suggest a role of these novel insulin resistance parameters as potential regulators of glucose and fat metabolism during VPA-therapy.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Diabetes Mellitus, Type 2; Fatty Liver; Female; Glucagon-Like Peptide 1; Glucose; Homeostasis; Humans; Insulin Resistance; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Retinol-Binding Proteins, Plasma; Valproic Acid; Young Adult

Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum stress in other tissues. Here we examine the cardiac effects of the glucagon-like peptide-1 analog liraglutide in a model of obesity, independent of changes in body weight.. C57Bl6 mice were placed on a 45% high-fat diet (HFD) or a regular chow diet. Mice on HFD developed 46±2% and 60±2% greater body weight relative to regular chow diet-fed mice at 16 and 32 weeks, respectively (both P<0.0001), manifesting impaired glucose tolerance, insulin resistance, and cardiac ceramide accumulation by 16 weeks. One-week treatment with liraglutide (30 µg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-α expression, nuclear factor kappa B translocation, obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis, in comparison with placebo-treated HFD controls. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function in animals on HFD by an AMP-activated protein kinase-dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nmol/L) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells and prevented adhesion of human monocytes to tumor necrosis factor-α-activated human endothelial cells in vitro.. Weight-neutral treatment with a glucagon-like peptide-1 analog activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, reduces monocyte vascular adhesion, and improves cardiac function in vivo by activating AMP-activated protein kinase. These data support a role for glucagon-like peptide-1 analogs in limiting the cardiovascular risks of obesity.

Topics: Animals; Blood Glucose; Cardiotonic Agents; Cell Line; Connexin 43; Coronary Vessels; Disease Models, Animal; Endoplasmic Reticulum Stress; Endothelial Cells; Gene Expression; Glucagon-Like Peptide 1; Heart Diseases; Humans; Hypercholesterolemia; Insulin Resistance; Liraglutide; Mice; Mice, Inbred C57BL; Monocytes; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Obesity; Risk Factors; Signal Transduction; Tumor Necrosis Factor-alpha

Shift work is associated with circadian rhythm disorder, impaired sleep and behavioural changes, including eating habits, predisposing to obesity and metabolic dysfunctions. It involves a neuro-hormonal dysregulation of appetite towards positive energy balance, including increased ghrelin and decreased leptin, but little is known about other hormones, such as xenin, derived from the upper gut (like ghrelin), and lower gut hormones. Our objective was to compare night workers with day workers in relation to appetite-regulating hormones and other metabolic parameters.. Cross-sectional, observational study.. Twenty-four overweight women, divided into night shift workers (n = 12) and day shift workers (n = 12).. BMI, waist circumference, fat mass percentage; diet composition; Pittsburgh Sleep Quality Index; lipids; adipokines; meal tolerance test curves of glucose, insulin, ghrelin, PYY3-36, oxyntomodulin, xenin, GLP-1; insulin sensitivity (Stumvoll index).. Night workers, as compared with day workers, had greater body fat mass percentage and tendency to greater waist circumference despite similar BMI; greater energy intake; impaired sleep; lower insulin sensitivity; increased triglycerides and tendency to increased C-reactive protein; similar levels of leptin and other adipokines. Night workers had a blunted post-meal suppression of ghrelin (AUCi(0-60 min) 19·4 ± 139·9 vs -141·9 ± 9·0 ng/ml·60 min, P < 0·01); blunted rise of xenin (AUC(0-180 min) 8690·9 ± 2988·2 vs 28 504·4 ± 20 308·3 pg/ml·180 min, P < 0·01) and similar curves of PYY3-36, oxyntomodulin and GPL-1.. Compared with day workers within the same BMI range, night workers presented a disrupted control of ghrelin and xenin, associated with behavioural changes in diet and sleep and increased adiposity and related metabolic alterations.

Topics: Adiposity; Adult; Appetite Regulation; Cross-Sectional Studies; Digestive System; Energy Intake; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Neurotensin; Overweight; Oxyntomodulin; Peptide Fragments; Peptide YY; Sleep Disorders, Circadian Rhythm; Work Schedule Tolerance

High-fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase-4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin-induced long-term depression and neuronal IR phosphorylation, IRS-1 phosphorylation and Akt/PKB-ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon-like-peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.

Topics: Adamantane; Animals; Brain; Cognition; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Gene Expression; Glucagon-Like Peptide 1; Insulin Receptor Substrate Proteins; Insulin Resistance; Long-Term Synaptic Depression; Male; Maze Learning; Membrane Potential, Mitochondrial; Memory; Mitochondria; Neurons; Nitriles; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrrolidines; Rats; Rats, Wistar; Receptor, Insulin; Vildagliptin

Topics: Animals; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Hyperlipidemias; Insulin Resistance; Intestines; Lipoproteins; Male; Postprandial Period

To elucidate the mechanisms of improvement/reversal of type 2 diabetes after Roux-en-Y gastric bypass (RYGB).. Fourteen morbidly obese subjects, 7 with normal glucose tolerance and 7 with type 2 diabetes, were studied before and 1 month after RYGB by euglycemic hyperinsulinemic clamp (EHC), by intravenous glucose tolerance test (IVGTT) and by oral glucose tolerance test (OGTT) in 3 different sessions. Intravenous glucose tolerance test IVGTT and OGTT insulin secretion rate (ISR) and sensitivity were obtained by the minimal model. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured. Six healthy volunteers were used as controls.. Total ISR largely increased in diabetic subjects only when glucose was administered orally (37.8 ± 14.9 vs 68.3 ± 22.8 nmol; P < 0.05, preoperatively vs postoperatively). The first-phase insulin secretion was restored in type 2 diabetic after the IVGTT (Φ1 × 10: 104 ± 54 vs 228 ± 88; P < 0.05, preoperatively vs postoperatively; 242 ± 99 in controls). Insulin sensitivity by EHC (M × 10) was slightly but significantly improved in both normotolerant and diabetic subjects (1.46 ± 0.22 vs 1.37 ± 0.55 mmol·min·kg; P < 0.05 and 1.53 ± 0.23 vs 1.28 ± 0.62 mmol·min·kg; P < 0.05, respectively). Quantitative insulin sensitivity check index was improved in all normotolerant (0.32 ± 0.02 vs 0.30 ± 0.02; P < 0.05) and diabetic subjects (0.33 ± 0.03 vs 0.31 ± 0.02; P < 0.05). GIP and GLP-1 levels increased both at fast and after OGTT mainly in type 2 diabetic subjects.. The large increase of ISR response to the OGTT together with the restoration of the first-phase insulin secretion in diabetic subjects might explain the reversal of type 2 diabetes after RYGB. The large incretin secretion after the oral glucose load might contribute to the increased ISR.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Obesity, Morbid; Treatment Outcome

Patients with hypothalamic pathology often develop morbid obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Glucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic patients and cause weight loss in obese patients by yet unknown mechanisms. Here we tested whether GLP-1 analogues were also effective in the treatment of obesity and associated metabolic alterations in patients with hypothalamic disease.. Nine patients (eight with type 2 diabetes mellitus) with moderate to severe hypothalamic obesity were treated with GLP-1 analogues for up to 51 months. Body weight, homeostasis model assessment - insulin resistance (HOMA-IR), HbA1c and lipids were assessed.. Eight patients experienced substantial weight loss (-13.1±5.1 kg (range -9 to -22)). Insulin resistance (HOMA-IR -3.2±3.5 (range -9.1 to 0.8)) and HbA1c values (-1.3±1.4% (range -4.5 to 0.0)) improved under treatment (24.3±18.9 months (range 6 to 51)). Five patients reported increased satiation in response to the treatment. Two of the eight patients complained about nausea and vomiting and one of them abandoned therapy because of sustained gastrointestinal discomfort after 6 months. One patient suffered from intolerable nausea and vomiting and discontinued treatment within 2 weeks.. GLP-1 analogues can cause substantial and sustained weight loss in obese patients with hypothalamic disease. This offers a new approach for medical treatment of moderate to severe hypothalamic obesity and associated metabolic alterations.

Topics: Adolescent; Adult; Blood Glucose; Craniopharyngioma; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Hypothalamic Diseases; Insulin Resistance; Liraglutide; Male; Middle Aged; Obesity; Peptides; Pituitary Neoplasms; Venoms

The prevalence of heart disease continues to rise, particularly in subjects with insulin resistance (IR), and improved therapies for these patients is an important challenge. In this study we evaluated cardiac function and energy metabolism in IR JCR:LA-cp rat hearts before and after treatment with an inotropic compound (glucagon), a glucagon-like peptide-1 (GLP-1) receptor agonist (ZP131) or a glucagon-GLP-1 dual-agonist (ZP2495).. Hearts from IR and lean JCR:LA rats were isolated and perfused in the working heart mode for measurement of cardiac function and metabolism before and after addition of vehicle, glucagon, ZP131 or ZP2495. Subsequently, cardiac levels of nucleotides and short-chain CoA esters were measured by HPLC.. Hearts from IR rats showed decreased rates of glycolysis and glucose oxidation, plus increased palmitate oxidation rates, although cardiac function and energy state (measured by ATP/AMP ratios) was normal compared with control rats. Glucagon increased glucose oxidation and glycolytic rates in control and IR hearts, but the increase was not enough to avoid AMP and ADP accumulation in IR hearts. ZP131 had no significant metabolic or functional effects in either IR or control hearts. In contrast, ZP2495 increased glucose oxidation and glycolytic rates in IR hearts to a similar extent to that of glucagon but with no concomitant accumulation of AMP or ADP.. Whereas glucagon compromised the energetic state of IR hearts, glucagon-GLP-1 dual-agonist ZP2495 appeared to preserve it. Therefore, a glucagon-GLP-1 dual-agonist may be beneficial compared with glucagon alone in the treatment of severe heart failure or cardiogenic shock in subjects with IR.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiotonic Agents; Glucagon; Glucagon-Like Peptide 1; Glucose; Glycolysis; Heart; Heart Rate; HEK293 Cells; Humans; Insulin Resistance; Male; Oxidation-Reduction; Palmitates; Peptides; Rats

The aims of this study were designed to determine whether liraglutide, a long-acting glucagon-like peptide, could reverse the adverse effects of a diet high in fat that also contained trans-fat and high-fructose corn syrup (ALIOS diet). Specifically, we examined whether treatment with liraglutide could reduce hepatic insulin resistance and steatosis as well as improve cardiac function. Male C57BL/6J mice were pair fed or fed ad libitum either standard chow or the ALIOS diet. After 8 wk the mice were further subdivided and received daily injections of either liraglutide or saline for 4 wk. Hyperinsulinemic-euglycemic clamp studies were performed after 6 wk, revealing hepatic insulin resistance. Glucose tolerance and insulin resistance tests were performed at 8 and 12 wk prior to and following liraglutide treatment. Liver pathology, cardiac measurements, blood chemistry, and RNA and protein analyses were performed. Clamp studies revealed hepatic insulin resistance after 6 wk of ALIOS diet. Liraglutide reduced visceral adiposity and liver weight (P < 0.001). As expected, liraglutide improved glucose and insulin tolerance. Liraglutide improved hypertension (P < 0.05) and reduced cardiac hypertrophy. Surprisingly, liver from liraglutide-treated mice had significantly higher levels of fatty acid binding protein, acyl-CoA oxidase II, very long-chain acyl-CoA dehydrogenase, and microsomal triglyceride transfer protein. We conclude that liraglutide reduces the harmful effects of an ALIOS diet by improving insulin sensitivity and by reducing lipid accumulation in liver through multiple mechanisms including, transport, and increase β-oxidation.

Topics: Adiposity; Animals; Cardiomegaly; Diet, High-Fat; Fatty Liver; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hypertension; Insulin Resistance; Liraglutide; Liver; Male; Mice; Mice, Inbred C57BL

Physical activity improves glycemic control in type 2 diabetes (T2D), but its contribution to preserving β-cell function is uncertain. We evaluated the role of physical activity on β-cell secretory function and glycerolipid/fatty acid (GL/FA) cycling in male Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats engaged in voluntary running for 6 wk (ZDF-A). Inactive Zucker lean and ZDF (ZDF-I) rats served as controls. ZDF-I rats displayed progressive hyperglycemia with β-cell failure evidenced by falling insulinemia and reduced insulin secretion to oral glucose. Isolated ZDF-I rat islets showed reduced glucose-stimulated insulin secretion expressed per islet and per islet protein. They were also characterized by loss of the glucose regulation of fatty acid oxidation and GL/FA cycling, reduced mRNA expression of key β-cell genes, and severe reduction of insulin stores. Physical activity prevented diabetes in ZDF rats through sustaining β-cell compensation to insulin resistance shown in vivo and in vitro. Surprisingly, ZDF-A islets had persistent defects in fatty acid oxidation, GL/FA cycling, and β-cell gene expression. ZDF-A islets, however, had preserved islet insulin mRNA and insulin stores compared with ZDF-I rats. Physical activity did not prevent hyperphagia, dyslipidemia, or obesity in ZDF rats. In conclusion, islets of ZDF rats have a susceptibility to failure that is possibly due to altered β-cell fatty acid metabolism. Depletion of pancreatic islet insulin stores is a major contributor to islet failure in this T2D model, preventable by physical activity.

Topics: Adrenocorticotropic Hormone; Animals; Body Weight; Diabetes Mellitus, Type 2; Dyslipidemias; Eating; Fatty Acids; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Muscle, Skeletal; Physical Conditioning, Animal; Rats; Rats, Zucker

Exendin-4 (Ex-4) mimics glucagon-like peptide-1 (GLP-1 or GCG as listed in the HUGO database), being anti-diabetic and anorectic, in stimulating glucose and lipid metabolism in extrapancreatic tissues. We studied the characteristics of Ex-4 and GLP-1 action, during prolonged treatment, on GLUTs expression (mRNA and protein), glycogen content (GC), glucose transport (GT), glycogen synthase a (GSa), and kinase (PI3K and MAPKs) activity, in liver, muscle, and fat of insulin-resistant (IR, by fructose) and type 2 diabetic (T2D, streptozotocin at birth) rats compared with normal rats. In both IR and T2D, the three tissues studied presented alterations in all measured parameters. In liver, GLP-1 and also Ex-4 normalized the lower than normal Glut2 (Slc2a2) expression and showed a trend to normalize the reduced GC in IR, and GLP-1, like Ex-4, also in T2D, effects mediated by PI3K and MAPKs. In skeletal muscle, neither GLP-1 nor Ex-4 modified Glut4 (Slc2a4) expression in either experimental model but showed normalization of reduced GT and GSa, in parallel with the normalization of reduced PI3K activity in T2D and MAPKs in both models. In adipose tissue, the altered GLUT4 expression in IR and T2D, along with reduced GT in IR and increased GT in T2D, and with hyperactivated PI3K in both, became normal after GLP-1 and Ex-4 treatment; yet, MAPKs, that were also higher, became normal only after Ex-4 treatment. The data shows that Ex-4, as well as GLP-1, exerts a normalizing effect on IR and T2D states through a distinct post-receptor mechanism, the liver being the main target for Ex-4 and GLP-1 to control glucose homeostasis.

Topics: Adipose Tissue; Animals; Biological Transport; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Transporter Type 2; Glucose Transporter Type 4; Glycogen Synthase; Insulin Resistance; Liver; Male; Mitogen-Activated Protein Kinases; Muscle, Skeletal; Peptides; Phosphatidylinositol 3-Kinases; Rats; Rats, Wistar; Venoms

Glucagon-like peptide-1 (GLP-1) receptor knockout (Glp1r(-/-)) mice exhibit impaired hepatic insulin action. High fat (HF)-fed Glp1r(-/-) mice exhibit improved, rather than the expected impaired, hepatic insulin action. This is due to decreased lipogenic gene expression and triglyceride accumulation. The present studies overcome these secondary adaptations by acutely modulating GLP-1R action in HF-fed wild-type mice. The central GLP-1R was targeted given its role as a regulator of hepatic insulin action. We hypothesized that acute inhibition of the central GLP-1R impairs hepatic insulin action beyond the effects of HF feeding. We further hypothesized that activation of the central GLP-1R improves hepatic insulin action in HF-fed mice. Insulin action was assessed in conscious, unrestrained mice using the hyperinsulinemic euglycemic clamp. Mice received intracerebroventricular (icv) infusions of artificial cerebrospinal fluid, GLP-1, or the GLP-1R antagonist exendin-9 (Ex-9) during the clamp. Intracerebroventricular Ex-9 impaired the suppression of hepatic glucose production by insulin, whereas icv GLP-1 improved it. Neither treatment affected tissue glucose uptake. Intracerebroventricular GLP-1 enhanced activation of hepatic Akt and suppressed hypothalamic AMP-activated protein kinase. Central GLP-1R activation resulted in lower hepatic triglyceride levels but did not affect muscle, white adipose tissue, or plasma triglyceride levels during hyperinsulinemia. In response to oral but not intravenous glucose challenges, activation of the central GLP-1R improved glucose tolerance. This was associated with higher insulin levels. Inhibition of the central GLP-1R had no effect on oral or intravenous glucose tolerance. These results show that inhibition of the central GLP-1R deteriorates hepatic insulin action in HF-fed mice but does not affect whole body glucose homeostasis. Contrasting this, activation of the central GLP-1R improves glucose homeostasis in HF-fed mice by increasing insulin levels and enhancing hepatic insulin action.

Topics: AMP-Activated Protein Kinases; Animals; Diet, High-Fat; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Clamp Technique; Glycogenolysis; Hypothalamus; Infusions, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neurons; Organ Specificity; Pancreas; Proto-Oncogene Proteins c-akt; Receptors, Glucagon; Signal Transduction

To validate the gubra DIO-rats as a useful animal model of human obesity.. The gubra diet-induced obesity (DIO) rat model was based on male Sprague-Dawley rats with ad libitum access to regular chow and a palatable diet rich in fat and sugar. To evaluate the versatility of the gubra DIO-rats as a valid model of human obesity syndrome, the efficacy of 2 weight loss compounds liraglutide and sibutramine with different mechanisms of action were examined in 7-month-old gubra DIO-rats. Liraglutide (200 μg/kg, sc) was administered bi-daily, and sibutramine (5 mg/kg, po) was administered once daily for 23 d.. Both the compounds effectively reduced the food intake, body weight and total fat mass as measured by nuclear magnetic resonance. Whereas the 5-HT reuptake inhibitor/5-HT receptor agonist sibutramine reduced the intake of both chow and the gubra-diet, the GLP-1 analogue liraglutide predominantly reduced the intake of the highly palatable diet, indicating a shift in food preference. Sibutramine lowered the insulin sensitivity index, primarily via reductions in glucose-stimulated insulin secretion.. This animal model responds well to 2 weight loss compounds with different mechanisms of action. Moreover, the gubra DIO-rat can be particularly useful for the testing of compounds with potential effects on diet preference.

Topics: Animals; Anti-Obesity Agents; Body Weight; Cyclobutanes; Eating; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin Resistance; Liraglutide; Male; Obesity; Rats; Rats, Sprague-Dawley

The early improvement of glucose control taking place shortly after gastric bypass surgery in obese diabetic patients has long been mysterious. A recent study in mice has highlighted some specific mechanisms underlying this phenomenon. The specificity of gastric bypass in obese diabetic mice relates to major changes in the sensations of hunger and to rapid improvement of glucose parameters. The induction of intestinal gluconeogenesis plays a major role in diminishing hunger, and in restoring insulin sensitivity of endogenous glucose production. In parallel, the restoration of the secretion of glucagon-like peptide 1 and insulin plays a key additional role, in this context of recovered insulin sensitivity, to improve postprandial glucose tolerance. Therefore, a synergy between an incretin effect and intestinal gluconeogenesis is a key feature accounting for the rapid improvement of glucose control in obese diabetic patients after bypass surgery.

Topics: Animals; Blood Glucose; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastroplasty; Glucagon-Like Peptide 1; Gluconeogenesis; Incretins; Insulin Resistance; Mice; Mice, Obese; Obesity

Ileal interposition (IT), in which the distal ileum is transposed isoperistaltically into the proximal jejunum, is considered as a procedure for metabolic or antidiabetes surgery. Our aim was to study the effects of IT on glycemic control, fat metabolism, and hormonal changes in obese rats with spontaneous diabetes.. Animals were divided into either an IT or a sham (SH) group. They underwent an oral glucose tolerance test (OGTT) before and 4 and 8 weeks after the operation. All animals were killed 10 weeks after operation for analyses of tissue weight (liver, pancreas, epididymal fat, brown fat), immunoblotting of uncoupling protein-1 (UCP1) protein in brown adipose tissue (BAT), and fasting plasma levels of glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and leptin.. Body weight increased postoperatively in both groups compared with preoperative weight, but it did not differ between the 2 groups. Eight weeks postoperatively, integrated blood glucose levels during the OGTT were decreased in IT compared with SH (P < .05). Fasting plasma levels of insulin, GLP-1, and GIP did not differ between the 2 groups, but PYY levels were higher in the IT animals (P < .01). The weight of epididymal and BATs, homeostasis model assessment insulin resistance, and fasting plasma leptin levels were decreased in the IT group (P < .05). Expression of UCP1 was higher in IT than SH animals (P < .05).. These results suggest that IT improves glucose and lipid metabolism by decreasing insulin resistance and epididymal fat, and increased expression of UCP1 in BAT might be among the mechanisms responsible.

Topics: Adipose Tissue, Brown; Animals; Body Weight; Comorbidity; Diabetes Mellitus; Disease Models, Animal; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Ileum; Insulin Resistance; Ion Channels; Jejunum; Leptin; Lipid Metabolism; Male; Mitochondrial Proteins; Obesity; Peptide YY; Rats, Inbred OLETF; Uncoupling Protein 1

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Calcium Signaling; Cell Differentiation; Diet, High-Fat; DNA Mutational Analysis; Energy Metabolism; Europe; Exons; Fatty Liver; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Lipogenesis; Liver; Macrophages; Mice; Mutation; Obesity; Receptors, G-Protein-Coupled; Signal Transduction; White People

Roux-en-Y gastric bypass (RYGB) surgery causes profound changes in secretion of gastrointestinal hormones and glucose metabolism. We present a detailed analysis of the early hormone changes after RYGB in response to three different oral test meals designed to provide this information without causing side effects (such as dumping).. We examined eight obese non-diabetic patients before and within 2 weeks after RYGB. On separate days, oral glucose tolerance tests (25 or 50 g glucose dissolved in 200 mL of water) and a liquid mixed meal test (200 mL 300 kcal) were performed. We measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY(3-36) (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance.. Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after surgery. Dumping symptoms did not differ before and after the operation or between the tests.. Within 2 weeks after RYGB, we found an increase in insulin secretion and insulin sensitivity. Responses of appetite-regulating intestinal hormones changed dramatically, all in the direction of reducing hunger.

Topics: Adult; Appetite; C-Peptide; Cholecystokinin; Confounding Factors, Epidemiologic; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Islet Amyloid Polypeptide; Leptin; Male; Middle Aged; Obesity, Morbid; Pancreatic Polypeptide; Peptide YY; Postprandial Period; Somatostatin; Time Factors; Weight Loss

Gut hormones play a role in diabetes remission after a Roux-en-Y gastric bypass (RYGB). Our aim was to investigate differences in gut hormone secretion according to diabetes remission after surgery. Second, we aimed to identify differences in insulin secretion and sensitivity according to diabetes remission after RYGB.. Twenty-two severely obese patients with type 2 diabetes underwent RYGB. A meal tolerance test (MTT) was performed 12 months after RYGB. The secretions of active glucagon-like peptide-1 (active GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY, C-peptide and insulin during the MTT test were calculated using total area under the curve values (AUC). Remission was defined as glycated haemoglobin (A(1C)) of <6.5% and a fasting glucose concentration of <126 mg/dL for 1 year or more without active pharmacological therapy.. Of the 22 patients, 16 (73%) had diabetes remission (remission group). The secretion CURVES of active GLP-1, GIP and peptide YY were not different between the groups. AUC of insulin and C-peptide were also not different. Homeostasis model assessment estimate of insulin resistance was significantly lower (1.26 ± 1.05 versus 2.37 ± 1.08, p = 0.006), and Matsuda index of insulin sensitivity was significantly higher in the remission group (10.5 ± 6.2 versus 5.8 ± 2.1, p = 0.039). The disposition index (functional reserve of beta cells) was significantly higher in the remission group compared with that in the non-remission group (5.34 ± 2.74 versus 1.83 ± 0.70, p < 0.001).. Remission of diabetes after RYGB is not associated with a difference in gut hormone secretion. Patients remaining diabetic had higher insulin resistance and decreased β cell functional reserve.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Obesity; Prognosis; Prospective Studies; Remission Induction; Young Adult

Oral meal consumption increases glucagon-like peptide 1 (GLP-1) release which maintains euglycemia by increasing insulin secretion. This effect is exaggerated during short-term follow-up of Roux-en-y gastric bypass (RYGB). We examined the durability of this effect in patient with type 2 diabetes (T2DM) >10 years after RYGB.. GLP-1 response to a mixed meal in the 10-year post-RYGB group (n = 5) was compared to lean (n = 9), obese (n = 6), and type 2 diabetic (n = 10) controls using a cross-sectional study design. Analysis of variance (ANOVA) was used to evaluate GLP-1 response to mixed meal consumption from 0 to 300 min, 0-20 min, 20-60 min, and 60-300 min, respectively. Weight, insulin resistance, and T2DM were also assessed.. GLP-1 response 0-300 min in the 10-year post-RYGB showed a statistically significant overall difference (p =  0.01) compared to controls. Furthermore, GLP-1 response 0-20 min in the 10-year post-RYGB group showed a very rapid statistically significant rise (p = 0.035) to a peak of 40 pM. GLP-1 response between 20 and 60 min showed a rapid statistically significant (p = 0.041) decline in GLP-1 response from ~40 pM to 10 pM. GLP-1 response in the 10-year post-RYGB group from 60 to 300 min showed no statistically significant difference from controls. BMI, HOMA, and fasting serum glucose before and >10 years after RYGB changed from 59.9 → 40.4, 8.7 → 0.88, and 155.2 → 87.6 mg/dl, respectively, and were statistically significant (p < 0.05).. An exaggerated GLP-1 response was noted 10 years after RYGB, strongly suggesting a durability of this effect. This phenomenon may play a key role in maintaining type 2 diabetes remission and weight loss after RYGB.

Topics: Analysis of Variance; Blood Glucose; Body Weight; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Eating; Female; Follow-Up Studies; Gastric Bypass; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Time Factors; Treatment Outcome; Weight Loss

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are known as incretins to stimulate insulin secretion. The aims of this study were to investigate the postoperative β-cell function and hormonal responses of GLP-1 and GIP after pancreatoduodenectomy (PD) and distal pancreatectomy (DP).. Oral glucose tolerance tests were performed in 34 patients (20 PD and 14 DP) before and 1 month after operation. The changes in the serum glucose and insulin concentrations, homeostasis model assessment of insulin resistance, and pancreatic β-cell function (BCF) were analyzed. GLP-1 and GIP were also measured.. There was no patient with postoperative deterioration of glucose tolerance after PD, whereas impairment of glucose metabolism was observed after DP. Homeostasis model assessment of insulin resistance decreased after PD, whereas those after DP showed no change. The postoperative BCF were lower than preoperative values in both groups. GLP-1 increased after DP but not after PD, whereas GIP decreased after PD but not after DP.. The changes in glucose metabolism and incretin responses were different between PD and DP. The increased level of GLP-1 after DP might reflect the relatively insufficient BCF; and thus, perioperative administration of GLP-1 might improve the diabetic condition after DP.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Japan; Male; Middle Aged; Pancreas; Pancreatectomy; Pancreaticoduodenectomy; Prospective Studies; Time Factors; Treatment Outcome

Chitosan is a natural product derived from chitin. To investigate the hypoglycemic and anti-obesity effects of chitosan, male Sprague-Dawley rats were divided into four groups: normal control, diabetic, and diabetic fed 5% or 7% chitosan. Diabetes was induced in rats by injecting streptozotocin/nicotinamide. After 10 weeks of feeding, the elevated plasma glucose, tumor necrosis factor-α, and interleukin-6 and lower adiponetin levels caused by diabetes were effectively reversed by chitosan treatment. In addition, 7% chitosan feeding also elevated plasma glucagon-like peptide-1 levels and lowered the insulin resistance index (homeostasis model assessment) in diabetic rats. Lower adipocyte granular intensities and higher lipolysis rates in adipose tissues were noted in the 7% chitosan group. Moreover, chitosan feeding reduced hepatic triglyceride and cholesterol contents and increased hepatic peroxisomal proliferator-activated receptor α expression in diabetic rats. Our results indicate that long-term administration of chitosan may reduce insulin resistance through suppression of lipid accumulation in liver and adipose tissues and amelioration of chronic inflammation in diabetic rats.

Topics: Adiponectin; Adipose Tissue; Animals; Biological Products; Blood Glucose; Chitosan; Cholesterol; Diabetes Mellitus, Experimental; Glucagon-Like Peptide 1; Hypoglycemic Agents; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Lipid Metabolism; Liver; Male; PPAR alpha; Rats; Rats, Sprague-Dawley; Triglycerides; Tumor Necrosis Factor-alpha

Topics: Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Male

Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.

Topics: Animals; Body Weight; Butyrates; Diet; Fatty Acids, Nonesterified; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Homeostasis; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Propionates; Receptors, G-Protein-Coupled

We previously showed that parenteral nutrition (PN) compared with formula feeding results in hepatic insulin resistance and steatosis in neonatal pigs. The current aim was to test whether the route of feeding (intravenous [IV] vs enteral) rather than other feeding modalities (diet, pattern) had contributed to the outcome.. Neonatal pigs were fed enterally or parenterally for 14 days with 1 of 4 feeding modalities as follows: (1) enteral polymeric formula intermittently (FORM), (2) enteral elemental diet (ED) intermittently (IEN), (3) enteral ED continuously (CEN), and (4) parenteral ED continuously (PN). Subgroups of pigs underwent IV glucose tolerance tests (IVGTT) and hyperinsulinemic-euglycemic clamps (CLAMP). Following CLAMP, pigs were euthanized and tissues collected for further analysis.. Insulin secretion during IVGTT was significantly higher and glucose infusion rates during CLAMP were lower in CEN and PN than in FORM and IEN. Endogenous glucose production rate was suppressed to zero in all groups during CLAMP. In the fed state, plasma glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide (GLP)-1, and GLP-2 were different between feeding modalities. Insulin receptor phosphorylation in liver and muscle was decreased in IEN, CEN, and PN compared with FORM. Liver weight was highest in PN. Steatosis and myeloperoxidase (MPO) activity tended to be highest in PN and CEN. Enterally fed groups had higher plasma GLP-2 and jejunum weight compared with PN.. PN and enteral nutrition (EN) when given continuously as an elemental diet reduces insulin sensitivity and the secretion of key gut incretins. The intermittent vs continuous pattern of EN produced the optimal effect on metabolic function.

Topics: Administration, Intravenous; Animals; Animals, Newborn; Blood Glucose; Endpoint Determination; Enteral Nutrition; Fatty Liver; Female; Food, Formulated; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Incretins; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Intestine, Small; Liver; Metabolic Diseases; Nonlinear Dynamics; Organ Size; Parenteral Nutrition; Swine

Exendin-4 is a stable peptide agonist of GLP-1 receptor that exhibits insulinotropic actions. Some in vivo studies indicated insulin-independent glucoregulatory actions of exendin-4. That finding prompted us to evaluate effects of exendin-4 on liver glucose metabolism. Acute and chronic treatment of exendin-4 resulted in increased hepatic glucokinase activity in db/db mice but not in lean C57 mice. The stimulatory effect of exendin-4 on glucokinase activity was abrogated by exendin 9-39, a GLP-1 antagonist. Exposure of hepatocytes isolated from db/db mice to exendin-4 elicited a rapid increase in cAMP, which was synergized by IBMX, an inhibitor of cAMP degradation. The GLP-1 antagonist, exendin 9-39, has abolished the cAMP generating effects of exendin-4 as well. Furthermore, chronic treatment of exendin-4 in streptozotocin-treated C57 mice resulted in restoration of hepatic glycogen, an indicator of improved glucose metabolism, without apparent changes in serum insulin levels. In conclusion, exendin-4 increased glucokinase enzyme protein and activity in liver via a mechanism parallel to and independent of insulin. Exendin-4-induced increase in hepatic glucokinase activity is more pronounced in the presence of hepatic insulin resistance. This beneficial effect of exendin-4 on liver glucokinase activity may be mediated by GLP-1 receptor.

Topics: Animals; Cyclic AMP; Diabetes Mellitus, Experimental; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucokinase; Glucose; Glycogen; Hepatocytes; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Peptides; Receptors, Glucagon; Venoms

Exenatide, a glucagon-like peptide-1 (GLP-1) analogue, is an effective glucoregulator for treating overweight individuals, not at target HbA1 c. This prospective study aimed to determine whether estimates of beta cell function (HOMA-B) and insulin sensitivity (HOMA-S) predict response to Exenatide treatment.Prospective data on 43 type 2 diabetes patients were collected for up to 2.8 years in UK primary care. HOMA-B and HOMA-S were estimated prior to initiating Exenatide, with monitoring of cardio-metabolic risk factors.Mean (SD) age and BMI pre-treatment were 54.1±10.5 years and 35.7±7.5 kg/m2 respectively. HbA1c decreased (mean reduction 0.9%, p=0.04; p for trend=0.01) in 61% of patients. In univariate analyses, HOMA-S as a measure of insulin sensitivity was inversely (β=- 0.41, p 0.009) related to change in HbA1c, with no relation for HOMA-B.In a random effects regression model that included age at baseline, weight, LDL-C, HDL-C and triglycerides, change in HbA1c (β= - 0.14, p<0.001) and HDL-C (β= - 0.52, p=0.011) were independently associated with increasing insulin sensitivity (r2=0.52). Thus patients with greater measured insulin sensitivity achieved greater reduction in HbA1c independent of the factors described above.In logistic regression those in the highest tertile of log-HOMA-S were 45% more likely to have a fall in HbA1c with an odds ratio (OR) of 0.55 (95% CI 0.47-0.66) p<0.0001 (log likelihood ratio for the model χ2=71.6, p<0.0001).Patients with greater measured insulin sensitivity achieve greater reduction in HbA1c with Exenatide. Determination of insulin sensitivity may assist in guiding outcome expectation in overweight patients treated with GLP-1 analogues.

Topics: Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lipids; Male; Middle Aged; Models, Biological; Peptides; Prospective Studies; Treatment Outcome; Venoms

Anionic exchange resins are bona fide cholesterol-lowering agents with glycemia lowering actions in diabetic patients. Potentiation of intestinal GLP-1 secretion has been proposed to contribute to the glycemia lowering effect of these non-systemic drugs. Here, we show that resin exposure enhances GLP-1 secretion and improves glycemic control in diet-induced animal models of "diabesity", effects which are critically dependent on TGR5, a G protein-coupled receptor that is activated by bile acids. We identified the colon as a major source of GLP-1 secretion after resin treatment. Furthermore, we demonstrate that the boost in GLP-1 release by resins is due to both enhanced TGR5-dependent production of the precursor transcript of GLP-1 as well as to the local enrichment of TGR5 agonists in the colon. Thus, TGR5 represents an essential component in the pathway mediating the enhanced GLP-1 release in response to anionic exchange resins.

Topics: Animals; Anion Exchange Resins; Bile Acids and Salts; Blood Glucose; CHO Cells; Cholic Acids; Colon; Cricetinae; Cricetulus; Diet, High-Fat; Enteroendocrine Cells; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Male; Mice; Mice, Knockout; Obesity; Proglucagon; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction

Obesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM).. We administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP-1) to an ob/ob mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage-specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor κB (NF-κB), extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro.. Fat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Macrophage populations (F4/80(+) and F4/80(+)CD11b(+)CD11c(+) cells), as well as the expression and production of IL-6, TNF-α and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated ob/ob mice. NF-κB and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM.. We suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Body Fat Distribution; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Inflammation; Insulin Resistance; Macrophages; Mice; Mice, Obese; NF-kappa B; Obesity; Real-Time Polymerase Chain Reaction; Receptors, Glucagon

Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285 kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285 kcal), and 2) a mixed meal (0.285 kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055 kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P=0.02), the peak intact GLP-1 levels (P=0.006) and the estimated β-cell function (P=0.005) were higher. Furthermore, the peak insulin (P=0.004) and intact GLP-1 (P=0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1.

Topics: Administration, Oral; Animals; Area Under Curve; Blood Glucose; Diet; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Linear Models; Mice; Mice, Inbred C57BL; Milk Proteins; Peanut Oil; Plant Oils; Whey Proteins

There is a worsening high prevalence of global obesity. Special attention has been paid to the gut-endocrine system, represented by the regulators of appetite. In particular, it has been suggested that ghrelin ("hunger" peptide), and obestatin and glucagon-like peptide-1 (GLP-1) ("satiety" peptides) could play important roles in the pathogenesis of obesity.. The aims of this study were to compare fasting plasma ghrelin, obestatin, and GLP-1 levels between obese and nonobese prepubertal children, and to assess their relations with fatness indexes and insulin resistance (IR).. Fifty-two prepubertal obese children and 22 controls were enrolled. Fasting levels of gastrointestinal hormones (ghrelin, obestatin, and GLP-1), glucose, and insulin were evaluated. IR was assessed using the homeostasis model assessment of IR (HOMA-IR) index. Analysis was performed by Mann-Whitney U-test, Kruskal-Wallis test, and Spearman's correlation.. Obese prepubertal children and normal-weight controls had similar age distribution. Obese children were more insulin resistant when compared to controls (HOMA-IR: p < 0.01 ). GLP-1 levels were significantly lower in obese children than in controls (p < 0.01). Obestatin was significantly higher in obese than normal-weight children (p < 0.01), while ghrelin was not different. There was a negative correlation between GLP-1 and standard deviation score-body mass index (r = -0.36, p = 0.009) and between GLP-1 and waist circumference (r = -0.45, p = 0.001), while no association was observed with HOMA-IR.. GLP-1 levels have been shown to be correlated with adiposity indexes, but not with HOMA-IR, suggesting that this hormone could play an important role in the early development of obesity.

Topics: Adiposity; Blood Glucose; Body Mass Index; Case-Control Studies; Child; Female; Gastrointestinal Hormones; Ghrelin; Glucagon-Like Peptide 1; Humans; Incretins; Insulin; Insulin Resistance; Leptin; Male; Obesity; Waist Circumference

We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)-deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1r(-/-) mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance.

Topics: Adipose Tissue, Brown; Animals; Central Nervous System; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Nerve Tissue Proteins; Neurons; Oxyntomodulin; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptors, Glucagon; Scapula; Signal Transduction; Sympathetic Nervous System; Thermogenesis; Trans-Activators; Transcription Factors; Uncoupling Protein 1; Up-Regulation

Low birthweight (BW) is associated with increased risk of type 2 diabetes. We compared glucose metabolism in adult BW-discordant monozygotic (MZ) twins, thereby controlling for genetic factors and rearing environment.. Among 77,885 twins in the Danish Twin Registry, 155 of the most BW-discordant MZ twin pairs (median BW difference 0.5 kg) were assessed using a 2 h oral glucose tolerance test with sampling of plasma (p-)glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. HOMA for beta cell function (HOMA-β) and insulin resistance (HOMA-IR), and also insulin sensitivity index (BIGTT-SI) and acute insulin response (BIGTT-AIR), were calculated. Subgroup analyses were performed in those with: (1) double verification of BW difference; (2) difference in BW >0.5 kg; and (3) no overt metabolic disease (type 2 diabetes, hyperlipidaemia or thyroid disease).. No intra-pair differences in p-glucose, insulin, C-peptide, incretin hormones, HOMA-β, HOMA-IR or BIGTT-SI were identified. p-Glucose at 120 min was higher in the twins with the highest BW without metabolic disease, and BIGTT-AIR was higher in those with the highest BW although not in pairs with a BW difference of >0.5 kg.. BW-discordant MZ twins provide no evidence for a detrimental effect of low BW on glucose metabolism in adulthood once genetic factors and rearing environment are controlled for.

Topics: Adult; Aged; Analysis of Variance; Birth Weight; Blood Glucose; C-Peptide; Denmark; Diabetes Mellitus, Type 2; Disease Susceptibility; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Infant, Low Birth Weight; Infant, Newborn; Insulin Resistance; Logistic Models; Male; Middle Aged; Risk Factors; Surveys and Questionnaires; Twins, Monozygotic

Pregnancy and obesity are frequently associated with diminished insulin sensitivity, which is normally compensated for by an expansion of the functional β cell mass that prevents chronic hyperglycemia and development of diabetes mellitus. The molecular basis underlying compensatory β cell mass expansion is largely unknown. We found in rodents that β cell mass expansion during pregnancy and obesity is associated with changes in the expression of several islet microRNAs, including miR-338-3p. In isolated pancreatic islets, we recapitulated the decreased miR-338-3p level observed in gestation and obesity by activating the G protein-coupled estrogen receptor GPR30 and the glucagon-like peptide 1 (GLP1) receptor. Blockade of miR-338-3p in β cells using specific anti-miR molecules mimicked gene expression changes occurring during β cell mass expansion and resulted in increased proliferation and improved survival both in vitro and in vivo. These findings point to a major role for miR-338-3p in compensatory β cell mass expansion occurring under different insulin resistance states.

Topics: Adaptation, Physiological; Animals; Cells, Cultured; Cytokines; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Islets of Langerhans; Male; Mice; Mice, Mutant Strains; MicroRNAs; Obesity; Organ Size; Postpartum Period; Pregnancy; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Glucagon; Signal Transduction

Liraglutide is a glucagon-like peptide-1 analogue that stimulates insulin secretion and improves β-cell function. However, it is not clear whether liraglutide achieves its glucose lowering effect only by its known effects or whether other as yet unknown mechanisms are involved. The aim of this study was to examine the effects of liraglutide on Fibroblast growth factor-21 (FGF-21) activity in High-fat diet (HFD) fed ApoE(-/-) mice with adiponectin (Acrp30) knockdown.. HFD-fed ApoE(-/-) mice were treated with adenovirus vectors expressing shAcrp30 to produce insulin resistance. Hyperinsulinemic-euglycemic clamp studies were performed to evaluate insulin sensitivity of the mouse model. QRT-PCR and Western blot were used to measure the mRNA and protein expression of the target genes.. The combination of HFD, ApoE deficiency, and hypoadiponectinemia resulted in an additive effect on insulin resistance. FGF-21 mRNA expressions in both liver and adipose tissues were significantly increased while FGF-21 receptor 1 (FGFR-1) and β-Klotho mRNA levels in adipose tissue, as well as FGFR-1-3 and β-Klotho mRNA levels in liver were significantly decreased in this model. Liraglutide treatment markedly improved insulin resistance and increased FGF-21 expression in liver and FGFR-3 in adipose tissue, restored β-Klotho mRNA expression in adipose tissue as well as FGFR-1-3, β-Klotho levels and phosphorylation of FGFR1 up to the levels observed in control mice in liver. Liraglutide treatment also further increased FGF-21 proteins in liver and plasma. In addition, as shown by hyperinsulinemic-euglycemic clamp, liraglutide treatment also markedly improved glucose metabolism and insulin sensitivity in these animals.. These findings demonstrate an additive effect of HFD, ApoE deficiency, and adiponectin knockdown on insulin resistance and unveil that the regulation of glucose metabolism and insulin sensitivity by liraglutide may be partly mediated via increased FGF-21 and its receptors action.

Topics: Adiponectin; Adipose Tissue; Animals; Apolipoproteins E; Blood Glucose; Diet, High-Fat; Fibroblast Growth Factors; Gene Expression Regulation; Gene Knockdown Techniques; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin Resistance; Liraglutide; Liver; Male; Mice; Mice, Knockout; Receptors, Fibroblast Growth Factor; RNA Interference; RNA, Messenger

Type 2 diabetes (T2D) is a strong risk factor for developing neurodegenerative pathologies. T2D patients have a deficiency in the intestinal incretin hormone GLP-1, which has been shown to exert neuroprotective and anti-inflammatory properties in the brain.. Here we investigate potential sources of GLP-1 in the CNS and the effect of diabetic conditions on the proglucagon mRNA expression in the CNS. The obese mouse model ob/ob, characterized by its high levels of free fatty acids, and the microglia cell line BV-2 were used as models. mRNA expression and protein secretion were analyzed by qPCR, immunofluorescence and ELISA.. We show evidence for microglia as a central source of GLP-1 secretion. Furthermore, we observed that expression and secretion are stimulated by cAMP and dependent on microglial activation state. We also show that insulin-resistant conditions reduce the central mRNA expression of proglucagon.. The findings that microglial mRNA expression of proglucagon and GLP-1 protein expression are affected by high levels of free fatty acids and that both mRNA expression levels of proglucagon and secretion levels of GLP-1 are affected by inflammatory stimuli could be of pathogenic importance for the premature neurodegeneration and cognitive decline commonly seen in T2D patients, and they may also be harnessed to advantage in therapeutic efforts to prevent or treat such disorders.

Topics: Animals; Arginase; CD11b Antigen; Cell Line, Transformed; Central Nervous System; Chitinases; Cyclic AMP; Disease Models, Animal; Gene Expression Regulation; Glucagon-Like Peptide 1; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Microglia; Obesity; Palmitates; Plant Proteins; Polysaccharides; Proglucagon; RNA, Messenger; Statistics, Nonparametric; Transfection; Tumor Necrosis Factor-alpha

Increased postprandial glucose-dependent insulinotropic polypeptide (GIP) and glucagon responses and reduced postprandial glucagon-like peptide-1 (GLP-1) responses have been observed in some patients with type 2 diabetes mellitus. The causality of these pathophysiological traits is unknown. We aimed to determine the impact of insulin resistance and reduced glucose tolerance on postprandial GIP, GLP-1, and glucagon responses in healthy subjects.. A 4-h 2200 KJ-liquid meal test was performed in 10 healthy Caucasian males without family history of diabetes [age, 24 ± 3 yr (mean ± sd); body mass index, 24 ± 2 kg/m(2); fasting plasma glucose, 4.9 ± 0.3 mm; hemoglobin A(1)c, 5.4 ± 0.1%] before and after intervention using high-calorie diet, relative physical inactivity, and administration of prednisolone (37.5 mg/d) for 12 d.. The intervention resulted in insulin resistance according to the homeostatic model assessment [1.1 ± 0.3 vs. 2.3 (mean ± SEM) ± 1.3; P = 0.02] and increased postprandial glucose excursions [area under curve (AUC), 51 ± 28 vs. 161 ± 32 mm · 4 h; P = 0.045], fasting plasma insulin (36 ± 3 vs. 61 ± 6 pm; P = 0.02), and postprandial insulin responses (AUC, 22 ± 6 vs. 43 ± 13 nm · 4 h; P = 0.03). This disruption of glucose homeostasis had no impact on postprandial GLP-1 responses (AUC, 1.5 ± 0.7 vs. 2.0 ± 0.5 nm · 4 h; P = 0.56), but resulted in exaggerated postprandial GIP (6.2 ± 1.0 vs. 10.0 ± 1.3 nm · 4 h; P = 0.003) and glucagon responses (1.6 ± 1.5 vs. 2.4 ± 3.2; P = 0.007).. These data suggest that increased postprandial GIP and glucagon responses may occur as a consequence of insulin resistance and/or reduced glucose tolerance. Our data suggest that acute disruption of glucose homeostasis does not result in reduced postprandial GLP-1 responses as observed in some individuals with type 2 diabetes mellitus.

Topics: Adult; Area Under Curve; Blood Glucose; C-Peptide; Diet; Energy Intake; Fasting; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Motor Activity; Postprandial Period; Prednisolone; Young Adult

Cardiovascular risk is closely associated with insulin resistance and type 2 diabetes. Therapy based on the actions of GLP-1 is currently seen as a novel approach to treat this disease. The aims of this study was therefore to use an animal model to determine whether (i) pre-treatment of obese, insulin resistant but pre-diabetic rats with a DPP4 inhibitor, PFK275-055, could protect the heart from ischaemia/reperfusion injury and (ii) the possible mechanisms involved in such protection. Obese, pre-diabetic rats (DIO) were treated for 4 weeks with 10 mg/kg/day of the DPP4 inhibitor PFK275-055. Ex vivo perfusion was used to subject hearts to ischaemia/reperfusion to determine infarct size, functional recovery and post-ischaemic activation of proteins associated with cardiac protection. Adult ventricular cardiomyocytes were isolated to determine insulin sensitivity. Other assessments included body weight, intra-peritoneal fat weight, insulin and GLP-1 levels as well as histological evaluation of the pancreata. Results showed that DIO animals had higher body mass and intra-peritoneal fat mass than chow-fed animals. They presented with elevated plasma insulin levels and lower GLP-1 levels. Treatment with the DPP4 inhibitor resulted in smaller infarct size development in hearts from DIO rats after ischaemia/reperfusion accompanied by activation of cardioprotective kinases. GLP-1 levels were elevated and plasma insulin levels lower after treatment. In addition, the beta-cell to alpha-cell ratio of the pancreas was improved. We conclude that treatment with PFK275-055 for 4 weeks protected the heart against ischaemia/reperfusion injury, elevated GLP-1 levels and improved metabolic control in obese, pre-diabetic rats.

Topics: Animals; Blood Glucose; Body Weight; Cardiotonic Agents; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Male; Myocardial Reperfusion Injury; Myocytes, Cardiac; Obesity; Pancreas; Phosphotransferases; Prediabetic State; Rats; Rats, Wistar

Cold acclimation is initially associated with shivering thermogenesis in skeletal muscle followed by adaptive non-shivering thermogenesis, particularly in brown adipose tissue (BAT). In response, hyperphagia occurs to meet increased metabolic demand and thermoregulation. The present study investigates the effects of cold (4 ± 1 °C) acclimation and hyperphagia on circulating and intestinal levels of gastric inhibitory polypeptide (GIP) in rats. Pair fed animals were used as additional controls in some experiments. Cold acclimation for 42 days significantly (p<0.01) increased daily food intake. There was no corresponding change in body weight. However, body weights of pair fed cold exposed rats were significantly (p<0.01) reduced compared to controls and ad libitum fed cold exposed rats. By day 42, non-fasting plasma glucose was increased (p<0.05) by chronic cold exposure regardless of food intake. Corresponding plasma insulin concentrations were significantly (p<0.01) lower in pair fed cold exposed rats. Circulating GIP levels were elevated (p<0.05) in ad libitum fed cold acclimated rats on days 18 and 24, but returned to normal levels by the end of the study. The glycaemic response to oral glucose was improved (p<0.01) in all cold exposed rats, with significantly (p<0.05) elevated GIP responses in ad libitum fed rats and significantly (p<0.05) reduced insulin responses in pair fed rats. In keeping with this, insulin sensitivity was enhanced (p<0.05) in cold exposed rats compared to controls. By the end of the study, cold acclimated rats had significantly (p<0.01) increased BAT mass and intestinal concentrations of GIP and GLP-1 compared to controls, independent of food intake. These data indicate that changes in the secretion and actions of GIP may be involved in the metabolic adaptations to cold acclimation in rats.

Topics: Acclimatization; Adipose Tissue, Brown; Animals; Blood Glucose; Body Temperature Regulation; Body Weight; Cold Temperature; Eating; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycemic Index; Hyperphagia; Insulin; Insulin Resistance; Intestinal Mucosa; Male; Organ Size; Rats; Rats, Wistar

Transcriptional regulation of small intestinal gene expression controls plasma total cholesterol (TC) and triglyceride (TG) levels, which are major determinants of metabolic diseases. GATA4, a zinc finger domain transcription factor, is critical for jejunal identity, and intestinal GATA4 deficiency leads to a jejunoileal transition. Although intestinal GATA4 ablation is known to misregulate jejunal gene expression, its pathophysiological impact on various components of metabolic syndrome remains unknown. Here, we used intestine-specific GATA4 knockout (GATA4iKO) mice to dissect the contribution of GATA4 on obesity development. We challenged adult GATA4iKO mice and control littermates with a Western-type diet (WTD) for 20 wk. Our findings show that WTD-fed GATA4iKO mice are resistant to diet-induced obesity. Accordingly, plasma TG and TC levels are markedly decreased. Intestinal lipid absorption in GATA4iKO mice was strongly reduced, whereas luminal lipolysis was unaffected. GATA4iKO mice displayed a greater glucagon-like peptide-1 (GLP-1) release on normal chow and even after long-term challenge with WTD remained glucose sensitive. In summary, our findings show that the absence of intestinal GATA4 has a beneficial effect on decreasing intestinal lipid absorption causing resistance to hyperlipidemia and obesity. In addition, we show that increased GLP-1 release in GATA4iKO mice decreases the risk for development of insulin resistance.

Topics: Adipose Tissue; Animals; Diet; Dietary Fats; Enzyme-Linked Immunosorbent Assay; Feces; Gastric Emptying; GATA4 Transcription Factor; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hyperlipidemias; Insulin Resistance; Intestinal Absorption; Intestinal Mucosa; Lipolysis; Magnetic Resonance Imaging; Mice; Mice, Knockout; Obesity; Reverse Transcriptase Polymerase Chain Reaction; RNA; Tissue Distribution

Microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT-130, a novel intestine-specific MTP inhibitor, on high fat diet-induced obesity and glucose intolerance.. Male Sprague-Dawley rats were fed a 3.1% fat diet or a 35% fat diet with or without JTT-130 as a food admixture (0.029%). Food intake, body weight, abdominal fat, hepatic triglyceride, faecal free fatty acids and plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were assessed. Plasma levels of glucose and insulin were measured during intraperitoneal glucose tolerance tests. In addition, indirect calorimetry was performed on rats fed with a 35% fat diet.. JTT-130 treatment decreased body weights, abdominal fat and hepatic triglyceride with suppression of food intake and elevation of faecal free fatty acids and plasma GLP-1 and PYY levels in rats fed with the 35% fat diet, whereas no significant effects on these parameters except for increased faecal free fatty acids were observed in rats fed with the 3.1% fat diet. JTT-130 treatment decreased plasma levels of glucose and insulin during intraperitoneal glucose tolerance tests on rats fed with the 35% fat diet, but not on rats fed with the 3.1% fat diet. JTT-130-treated rats showed increased O(2) consumption and CO(2) production on a 35% fat diet.. JTT-130 suppresses high fat diet-induced obesity and glucose intolerance with suppression of food intake and fat absorption and could be useful for prevention and treatment of obesity and obesity-related insulin resistance.

Topics: Animals; Benzamides; Biomarkers; Blood Glucose; Carrier Proteins; Diet, High-Fat; Dietary Fats; Eating; Fatty Acids; Feces; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Male; Malonates; Obesity; Peptide YY; Rats; Rats, Sprague-Dawley; Triglycerides

Hyperglycemia with insulin resistance is commonly seen in severely burned patients and tight glycemia control with insulin may be beneficial in this condition. The most potent insulinotropic hormone, glucagon-like peptide 1 (GLP-1), stimulates insulin secretion in a glucose-dependent manner. Because infusion of GLP-1 never reduces glucose levels to below ∼70 mg/dL, the risk of hypoglycemia by using insulin is reduced. In this study we investigated the metabolic effects of GLP-1 infusion after burn injury in an animal model.. Male CD rats were divided in 3 groups: burn injury with saline, burn injury with GLP-1 treatment, and sham burn (SB). Burn injury was full thickness 40% total body surface area. The burn injury with GLP-1 treatment group received GLP-1 infusion via osmotic pump. Fasting blood glucose, plasma insulin, and plasma GLP-1 levels were measured during intraperitoneal glucose tolerance tests. Expressions of caspase 3 and bcl-2 were evaluated in pancreatic islets. In a subset of animals, protein metabolism and total energy expenditure were measured.. Fasting GLP-1 was reduced in burn injury with saline compared to SB or burn injury with GLP-1 treatment. Burn injury with GLP-1 treatment showed reduced fasting blood glucose, improved intraperitoneal glucose tolerance test results, with increased plasma insulin and GLP-1 responses to glucose. GLP-1 reduced protein breakdown and total energy expenditure in burn injury with GLP-1 treatment versus burn injury with saline, with improved protein balance. Increased expression of caspase 3 and decreased expression of bcl-2 in islet cells by burn injury were ameliorated by GLP-1.. Burn injury reduced plasma GLP-1 in association with insulin resistance. GLP-1 infusion improved glucose tolerance and showed anabolic effects on protein metabolism and reduced total energy expenditure after burn injury, possibly via insulinotropic and non insulinotropic mechanisms.

Topics: Animals; Blood Glucose; Burns; Caspase 3; Energy Metabolism; Glucagon-Like Peptide 1; Hyperglycemia; Incretins; Insulin; Insulin Resistance; Islets of Langerhans; Male; Models, Animal; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Inbred Strains

The increase in insulin secretion caused by glucagon-like peptide-1 (GLP-1) and GLP-1 mimetics observed during an intravenous glucose test (IVGTT) has been reported in both normal and disease animal models, as well as in humans. In this study, a hierarchical population modeling approach is used, together with a previously reported model relating glucose to insulin appearance, to determine quantitative in vivo dose-response relationships between GLP-1 dose level and both first- and second-phase insulin release. Parameters of the insulin kinetic model were estimated from the complete set of glucose and insulin data collected in 219 anesthetized nonfasted NMR-imaged mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). The resulting dose-response curves indicate a difference in GLP-1 effect on the two release phases, as is also evident from the different ED(50) parameter values (0.107 vs. 6.65 nmol/kg for phase 1 vs. phase 2 insulin release parameters). The first phase of insulin release is gradually augmented with increasing GLP-1 dose, reaching saturation at a dose of ~1 nmol/kg, while the second-phase release changes more abruptly at GLP-1 doses between 3 and 10 nmol/kg and shows a more pronounced 100-fold increase between control and the high GLP-1 dose of 100 nmol/kg Moreover, separate disposition indices calculated for phase 1 and 2 insulin release, show a different pattern of increase with increasing GLP-1 dose.

Topics: Animals; Biomarkers; Blood Glucose; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Infusions, Intravenous; Insulin; Insulin Resistance; Kinetics; Magnetic Resonance Spectroscopy; Mice; Models, Biological

Bypass of the foregut following Roux-en-Y gastric bypass (RYGB) surgery results in altered nutrient absorption, which is proposed to underlie the improvement in glucose tolerance and insulin sensitivity. We conducted a prospective crossover study in which a mixed meal was delivered orally before RYGB (gastric) and both orally (jejunal) and by gastrostomy tube (gastric) postoperatively (1 and 6 wk) in nine subjects. Glucose, insulin, and incretin responses were measured, and whole-body insulin sensitivity was estimated with the insulin sensitivity index composite. RYGB resulted in an improved glucose, insulin, and glucagon-like peptide-1 (GLP-1) area under the curve (AUC) in the first 6 wk postoperatively (all P ≤ 0.018); there was no effect of delivery route (all P ≥ 0.632) or route × time interaction (all P ≥ 0.084). The glucose-dependent insulinotropic polypeptide (GIP) AUC was unchanged after RYGB (P = 0.819); however, GIP levels peaked earlier after RYGB with jejunal delivery. The ratio of insulin AUC to GLP-1 and GIP AUC decreased after surgery (P =.001 and 0.061, respectively) without an effect of delivery route over time (both P ≥ 0.646). Insulin sensitivity improved post-RYGB (P = 0.001) with no difference between the gastric and jejunal delivery of the mixed meal over time (P = 0.819). These data suggest that exclusion of nutrients from the foregut with RYGB does not improve glucose tolerance or insulin sensitivity. However, changes in the foregut response post-RYGB due to lack of nutrient exposure cannot be excluded. Our findings suggest that foregut bypass may alter the incretin response by enhanced nutrient delivery to the hindgut.

Topics: Adult; Anastomosis, Roux-en-Y; Area Under Curve; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Duodenum; Female; Food; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Jejunum; Laparoscopy; Male; Metabolism; Middle Aged

Patients with insulin-treated type 2 diabetes and high insulin requirements are subject to undesirable treatment-related weight gain. These patients would potentially benefit from the insulin-sparing and weight loss benefits of glucagon-like peptide 1 (GLP-1) receptor agonist therapy; however, GLP-1 receptor agonists currently are not approved for use in combination with insulin. We examined the effects of adding liraglutide at a daily dose of 1.2 or 1.8 mg to an intensive regimen (either multiple daily injections or continuous subcutaneous insulin infusion) of U-500 insulin on hemoglobin A1c (HbA1c), total daily insulin dose, and weight in 15 patients with type 2 diabetes and high insulin requirements (initial mean daily insulin dose of 192 ± 77 units per day; initial mean weight, 300.9 ± 55.7 lbs) in a clinical practice setting.. In this observational case series, we identified 15 patients treated with a combination of U-500 insulin and liraglutide for at least 12 weeks at routine follow-up office visits. The U-500 insulin dose was reduced by 0-30% upon initiation of liraglutide. Insulin doses were subsequently adjusted to optimize glycemic control. Endpoints included change in HbA1c, change in total daily insulin dose, change in weight, and incidence of hypoglycemia. Comparisons of 12-week and baseline values were evaluated by paired two-tailed t tests.. At 12 weeks, the reduction in HbA1c from baseline (8.48%) was 1.4% (P = 0.0001). Weight fell by an average of 11.2 LB (5.1 KG) (P = 0.0001). Total daily insulin dose was reduced by 28% (P = 0.0001). No severe episodes of hypoglycemia occurred.. Adding liraglutide to U-500 insulin resulted in significant improvements in glycemic control, weight loss, and reduced insulin requirements in patients with type 2 diabetes and high insulin requirements.

Topics: Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Liraglutide; Male; Medical Records; Middle Aged; Obesity; Receptors, Glucagon; Retrospective Studies; Severity of Illness Index; Weight Loss

Exendin 1-39 amide (Ex-4) and its truncated form exendin 9-39 amide (Ex-9) are peptides of non-mammalian nature, which act as an agonist and antagonist, respectively, of the glucagon-like peptide-1 (GLP-1) receptor in mammals. GLP-1 is an intestinal peptide that plays an important role in the regulation of glucose metabolism and glucose uptake in skeletal muscle; however, the effects of its two analogs (Ex-4 and Ex-9) on myofiber properties are still unclear. Here, we report the effects of Ex-4 and Ex-9 alone or in combination on the myosin heavy chain (MyHC) type composition and the glucose uptake capacity in differentiated C2C12 myotubes. Neither Ex-4 nor Ex-9 altered basal glucose uptake, whereas Ex-9 significantly increased insulin-stimulated glucose uptake, suggesting enhanced insulin sensitivity. The mRNA expression of MyHC I and 2A as well as the percentage of MyHC I protein was remarkably increased in Ex-9-treated myotubes. In contrast, Ex-4, alone or in combination with Ex-9, caused a significant reduction in MyHC 2A mRNA expression and the percentage of MyHC I protein. Consistent with the MyHC type switching peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α expression in myotubes was remarkably increased by Ex-9 yet was significantly inhibited by Ex-4. In addition, intracellular concentrations of free Ca(2+) were increased in all treatment groups, but only Ex-9-treated myotubes showed higher calcineurin A protein content. Taken together, our data suggest that Ex-9 promotes oxidative differentiation in myotubes to improve cell insulin sensitivity, probably through calcineurin and PGC-1α mediated pathways.

Topics: Animals; Blotting, Western; Calcineurin; Calcium; Cell Differentiation; Cell Line; Cytosol; Exenatide; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Hypoglycemic Agents; Insulin; Insulin Resistance; Mice; Muscle Fibers, Skeletal; Myoblasts; Myosin Heavy Chains; Peptide Fragments; Peptides; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Protein Isoforms; Receptors, Glucagon; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trans-Activators; Transcription Factors; Venoms

The hormonal mediators of obesity-induced insulin resistance and compensatory hyperinsulinemia in dogs have not been identified. Plasma samples were obtained after a 24-h fast from 104 client-owned lean, overweight, and obese dogs. Plasma glucose and insulin concentrations were used to calculate insulin sensitivity and β-cell function with the use of the homeostasis model assessment (HOMA(insulin sensitivity) and HOMA(β-cell function), respectively). Path analysis with multivariable linear regression was used to identify whether fasting plasma leptin, adiponectin, or glucagon-like peptide-1 concentrations were associated with adiposity, insulin sensitivity, and basal insulin secretion. None of the dogs were hyperglycemic. In the final path model, adiposity was positively associated with leptin (P < 0.01) and glucagon-like peptide-1 (P = 0.04) concentrations. No significant total effect of adiposity on adiponectin in dogs (P = 0.24) was observed. If there is a direct effect of leptin on adiponectin, then our results indicate that this is a positive relationship, which at least partly counters a negative direct relationship between adiposity and adiponectin. Fasting plasma leptin concentration was directly negatively associated with fasting insulin sensitivity (P = 0.01) and positively associated with β-cell function (P < 0.01), but no direct association was observed between adiponectin concentration and either insulin sensitivity or β-cell function (P = 0.42 and 0.11, respectively). We conclude that dogs compensate effectively for obesity-induced insulin resistance. Fasting plasma leptin concentrations appear to be associated with obesity-associated changes in insulin sensitivity and compensatory hyperinsulinemia in naturally occurring obese dogs. Adiponectin does not appear to be involved in the pathophysiology of obesity-associated changes in insulin sensitivity.

Topics: Adiponectin; Adiposity; Animals; Blood Glucose; Dog Diseases; Dogs; Fasting; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Insulin-Secreting Cells; Leptin; Obesity

The aim of this study was to investigate the effects of Roux-en-Y gastric bypass (RYGB) on glucose tolerance and insulin resistance in type 2 diabetic rats and the possible mechanisms involved in this process.. Thirty Goto-Kakizaki (GK) rats were randomly divided into three groups: RYGB operation, sham operation, and food restriction groups. Ten Wistar rats were used as non-diabetic control. The body weight and food consumption of rats were recorded 1 week before or every week after surgery. The fasting blood sugar and oral glucose tolerance test were performed using blood glucose meter. The levels of plasma insulin or glucagon-like peptide-1 (GLP-1) were evaluated by enzyme-linked immunosorbent assay. The insulin resistance was quantified using homeostasis model assessment method. The expression of GLP-1 receptor, Bcl-2, Bax, and caspase-3 was determined by Western blotting.. Our results revealed that RYGB efficiently improved both glucose tolerance and insulin resistance in GK diabetic rats by upregulating GLP-1/GLP-1R expression. In addition, GLP-1R agonist exendin-4 dose-dependently increased insulin secretion in RIN-m5F cells and regulated the proliferation and apoptosis of these cells.. RYGB provides a valuable therapeutic option for patients with type 2 diabetes. GLP-1 may contribute to the regulation of pancreatic β-cell function through its receptor following RYGB.

Topics: Animals; Blood Glucose; Blotting, Western; Body Weight; Cell Line; Diabetes Mellitus, Type 2; Eating; Enzyme-Linked Immunosorbent Assay; Exenatide; Gastric Bypass; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Peptides; Random Allocation; Rats; Rats, Wistar; Receptors, Glucagon; Venoms

Roux-en-Y-Gastric-Bypass (RYGB) reduces overall and diabetes-specific mortality by 40% and over 90%. This study aims to gain insight into the underlying mechanisms of this effect. We evaluated time-courses of glucose, insulin, C-peptide, and the incretin glucagon like peptide-1 (GLP-1) following an oral glucose load. Insulin-sensitivity was measured by a hyperinsulinemic-isoglycemic-clamp-test; glucose-turnover was determined using D-[6,6-(2)H(2)] glucose. Examinations were performed in six nondiabetic patients with excess weight before (PRE: BMI: 49.3 ± 3.2 kg/m(2)) and 7 months after RYGB (POST: BMI: 36.7 ± 2.9 kg/m(2)), in a lean (CON: BMI: 22.6 ± 0.6 kg/m(2)) and an obese control group (CONob) without history of gastrointestinal surgery (BMI: 34.7 ± 1.2 kg/m(2)). RYGB reduced fasting plasma concentrations of insulin and C-peptide (P < 0.01, respectively) whereas fasting glucose concentrations remained unchanged. After RYGB increase of C-peptide concentration following glucose ingestion was significantly higher compared to all other groups (dynamic-area under the curve (Dyn-AUC): 0-90 min: POST: 984 ± 115 ng·min/ml, PRE: 590 ± 67 ng·min/ml, CONob: 440 ± 44 ng·min/ml, CON: 279 ± 22 ng·min/ml, P < 0.01 respectively). Early postprandial increase of glucose concentration was however not affected. GLP-1 concentrations following glucose ingestion were sixfold higher after RYBG than before (P = 0.01). Insulin-stimulated glucose uptake tended to increase postoperatively (M-value: PRE: 1.8 ± 0.5, POST: 3.0 ± 0.3, not significant (n.s.)). Endogenous glucose production (EGP) was unaffected by RYGB. Hepatic insulin resistance index improved after RYGB and was then comparable to both control groups (PRE: 29.2 ± 4.3, POST: 12.6 ± 1.1, P < 0.01). RYGB results in hyper-secretion of insulin and C-peptide, whereas improvements of insulin resistance are minor and seem to occur rather in the liver and the adipose tissue than in the skeletal muscle.

Topics: Adult; Blood Glucose; Body Mass Index; C-Reactive Protein; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Obesity, Morbid; Postprandial Period

The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1(28-36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome.. Three- to 11-week infusions of GLP-1(28-36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28-36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP-1(28-36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25-70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight.. GLP-1(28-36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome.

Topics: Animals; Diabetes Mellitus, Type 2; Dietary Fats; Eating; Fatty Liver; Glucagon-Like Peptide 1; Hyperglycemia; Hyperinsulinism; Insulin Resistance; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Peptide Fragments; Triglycerides; Weight Gain

A 22 year old obese woman with type 1 diabetes for 17 years and poor metabolic control despite continuous insulin infusion (case 1). Case 2 was a 16 year-old girl of normal weight in whom diabetes mellitus type 1 was diagnosed accidentally. Her 54 year old father was and had been treated for diabetes mellitus type 1 for 10 years. He was poorly controlled and associated with polyneuropathy and history of myocardial infarction (case 3).. In Case 1 the C-peptide test was negative, glutamic acid decarboxylase- and IA2-antibodies were not demonstrated. Cases 2 and 3 showed normal C-peptide, tests for GAD-, IA2- and ICA antibodies were negative. A nucleotid substitution in intron 1 of the HNF-4α gene was demonstrated.. All three patients were treated with liraglutide. There was a reduction in HbA(1c), glucose fluctuations, hypoglycaemia, daily insulin dose and body weight, as well as an improvement of well-being and quality of life.. These case reports indicate that GLP-1 analogs may reduce postprandial and fasting glucose levels in non-type 2 diabetic patients, independently or residual beta cell function. Further studies are needed to evaluate the benefits of treatment with liraglutide in patients with type 1 or type 3 diabetes.

Topics: Adolescent; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Drug Therapy, Combination; Female; Genetic Predisposition to Disease; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidental Findings; Insulin; Insulin Resistance; Liraglutide; Male; Middle Aged; Young Adult

Weight-loss independent mechanisms may play an important role in the improvement of glucose homeostasis after Roux-en-Y gastric bypass (RYGB). The objective of this analysis was to determine whether RYGB causes greater improvement in glucostatic parameters as compared with laparoscopic adjustable gastric banding (LAGB) or low calorie diet (LCD) after equivalent weight loss and independent of enteral nutrient passage. Study 1 recruited participants without type 2 diabetes mellitus (T2DM) who underwent LAGB (n = 8) or RYGB (n = 9). Study 2 recruited subjects with T2DM who underwent LCD (n = 7) or RYGB (n = 7). Insulin-supplemented frequently-sampled intravenous glucose tolerance test (fsIVGTT) was performed before and after equivalent weight reduction. MINMOD analysis of insulin sensitivity (Si), acute insulin response to glucose (AIRg) and C-peptide (ACPRg) response to glucose, and insulin secretion normalized to the degree of insulin resistance (disposition index (DI)) were analyzed. Weight loss was comparable in all groups (7.8 ± 0.4%). In Study 1, significant improvement of Si, ACPRg, and DI were observed only after LAGB. In Study 2, Si, ACPRg, and plasma adiponectin increased significantly in the RYGB-DM group but not in LCD. DI improved in both T2DM groups, but the absolute increase was greater after RYGB (258.2 ± 86.6 vs. 55.9 ± 19.9; P < 0.05). Antidiabetic medications were discontinued after RYGB contrasting with 55% reduction in the number of medications after LCD. No intervention affected fasting glucagon-like peptide (GLP)-1, peptide YY (PYY) or ghrelin levels. In conclusion, RYGB produced greater improvement in Si and DI compared with diet at equivalent weight loss in T2DM subjects. Such a beneficial effect was not observed in nondiabetic subjects at this early time-point.

Topics: Adiponectin; Adult; Blood Glucose; C-Peptide; Caloric Restriction; Diabetes Mellitus, Type 2; Diet, Reducing; Female; Gastric Bypass; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Laparoscopy; Male; Middle Aged; Obesity; Peptide YY; Weight Loss

The aim of this study was to evaluate the possible role of sleeve gastrectomy (SG) per se in the reversibility of diabetes.. Insulin secretion and peripheral insulin sensitivity using the intravenous glucose tolerance test (IVGTT) were assessed in 18 obese type 2 diabetic patients and in 10 nondiabetic obese patients before and 3 days after SG, before any food intake and any weight change occurrence. At the same time, ghrelin, GLP-1, and PYY levels were determined.. In diabetic patients who had the disease less than 10.5 years, the first phase of insulin secretion promptly improved after SG. The early insulin area under the curve (AUC) significantly increased at the postoperative IVGTT, indicating an increased glucose-induced insulin secretion. The second phase of insulin secretion (late AUC) significantly decreased after SG in all groups, indicating an improved insulin peripheral sensitivity. In all groups, pre- and postoperatively, intravenous glucose stimulation determined a decrease in ghrelin values and an increase in GLP-1 and PYY values. However, in the group of patients with disease duration >10.5 years, the differences were not significant except for the late insulin AUC. Postoperative basal and intravenous glucose-stimulated ghrelin levels were lower than preoperative levels in all groups of patients. Basal and intravenous stimulated GLP-1 and PYY postoperative values were higher than preoperative levels in all groups.. Restoration of the first phase of insulin secretion and improved insulin sensitivity in diabetic obese patients immediately after SG, before any food passage through the gastrointestinal tract and before any weight loss, seem to be related to ghrelin, GLP-1, and PYY hormonal changes of possible gastric origin and was neither meal- nor weight-change-related. Duration of the disease up to 10.5 years seems to be a major cut off in the pathophysiological changes induced by SG. A "gastric" hypothesis may be put forward to explain the antidiabetes effect of SG.

Topics: Diabetes Mellitus, Type 2; Female; Gastrectomy; Ghrelin; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Peptide YY

Dietary prebiotics show potential in anti-diabetes. Dietary resistant starch (RS) has a favorable impact on gut hormone profiles, including glucagon-like peptide-1 (GLP-1) consistently released, a potent anti-diabetic incretin. Also RS reduced body fat and improved glucose tolerance in rats and mice. In the current project, we hypothesize that dietary-resistant starch can improve insulin sensitivity and pancreatic β cell mass in a type 2 diabetic rat model. Altered gut fermentation and microbiota are the initial mechanisms, and enhancement in serum GLP-1 is the secondary mechanism.. In this study, GK rats were fed an RS diet with 30% RS and an energy control diet. After 10 wk, these rats were mated and went through pregnancy and lactation. At the end of the study, pancreatic β cell mass, insulin sensitivity, pancreatic insulin content, total GLP-1 levels, cecal short-chain fatty acid concentrations and butyrate producing bacteria in cecal contents were greatly improved by RS feeding. The offspring of RS-fed dams showed improved fasting glucose levels and normal growth curves.. Dietary RS is potentially of great therapeutic importance in the treatment of diabetes and improvement in outcomes of pregnancy complicated by diabetes.

Topics: Animals; Animals, Newborn; Blood Glucose; Body Weight; Butyrates; Cecum; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Fatty Acids, Volatile; Female; Glucagon-Like Peptide 1; Hydrogen-Ion Concentration; Hyperglycemia; Insulin Resistance; Insulin-Secreting Cells; Intestinal Mucosa; Ion Channels; Mitochondrial Proteins; Pregnancy; Pregnancy in Diabetics; Rats; Starch; Uncoupling Protein 1

It has been demonstrated that biliopancreatic diversion (BPD) and ileal transposition (IT) effectively induce weight loss and long-term control of type 2 diabetes in morbidly obese individuals. It is unknown whether the control of diabetes is better after IT or after BPD. The objective of this study was to investigate the effects of IT and BPD on the control of diabetes in an animal model.. We performed IT and BPD on 10- to 12-week-old Goto-Kakizaki rats with a spontaneous nonobese model of type 2 diabetes, and we performed a series of detection. The rats were observed for 24 weeks after surgery.. Animals who underwent IT and BPD demonstrated improved glucose tolerance, insulin sensitivity and the secretion of glucagon-like peptide-1 compared with the sham-operated animals. Furthermore, IT resulted in a shorter duration of surgery and better postoperative recovery than BPD.. This study provides strong evidence for the crucial role of the hindgut in the resolution of diabetes after duodenum-jejunum bypass or IT. We confirmed that IT was associated with better postoperative recovery than BPD and had a similar control of diabetes as BPD in nonobese animals with type 2 diabetes.

Topics: Anastomosis, Surgical; Animals; Biliopancreatic Diversion; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Ileum; Insulin Resistance; Male; Rats

The atypical antipsychotic drug olanzapine induces weight gain and defects in glucose metabolism in patients. Using a rat model we investigated the effects of acute and long term olanzapine treatment on weight gain, food preference and glucose metabolism. Olanzapine treated rats fed a chow diet grew more slowly than vehicle controls but olanzapine treated animals fed a high fat/sugar diet grew faster than control animals on the same diet. These changes in weight were paralleled by changes in fat mass. Olanzapine also induced a strong preference for a high fat/high sugar diet. Acute exposure to olanzapine rapidly induced severe impairments of glucose tolerance and increased insulin secretion but did not impair insulin tolerance. These results indicate the defect in glucose metabolism induced by acute olanzapine treatment was most likely due to increased hepatic glucose output associated with a reduction in active GLP-1 levels and correspondingly high glucagon levels.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Diet, High-Fat; Food Preferences; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Liver; Male; Obesity; Olanzapine; Rats; Schizophrenia; Weight Gain

Skeletal muscle is a key tissue site of insulin resistance in type 2 diabetes. Human myotubes are primary skeletal muscle cells displaying both morphological and biochemical characteristics of mature skeletal muscle and the diabetic phenotype is conserved in myotubes derived from subjects with type 2 diabetes. Several abnormalities have been identified in skeletal muscle from type 2 diabetic subjects, however, the exact molecular mechanisms leading to the diabetic phenotype has still not been found. Here we present a large-scale study in which we combine a quantitative proteomic discovery strategy using isobaric peptide tags for relative and absolute quantification (iTRAQ) and a label-free study with a targeted quantitative proteomic approach using selected reaction monitoring to identify, quantify, and validate changes in protein abundance among human myotubes obtained from nondiabetic lean, nondiabetic obese, and type 2 diabetic subjects, respectively. Using an optimized protein precipitation protocol, a total of 2832 unique proteins were identified and quantified using the iTRAQ strategy. Despite a clear diabetic phenotype in diabetic myotubes, the majority of the proteins identified in this study did not exhibit significant abundance changes across the patient groups. Proteins from all major pathways known to be important in type 2 diabetic subjects were well-characterized in this study. This included pathways like the trichloroacetic acid (TCA) cycle, lipid oxidation, oxidative phosphorylation, the glycolytic pathway, and glycogen metabolism from which all but two enzymes were found in the present study. None of these enzymes were found to be regulated at the level of protein expression or degradation supporting the hypothesis that these pathways are regulated at the level of post-translational modification. Twelve proteins were, however, differentially expressed among the three different groups. Thirty-six proteins were chosen for further analysis and validation using selected reaction monitoring based on the regulation identified in the iTRAQ discovery study. The abundance of adenosine deaminase was considerably down-regulated in diabetic myotubes and as the protein binds propyl dipeptidase (DPP-IV), we speculate whether the reduced binding of adenosine deaminase to DPP-IV may contribute to the diabetic phenotype in vivo by leading to a higher level of free DPP-IV to bind and inactivate the anti-diabetic hormones, glucagon-like peptide-1 and glucos

Topics: Adenosine Deaminase; Body Mass Index; Case-Control Studies; Cells, Cultured; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Down-Regulation; Energy Metabolism; Gastric Inhibitory Polypeptide; Gene Expression; Gene Expression Profiling; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Middle Aged; Muscle Fibers, Skeletal; Obesity; Protein Binding; Proteomics; Thinness

Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG.. Rats underwent RYGB or VSG and were compared to sham-operated rats fed ad lib or pair-fed to animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function independent of incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance test was used to assess the effect of each surgery on postprandial release of glucagon-like peptide 1 (GLP-1)(7-36) and glucose tolerance, and was also performed in rats given GLP-1 receptor antagonist exendin(9-39).. Following RYGB or VSG, glucose tolerance and insulin sensitivity improved in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7-36) and insulin were greatly and comparably increased in rats that received RYGB and VSG compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG.. In obese rats, VSG is as effective as RYGB for increasing secretion of GLP-1 and insulin and improving hepatic sensitivity to insulin; these effects are independent of weight loss.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Disease Models, Animal; Eating; Gastrectomy; Gastric Bypass; Glucagon-Like Peptide 1; Homeostasis; Insulin; Insulin Resistance; Male; Obesity; Postprandial Period; Rats; Rats, Long-Evans; Stomach

Liraglutide is a glucagonlike peptide (GLP)-1 analog that reduces blood glucose levels, increases insulin secretion and improves insulin sensitivity through mechanisms that are not completely understood. Therefore, we aimed to evaluate the metabolic impact and underlying mechanisms of liraglutide in a hypoadiponectinemia and high-fat diet (HFD)-induced insulin resistance (IR) model. Adiponectin gene targeting was achieved using adenovirus-transduced RNAi and was used to lower plasma adiponectin levels. Liraglutide (1 mg/kg) was given twice daily for 8 wks to HFD-fed apolipoprotein (Apo)E⁻/⁻ mice. Insulin sensitivity was examined by a hyperinsulinemic-euglycemic clamp. Gene mRNA and protein expressions were measured by quantitative real-time polymerase chain reaction (PCR) and Western blot, respectively. Administration of liraglutide prevented hypoadiponectinemia-induced increases in plasma insulin, free fatty acids, triglycerides and total cholesterol. Liraglutide also attenuated hypoadiponectinemia-induced deterioration in peripheral and hepatic insulin sensitivity and alterations in key regulatory factors implicated in glucose and lipid metabolism. These findings demonstrated for the first time that liraglutide could be used to rescue IR induced by hypoadiponectinemia and HFD via regulating gene and protein expression involved in glucose and lipid metabolism.

Topics: 3T3-L1 Cells; Adiponectin; Animals; Blotting, Western; Cholesterol; Gene Expression Regulation; Gene Knockdown Techniques; Gene Silencing; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Hyperinsulinism; Insulin Resistance; Lipid Metabolism; Liraglutide; Liver; Male; Mice; Real-Time Polymerase Chain Reaction; Triglycerides

The eating disorder bulimia nervosa (BN) is characterized by frequent episodes of binge eating, followed regularly by inappropriate compensatory behavior, such as self-induced vomiting.. The current investigation was designed to examine possible alterations in the secretion of the gastrointestinal satiety peptides glucagon-like peptide 1 (GLP-1) and pancreatic polypeptide (PP) in women with BN.. Twenty-one women with BN and 17 healthy control subjects of comparable age and BMI were recruited. After fasting overnight, the subjects provided blood samples during ingestion of a standardized meal and self-rated their appetite on a visual analog scale. Fasting and meal-related secretion of the incretin GLP-1 and the meal-related feedback signal PP and insulin and glucose as indicators of the metabolic homeostasis were analyzed.. Women with BN had significantly lower fasting and postprandial serum concentrations of GLP-1 (P < 0.01) and PP (P < 0.05) than did the control subjects. Furthermore, both the basal (P < 0.001) and peak (P < 0.05) concentrations of insulin were significantly attenuated in the bulimic subjects, whereas glucose concentrations were normal. As a consequence, the bulimic homeostasis model assessment of insulin index values were also lower (P < 0.001).. Women with BN secrete abnormally low amounts of GLP-1 and PP, possibly because of the adaption to large meals in the form of enlarged gastric capacity and reduced muscle tone in the gastric wall. Attenuated secretion of these gastrointestinal satiety peptides may play a role in the maintenance of bulimic behavior.

Topics: Adult; Appetite Regulation; Body Mass Index; Bulimia Nervosa; Female; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Pancreatic Polypeptide; Postprandial Period; Protein Precursors; Sweden; Time Factors; Young Adult

The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits.. GCG was re-sequenced as a candidate gene in 865 European individuals. Twenty-nine variants were identified. Four variants that were considered to have a likelihood for altered functionality: rs4664447, rs7581952, Ile158Val and Trp169Ter, were genotyped in 17,584 Danes.. When examined in 5,760 treatment-naive individuals, homozygous carriers of the low frequency (minor allele frequency 2.3%) G allele of rs4664447, predicted to disrupt an essential splice enhancer binding site, had lower levels of fasting plasma glucose (mean ± SD, 4.8 ± 1.2 vs 5.5 ± 0.8 mmol/l, p = 0.004); fasting serum insulin (22 ± 14 vs 42 ± 27 pmol/l, p = 0.04); glucose-stimulated serum insulin (159 ± 83 vs 290 ± 183 pmol/l, p = 0.01) and adult height (165 ± 10 vs 172 ± 9 cm, p = 0.0009) compared with A allele carriers. During oral glucose tolerance and hyperglycaemic arginine stimulation tests, the plasma AUC for GLP-1 (730 ± 69 vs 1,334 ± 288 pmol/l × min, p = 0.0002) and basal and stimulated levels of serum insulin and plasma glucagon were ∼50% decreased (p < 0.001) among three homozygous carriers compared with nine matched wild-type carriers. rs7581952, Ile158Val and Trp169Ter (where 'Ter' indicates 'termination') variants of GCG did not significantly associate or co-segregate with the metabolic traits examined.. Re-sequencing of GCG revealed a low frequency intronic variant, rs4664447, and follow-up physiological studies suggest that this variant in homozygous form may cause decreased fasting and stimulated levels of insulin, glucagon and GLP-1. Overall, our findings suggest that variation in GCG has no major impact on carbohydrate metabolism in the study populations examined.

Topics: Adolescent; Adult; Age of Onset; Aged; Case-Control Studies; Child; Child, Preschool; Czechoslovakia; Denmark; Diabetes Mellitus, Type 2; Europe; Female; Genetic Association Studies; Glucagon; Glucagon-Like Peptide 1; Homozygote; Humans; Infant; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Obesity; Polymorphism, Single Nucleotide

The increase in glucagon-like peptide-1 (GLP-1) activity has emerged as a useful therapeutic tool for the treatment of type 2 diabetes mellitus. The actions of GLP-1 on β-cells and the nervous and digestive systems are well known. The action of this peptide in adipose tissue (AT), however, is still poorly defined. Furthermore, no relationship has been established between GLP-1 receptor (GLP-1R) in AT and obesity and insulin resistance (IR). We provide evidence for the presence of this receptor in AT and show that its mRNA and protein expressions are increased in visceral adipose depots from morbidly obese patients with a high degree of IR. Experiments with the 3T3-L1 cell line showed the lipolytic and lipogenic dose-dependent effect of GLP-1. Moreover, GLP-1 stimulated lipolysis in 3T3-L1 adipocytes in a receptor-dependent manner involving downstream adenylate cyclase/cAMP signaling. Our data also demonstrate that the expression of the GLP-1R in AT correlated positively with the homeostasis model assessment index in obese IR subjects. Furthermore, prospective studies carried out with patients that underwent biliopancreatic diversion surgery showed that subjects with high levels of GLP-1R expression in AT, which indicates a deficit of GLP-1 in this tissue, were those whose insulin sensitivity improved after surgery, suggesting the potential relationship between AT GLP-1R and insulin sensitivity amelioration in obese subjects. Altogether these results indicate that the GLP-1/GLP-1R system in AT represents another potential candidate for improving insulin sensitivity in obese patients.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Cells, Cultured; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Insulin Resistance; Mice; Obesity, Morbid; Prospective Studies; Receptors, Glucagon

Poor control of glucose homeostasis accounts for diabetes-related bone loss. Incretins - GLP-1 and GIP - have been proposed to affect bone turnover. GLP-1, apart from its anti-diabetic and other actions, has shown to exert a bone anabolic effect in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rats. Exendin-4 (Ex-4), a peptide of non-mammalian nature, is sharing with GLP-1 part of its structural sequence, and also several glucoregulatory effects in mammals in an even more efficient manner. We have explored the effect of continuous administration (3 days by osmotic pump) of Ex-4 or saline (control) on bone turnover factors and bone structure in T2D and IR rats, compared to N, and the possible interaction of Ex-4 with the Wnt signalling pathway. Blood was taken before and after treatment for plasma measurements; tibiae and femurs were collected for gene expression of bone markers (RT-PCR) and structure (microCT) analysis; we also measured the mRNA levels of LRP5 - an activator of the Wnt pathway - and those of DKK1 and sclerostin (SOST) - both blockers of LRP5 activity. Compared to N-control, plasma glucose and insulin were respectively higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b (TRAP5b) were lower; after Ex-4, these turnover markers were further reduced in T2D and IR, while TRAP5b increased in N. Bone OC, osteoprogeterin (OPG) and receptor activator of NF-kB ligand (RANKL) mRNA were lower in T2D and IR; Ex-4 increased OC in all groups and OPG in N and IR, reduced RANKL in N and T2D but increased it in IR; the LRP5/DKK1 and LRP5/SOST mRNA ratios were similarly decreased in T2D, but in IR, the latter ratio was reduced while the former was increased; after Ex-4, both ratios augmented in N, and that of LRP5/DKK1 tended to normalize in T2D and IR. In conclusion, Ex-4 exerts osteogenic effects in T2D and IR models, and interacts with the Wnt pathway to promote bone formation.

Topics: Animals; Blood Glucose; Bone Morphogenetic Proteins; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exenatide; Fructose; Gastric Inhibitory Polypeptide; Genetic Markers; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Male; Osteocalcin; Osteogenesis; Osteoporosis; Peptides; Rats; Rats, Wistar; Sweetening Agents; Venoms; Wnt Proteins

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are cleaved by dipeptidyl peptidase-4 (DPP-4); plasma activity of DPP-4 may be increased in obesity. The impact of this increase on incretin hormone secretion and metabolism is not known.. The aim of the study was to assess incretin hormone secretion and degradation in lean and obese nondiabetic subjects.. We studied the ingestion of a mixed meal (560 kcal) or oral glucose (2 g/kg) in healthy lean (n = 12; body mass index, 20-25 kg/m(2)) or obese (n = 13; body mass index, 30-35 kg/m(2)) males at a University Clinical Research Unit.. We measured the area under the curve of plasma intact (i) and total (t) GIP and GLP-1 after meal ingestion and oral glucose.. Plasma DPP-4 activity was higher in the obese subjects (38.5 +/- 3.0 vs. 26.7 +/- 1.6 mmol/min . microl; P = 0.002). Although GIP secretion (AUC(tGIP)) was not reduced in obese subjects after meal ingestion or oral glucose, AUC(iGIP) was lower in obese subjects (8.5 +/- 0.6 vs. 12.7 +/- 0.9 nmol/liter x 300 min; P < 0.001) after meal ingestion. GLP-1 secretion (AUC(tGLP-1)) was reduced in obese subjects after both meal ingestion (7.3 +/- 0.9 vs. 10.0 +/- 0.6 nmol/liter x 300 min; P = 0.022) and oral glucose (6.6 +/- 0.8 vs. 9.6 +/- 1.1 nmol/liter x 180 min; P = 0.035). iGLP-1 was reduced in parallel to tGLP-1.. 1) Release and degradation of the two incretin hormones show dissociated changes in obesity: GLP-1 but not GIP secretion is lower after meal ingestion and oral glucose, whereas GIP but not GLP-1 metabolism is increased after meal ingestion. 2) Increased plasma DPP-4 activity in obesity is not associated with a generalized augmented incretin hormone metabolism.

Topics: Acetaminophen; Adult; Area Under Curve; Dipeptidyl Peptidase 4; Food; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Insulin Resistance; Male; Obesity; Thinness; Young Adult

Bile acid sequestrants have been shown to lower glucose levels in patients with type 2 diabetes. To investigate how colesevelam (CL) HCl improves hyperglycemia, studies were conducted in diet-induced obesity (F-DIO) rats, which develop insulin resistance when fed a high-energy (high fat/high sucrose) diet (HE). The rats were fed HE; HE + 2% CL; HE + 0.02% SC-435 (SC), an apical sodium-dependent bile acid transporter inhibitor; and regular chow (controls). After 4 wk of treatment, both in the HE group and the SC + HE group, plasma glucose and insulin levels remained elevated compared with baseline values throughout an oral glucose tolerance test (OGTT). In contrast, in the CL + HE group, plasma glucose levels returned to baseline by the end of the test, and insulin peaked in 15-30 min and then returned to baseline. CL induced release of glucagon-like peptide-1 (GLP-1) because the area under the curve of plasma total GLP-1 in the CL + HE group was significantly greater than in the HE group during the OGTT. Bile acid concentrations in the portal blood did not decrease in the HE group but declined significantly both in the CL + HE and SC + HE groups with reduced farnesoid X receptor activation compared with controls. We concluded that CL reduces plasma glucose levels by improving insulin resistance in this rat model. It is unlikely that the improvement is attributable to decreased bile acid flux to the liver but is likely secondary to induced GLP-1 secretion, which improves insulin release.

Topics: Allylamine; Animals; Anticholesteremic Agents; Bile Acids and Salts; Blood Glucose; Body Weight; Carrier Proteins; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Colesevelam Hydrochloride; Cyclic N-Oxides; Dietary Carbohydrates; Dietary Fats; Gene Expression; Glucagon-Like Peptide 1; Glucose Tolerance Test; Ileum; Insulin; Insulin Resistance; Liver; Male; Membrane Glycoproteins; Obesity; Organic Anion Transporters, Sodium-Dependent; Portal Vein; Rats; Rats, Inbred F344; Receptors, Cytoplasmic and Nuclear; Symporters; Triglycerides; Tropanes

Exendin-4 (Ex-4), a peptide secreted from the salivary glands of the Gila monster lizard, can increase pancreatic beta-cell growth and insulin secretion by activating glucagon-like peptide-1 receptor. In this study, we expressed a fusion protein consisting of exendin-4 and the human immunoglobulin heavy chain (Ex-4/IgG-Fc) in E. coli and explored its potential therapeutic use for the treatment of insulin-resistant type 2 diabetes. Here, we show that the Ex-4/IgG-Fc fusion protein induces expression of insulin receptor substrate-2 in rat insulinoma INS-1 cells. Our findings therefore suggest that Ex-4/IgG-Fc overexpressed in E. coli could be used as a potential, long-acting glucagon-like peptide-1 mimetic.

Topics: Animals; Cell Line, Tumor; Diabetes Mellitus, Type 2; Escherichia coli; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Immunoglobulin Heavy Chains; Insulin Receptor Substrate Proteins; Insulin Resistance; Peptides; Rats; Receptors, Glucagon; Recombinant Fusion Proteins; Venoms

The loss of incretin effect in patients with type 2 diabetes mellitus may be secondary to impaired glucose homeostasis. We investigated whether reduced glucose tolerance and insulin resistance induced by steroid treatment, relative physical inactivity, and high-calorie diet in healthy young males would impair the incretin effect.. The incretin effect was measured using 75 g oral glucose tolerance test (OGTT) and isoglycemic iv glucose infusion (IIGI) in 10 healthy Caucasian normal glucose-tolerant male subjects without any family history of diabetes [age 24 + or - 3 yr (mean + or - sd); body mass index 23 + or - 2 kg/m(2); glycosylated hemoglobin 5.4 + or - 0.1%] before and at the end of a 12-d period with oral administration of prednisolone (37.5 mg once daily), high-calorie diet, and relative physical inactivity.. The 12-d intervention period resulted in significant increases in body weight [79 + or - 5 vs. 80 + or - 6 kg (mean + or - sd), P = 0.03] and fasting plasma glucose (5.1 + or - 0.1 vs. 5.6 + or - 0.2 mm, P = 0.016), whereas insulin sensitivity (Matsuda index 17.6 + or - 1.7 vs. 9.2 + or - 1.0, P = 0.0001) decreased. Glucose tolerance [as assessed by the 120-min plasma glucose value after OGTT (4.9 + or - 1.1 vs. 7.8 + or - 2.5 mm, P < 0.0001) and area under curve (AUC) (152 + or - 45 vs. 384 + or - 53 mm.4 h, P = 0.002)] during the OGTT deteriorated. Also, the incretin effect [incretin effect (percent) = 100% x (AUC(insulin,OGTT) - AUC(insulin,IIGI))/AUC(insulin,OGTT))] deteriorated (72 + or - 5 vs. 43 + or - 7%, P = 0.002). An increase in glucose-dependent insulinotropic polypeptide response during OGTT, but no significant changes in glucagon-like peptide-1 or glucagon responses, was observed after glucose homeostatic dysregulation.. Impairment of the incretin effect can be elicited by a short period of reduced glucose tolerance and insulin resistance in healthy male subjects not disposed for type 2 diabetes.

Topics: Adult; Area Under Curve; Blood Glucose; Body Weight; C-Peptide; Diet; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Male; Motor Activity; Prednisolone

Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic beta-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.

Topics: Animals; Blood Glucose; Cholestyramine Resin; Diabetes Mellitus, Experimental; Gene Expression; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Insulin Resistance; Intestinal Mucosa; Liver; Liver X Receptors; Male; Obesity; Orphan Nuclear Receptors; Peptide YY; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.. To examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).. Fasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.. Circulating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Chi-Square Distribution; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Resistance; Japan; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Obesity, Abdominal; Odds Ratio; Risk Assessment; Risk Factors; Triglycerides; Up-Regulation; Uric Acid; Waist Circumference

The availability of useful animal models reflecting the human obesity syndrome is crucial in the search for novel compounds for the pharmacological treatment of obesity. In the current study, we have performed an extensive characterization of the obesity syndrome in a polygenetic animal model, namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome. DIO and DR rats were fed either a high-energy (HE) or a standard chow (Chow) diet from weaning to 9 months of age. Metabolic characterization including blood biochemistry and glucose homeostasis was examined at 2, 3, 6, and 9 months of age. Furthermore, in 6-month-old HE-fed DIO rats, the anti-obesity effects of liraglutide and sibutramine were examined in a 28-day study. Only HE-fed DIO rats developed visceral obesity, hyperleptinemia, hyperinsulinemia, and dyslipidemia, and showed a worsening of glucose tolerance over time. In line with the hyperlipidemic profile, a severe hepatic fat infiltration was observed in DIO rats at 6 months of age. The effects of liraglutide and sibutramine were tested in 6-month-old DIO rats. Both compounds effectively reduced food intake and body weight in DIO rats. Liraglutide furthermore improved glucose tolerance when compared with sibutramine. Our data highlights the usefulness of a polygenetic animal model for screening of compounds affecting food intake, body weight, and glucose homeostasis. Furthermore, the results underscore the effectiveness of GLP-1 mimetics both as anti-diabetes and anti-obesity agents.

Topics: Analysis of Variance; Animals; Appetite Depressants; Blood Glucose; Cyclobutanes; Diet; Disease Models, Animal; Eating; Enzyme-Linked Immunosorbent Assay; Feeding Behavior; Glucagon-Like Peptide 1; Insulin; Insulin Resistance; Leptin; Liraglutide; Metabolic Syndrome; Obesity; Rats; Rats, Sprague-Dawley

Glucagon-like peptide-1 (GLP-1) improves insulin sensitivity in humans and rodents. It is currently unknown to what extent the (metabolic) effects of GLP-1 treatment are mediated by central GLP-1 receptors. We studied the impact of central GLP-1 receptor (GLP-1R) antagonism on the metabolic effects of peripheral GLP-1 administration in mice. High-fat-fed insulin-resistant C57Bl/6 mice were treated with continuous subcutaneous infusion of GLP-1 or saline (PBS) for 2 wk, whereas the GLP-1R antagonist exendin-9 (EX-9) and cerebrospinal fluid (CSF) were simultaneously infused in the left lateral cerebral ventricle (icv). Glucose and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp. VLDL-triglyceride (VLDL-TG) production was determined in hyperinsulinemic conditions. Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by GLP-1. Simultaneous icv infusion of EX-9 diminished this effect by 62%. The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by GLP-1. Simultaneous icv infusion of EX-9 significantly diminished the latter effect. Central GLP-1R antagonism alone did not affect glucose metabolism. Also, GLP-1 treatment reinforced the inhibitory action of insulin on VLDL-TG production. In conclusion, peripheral administration of GLP-1 reinforces the ability of insulin to suppress endogenous glucose and VLDL-TG production (but not lipolysis) and boosts its capacity to stimulate glucose disposal in high-fat-fed C57Bl/6 mice. Activation of central GLP-1Rs contributes substantially to the inhibition of endogenous glucose production by GLP-1 treatment in this animal model.

Topics: Animals; Blood Glucose; Body Weight; Cerebral Ventricle Neoplasms; Dietary Fats; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Clamp Technique; Hyperinsulinism; Insulin; Insulin Resistance; Lipoproteins, VLDL; Male; Mice; Mice, Inbred C57BL; Receptors, Glucagon; Triglycerides

Activation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats.. DSS rats were fed low salt (LS, 0.3% NaCl) or high salt (HS, 8% NaCl) diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min), or GLP-1 (25 pmol/kg/min) for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day) or AC3174 plus captopril.. HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP) was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p < 0.05). AC3174 plus captopril attenuated the deleterious effects of high salt on posterior wall thickness, LV mass, and the ratio of LV mass to body weight (P < or = 0.05). In contrast, GLP-1 had no effect on these cardiovascular parameters. All treatments reduced LV wall stress. GLP-1, AC3174, captopril, or AC3174 plus captopril normalized fasting insulin and HOMA-IR (P < or = 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P < or = 0.05). Renal morphology in HS rats was associated with extensive sclerosis. Monotherapy with AC3174, captopril, or GLP-1 attenuated renal damage. However, AC3174 plus captopril produced the most effective improvement.. Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Captopril; Cardiotonic Agents; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Hyperglycemia; Hypertension, Renal; Hypoglycemic Agents; Insulin Resistance; Kidney Diseases; Male; Peptides; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Venoms

Extensive experience from randomized clinical trials demonstrates the efficacy of GLP-1 agonists and DPP-4 inhibitors as monotherapy and in combination with metformin and other agents, although reductions in FPG and PPG, and consequently A1C, are greater with GLP-1 agonists than with DPP-4 inhibitors. This difference may result from the pharmacologic levels of GLP-1 activity that are achieved with the GLP-1 agonists and their direct action on the GLP-1 receptor. The GLP-1 agonists have attributes that would make either of them an appropriate choice in the management of all 3 patients in our case studies, while either DPP-4 inhibitor would be an appropriate choice for Case 1. Differences in dosing, administration, safety, and tolerability should be considered.

Topics: Adamantane; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Liraglutide; Male; Metformin; Middle Aged; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Topics: Adamantane; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Liraglutide; Male; Metformin; Middle Aged; Patient Education as Topic; Peptides; Pyrazines; Receptors, Glucagon; Self Care; Sitagliptin Phosphate; Triazoles; Venoms

The "treat to target" approach is to quickly achieve the target glycosylated hemoglobin (AIC) goal of <7% in most people, and then intensify or change therapy as needed to maintain glycemic control. Results of an online survey demonstrate uncertainty regarding the clinical differences between glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase (DPP)-4 inhibitors. The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liraglutide; Metformin; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms

Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic which is a treatment option for type 2 diabetes. GLP-1 peptides, including Liraglutide, cross the blood-brain barrier and may additionally act to improve brain function. The present study tested the hypothesis that, in addition to its antihyperglycaemic actions, peripheral administration of Liraglutide exerts positive actions on cognitive function in mice with high fat dietary-induced obesity and insulin resistance.. Young Swiss TO mice maintained on high fat diet for 20 weeks received twice-daily injections of Liraglutide (200 µg/kg bw; sc) or saline vehicle over 28 days. An additional group of mice on standard diet received twice-daily saline injections. Energy intake, bodyweight, non-fasting plasma glucose and insulin concentrations were monitored at regular intervals. Glucose tolerance, open field assessment, object recognition testing and electrophysiological long-term potentiation (LTP) were performed at termination of the study.. Liraglutide treatment resulted in significant time-dependent reduction in bodyweight and energy intake, whilst improving non-fasting glucose and normalizing glucose tolerance. Although Liraglutide did not alter general behaviour, treated mice exhibited marked increase in recognition index (RI) during object recognition testing, indicative of enhanced learning and memory ability. Furthermore, Liraglutide rescued the deleterious effects of high fat diet on hippocampal LTP of neurotransmission following both chronic and direct intracerebroventricular (icv) administration.. Liraglutide administered peripherally not only improves metabolic parameters but exerts additional beneficial effects on cognitive function and hippocampal synaptic plasticity. Whether therapy with GLP-1 mimetics has similar effects in humans with type 2 diabetes needs to be established.

Topics: Animals; Blood Glucose; Cognition; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Male; Memory; Mice; Obesity

Topics: Animals; Cytokines; Docosahexaenoic Acids; Glucagon-Like Peptide 1; Humans; Inflammation Mediators; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Intestinal Mucosa; Macrophage Activation; Mice; Receptors, G-Protein-Coupled

It has been proposed that there is improvement in glucose and insulin metabolism after weight loss in patients who underwent diet restriction and bariatric surgery.. Eleven normal glucose tolerant (NGT) morbidly obese patients [body mass index (BMI), 46.1+/-2.27 g/m2] and eight abnormal glucose metabolism (AGM) obese patients (BMI, 51.20 kg/m2) were submitted to diet-restriction and bariatric surgery. Prospective study on weight loss changes, over the glucose, insulin metabolism, glucagon-like peptide-1 (GLP-1), and adiponectin levels were evaluated by oral glucose tolerance test during three periods: T1 (first evaluation), T2 (pre-surgery), and T3 (9 months after surgery).. Insulin levels improved after surgery. T1 was 131.1+/-17.60 pmol/l in the NGT group and 197.57+/-57.94 pmol/l in the AGM group, and T3 was 72.48+/-3.67 pmol/l in the NGT group and 61.2+/-9.33 pmol/l in the AGM group. The major reduction was at the first hour of the glucose load as well as fasting levels. At 9 months after surgery (T3), GLP-1 levels at 30 and 60 min had significantly increased in both groups. It was observed that the AGM group had higher levels of GLP-1 at 30 min (34.06+/-6.18 pmol/l) when compared to the NGT group (22.69+/-4.04 pmol/l). Homeostasis model assessment of insulin resistance from the NGT and AGM groups had a significant reduction at periods T3 in relation to T1 and T2. Adiponectin levels had increased concentration in both groups before and after surgical weight loss. However, it did not have any statistical difference between periods T1 vs. T2.. Weight loss by surgery leads to improvement in the metabolism of carbohydrates in relation to sensitivity to the insulin, contributing to the reduction of type 2 diabetes incidence. This improvement also was expressed by the improvement of the levels of adiponectin and GLP-1.

Topics: Adiponectin; Adult; Blood Glucose; Body Mass Index; Case-Control Studies; Cohort Studies; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Metabolism Disorders; Humans; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Treatment Outcome; Weight Loss

Insulin resistance and type 2 diabetes mellitus are associated with impaired postprandial secretion of glucagon-like peptide-1 (GLP-1), a potent insulinotropic hormone. The direct effects of insulin and insulin resistance on the L cell are unknown. We therefore hypothesized that the L cell is responsive to insulin and that insulin resistance impairs GLP-1 secretion. The effects of insulin and insulin resistance were examined in well-characterized L cell models: murine GLUTag, human NCI-H716, and fetal rat intestinal cells. MKR mice, a model of chronic hyperinsulinemia, were used to assess the function of the L cell in vivo. In all cells, insulin activated the phosphatidylinositol 3 kinase-Akt and MAPK kinase (MEK)-ERK1/2 pathways and stimulated GLP-1 secretion by up to 275 +/- 58%. Insulin resistance was induced by 24 h pretreatment with 10(-7) m insulin, causing a marked reduction in activation of Akt and ERK1/2. Furthermore, both insulin-induced GLP-1 release and secretion in response to glucose-dependent insulinotropic peptide and phorbol-12-myristate-13-acetate were significantly attenuated. Whereas inhibition of phosphatidylinositol 3 kinase with LY294002 potentiated insulin-induced GLP-1 release, secretion was abrogated by inhibiting the MEK-ERK1/2 pathway with PD98059 or by overexpression of a kinase-dead MEK1-ERK2 fusion protein. Compared with controls, MKR mice were insulin resistant and displayed significantly higher fasting plasma insulin levels. Furthermore, they had significantly higher basal GLP-1 levels but displayed impaired GLP-1 secretion after an oral glucose challenge. These findings indicate that the intestinal L cell is responsive to insulin and that insulin resistance in vitro and in vivo is associated with impaired GLP-1 secretion.

Topics: Animals; Cells, Cultured; Enteroendocrine Cells; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Male; Mice; Mice, Knockout; Pregnancy; Rats; Rats, Wistar; Receptor, IGF Type 1; Receptor, Insulin; Signal Transduction

GLP-1 and GIP are the two key incretin hormones that regulate post-prandial glucose homeostasis. Furthermore, potent enzyme-resistant GIP and GLP-1 receptor agonists such as N-AcGIP and exendin-4 have now been developed. In the present study the effects of stable incretins, exendin-4 and N-AcGIP alone and in combination were examined in mice with high fat feeding induced glucose intolerance. Daily s.c. injections of exendin-4 (50 nmol/kg bw) for 12 days restored glycaemic control and significantly (P<0.05) decreased glucose intolerance compared to saline-treated controls. Food intake was transiently decreased (P<0.05) without effect on body weight. In the following 12 day period, mice either continued the original treatment or were administered an additional dose of N-AcGIP (50 nmol/kg body weight; s.c.). Under these circumstances sub-chronic administration of exendin-4 alone or particularly when combined with N-AcGIP significantly (P<0.05) reduced body weight. Exendin-4, N-AcGIP and combined treatment groups displayed significantly (P<0.05) decreased plasma glucose levels and less severe glucose intolerance. Non-fasting 24-h glycaemic profiles revealed marked (P<0.05 to P<0.01) beneficial effects of all treatment regimes. Insulin resistance was also reduced (P<0.01 to P<0.001) in all exendin-4 treated mice compared to saline controls. Adipose tissue mRNA levels of adiponectin, leptin, resistin, GIP-R, LPL and DGAT-1 were not significantly altered. These results illustrate efficacy of enzyme resistant GIP and GLP-1 analogues for treatment of glucose intolerance induced by high fat feeding.

Topics: Animals; Body Weight; Diabetes Mellitus, Experimental; Dietary Fats; Eating; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin Resistance; Mice; Peptides; Receptors, Gastrointestinal Hormone; Venoms

Mice are increasingly used in studies where measuring insulin sensitivity (IS) is a common procedure. The glucose clamp is labor intensive, cannot be used in large numbers of animals, cannot be repeated in the same mouse, and has been questioned as a valid tool for IS in mice; thus, the minimal model with 50-min intravenous glucose tolerance test (IVGTT) data was adapted for studies in mice. However, specific software and particular ability was needed. The aim of this study was to establish a simple procedure for evaluating IS during IVGTT in mice (CS(I)). IVGTTs (n = 520) were performed in NMRI and C57BL/6J mice (20-25g). After glucose injection (1 g/kg), seven samples were collected for 50 min for glucose and insulin measurements, analyzed with a minimal model that provided the validated reference IS (S(I)). By using the regression CS(I) = alpha(1) + alpha(2) x K(G)/AUC(D), where K(G) is intravenous glucose tolerance index and AUC(d) is the dynamic area under the curve, IS was calculated in 134 control animals randomly selected (regression CS(I) vs. S(I): r = 0.66, P < 0.0001) and yielded alpha(1) = 1.93 and alpha(2) = 0.24. K(G) is the slope of log (glucose(5-20)) and AUC(D) is the mean dynamic area under insulin curve in the IVGTT. By keeping fixed alpha(1) and alpha(2), CS(I) was validated in 143 control mice (4.7 +/- 0.2 min*microU(-1)*ml(-1), virtually identical to S(I): 4.7 +/- 0.3, r = 0.89, P < 0.0001); and in 123 mice in different conditions: transgenic, addition of neuropeptides, incretins, and insulin (CS(I): 6.0 +/- 0.4 vs. S(I): 6.1 +/- 0.4, r = 0.94, P < 0.0001). In the other 120 animals, CS(I) revealed its ability to segregate different categories, as does S(I). This easily usable formula for calculating CS(I) overcomes many experimental obstacles and may be a simple alternative to more complex procedures when large numbers of mice or repeated experiments in the same animals are required.

Topics: Animals; Blood Glucose; Galanin; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Injections, Intravenous; Insulin; Insulin Resistance; Linoleic Acid; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Animal; Models, Biological; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide

It has been suggested that hormones released after nutrient absorption, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 2 (GLP-2), could be responsible for changes in bone resorption. However, information about the role of GLP-1 in this regard is scanty. Diabetes-related bone loss occurs as a consequence of poor control of glucose homeostasis, but the relationship between osteoporosis and type 2 diabetes remains unclear. Since GLP-1 is decreased in the latter condition, we evaluated some bone characteristics in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rat models compared to normal (N) and the effect of GLP-1 or saline (control) treatment (3 days by osmotic pump). Blood was taken before and after treatment for plasma measurements; tibiae and femora were collected for gene expression of bone markers (RT-PCR) and structure (microCT) analysis. Compared to N, plasma glucose and insulin were, respectively, higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b were lower; phosphate in IR showed a tendency to be higher; PTH was not different in T2D and IR; all parameters were unchanged after GLP-1 infusion. Bone OC, osteoprotegerin (OPG) and RANKL mRNA were lower in T2D and IR; GLP-1 increased OC and OPG in all groups and RANKL in T2D. Compared to N, trabecular bone parameters showed an increased degree of anisotropy in T2D and IR, which was reduced after GLP-1. These findings show an insulin-independent anabolic effect of GLP-1 and suggest that GLP-1 could be a useful therapeutic agent for improving the deficient bone formation and bone structure associated with glucose intolerance.

Topics: Acid Phosphatase; Animals; Bone and Bones; Bone Resorption; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose; Insulin; Insulin Resistance; Isoenzymes; Male; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; RANK Ligand; Rats; Rats, Wistar; Tartrate-Resistant Acid Phosphatase

We tested the hypothesis that the reversibility of insulin resistance and diabetes observed after biliopancreatic diversion (BPD) is related to changes in circadian rhythms of gastrointestinal hormones.. Ten morbidly obese participants, five with normal glucose tolerance (NGT) and five with type 2 diabetes, were studied before and within 2 weeks after BPD. Within-day variations in glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) levels were assessed using a single cosinor model. Insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp.. Basal GLP1 relative amplitude (amplitude/mesor x 100) was 25.82-4.06% in NGT; it increased to 41.38-4.32% after BPD but was unchanged in diabetic patients. GLP1 and GIP mesor were shifted in time after surgery in diabetic patients but not in NGT participants. After BPD, the GLP1 AUC significantly increased from 775 +/- 94 to 846 +/- 161 pmol l(-1) min in NGT, whereas GIP AUC decreased significantly from 1,373 +/- 565 to 513 +/- 186 pmol l(-1) min in diabetic patients. Two-way ANOVA showed a strong influence of BPD on both GIP (p = 0.010) and GLP1 AUCs (p = 0.033), which was potentiated by the presence of diabetes, particularly for GIP (BPD x diabetes, p = 0.003). Insulin sensitivity was markedly improved (p < 0.01) in NGT (from 9.14 +/- 3.63 to 36.04 +/- 8.55 micromol [kg fat-free mass](-1) min(-1)) and diabetic patients (from 9.49 +/- 3.56 to 38.57 +/- 4.62 micromol [kg fat-free mass](-1) min(-1)).. An incretin circadian rhythm was shown for the first time in morbid obesity. The effect of BPD on the 24 h pattern of incretin differed between NGT and diabetic patients. GLP1 secretion impairment was reversed in NGT and could not be overcome by surgery in diabetes. On the other hand, GIP secretion was blunted after the operation only in diabetic patients, suggesting a role in insulin resistance and diabetes.

Topics: Adipose Tissue; Adult; Biliopancreatic Diversion; Blood Glucose; Body Mass Index; Circadian Rhythm; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Incretins; Insulin; Insulin Resistance; Middle Aged; Obesity, Morbid

In normal subjects, the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for 70% of the insulin response during a meal; but in diabetic subjects and other insulin-resistant conditions, the incretin effect is impaired. Polycystic ovary syndrome (PCOS) is associated with insulin resistance, and the pathophysiologic mechanisms behind PCOS resemble those of type 2 diabetes mellitus; therefore, women with PCOS may have alterations in the incretin hormone response. Metformin is widely used in the treatment of both type 2 diabetes mellitus and PCOS. Metformin may exert some of its effect on glucose metabolism by increasing GLP-1 biosynthesis and secretion and thereby increasing the incretin effect. The objective of the study was to measure incretin hormone secretion in women with PCOS and to evaluate the effect of metformin treatment. Cross-sectional comparison of 40 women with PCOS (19 lean and 21 obese) and 26 healthy control women (9 lean and 17 obese) and longitudinal evaluation of the effects of 8 months of metformin 1000 mg twice daily in women with PCOS were performed. Plasma concentrations of GIP and GLP-1 were determined frequently during a 75-g glucose tolerance test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp. The incretin hormone response did not differ between subjects with and without PCOS. Subgroup analysis showed lower GIP (area under the curve [AUC]) levels in obese women with PCOS compared with obese control women (P < .05) and compared with lean women with PCOS (P < .05). Metformin increased GIP (AUC) and GLP-1 (AUC) in lean women with PCOS (P < .05), and a similar trend was seen in the obese women (P = .07). The GIP secretion is attenuated in obese women with PCOS, whereas treatment with metformin increases the levels of both GIP and GLP-1 in women with PCOS.

Topics: Adult; Blood Glucose; Cross-Sectional Studies; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Longitudinal Studies; Metformin; Obesity; Polycystic Ovary Syndrome

The objective of this study was to quantify hormones that regulate energy and glucose homeostasis to establish possible mechanisms for the greater efficacy of Roux-en-Y gastric bypass (RYGB) compared with laparoscopic adjustable gastric banding (LAGB) in achieving weight loss and improved insulin sensitivity.. Longitudinal study of patients undergoing LAGB (n=15) and RYGB (n=28) who were studied before surgery and at 2, 12, 26 and 52 weeks afterwards.. Fasting blood samples were drawn at each visit. Postprandial blood samples were also obtained before surgery and at 26 and 52 weeks. Samples were assayed for peptide YY (PYY), ghrelin, glucagon-like peptide-1 (GLP-1), glucose, insulin, leptin, thyrotropic hormone, free T(4) and free T(3).. At 1 year there was greater weight loss in RYGB compared with LAGB patients (30 vs 15%), but final body mass index was similar (34 vs 33 kg m(-2)). At week 52, area under the curve (AUC) for PYY in RYGB subjects was greater than LAGB (P<0.01). GLP-1 levels at 30 min after meal were threefold greater after RYGB compared with LAGB (P<0.001). Conversely, ghrelin AUC increased after LAGB at week 52 (P<0.05) but tended to decrease after RYGB. Fasting glucose, insulin, and leptin and homeostasis model of assessment (HOMA-IR) decreased in both groups over time but were significantly lower at week 52 after RYGB compared with LAGB. The change in leptin correlated significantly with weight loss in LAGB (r=0.86) and RYGB (r=0.77), however, HOMA-IR correlated significantly with weight loss only in LAGB (r=0.78), and not RYGB (r=0.15). There was a significant decrease in free T(3) (P<0.01) after RYGB.. Differences in levels of gut hormones may play a role in promoting greater weight loss and insulin sensitivity after RYGB compared with LAGB, however, weight loss may be limited by decreases in free T(3) and leptin.

Topics: Blood Glucose; Female; Gastric Bypass; Gastroplasty; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Postprandial Period; Prospective Studies; Weight Loss

The cornerstone to treat metabolic syndrome and insulin resistance is dietary intervention. Both low-carbohydrate diet (LCD) and low-fat diet (LFD) have been reported to induce weight loss and improve these conditions. One of the factors associated with a subject's adherence to the diet is satiety. The aim of this study was to evaluate the effects of LCD and LFD on body weight, appetite hormones, and insulin resistance. Twenty guinea pigs were randomly assigned to LCD or LFD (60%:10%:30% or 20%:55%:25% of energy from fat/carbohydrate/protein, respectively) for 12 weeks. Weight and food intake were recorded every week. After this period, animals were killed and plasma was obtained to measure plasma glucose and insulin, appetite hormones, and ketone bodies. Guinea pigs fed LCD gained more weight than those fed LFD. The daily amount of food intake in grams was not different between groups, suggesting that food density and gastric distension played a role in satiety. There was no difference in leptin levels, which excludes the hypothesis of leptin resistance in the LCD group. However, plasma glucagon-like peptide-1 was 47.1% lower in animals fed LCD (P < .05). Plasma glucose, plasma insulin, and insulin sensitivity were not different between groups. However, the heavier animals that were fed LFD had impairment in insulin sensitivity, which was not observed in those fed LCD. These findings suggest that satiety was dependent on the amount of food ingested. The weight gain in animals fed LCD may be related to their greater caloric intake, lower levels of glucagon-like peptide-1, and higher protein consumption. The adoption of LCD promotes a unique metabolic state that prevents insulin resistance, even in guinea pigs that gained more weight. The association between weight gain and insulin resistance seems to be dependent on high carbohydrate intake.

Topics: Animals; Blood Glucose; Body Weight; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Eating; Energy Intake; Fasting; Glucagon-Like Peptide 1; Gluconeogenesis; Guinea Pigs; Insulin; Insulin Resistance; Linear Models; Male; Satiation; Weight Gain

Severe obesity is associated with type 2 diabetes mellitus, and both resolve with weight loss after bariatric operations. Intestinal hormones have been identified which are stimulated by rapid nutrient delivery to the lower small bowel after certain weight-loss operations. These incretins stimulate secretion and hypertrophy of the pancreatic beta cells. Surgical procedures are now being performed to treat diabetes in adults of lesser weight, and the importance of ruling out latent autoimmune diabetes in the adult (a variety of type 1) is suggested, before experimenting with these procedures.

Topics: Adult; Bariatric Surgery; Body Mass Index; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Obesity; Weight Loss

The aim of this study was to investigate the mechanisms of the change in glucose metabolism after a pancreatoduodenectomy (PD).. Oral glucose tolerance tests were performed in 17 patients before and 1 month after a PD. The changes in plasma glucose and insulin concentrations, homeostasis model of insulin resistance, and insulinogenic index (beta-cell function) were analyzed. Two additional factors, gastric emptying function and plasma glucagon-like peptide-1 (GLP-1) concentration, that possibly affect perioperative glucose metabolism were also assessed.. The plasma glucose and insulin concentrations were significantly lower after the operation, especially in preoperative diabetic patients. beta-Cell function did not change after the operation. On the other hand, insulin resistance became normal 1 month after the operation. The value of gastric emptying function after the operation was not statistically different in comparison with that before the operation. Postoperative plasma GLP-1 concentration was significantly higher than the preoperative value.. beta-Cell function is maintained after a PD, whereas the improvement of insulin resistance may cause a short-term transient improvement of the glucose metabolism after the operation. The significance of increased postoperative GLP-1 concentration remains an unsolved issue.

Topics: Adult; Aged; Aged, 80 and over; Biliary Tract Neoplasms; Blood Glucose; Diabetes Complications; Duodenal Neoplasms; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Pancreatic Neoplasms; Pancreaticoduodenectomy; Prospective Studies

Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (D-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice.. Mice on high-fat diet for 155 days were injected once daily with (D-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (D-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes.. Daily intraperitoneal injections of (D-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p < 0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (D-Ala(8))GLP-1 alone (p < 0.05) or in combination with (Pro(3))GIP (p < 0.01) compared with normal chow-fed controls.. These results illustrate efficacy of (Pro(3))GIP and (D-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.

Topics: Animals; Blood Glucose; Dietary Fats; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Injections, Intraperitoneal; Insulin; Insulin Resistance; Mice; Receptors, Gastrointestinal Hormone; Receptors, Glucagon; Treatment Outcome

The clinical value of glucagon-like peptide-1 (GLP-1) is restricted because of its short half-life. To overcome this limitation, a new polymer of GLP-1 was developed by prodrug strategy, termed Poly-GLP-1, and its pharmacological properties were investigated.. The in vitro release kinetics of GLP-1 from Poly-GLP-1 was analysed by Western blot. Plasma GLP-1 levels following a single administration of Poly-GLP-1 were determined by enzyme-linked immunosorbent assay. The in vitro effects of Poly-GLP-1 were evaluated using isolated pancreatic islets. The acute effects on glycaemic control and food intake were investigated in C57BL/6J mice s.c. administered with Poly-GLP-1. The chronic effects of Poly-GLP-1 on glycaemic control were further assessed in C57BL/6J and db/db mice treated twice daily for 6 weeks.. Pro-GLP-1 dose dependently increased insulin secretion and decreased glucose, but did not exhibit the insulinotropic action in isolated pancreatic islets without plasma. The glucose-lowering actions of Poly-GLP-1 (3 nmol/kg) remained no less than 12 h after a single injection. Poly-GLP-1 caused a durable restoration of glycaemic control, food intake and body weight gain in db/db mice following 6-week administration. The chronic treatment with Poly-GLP-1 improved glucose tolerance and insulin sensitivity and increased beta-cell mass and proliferation in db/db mice. There was little effect on normal mice treated in the same manner.. Our results indicated that Poly-GLP-1, a novel GLP-1 polymer, has long-lasting and potent effects on glycaemic control in vivo, and these beneficial effects may be because of improvement of insulin sensitivity and promotion of islet growth and function.

Topics: Animals; Blood Glucose; Blotting, Western; Cell Proliferation; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Glucagon-Like Peptide 1; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Mice; Mice, Inbred BALB C; Polymers; Prodrugs

Second generation antipsychotic drug (SGA) treatment is associated with detrimental effects on glucose metabolism which is often attributed to the development of obesity and insulin resistance. However, we have recently demonstrated that clozapine and quetiapine also have direct effects of glucose metabolism in animals. This study compares clozapine and quetiapine and investigates the effects of these on the development of obesity and the direct effects of these drugs on glucose metabolism compared with those caused by the obesity per se.. Three groups of male Sprague-Dawley rats were fed a high fat/high sugar diet to induce obesity while another three groups were fed a chow diet. One group on each diet was injected daily with vehicle, clozapine or quetiapine and effects on glucose metabolism were monitored.. Clozapine and quetiapine treatment did not directly cause obesity or potentiate diet induced obesity but did induce a preference for the high fat/high sugar diet. Neither drug caused a impairment in insulin tolerance over that caused by obesity but both drugs acutely induced impairments in glucose tolerance that were additive with the effects induced by the diet induced obesity. Both drugs caused increases in glucagon levels and a suppression of GLP-1. We investigated two strategies for restoring GLP-1 signalling. The DPP-IV inhibitor sitagliptin only partially restored GLP-1 levels and did not overcome the deleterious effects on glucose tolerance whereas the GLP-1 receptor agonist exendin-4 normalised both glucagon levels and glucose metabolism.. Our findings indicate that the clozapine and quetiapine induced impairments in glucose tolerance in rats are independent of insulin resistance caused by obesity and that these defects are linked with a suppression of GLP-1 levels. These studies suggest the need to perform follow up studies in humans to determine whether clozapine and quetiapine induce acute derangements in glucose metabolism and whether GLP-1 replacement therapy might be the most appropriate therapeutic strategy for treating derangements in glucose metabolism in subjects taking these drugs.

Topics: Analysis of Variance; Animals; Antipsychotic Agents; Body Composition; Body Weight; Clozapine; Dibenzothiazepines; Dietary Fats; Disease Models, Animal; Eating; Exenatide; Food Preferences; Gene Expression Regulation; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Male; Obesity; Peptides; Pyrazines; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate; Triazoles; Venoms

Bile acids are signaling molecules with important endocrine functions. Some of these, including the induction of energy expenditure in brown adipose tissue and skeletal muscle as well as the stimulation of glucagon-like peptide-1 (GLP-1) production in enteroendocrine L-cells, are mediated by the G-protein-coupled bile acid receptor 1 (GPBAR1). Therefore, we investigated in a cohort of white subjects at increased risk for type 2 diabetes mellitus whether a genetic variation within the GPBAR1 gene contributes to prediabetic phenotypes, such as disproportionate fat distribution, insulin resistance, or beta-cell dysfunction. We genotyped 1576 subjects (1043 women, 533 men) for the single nucleotide polymorphism rs3731859 in the GPBAR1 gene. All subjects underwent an oral glucose tolerance test; a subset additionally had a hyperinsulinemic-euglycemic clamp. Regional fat distribution, ectopic hepatic and intramyocellular lipids were determined by magnetic resonance techniques. Peak aerobic capacity, a surrogate parameter for oxidative capacity of skeletal muscle, was measured by an incremental exercise test on a motorized treadmill. Total GLP-1 and gastric inhibitory peptide levels were determined by radioimmunoassay. After appropriate adjustment and Bonferroni correction for multiple comparisons, rs3731859 was not significantly associated with regional or ectopic fat distribution, peak aerobic capacity, levels of incretins, insulin sensitivity, or indices of insulin secretion. Nominal associations were found between rs3731859 and body mass index, waist circumference, fasting GLP-1 levels, and intramyocellular lipids in the soleus muscle (P = .02, P = .02, P = .05, and P = .03, respectively). Our data suggest that a common genetic variation within the GPBAR1 gene may not play a major role in the development of prediabetic phenotypes in our white population.

Topics: Adipose Tissue; Cohort Studies; Diabetes Mellitus, Type 2; Exercise Test; Female; Genetic Variation; Genotype; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Insulin Resistance; Lipid Metabolism; Magnetic Resonance Imaging; Male; Muscle, Skeletal; Polymorphism, Single Nucleotide; Receptors, G-Protein-Coupled; Risk Factors; White People

The control of glucose metabolism is a complex process, and dysregulation at any level can cause impaired glucose tolerance and insulin resistance. These two defects are well-known characteristics associated with obesity and onset of type 2 diabetes. Here we introduce the N-terminal dipeptidase, DPP2, as a novel regulator of the glucose metabolism. We generated mice with a neurogenin 3 (NGN3)-specific DPP2 knockdown (kd) to explore a possible role of DPP2 in maintaining metabolic homeostasis. These mice spontaneously developed hyperinsulinemia, glucose intolerance, and insulin resistance by 4 months of age. In addition, we observed an increase in food intake in DPP2 kd mice, which was associated with a significant increase in adipose tissue mass and enhanced liver steatosis but no difference in body weight. In accordance with these findings, the mutant mice had a higher rate of respiratory exchange than the control littermates. This phenotype was exacerbated with age and when challenged with a high-fat diet. We report, for the first time, that DPP2 enzyme activity is essential for preventing hyperinsulinemia and maintaining glucose homeostasis. Interestingly, the phenotype of NGN3-DPP2 kd mice is opposite that of DPP4 knockout mice with regard to glucose metabolism, namely the former have normal glucagon-like peptide 1 levels but present with glucose intolerance, whereas the latter have increased glucagon-like peptide 1, which is accompanied by augmented glucose tolerance.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Transcription Factors; Blood Glucose; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Eating; Fasting; Fatty Liver; Female; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Mice; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Obesity

Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that has been used as a drug injected subcutaneously for treatment of type 2 diabetes. Many studies have revealed molecular targets of Ex-4, but its influence on adipokines has not been determined. Our study showed that Ex-4 induced secretion of adiponectin into the culture medium of 3T3-L1 adipocytes. This effect of Ex-4 is due to increased adiponectin mRNA level through the GLP-1R. Both forskolin and 3-isobutyl-1-methylxanthine (IBMX), which may finally elevate cyclic adenosine monophosphate (cAMP) concentration, prevented the induction of adiponectin expression by Ex-4. Moreover, H89, a protein kinase A inhibitor, blocked the effect of Ex-4 on adiponectin. On the other hand, Ex-4 decreased the mRNA levels of inflammatory adipokines. The results indicate that Ex-4 directly promotes adiponectin secretion via the protein kinase A pathway in 3T3-L1 adipocytes and may ameliorate insulin resistance.

Topics: 1-Methyl-3-isobutylxanthine; 3T3-L1 Cells; Adipocytes; Adipokines; Adiponectin; Animals; Colforsin; Cyclic AMP-Dependent Protein Kinases; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Inflammation; Insulin Resistance; Isoquinolines; Mice; Peptides; Phosphodiesterase Inhibitors; Protein Kinase Inhibitors; Receptors, Glucagon; RNA, Messenger; Sulfonamides; Venoms

Polycystic ovary syndrome (PCOS) has been linked to a high risk of type 2 diabetes mellitus. Disturbances in the secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been observed in states with impaired glucose regulation. This paper considers the secretion of GIP and GLP-1 after oral glucose load in a group of lean, glucose-tolerant PCOS women in comparison with age- and body mass index (BMI)-matched healthy women.. Case control.. PCOS (n=21, 25.8+/-4.1 years, BMI 21.6+/-1.7 kg/m(2)) and control healthy women (CT, n=13, 28.5+/-7.2 years, BMI 20.3+/-2.5 kg/m(2)) underwent oral glucose tolerance test (OGTT) with blood sampling for glucose, insulin, C-peptide, total GIP, and active GLP-1. Insulin sensitivity was determined both at fasting and during the test.. Repeated measures ANOVA.. Glucose levels and insulin sensitivity did not differ between PCOS and CT. PCOS had significantly higher levels of C-peptide (P<0.05) and tended to have higher insulin levels. The levels of total GIP were significantly higher in PCOS than in CT (P<0.001). Active GLP-1 levels exhibited a significantly different time-dependent pattern in PCOS (P<0.002 for PCOS versus time interaction). GLP-1 concentrations were similar in PCOS and CT in the early phase of OGTT and then reached significantly lower levels in PCOS than in CT at 180 min (P<0.05).. Increased total GIP and lower late phase active GLP-1 concentrations during OGTT characterize PCOS women with higher C-peptide secretion in comparison with healthy controls, and may be the early markers of a pre-diabetic state.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Incretins; Insulin; Insulin Resistance; Polycystic Ovary Syndrome; Time Factors

The effect of high multivitamin intake during pregnancy on the metabolic phenotype of rat offspring was investigated. Pregnant Wistar rats (n=10 per group) were fed the AIN-93G diet with the recommended vitamin (RV) content or a 10-fold increase [high vitamin (HV) content]. In experiment 1, male and female offspring were followed for 12 wk after weaning; in experiment 2, only males were followed for 28 wk. Body weight (BW) was measured weekly. Every 4 wk, after an overnight fast, food intake over 1 h was measured 30 min after a gavage of glucose or water. An oral glucose tolerance test was performed every 3-5 wk. Postweaning fasting glucose, insulin, ghrelin, glucagon-like peptide-1, and systolic blood pressure were measured. No difference in BW at birth or litter size was observed. Food intake was greater in males born to HV dams (P<0.05), and at 28 wk after weaning, BW was 8% higher (P<0.05) and fat pad mass was 27% higher (P<0.05). Food intake reduction after the glucose preload was nearly twofold less in males born to HV dams at 12 wk after weaning (P<0.05). Fasting glucose, insulin, and ghrelin were 11%, 62%, and 41% higher in males from HV dams at 14 wk after weaning (P<0.05). Blood glucose response was 46% higher at 23 wk after weaning (P<0.01), and systolic blood pressure was 16% higher at 28 wk after weaning (P<0.05). In conclusion, high multivitamin intake during pregnancy programmed the male offspring for the development of the components of metabolic syndrome in adulthood, possibly by its effects on central mechanisms of food intake control.

Topics: Adipose Tissue; Animal Nutritional Physiological Phenomena; Animals; Appetite Regulation; Blood Glucose; Blood Pressure; Body Weight; Dietary Supplements; Eating; Fasting; Female; Ghrelin; Glucagon-Like Peptide 1; Glucose Intolerance; Insulin; Insulin Resistance; Male; Maternal Nutritional Physiological Phenomena; Metabolic Syndrome; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Time Factors; Vitamins

The aim of the present research was to characterize the pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel quinazolinone-based dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin potently inhibited human DPP-4 in vitro (mean IC(50), ~ 6.9 nM) and exhibited > 10,000-fold selectivity for DPP-4 over the closely related serine proteases DPP-2, DPP-8, DPP-9, fibroblast activation protein/seprase, prolyl endopeptidase, and tryptase (IC(50) > 100,000 nM). Absolute oral bioavailability of alogliptin in rats, dogs, and monkeys was 45%, 86%, and 72% to 88%, respectively. After a single oral dose of alogliptin, plasma DPP-4 inhibition was observed within 15 min and maximum inhibition was > 90% in rats, dogs, and monkeys; inhibition was sustained for 12 h in rats (43%) and dogs (65%) and 24 h in monkeys (> 80%). From E(max) modeling, 50% inhibition of DPP-4 activity was observed at a mean alogliptin plasma concentration (EC(50)) of 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) in rats, dogs, and monkeys. In Zucker fa/fa rats, a single dose of alogliptin (0.3, 1, 3, and 10 mg/kg) inhibited plasma DPP-4 (91% to 100% at 2 h and 20% to 66% at 24 h), increased plasma GLP-1 (2- to 3-fold increase in AUC(0-20 min)) and increased early-phase insulin secretion (1.5- to 2.6-fold increase in AUC(0-20 min)) and reduced blood glucose excursion (31%-67% decrease in AUC(0-90 min)) after oral glucose challenge. Alogliptin (30 and 100 mg/kg) had no effect on fasting plasma glucose in normoglycemic rats. In summary, these data suggest that alogliptin is a potent and highly selective DPP-4 inhibitor with demonstrated efficacy in Zucker fa/fa rats and potential for once-daily dosing in humans.

Topics: Administration, Oral; Animals; Biological Availability; Blood Glucose; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Glucagon-Like Peptide 1; Glucose Metabolism Disorders; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Macaca fascicularis; Male; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Zucker; Uracil

Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity.

Topics: Animals; Blood Glucose; Body Temperature Regulation; Brain Stem; Carbon Dioxide; Diabetes Mellitus, Type 2; Dietary Fats; Energy Metabolism; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperinsulinism; Insulin Resistance; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Motor Activity; Muscle, Skeletal; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxygen Consumption; Peptide Fragments; Physical Endurance; Proglucagon; RNA, Messenger; Signal Transduction; Uncoupling Protein 2

To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood.. Awake free-moving mice were infused with the GLP-1 receptor agonist exendin-4 (Ex4) into the lateral ventricle of the brain in the basal state or during hyperinsulinemic eu-/hyperglycemic clamps. Arterial femoral blood flow, whole-body insulin-stimulated glucose utilization, and heart rates were continuously recorded.. A continuous 3-h brain infusion of Ex4 decreased femoral arterial blood flow and whole-body glucose utilization in the awake free-moving mouse clamped in a hyperinsulinemic-hyperglycemic condition, only demonstrating that this effect was strictly glucose dependent. However, the heart rate remained unchanged. The metabolic and vascular effects of Ex4 were markedly attenuated by central infusion of the GLP-1 receptor (GLP-1R) antagonist exendin-9 (Ex9) and totally abolished in GLP-1 receptor knockout mice. A correlation was observed between the metabolic rate and the vascular flow in control and Ex4-infused mice, which disappeared in Ex9 and GLP-1R knockout mice. Moreover, hypothalamic nitric oxide synthase activity and the concentration of reactive oxygen species (ROS) were also reduced in a GLP-1R-dependent manner, whereas the glutathione antioxidant capacity was increased. Central GLP-1 activated vagus nerve activity, and complementation with ROS donor dose-dependently reversed the effect of brain GLP-1 signaling on peripheral blood flow.. Our data demonstrate that central GLP-1 signaling is an essential component of circuits integrating cardiovascular and metabolic responses to hyperglycemia.

Topics: Animals; Arteries; Blood Flow Velocity; Brain; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Rate; Hemodynamics; Hypothalamus; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptides; Reactive Oxygen Species; Receptors, Glucagon; Venoms

Compared with Caucasians, obese African-American adolescents have a higher risk for type 2 diabetes. Subclinical inflammation and reduced glucagon-like peptide 1 (GLP-1) concentration are linked to the pathogenesis of the disease. We determined the relationship between insulin resistance, beta-cell activity, and subclinical inflammation with GLP-1 concentrations and whether racial disparities in GLP-1 response were present in 49 obese adolescents (14 +/- 3 years; 76% African American; 71% female).. Subjects underwent physical examination and an oral glucose tolerance test. We measured levels of high-sensitivity CRP (CRP(hs)), fibrinogen, glucose, GLP-1(total), GLP-1(active), and insulin. Insulin and glucose area under the curve (AUC), insulinogenic index (DeltaI30/DeltaG30), and composite insulin sensitivity index (CISI) were computed. Subjects were categorized by race and as inflammation positive (INF+) if CRP(hs) or fibrinogen were elevated.. No racial differences were seen in mean or relative BMI. Thirty-five percent of subjects had altered fasting or 2-h glucose levels (African American vs. Caucasian, NS), and 75% were INF+ (African American vs. Caucasian, P = 0.046). Glucose and insulin, CISI, and DeltaI30/DeltaG30 values were similar; African Americans had lower GLP-1(total) AUC (P = 0.01), GLP-1(active) at 15 min (P = 0.03), and GLP-1(active) AUC (P = 0.06) and higher fibrinogen (P = 0.01) and CRP(hs) (NS) compared with Caucasians.. African Americans exhibited lower GLP-1 concentrations and increased inflammatory response. Both mechanisms may act synergistically to enhance the predisposition of obese African Americans to type 2 diabetes. Our findings might be relevant to effective deployment of emerging GLP-1-based treatments across ethnicities.

Topics: Adolescent; Biomarkers; Black People; Blood Pressure; C-Reactive Protein; Child; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Inflammation; Insulin Resistance; Male; Obesity; White People

We have shown that individually, dietary fiber and protein increase secretion of the anorexigenic and insulinotropic hormone, glucagon-like peptide-1 (GLP-1).. Our objective was to combine, in one diet, high levels of fiber and protein to maximize GLP-1 secretion, improve glucose tolerance, and reduce weight gain.. Lean (+/?) and obese (cp/cp) male James C Russell corpulent (JCR:LA-cp) rats lacking a functional leptin receptor were fed one of four experimental diets (control, high protein (HP), high fiber (HF, prebiotic fiber inulin), or combination (CB)) for 3 weeks. An oral glucose tolerance test (OGTT) was performed to evaluate plasma GLP-1, insulin and glucose. Plasma lipids and intestinal proglucagon mRNA expression were determined.. Energy intake was lower with the HF diet in lean and obese rats. Weight gain did not differ between diets. Higher colonic proglucagon mRNA in lean rats fed a CB diet was associated with higher GLP-1 secretion during OGTT. The HP diet significantly reduced plasma glucose area under the curve (AUC) during OGTT in obese rats, which reflected both an increased GLP-1 AUC and higher fasting insulin. Diets containing inulin resulted in the lowest plasma triglyceride and total cholesterol levels.. Overall, combining HP with HF in the diet increased GLP-1 secretion in response to oral glucose, but did not improve glucose tolerance or lipid profiles more than the HF diet alone did. We also suggest that glycemic and insulinemic response to prebiotics differ among rat models and future research work should examine their role in improving glucose tolerance in diet-induced vs. genetic obesity with overt hyperleptinemia.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fiber; Dietary Proteins; Disease Models, Animal; Duodenum; Glucagon-Like Peptide 1; Glucose Tolerance Test; Insulin Resistance; Inulin; Jejunum; Lipids; Male; Obesity; Proglucagon; Rats; Rats, Inbred Strains; RNA, Messenger; Weight Gain

Type II diabetes mellitus (T2D) develops as the consequence of relative insulin insufficiency. The onset of T2D is characterized by insulin resistance, and in most cases, with hyperinsulinemia for compensation. Extensive basic and clinical examinations have identified a large profile of T2D susceptibility genes and multiple risk factors, including obesity and sedentary life style, which are shared by colon cancer development. The intestinal endocrine L cells produce an incretin hormone, namely glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion in blood glucose dependent manner, pancreatic beta cell proliferation and neogenesis. It has been shown that in T2D patients, postprandial GLP-1 secretion level is reduced. I hypothesize that during the development of insulin resistance, intestinal endocrine L cells produce more GLP-1 for compensation. This compensatory response involves the activation of Wnt signaling pathway and the cross-talk between Wnt and insulin signaling pathways. A pathological consequence of this compensation will be the stimulated expression of proto-oncogenes, including c-Myc.

Topics: Apoptosis; Colonic Neoplasms; Comorbidity; Diabetes Complications; Diabetes Mellitus; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Models, Biological; Models, Theoretical; Signal Transduction; Wnt Proteins

Obesity is strongly associated with hyperinsulinemia and insulin resistance, both primary risk factors for type 2 diabetes. It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels, which would then signal for compensatory hyperinsulinemia. But when obesity is induced by fat feeding in the dog model, there is development of insulin resistance and a marked increase in fasting insulin despite constant fasting FFA and glucose. We examined the 24-h plasma profiles of FFA, glucose, and other hormones to observe any potential longitudinal postprandial or nocturnal alterations that could lead to both insulin resistance and compensatory hyperinsulinemia induced by a high-fat diet in eight normal dogs. We found that after 6 wk of a high-fat, hypercaloric diet, there was development of significant insulin resistance and hyperinsulinemia as well as accumulation of both subcutaneous and visceral fat without a change in either fasting glucose or postprandial glucose. Moreover, although there was no change in fasting FFA, there was a highly significant increase in the nocturnal levels of FFA that occurred as a result of fat feeding. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia in the fat-fed dog model.

Topics: Animals; Blood Glucose; Body Composition; C-Peptide; Circadian Rhythm; Diet; Dogs; Fasting; Fatty Acids, Nonesterified; Glucagon-Like Peptide 1; Glycerol; Hormones; Hyperinsulinism; Insulin; Insulin Resistance; Male; Triglycerides

Glucagon-like peptide-1 (GLP-1) plays a significant role in glucose homeostasis through its incretin effect on insulin secretion. However, GLP-1 also exhibits extrapancreatic actions, and in particular its possible influences on insulin sensitivity are controversial. To study the dynamic action of GLP-1 on insulin sensitivity, we applied advanced statistical modeling methods to study glucose disappearance in mice that underwent intravenous glucose tolerance test with administration of GLP-1 at various dose levels. In particular, the minimal model of glucose disappearance was exploited within a population estimation framework for accurate detection of relationships between glucose disappearance parameters and GLP-1. Minimal model parameters were estimated from glucose and insulin data collected in 209 anesthetized normal mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). Insulin secretion markedly increased, as expected, with increasing GLP-1 dose. However, minimal model-derived indexes, i.e., insulin sensitivity and glucose effectiveness, did not significantly change with GLP-1 dose. Instead, fractional turnover rate of insulin action [P2 = 0.0207 +/- 24.3% (min) at zero GLP-1 dose] increased steadily with administered GLP-1 dose, with significant differences at 10.4 nmol/kg (P2 = 0.040 +/- 15.5%, P = 0.0046) and 31.2 nmol/kg (P2 = 0.050 +/- 29.2%, P = 0.01). These results show that GLP-1 influences the dynamics of insulin action by accelerating insulin action following glucose challenge. This is a novel mechanism contributing to the glucose-lowering action of GLP-1.

Topics: Animals; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose; Injections, Intravenous; Insulin; Insulin Resistance; Insulin Secretion; Mice; Mice, Inbred Strains; Models, Biological; Time Factors

The aim of the study was to determine physicians' knowledge of specific concepts generally implicated in the pathophysiology of type 2 diabetes (T2D).. A multiple choice online survey was completed by 847 physicians, of which 516 were engaged in primary care (PCP) and 331 in specialized care (SCP) in the US, the UK, Germany and France (3-30 years in practice, at least 40 patients with T2D). A continuous rating system was used to measure familiarity ("totally familiar" to "never heard of") or agreement with a statement (from "totally agree" to "totally disagree").. The term "insulin resistance" was recognized by 74% of PCPs and 90% of SCPs (p<0.05) and 76% felt that it was "a key but not the sole determinant of T2D". Only 47% agreed that "beta cell dysfunction is a key determinant of T2D onset" and 57% agreed with "beta cell dysfunction being a key determinant of T2D progression". Even among SCPs, 6% were not familiar with the term "beta cell dysfunction" (16% among PCPs, p<0.05). The overall familiarity with the following terms was: 55% with "beta cell dysfunction", 56% with "beta cells", 38% with "glucagon", 32% with "alpha cells", 55% with "hepatic glucose output", 15% with "incretins" and 18% with "GLP-1". SCPs were significantly more familiar with all terms than PCPs (all p-values <0.05).. The pathogenetic role of beta cell dysfunction in the onset and progression of T2D did not seem to be well established. "Insulin resistance" was a well known concept even among PCPs, while "hepatic glucose output", "pancreatic alpha cells" and "glucagon" were not. Incretin hormones and GLP-1 were widely unknown. This may effect prescribing behaviour and how well an individual's therapy is based on pathophysiology.

Topics: Clinical Competence; Diabetes Mellitus, Type 2; Family Practice; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Humans; Insulin Resistance; Insulin-Secreting Cells; Liver; Online Systems; Primary Health Care; Surveys and Questionnaires

To study the relationships between glucagon-like peptide-1 (GLP-1), weight status, insulin, and insulin resistance in the fasting state.. Fasting GLP-1, glucose and insulin concentrations, insulin resistance index as homeostasis model assessment (HOMA), body mass index (BMI), and percentage body fat based on skinfold thickness measurements were determined in 42 obese (median age 11 years) and in 16 lean children of the same age. The HOMA model was used to calculate degree of insulin resistance. Furthermore, the changes in GLP-1, glucose, insulin, and HOMA in the course of 1 year were analyzed in the 42 obese children participating in an obesity intervention.. GLP-1 concentrations did not differ significantly between obese and lean children. In multiple linear regression analyses, GLP-1 was significantly related to insulin (P = 0.028) and HOMA (P = 0.019) but not to glucose, age, sex, pubertal stage, BMI, or percentage body fat. The 15 obese children with substantial weight reduction demonstrated significantly (P < 0.05) decreased GLP-1, insulin, and HOMA levels, whereas these parameters did not change in 27 obese children without substantial weight loss. Changes in GLP-1 correlated significantly with changes in insulin (r = 0.46, P = 0.001) and HOMA (r = 0.28, P = 0.036) but not with changes in glucose, BMI, or percentage of body fat.. In children, fasting GLP-1 concentrations are independent of age, sex, and pubertal stage. Although GLP-1 did not differ between lean and obese children, weight loss was associated with decreasing GLP-1. Inasmuch as GLP-1 levels were related to insulin concentrations in both cross-sectional and longitudinal analyses, we hypothesize a relationship between GLP-1 and insulin in the fasting state.

Topics: Child; Cross-Sectional Studies; Fasting; Female; Glucagon-Like Peptide 1; Homeostasis; Humans; Insulin; Insulin Resistance; Longitudinal Studies; Male; Models, Biological; Obesity; Weight Loss

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the two key incretin hormones released from the gastrointestinal tract that regulate blood glucose homeostasis through potent insulin secretion. The rapid degradation of GIP and GLP-1 by the ubiquitous enzyme dipeptidyl peptidase IV (DPP IV) renders both peptides noninsulinotropic. However, DPP IV stable agonists, such as N-AcGIP and (Val8)GLP-1, have now been developed. The present study has examined and compared the metabolic effects of subchronic administration of daily i.p. injections of N-AcGIP, (Val8) GLP-1 and a combination of both peptides (all at 25 nmol/kg bw) in obese diabetic (ob/ob) mice. Initial in vitro experiments confirmed the potent insulinotropic properties of N-AcGIP and (Val8)GLP-1 in the clonal pancreatic BRIN BD11 cell line. Subchronic administration of N-AcGIP, (Val8)GLP-1 or combined peptide administration had no significant effects on the body weight, food intake and plasma insulin concentrations. However, all treatment groups had significantly (p < 0.05) decreased plasma glucose levels and improved glucose tolerance by day 14. The effectiveness of the peptide groups was similar, and glucose concentrations were substantially reduced following injection of insulin to assess insulin sensitivity compared to control. These results provide evidence for an improvement of glucose homeostasis following treatment with enzyme-resistant GIP and GLP-1 analogues.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Hypoglycemic Agents; Insulin; Insulin Resistance; Mice; Obesity

It has been hypothesized that glucagon-like peptide-1 (GLP-1), secreted by ileal L cells, plays a key-role in the resolution of type 2 diabetes after bariatric operations whose common feature is an expedite nutrient delivery to the hindgut. Ileal transposition (IT), an operation that permits L-cell stimulation by undigested food, was employed to verify this theory.. IT was carried out in Goto-Kakizaki (GK) type 2 diabetic rats and in euglycemic Sprague-Dawley (SD) rats. Glucose tolerance, insulin resistance, food-intake, body weight, pancreas morphology, and function were evaluated to track the effects of IT on diabetes. Intact GLP-1 secretion and gene expression pattern of the transposed ileum were investigated to verify the molecular bases of the hindgut action.. In GK rats, IT significantly improved glucose tolerance, insulin sensitivity, and acute insulin response without affecting body weight and food intake. Immunohistochemistry revealed remodeled islets strictly resembling that of euglycemic rats and signs of beta-cell neogenesis starting with exocrine structures. GLP-1 secretion in GK transposed rats was characterized by a more sustained response to oral glucose compared with nontreated rats. Gene expression of Proglucagon, Proconvertase 1/3 (PC1/3), and Chromogranin A in the transposed ileum significantly enhanced. Effects on glucose metabolism and pancreas morphology were not observed in the euglycemic rats as a consequence of the glucose-dependent action of GLP-1.. This study gives strong evidences for the crucial role of the hindgut in the resolution of diabetes after Roux-en-Y gastric bypass (GBP) and biliopancreatic diversion (BPD). Moreover, these findings confirm at the preclinical level that IT is a surgical procedure of possible relevance in the therapy of type 2 diabetes in non-overweight and mildly obese patients.

Topics: Administration, Oral; Animals; Blood Glucose; Chromogranin A; Diabetes Mellitus, Type 2; Eating; Enteroendocrine Cells; Gene Expression; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Ileum; Insulin Resistance; Insulin-Secreting Cells; Proglucagon; Proprotein Convertase 1; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; RNA, Messenger; Weight Gain

Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes and reduced insulin secretion. The transcription factor TCF7L2 is an essential factor for glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells. We studied whether a defect in the enteroinsular axis contributes to impaired insulin secretion in carriers of TCF7L2 polymorphisms.. We genotyped 1,110 non-diabetic German participants for five single nucleotide polymorphisms in TCF7L2. All participants underwent an OGTT; GLP-1 secretion was measured in 155 participants. In 210 participants, an IVGTT combined with a hyperinsulinaemic-euglycaemic clamp was performed. In another 160 participants from the Netherlands and 73 from Germany, a hyperglycaemic clamp (10 mmol/l) was performed. In 73 German participants this clamp was combined with a GLP-1 infusion and an arginine bolus.. The OGTT data confirmed that variants in TCF7L2 are associated with reduced insulin secretion. In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 concentrations during the OGTT were not influenced by the TCF7L2 variants. However, GLP-1-infusion combined with a hyperglycaemic clamp showed a significant reduction in GLP-1-induced insulin secretion in carriers of the risk allele in two variants (rs7903146, rs12255372, p < 0.02).. Variants of TCF7L2 specifically impair GLP-1-induced insulin secretion. This seems to be rather the result of a functional defect in the GLP-1 signalling in beta cells than a reduction in GLP-1 secretion. This defect might explain the impaired insulin secretion in carriers of the risk alleles and confers the increased risk of type 2 diabetes.

Topics: Adult; Arginine; Blood Glucose; Female; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Heterozygote; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Polymorphism, Single Nucleotide; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein

The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro(3))GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro(3))GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. (Pro(3))GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in (Pro(3))GIP-treated high-fat-fed mice. (Pro(3))GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro(3))GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.

Topics: Adipokines; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Corticosterone; Dietary Fats; Eating; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Intolerance; Incretins; Insulin; Insulin Resistance; Lipids; Liver; Male; Mice; Motor Activity; Muscle, Skeletal; Obesity; Pancreas; Receptors, Gastrointestinal Hormone

Hyperinsulinemic hypoglycemia is newly recognized as a rare but important complication after Roux-en-Y gastric bypass (GB). The etiology of the syndrome and metabolic characteristics remain incompletely understood. Recent studies suggest that levels of incretin hormones are increased after GB and may promote excessive beta-cell function and/or growth.. We performed a cross-sectional analysis of metabolic variables, in both the fasting state and after a liquid mixed-meal challenge, in four subject groups: 1) with clinically significant hypoglycemia [neuroglycopenia (NG)] after GB surgery, 2) with no symptoms of hypoglycemia at similar duration after GB surgery, 3) without GB similar to preoperative body mass index of the surgical cohorts, and 4) without GB similar to current body mass index of the surgical cohorts.. Insulin and C-peptide after the liquid mixed meal were both higher relative to the glucose level achieved in persons after GB with NG compared with asymptomatic individuals. Glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide levels were higher in both post-GB surgical groups compared with both overweight and morbidly obese persons, and glucagon-like peptide 1 was markedly higher in the group with NG. Insulin resistance, assessed by homeostasis model assessment of insulin resistance, the composite insulin sensitivity index, or adiponectin, was similar in both post-GB groups. Dumping score was also higher in both GB groups but did not discriminate between asymptomatic and symptomatic patients. Notably, the frequency of asymptomatic hypoglycemia after a liquid mixed meal was high in post-GB patients.. A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; C-Peptide; Eating; Female; Food; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Postoperative Complications

Among the products of enteroendocrine cells are the incretins glucagon-like peptide-1 (GLP-1, secreted by L cells) and glucose-dependent insulinotropic peptide (GIP, secreted by K cells). These are key modulators of insulin secretion, glucose homeostasis, and gastric emptying. Because of the rapid early rise of GLP-1 in plasma after oral glucose, we wished to definitively establish the absence or presence of L cells, as well as the relative distribution of the incretin cell types in human duodenum. We confirmed the presence of proglucagon and pro-GIP genes, their products, and glucosensory molecules by tissue immunohistochemistry and RT-PCR of laser-captured, single duodenal cells. We also assayed plasma glucose, incretin, and insulin levels in subjects with normal glucose tolerance and type 2 diabetes for 120 min after they ingested 75 g of glucose. Subjects with normal glucose tolerance (n=14) had as many L cells (15+/-1), expressed per 1,000 gut epithelial cells, as K cells (13+/-1), with some containing both hormones (L/K cells, 5+/-1). In type 2 diabetes, the number of L and L/K cells was increased (26+/-2; P<0.001 and 9+/-1; P < 0.001, respectively). Both L and K cells contained glucokinase and glucose transporter-1, -2, and -3. Newly diagnosed type 2 diabetic subjects had increased plasma GLP-1 levels between 20 and 80 min, concurrently with rising plasma insulin levels. Significant coexpression of the main incretin peptides occurs in human duodenum. L and K cells are present in equal numbers. New onset type 2 diabetes is associated with a shift to the L phenotype.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Biopsy; Diabetes Mellitus, Type 2; Duodenum; Enteroendocrine Cells; Enzyme-Linked Immunosorbent Assay; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Tolerance Test; Humans; Immunohistochemistry; Insulin; Insulin Resistance; Male; Middle Aged; Peptide Fragments; Reverse Transcriptase Polymerase Chain Reaction

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. Ob/ob mice, or their lean littermates, were treated with Exendin-4 [10 microg/kg or 20 microg/kg] for 60 days. Serum was collected for measurement of insulin, adiponectin, fasting glucose, lipids, and aminotransferase concentrations. Liver tissue was procured for histological examination, real-time RT-PCR analysis and assay for oxidative stress. Rat hepatocytes were isolated and treated with GLP-1. Ob/ob mice sustained a reduction in the net weight gained during Exendin-4 treatment. Serum glucose and hepatic steatosis was significantly reduced in Exendin-4 treated ob/ob mice. Exendin-4 improved insulin sensitivity in ob/ob mice, as calculated by the homeostasis model assessment. The measurement of thiobarbituric reactive substances as a marker of oxidative stress was significantly reduced in ob/ob-treated mice with Exendin-4. Finally, GLP-1-treated hepatocytes resulted in a significant increase in cAMP production as well as reduction in mRNA expression of stearoyl-CoA desaturase 1 and genes associated with fatty acid synthesis; the converse was true for genes associated with fatty acid oxidation. In conclusion, Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Blood Glucose; Cyclic AMP; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Insulin Resistance; Lipid Peroxidation; Liver; Male; Mice; Mice, Obese; Peptides; PPAR alpha; Receptors, Glucagon; RNA, Messenger; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Venoms; Weight Gain

Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released in response to nutrient ingestion. Postprandial GLP-1 release has been reported to be attenuated in obese subjects, but reports on the effect of weight loss on GLP-1 are conflicting. The aim of the present study was to clarify the effect of a weight-loss period and a consecutive weight-maintenance period on nutrient-stimulated GLP-1 release in obese subjects. Nutrient-stimulated (standard breakfast; 1.9 MJ) GLP-1 release was investigated in thirty-two obese subjects on three occasions: before weight loss (T1) (BMI 30.0 (sd 2.5) kg/m(2)); after a 6-week very-low-energy diet (VLED) (T2) (BMI 27.6 (sd 2.3) kg/m(2)); after a 3-month weight-maintenance period (T3) (BMI 27.9 (sd 2.3) kg/m(2)). At each occasion, following a fasting blood sample the test meal was fed and blood was drawn every 30 min for 2 h relative to ingestion in order to determine plasma GLP-1, insulin, glucose and NEFA concentrations. Subjects lost 7 (sd 3.4) kg during the VLED (P<0.0001) and regained 1 (sd 3.2) kg during the weight-maintenance period (NS). The area under the curve for nutrient-stimulated plasma GLP-1 (pmol/l x h) was significantly decreased (P=0.01) at T2 (6.8 (sd 1)) compared with T1 (12.8 (sd 2.9)) and T3 (11.1 (sd 1.5)). Since we found a rebound of concentrations after a weight-maintenance period, decrease after weight loss seems to be transient and possibly due to a negative energy balance.

Topics: Adipose Tissue; Adult; Appetite; Blood Glucose; Body Composition; Body Mass Index; Body Weight; Diet; Energy Intake; Energy Metabolism; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Weight Loss

Inadequate islet adaptation to insulin resistance leads to glucose intolerance and type 2 diabetes. Here we investigate whether beta-cell cAMP is crucial for islet adaptation and prevention of glucose intolerance in mice. Mice with a beta-cell-specific, 2-fold overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (RIP-PDE3B/2 mice) were metabolically challenged with a high-fat diet. We found that RIP-PDE3B/2 mice early and rapidly develop glucose intolerance and insulin resistance, as compared with wild-type littermates, after 2 months of high-fat feeding. This was evident from advanced fasting hyperinsulinemia and early development of hyper-glycemia, in spite of hyperinsulinemia, as well as impaired capacity of insulin to suppress plasma glucose in an insulin tolerance test. In vitro analyses of insulin-stimulated lipogenesis in adipocytes and glucose uptake in skeletal muscle did not reveal reduced insulin sensitivity in these tissues. Significant steatosis was noted in livers from high-fat-fed wild-type and RIP-PDE3B/2 mice and liver triacyl-glycerol content was 3-fold higher than in wild-type mice fed a control diet. Histochemical analysis revealed severe islet perturbations, such as centrally located alpha-cells and reduced immunostaining for insulin and GLUT2 in islets from RIP-PDE3B/2 mice. Additionally, in vitro experiments revealed that the insulin secretory response to glucagon-like peptide-1 stimulation was markedly reduced in islets from high-fat-fed RIP-PDE3B/2 mice. We conclude that accurate regulation of beta-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adaptation, Physiological; Animals; Blood Glucose; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Diabetes Mellitus, Type 2; Dietary Fats; Gene Expression; Glucagon-Like Peptide 1; Glucose Transporter Type 2; Immunohistochemistry; Insulin; Insulin Resistance; Insulin-Secreting Cells; Liver; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Triglycerides

Topics: Adamantane; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Nitriles; Pyrrolidines; Randomized Controlled Trials as Topic; Vildagliptin

The aim of this study was to determine the role of fatty acid signalling in islet beta cell compensation for insulin resistance in the Zucker fatty fa/fa (ZF) rat, a genetic model of severe obesity, hyperlipidaemia and insulin resistance that does not develop diabetes.. NEFA augmentation of insulin secretion and fatty acid metabolism were studied in isolated islets from ZF and Zucker lean (ZL) control rats.. Exogenous palmitate markedly potentiated glucose-stimulated insulin secretion (GSIS) in ZF islets, allowing robust secretion at physiological glucose levels (5-8 mmol/l). Exogenous palmitate also synergised with glucagon-like peptide-1 and the cyclic AMP-raising agent forskolin to enhance GSIS in ZF islets only. In assessing islet fatty acid metabolism, we found increased glucose-responsive palmitate esterification and lipolysis processes in ZF islets, suggestive of enhanced triglyceride-fatty acid cycling. Interruption of glucose-stimulated lipolysis by the lipase inhibitor Orlistat (tetrahydrolipstatin) blunted palmitate-augmented GSIS in ZF islets. Fatty acid oxidation was also higher at intermediate glucose levels in ZF islets and steatotic triglyceride accumulation was absent.. The results highlight the potential importance of NEFA and glucoincretin enhancement of insulin secretion in beta cell compensation for insulin resistance. We propose that coordinated glucose-responsive fatty acid esterification and lipolysis processes, suggestive of triglyceride-fatty acid cycling, play a role in the coupling mechanisms of glucose-induced insulin secretion as well as in beta cell compensation and the hypersecretion of insulin in obesity.

Topics: Animals; Binding Sites; Colforsin; Fatty Acids, Nonesterified; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose; In Vitro Techniques; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Lactones; Lipase; Lipid Metabolism; Lipolysis; Models, Biological; Orlistat; Oxidation-Reduction; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

To review the pathophysiology of type 2 diabetes (T2DM), the role of incretins, the potential of incretin-based therapies to address unmet therapeutic needs in T2DM, and the potential impact this will have on the contribution of managed care pharmacy to diabetes therapy.. Diabetes, the fifth leading cause of death by disease in the United States, costs approximately $132 billion per year in direct and indirect medical expenses. According to the Centers for Disease Control and Prevention.s National Health and Nutrition Examination Survey, a majority of diabetes patients do not achieve target A1C levels with their current treatment regimens. Advances in understanding the pathophysiologic abnormalities underlying the metabolic dysfunctions associated with T2DM are leading to the development of new treatment approaches and new therapeutic classes of drugs. Novel incretin-based therapies currently available, and in late-stage development, are among those showing the greatest promise for addressing the unmet needs of traditional therapies.

Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Management; Drug Design; Drugs, Investigational; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycoproteins; Humans; Hypoglycemic Agents; Insulin Resistance; Managed Care Programs; Obesity; Prevalence

Glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important enteroendocrine hormones that are rapidly degraded by an ubiquitous enzyme dipeptidyl peptidase IV to yield truncated metabolites GIP(3-42) and GLP-1(9-36)amide. In this study, we investigated the effects of sub-chronic exposure to these major circulating forms of GIP and GLP-1 on blood glucose control and endocrine pancreatic function in obese diabetic (ob/ob) mice. A once daily injection of either peptide for 14 days had no effect on body weight, food intake or pancreatic insulin content or islet morphology. GLP-1(9-36)amide also had no effect on plasma glucose homeostasis or insulin secretion. Mice receiving GIP(3-42) exhibited small but significant improvements in non-fasting plasma glucose, glucose tolerance and glycaemic response to feeding. Accordingly, plasma insulin responses were unchanged suggesting that the observed enhancement of insulin sensitivity was responsible for the improvement in glycaemic control. These data indicate that sub-chronic exposure to GIP and GLP-1 metabolites does not result in physiological impairment of insulin secretion or blood glucose control. GIP(3-42) might exert an overall beneficial effect by improving insulin sensitivity through extrapancreatic action.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Eating; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Homeostasis; Immunohistochemistry; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Obese; Obesity; Organ Size; Peptide Fragments; Peptides; Receptors, Gastrointestinal Hormone

It has been proposed, that the dramatic amelioration of type 2 diabetes following Roux-en-Y gastric bypass (RYGBP) could by accounted for, at least in part, by changes in glucagon-like peptide-1 (GLP-1) secretion. However, human data supporting this hypothesis is scarce.. A 12-month prospective study on the changes in glucose homeostasis, and active GLP-1 in response to a standard test meal (STM) was conducted in 34 obese subjects (BMI 49.1+/-1.0 kg/m(2)) who had different degrees of glucose tolerance: normal glucose tolerance (NGT, n=12), impaired glucose tolerance (IGT, n=12), and type 2 diabetes (n=10).. At 6 weeks after RYGBP, despite the subjects still being markedly obese (BMI 43.5+/-0.9 kg/m(2)), fasting plasma glucose and HbA1c decreased in the 3 study groups (P<0.05). Insulin sensitivity improved, but was still abnormal in a comparable proportion of subjects among groups (P=0.717). When insulin secretion was accounted for the prevailing insulin sensitivity, an increase was found in subjects with diabetes (P<0.05) although it remained lower compared to NGT- and IGT-subjects (P<0.01). At 12 months follow-up, no differences among groups were found in the evaluated glucose homeostasis parameters. Compared to baseline, at 6 weeks the incremental AUC(0-120') of active GLP-1 in response to the STM increased in NGT and IGT (P<0.05) but not in subjects with diabetes (P=0.285). However, the GLP-1 response to a STM was comparable among groups at 12 months follow-up (P=0.887).. 1) RYGBP was associated with an improvement but not complete restoration of glucose homeostasis at 6 weeks after surgery. 2) GLP-1 is not a critical factor for the early changes in glucose tolerance.

Topics: Adult; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gastric Bypass; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Time Factors; Treatment Outcome; Weight Loss

To investigate early secretory defects in prediabetes, we evaluated beta-Cell function and insulin sensitivity (M value, by euglycemic clamp) in 26 normotolerant first-degree relatives of type 2 diabetic patients (FDR) and 17 age- and weight-matched control subjects. beta-Cell function was assessed by modeling analysis of glucose and C-peptide concentrations measured during 24 h of standardized living conditions. Fasting and total insulin secretion (ISR) were increased in FDR, as was ISR at a reference 5 mM glucose level (ISR5, 107 +/- 6 vs. 87 +/- 6 pmol x min(-1) x m(-2), P < 0.05). ISR5 was inversely related to M in controls (ISR5 = k/M1.23, rho = -0.74, P < 0.005) but not in FDR; when M was accounted for (by calculating a compensation index ISR5 x M1.23), compensation for insulin resistance was impaired in FDR (10.8 +/- 1.0 vs. 13.4 +/- 0.6 units, P < 0.05). Potentiation of ISR, expressing relative transient increases in glucose-stimulated ISR during meals, was impaired in FDR (1.29 +/- 0.08 vs. 1.62 +/- 0.08 during 1st meal, P < 0.02). Moreover, the potentiation time course was related to glucose-dependent insulin-releasing polypeptide (GIP) concentrations in both groups, and the sensitivity of potentiation to GIP derived from this relationship tended to be impaired in FDR. Compensation index, potentiation, and sensitivity to GIP were interrelated parameters (P < 0.05 or less). beta-Cell function parameters were also related to mean 24-h glucose levels (r2 = 0.63, P < 0.0001, multivariate model). In conclusion, although in absolute terms ISR is increased in insulin-resistant FDR, beta-cell function shows a cluster of interrelated abnormalities involving compensation for insulin resistance, potentiation, and sensitivity to GIP, suggesting a beta-cell defect in the amplifying pathway of insulin secretion.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet; Energy Intake; Family; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Linear Models; Male; Models, Biological; Multivariate Analysis; Peptide Fragments; Protein Precursors

Topics: Diabetes Mellitus, Type 2; Disease Progression; Exenatide; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Peptide Fragments; Peptides; Protein Precursors; Venoms

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.

Topics: Adamantane; Animals; Area Under Curve; Blood Glucose; Dietary Fats; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Oxidase; Glucose Tolerance Test; Insulin Resistance; Male; Nitriles; Pyrrolidines; Rats; Rats, Zucker; Tachyphylaxis; Time Factors; Vildagliptin; Weight Gain

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Infant, Newborn; Insulin Resistance; Lizards; Peptide Fragments; Peptides; Protein Precursors; Time Factors; Venoms

The G protein G(s)alpha is essential for hormone-stimulated cAMP generation and is an important metabolic regulator. We investigated the role of liver G(s)-signaling pathways by developing mice with liver-specific G(s)alpha deficiency (LGsKO mice). LGsKO mice had increased liver weight and glycogen content and reduced adiposity, whereas survival, body weight, food intake, and metabolic rates at ambient temperature were unaffected. LGsKO mice had increased glucose tolerance with both increased glucose-stimulated insulin secretion and increased insulin sensitivity in liver and muscle. Fed LGsKO mice were hypoglycemic and hypoinsulinemic, with low expression of hepatic gluconeogenic enzymes and PPARgamma coactivator-1. However, LGsKO mice maintained normal fasting glucose and insulin levels, probably due to prolonged breakdown of glycogen stores and possibly increased extrahepatic gluconeogenesis. Lipid metabolism was unaffected in fed LGsKO mice, but fasted LGsKO mice had increased lipogenic and reduced lipid oxidation gene expression in liver and increased serum triglyceride and FFA levels. LGsKO mice had very high serum glucagon and glucagon-like peptide-1 levels and pancreatic alpha cell hyperplasia, probably secondary to hepatic glucagon resistance and/or chronic hypoglycemia. Our results define novel roles for hepatic G(s)-signaling pathways in glucose and lipid regulation, which may prove useful in designing new therapeutic targets for diabetes and obesity.

Topics: Adiposity; Animals; Eating; Fasting; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; GTP-Binding Protein alpha Subunits, Gs; Hypoglycemia; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Lipid Metabolism; Liver; Male; Mice; Mice, Knockout; Mice, Transgenic; Oxygen Consumption; Signal Transduction

Surgical operations which shorten the intestinal tract between the stomach and the terminal ileum result in an early improvement in type 2 diabetes, and one possible explanation is the arrival of undigested food in the terminal ileum. This study was designed to evaluate the role of the distal ileum in the improvement of glucose control in type 2 diabetic patients who underwent bariatric surgery.. An ileal transposition (IT) to the jejunum was performed in lean diabetic Goto-Kakizaki (GK) rats. The IT was compared to sham-operated diabetic rats and a control group of diabetic rats. Non-diabetic controls were age-matched Sprague-Dawley (SD) rats, which underwent IT and no operation. Food intake and body weight were measured. An oral glucose tolerance test (OGTT) was performed 10 days before the operation and 10 days, 30 days and 45 days after the surgery. GLP-1 and insulin were measured during the OGTT 45 days after surgery. An insulin tolerance test (ITT) was performed 50 days after surgery.. Glucose tolerance improved in the IT diabetic group compared with both the sham-operated animals and control diabetic group 30 days and 45 days after surgery (P=0.029 and P=0.023, respectively). Insulin sensitivity, as measured by an ITT, was not significantly different between diabetic groups and the normal groups respectively after surgery. No differences in basal glucose and glucose tolerance were noted between non-diabetic operated animals and control non-diabetic rats. No differences were recorded between the diabetic rat groups and the non-diabetic rats in terms of weight and food intake. GLP-1 levels were significantly higher in the IT diabetic group compared with the sham-operated rats (P=0.05).. Ileal transposition is effective in inducing an improvement in glucose tolerance in lean diabetic rats without affecting weight and food intake. The possible mechanism underlying the early improvement of diabetes after bariatric surgery may be due to the action of the terminal ileum through an insulin-independent action.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Ileum; Insulin; Insulin Resistance; Jejunum; Male; Rats; Rats, Sprague-Dawley; Weight Gain

Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

Topics: Adipose Tissue; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Brain; Dose-Response Relationship, Drug; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Glycogen; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscles; Nuclear Proteins; Osmosis; Peptide Fragments; Phosphatidylinositol 3-Kinases; Phosphorylation; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Transcription Factors

Type 2 diabetic patients pass through a phase of impaired glucose tolerence and/or impaired fasting glucose known as 'prediabetic state'. Prediabetic state form a part of syndrome X, other components being obesity, hypertension, dyslipidaemia, hyperinsulinaemia and insulin resistance. The pathophysiology of prediabetes is similar to type 2 diabetes mellitus, two basic defects are insulin resistance and early beta cell failure. In prediabetes, the rapid oscillations of insulin secretion are lost and amplitude of large pulses are decreased. When insulin is delivered in a pulsatile fashion that mimics the normal rapid oscillation, its hypoglycaemic effects are greater. In prediabetes, the glycaemic excursions after each meal are high and early insulin responses to meals tend to be lower than normal but the second phase of insulin secretion is delayed and prolonged.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin; Insulin Resistance; Metabolic Syndrome; Prediabetic State

Whether glucagon-like peptide-1 (GLP-1) has insulin-independent effects on glucose disposal in vivo was assessed in conscious dogs by use of tracer and arteriovenous difference techniques. After a basal period, each experiment consisted of three periods (P1, P2, P3) during which somatostatin, glucagon, insulin, and glucose were infused. The control group (C) received saline in P1, P2, and P3, the PePe group received saline in P1 and GLP-1 (7.5 pmol.kg(-1).min(-1)) peripherally (Pe; iv) in P2 and P3, and the PePo group received saline in P1 and GLP-1 peripherally (iv) (P2) and then into the portal vein (Po; P3). Glucose and insulin concentrations increased to two- and fourfold basal, respectively, and glucagon remained basal. GLP-1 levels increased similarly in the PePe and PePo groups during P2 ( approximately 200 pM), whereas portal GLP-1 levels were significantly increased (3-fold) in PePo vs. PePe during P3. In all groups, net hepatic glucose uptake (NHGU) occurred during P1. During P2, NHGU increased slightly but not significantly in all groups. During P3, NHGU increased in PePe and PePo groups to a greater extent than in C, but no significant effect of the route of infusion of GLP-1 was demonstrated (16.61 +/- 2.91 and 14.67 +/- 2.09 vs. 4.22 +/- 1.57 micromol.kg(-1).min(-1), respectively).. GLP-1 increased glucose disposal in the liver independently of insulin secretion; its full action required long-term infusion. The route of infusion did not modify the hepatic response.

Topics: Animals; Blood Glucose; Dogs; Dose-Response Relationship, Drug; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Infusions, Intravenous; Insulin; Insulin Resistance; Liver; Male; Metabolic Clearance Rate; Peptide Fragments; Portal System; Protein Precursors

Plasma ghrelin is elevated in Prader-Willi syndrome (PWS). This might contribute to obesity or GH deficiency in such patients. Visceral adiposity and insulin resistance are reduced in PWS, which might lead to hyperghrelinemia. We measured fasting plasma ghrelin in control female (n = 39), PWS female (n = 12), and PWS male (n = 6) adults. In controls and PWS, ghrelin was negatively correlated with visceral adiposity, fasting insulin, and homeostasis model insulin resistance index. There was no significant correlation with serum IGF-I in PWS. In stepwise linear regression, visceral adiposity (P < 0.02) had a stronger inverse correlation with ghrelin than sc fat depots in controls and PWS, possibly through hyperinsulinemia, as the correlations with insulin resistance were even stronger (P < 0.01). PWS females had significantly (P < 0.001) elevated ghrelin (mean +/- SD, 661 +/- 360 pg/ml), compared with both nonobese (363 +/- 163) and obese (191 +/- 66) controls. Ghrelin was increased 3.4- to 3.6-fold in PWS females adjusting for total adiposity, 3.2- to 3.4-fold adjusting for visceral adiposity, and 3.0-fold adjusting for insulin resistance. Fasting plasma glucagon-like peptide-1 was normal in PWS females. The hyperghrelinemia in PWS adults is therefore not solely explained by their reduced visceral adiposity and relative hypoinsulinemia. Its cause and consequences await further elucidation.

Topics: Adipose Tissue; Adult; Case-Control Studies; Fasting; Female; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Male; Middle Aged; Peptide Fragments; Peptide Hormones; Prader-Willi Syndrome; Protein Precursors; Regression Analysis; Viscera

Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean +/- SD] years) and body mass index (BMI; 26.0 +/- 4.0 kg/m(2)) did not differ between the groups. Subjects with IGT displayed lower TIS during the initial 30 minutes after oral glucose (0.97 +/- 0.17 [mean +/- SEM] v 1.75 +/- 0.23 nmol/L in NGT; P =.018) and lower OGIS (397 +/- 21 v 463 +/- 12 mL/min/m(2); P =.005). The incremental 30-minute TIS times OGIS (reflecting insulin secretion in relation to insulin sensitivity) was significantly reduced in IGT (359 +/- 51 v 774 +/- 91 nmol/min/m(2), P =.001). This measure correlated inversely to the 2-hour glucose level (r = -0.71; P <.001). In contrast, TIS over the whole 180-minute period was higher in IGT (26.2 +/- 2.4 v 20.0 +/- 2.0 nmol/L; P =.035). Hepatic insulin extraction correlated linearly with OGIS (r = 0.71; P <.001), but was not significantly different between the groups although there was a trend with lower extraction in IGT (P =.055). Plasma levels of GLP-1 and GIP increased after oral glucose. Total secretion of these incretin hormones during the 3-hour test did not differ between the 2 groups. However, the 30-minute increase in GLP-1 concentrations was lower in IGT than in NGT (P =.036). We conclude that also in non-obese subjects with IGT, when adiposity is controlled for in relation to NGT, defective early insulin secretion after oral glucose is a key factor. This defective beta-cell function is associated with, and may be caused by, a reduced early GLP-1 response.

Topics: Administration, Oral; Area Under Curve; Blood Glucose; Body Weight; C-Peptide; Case-Control Studies; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Liver; Middle Aged; Peptide Fragments; Protein Precursors; Regression Analysis; Time Factors

The failing heart demonstrates a preference for glucose as its metabolic substrate. Whether enhancing myocardial glucose uptake favorably influences left ventricular (LV) contractile performance in heart failure remains uncertain. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with potent insulinotropic effects the action of which is attenuated when glucose levels fall below 4 mmol. We examined the impact of recombinant GLP-1 (rGLP-1) on LV and systemic hemodynamics and myocardial substrate uptake in conscious dogs with advanced dilated cardiomyopathy (DCM) as a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake.. Thirty-five dogs were instrumented and studied in the fully conscious state. Advanced DCM was induced by 28 days of rapid pacing. Sixteen dogs with advanced DCM received a 48-hour infusion of rGLP-1 (1.5 pmol x kg(-1) x min(-1)). Eight dogs with DCM served as controls and received 48 hours of a saline infusion (3 mL/d). Infusion of rGLP-1 was associated with significant (P<0.02) increases in LV dP/dt (98%), stroke volume (102%), and cardiac output (57%) and significant decreases in LV end-diastolic pressure, heart rate, and systemic vascular resistance. rGLP-1 increased myocardial insulin sensitivity and myocardial glucose uptake. There were no significant changes in the saline control group.. rGLP-1 dramatically improved LV and systemic hemodynamics in conscious dogs with advanced DCM induced by rapid pacing. rGLP-1 has insulinomimetic and glucagonostatic properties, with resultant increases in myocardial glucose uptake. rGLP-1 may be a useful metabolic adjuvant in decompensated heart failure.

Topics: Animals; Blood Glucose; Cardiac Pacing, Artificial; Cardiomyopathy, Dilated; Consciousness; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Energy Metabolism; Fatty Acids; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Clamp Technique; Heart Failure; Hemodynamics; Hyperinsulinism; Infusions, Intravenous; Insulin Resistance; Male; Myocardium; Oxygen Consumption; Peptide Fragments; Protein Precursors; Recombinant Proteins; Ventricular Dysfunction, Left

Topics: Acetanilides; Animals; Dogs; Energy Metabolism; Epoxy Compounds; Fatty Acids; Forecasting; Glucagon; Glucagon-Like Peptide 1; Glucose; Heart Failure; Humans; Insulin Resistance; Myocardium; Peptide Fragments; Piperazines; Protein Precursors; Ranolazine; Recombinant Proteins

We previously developed a canine model of central obesity and insulin resistance by supplementing the normal chow diet with 2 g cooked bacon grease/kg body weight. Dogs fed this fatty diet maintained glucose tolerance with compensatory hyperinsulinemia. The signal(s) responsible for this up-regulation of plasma insulin is unknown. We hypothesized that meal-derived factors such as glucose, fatty acids, or incretin hormones may signal beta-cell compensation in the fat-fed dog. We fed the same fat-supplemented diet for 12 wk to six dogs and compared metabolic responses with seven control dogs fed a normal diet. Fasting and stimulated fatty acid and glucose-dependent insulinotropic peptide concentrations were not increased by fat feeding, whereas glucose was paradoxically decreased, ruling out those three factors as signals for compensatory hyperinsulinemia. Fasting plasma glucagon-like peptide-1 (GLP-1) concentration was 2.5-fold higher in the fat-fed animals, compared with controls, and 3.4-fold higher after a mixed meal. Additionally, expression of the GLP-1 receptor in whole pancreas was increased 2.3-fold in the fat-fed dogs. The increase in both circulating GLP-1 and its target receptor may have increased beta-cell responsiveness to lower glucose. Glucose is not the primary cause of hyperinsulinemia in the fat-fed dog. Corequisite meal-related signals may be permissive for development of hyperinsulinemia.

Topics: Animals; Blood Glucose; Blotting, Northern; Dietary Fats; Dogs; Fasting; Fatty Acids, Nonesterified; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucose; Glucose Tolerance Test; Hyperinsulinism; Insulin; Insulin Resistance; Islets of Langerhans; Kinetics; Magnetic Resonance Imaging; Male; Obesity; Peptide Fragments; Receptors, Glucagon; Reverse Transcriptase Polymerase Chain Reaction

Although the incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), as well as glucagon and cortisol, are known to influence islet function, the role of these hormones in conditions of insulin resistance and development of type 2 diabetes is unknown. An interesting model for the study of hormonal perturbations accompanying marked insulin resistance without concomitant diabetes is myotonic dystrophy (DM1).. The work was carried out in an out-patient setting.. An oral glucose tolerance test was performed in 18 males with DM1 and 18 controls to examine the release of incretins and counter-regulatory hormones. Genetic analyses were also performed in patients.. We found that the increment in GLP-1 after oral glucose was significantly greater in patients, while there was no significant difference in GIP or glucagon responses between patients and controls, although long CTG repeat expansions were associated with a more pronounced GIP response. Interestingly, the GLP-1 response to oral glucose correlated with the insulin response in patients but not in controls whereas, in controls, the insulin response closely correlated with the GIP response. Furthermore, cortisol and ACTH levels increased paradoxically in patients after glucose; this was more pronounced in patients with long CTG repeat expansions.. This study showed that the GLP-1 and ACTH/cortisol responses to oral glucose are abnormal in insulin-resistant DM1 patients and that CTG triplet repeats are linked to GIP release. These abnormalities may contribute both to the severe insulin resistance and hyperinsulinemia in DM1 and to the preservation of adequate islet function, enabling glucose tolerance to be normal in spite of this marked insulin resistance in DM1.

Topics: Adult; Body Composition; DNA; Dose-Response Relationship, Drug; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Humans; Hydrocortisone; Insulin Resistance; Male; Middle Aged; Myotonic Dystrophy; Peptide Fragments; Regression Analysis; Repetitive Sequences, Nucleic Acid

The insulinotropic agent, exendin-4, is a long-acting analogue of glucagon-like peptide-1 (GLP-1) which improves glucose tolerance in humans and animals with diabetes, but the underlying mechanisms and the effects of exendin-4 on peripheral (muscle/fat) insulin action are unclear. Previous in vivo and clinical studies have been difficult to interpret because of complex, simultaneous changes in insulin and glucagon levels and possible effects on hepatic metabolism. Thus, the comparative effects of exendin-4 and GLP-1 on insulin-stimulated 2-[3H]deoxyglucose (2-DOG) uptake were measured in fully differentiated L6 myotubes and 3T3-adipocytes, including co-incubation with inhibitors of the PI-3-kinase (wortmannin) and mitogen-activated protein (MAP) kinase (PD098059) pathways. In L6 myotubes, there was a concentration-dependent and PI-3-kinase-dependent increase in insulin-stimulated 2-DOG uptake with exendin-4 and GLP-1, e.g. for exendin-4 the C(I-200) value (concentration of insulin required to increase 2-DOG uptake 2-fold) decreased from 1.3 +/- 1.4 x 10(-7)M (insulin alone, n=16) to 5.9 +/- 1.3 x 10(-8)M (insulin+exendin-4 0.1nM, n=18, P<0.03). A similar insulin-sensitizing effect was observed with exendin-4 in 3T3-adipocytes, but GLP-1 had no effect on adipocyte insulin sensitivity. In conclusion, this is the first direct evidence showing that exendin-4 increases insulin-stimulated glucose uptake in muscle and fat derived cells via a pathway that involves PI-3-kinase activation. Furthermore, the contrasting responses of exendin and GLP-1 in 3T3-adipocytes suggest that the peripheral insulin-sensitizing effect of exendin-4 (in contrast to the insulinotropic effect) does not involve the GLP-1 receptor pathway.

Topics: Animals; Drug Interactions; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucose; Insulin Resistance; Muscle, Skeletal; Peptide Fragments; Peptides; Phosphatidylinositol 3-Kinases; Protein Precursors; Rats; Tumor Cells, Cultured; Venoms

Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet.. In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 micromol/g body weight) was administered in the drinking water for an 8 week period.. DPPIV inhibition reduced plasma DPPIV activity to 0.01+/-0.03 mU/ml vs 3.26+/-0.19 mU/ml in controls (P<0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P=0.029) and in mice fed a high-fat diet (P=0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P<0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7+/-2.6 x 10(3) microm(2) in controls to 7.6+/-1.0 x 10(3) microm(2) (P=0.0019).. Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance.

Topics: Animals; Blood Glucose; Body Weight; Dietary Fats; Dipeptidyl Peptidase 4; Drinking; Eating; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Intolerance; Insulin; Insulin Resistance; Intubation, Gastrointestinal; Islets of Langerhans; Mice; Mice, Inbred C57BL; Nitriles; Organ Size; Peptide Fragments; Protease Inhibitors; Protein Precursors; Pyrrolidines; Time Factors

Topics: Amyloid; Animals; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Islet Amyloid Polypeptide; Leptin; Mice; Peptide Fragments; Protein Precursors; Tumor Necrosis Factor-alpha

Previous studies have indicated that the secretion of the intestinal satiety hormone glucagon-like peptide-1 (GLP-1) is attenuated in obese subjects.. To compare meal-induced response of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in obese and lean male subjects, to investigate the effect of a major weight reduction in the obese subjects, and to look for an association between these hormones and ad libitum food intake.. Plasma concentrations of intestinal hormones and appetite sensations were measured prior to, and every 30 min for 180 min after, ingestion of a 2.5 MJ solid test meal. Gastric emptying was estimated scintigraphically. An ad libitum lunch was served 3 h after the test meal.. Nineteen non-diabetic obese (body mass index (BMI) 34.1--43.8 kg/m(2)) and 12 lean (BMI 20.4--24.7 kg/m(2)) males. All obese subjects were re-examined after a mean stabilised weight loss of 18.8 kg (95% CI 14.4--23.2).. Total area under the GLP-1 response curve (AUC(total, GLP-1)) was lower in obese before and after the weight loss compared to lean subjects (P<0.05), although weight loss improved the response from 80 to 88% of that of the lean subjects (P=0.003). The GIP response was similar in obese and lean subjects. However, after the weight loss both AUC(total, GIP) and AUC(incremental, GIP) were lowered (P<0.05). An inverse correlation was observed between AUC(incremental, GIP) and energy intake at the subsequent ad libitum meal in all groups. In lean subjects ad libitum energy intake was largely predicted by the insulin response to the preceding meal (r(2)=0.67, P=0.001).. Our study confirmed previous findings of a reduced postprandial GLP-1 response in severely obese subjects. Following weight reduction, GLP-1 response in the obese subjects apparently rose to a level between that of obese and lean subjects. The data suggests that postprandial insulin and GIP responses are key players in short-term appetite regulation.

Topics: Absorptiometry, Photon; Adult; Appetite; Area Under Curve; Energy Intake; Gastric Emptying; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Obesity; Peptide Fragments; Postprandial Period; Satiation; Weight Loss

The Wistar fatty (WF) rat is a model of obese Type 2 diabetes mellitus (DM). These rats were bred by crossing Zucker fatty (ZF) and Wistar-Kyoto (WKY) rats. A homo-allelic leptin receptor gene mutation has been reported in ZF rats. We report here how these genetic factors contribute to plasma insulin regulation. The fasting plasma insulin levels were higher in WKY and Wistar lean (WL) rats than in Zucker lean (ZL) rats (p<0.05). The levels in WF and ZF rats were higher than in their respective lean littermates, WL and ZL rats (p<0.05). After intragastric glucose load, the plasma insulin increase was reduced upon pretreatment by intracerebroventricular (i. c.v.) methylatropine (an antagonist of the cholinergic receptor) injection in WL rats (p<0.05) but not in WF rats. Plasma glucagon-like peptide-1 (GLP-1) response to intragastric glucose load was not affected by methylatropine. After selective hepatic-vagotomy, plasma insulin levels increased in wild-type ZL rats (p<0.05). This increase was not observed in heterozygote ZL rats. Surprisingly, this response of plasma insulin was not shown in wild-type WL and WKY rats. ZF and WF rats did show a prominent decrease in insulin response (p<0.05). These results indicate that the genetic factor in ZF rats is associated with impaired vagal nerve-mediated control of insulin secretion. The genetic factor in WKY rats may diminish sensitivity to the vagal information of insulin release and contribute to insulin resistance. Therefore, we conclude that the presence of both genetic factors in a homo-allelic state is important to the development of DM in WF rats.

Topics: Animals; Atropine Derivatives; Blood Glucose; Carrier Proteins; Crosses, Genetic; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Injections, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Mutation; Obesity; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred WKY; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Vagotomy; Vagus Nerve

Insulin resistance syndrome has recently been described as a unifying hypothesis to explain the relationship between the many risk factors of coronary heart disease. Carbohydrate that is malabsorbed and fermented in the colon has been demonstrated to decrease insulin response to a glucose load and improve other risk factors associated with coronary heart disease, although the mechanism remains unclear. The object of the present study was to investigate whether this observation could be explained by the production of fermentation products induced by malabsorbed carbohydrate in the colon, or by stimulating the incretin glucagon-like peptide 1 (7-36) amide that is released from the large bowel. We used lactulose as a model for resistant starch carbohydrate. Ten insulin-resistant male volunteers, who had undergone previous coronary artery bypass grafting, volunteered to take part in the study and underwent 6 d of lactulose loading (15 g/d for 2 d and 30 g/d for 4 d). There was no significant change in insulin, glucose, free fatty acids, or glucagon-like peptide 1 (7-36) amide response to an oral glucose tolerance test following the lactulose despite a significant rise in breath hydrogen. Large bowel fermentation stimulated by lactulose appears to have no significant effect on insulin, glucose, free fatty acids, and glucagon-like peptide 1 (7-36) response in patients with coronary heart disease.

Topics: Aged; Blood Glucose; Coronary Disease; Fatty Acids, Nonesterified; Fermentation; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Intestinal Absorption; Intestine, Large; Lactulose; Male; Middle Aged; Peptide Fragments; Risk Factors

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Obesity; Peptide Fragments; Protein Precursors

Topics: Animals; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Papio; Peptide Fragments; Protein Precursors

We examined the dose-related net effects of glucagon-like peptide 1 (GLP-1) on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance in anesthetized mice. GLP-1 dose dependently potentiated insulin secretion after glucose administration, with the half-maximal effect at 1 nmol/kg. GLP-1 also dose dependently reduced the area under the glucose curve (AUC(glucose)) and increased the glucose elimination rate (K(G)) but did not affect the glucose effectiveness (S(G)). Furthermore, the insulin sensitivity index (S(I)) was reduced after administration of GLP-1. Because insulin secretion was stimulated to a larger degree than S(I) was reduced, the peptide increased the global disposition index (GDI = AUC(insulin) x S(I)). Matching plasma insulin levels after GLP-1 by exogenous insulin reproduced the influences of GLP-1 on AUC(glucose), K(G), S(I), and GDI. Finally, the GLP-1 receptor antagonist exendin-3-(9-39) inhibited the actions of GLP-1. We conclude that GLP-1 increases glucose tolerance in the mouse mainly by potently stimulating insulin secretion.

Topics: Animals; Blood Glucose; Dose-Response Relationship, Drug; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin Secretion; Mice; Mice, Inbred Strains; Peptide Fragments; Peptides; Protein Precursors

Mice with a targeted mutation of the gastric inhibitory polypeptide (GIP) receptor gene (GIPR) were generated to determine the role of GIP as a mediator of signals from the gut to pancreatic beta cells. GIPR-/- mice have higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after meal ingestion are not increased by high-fat diet in GIPR+/+ mice because of compensatory higher insulin secretion, they are significantly increased in GIPR-/- mice because of the lack of such enhancement. Accordingly, early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load in vivo, and because GIP plays an important role in the compensatory enhancement of insulin secretion produced by a high insulin demand, a defect in this entero-insular axis may contribute to the pathogenesis of diabetes.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Type 2; Dietary Fats; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Glucose Intolerance; Glucose Tolerance Test; Homeostasis; Injections, Intraperitoneal; Insulin; Insulin Resistance; Insulin Secretion; Intestines; Islets of Langerhans; Mice; Mice, Knockout; Models, Biological; Peptide Fragments; Protein Precursors; Receptors, Gastrointestinal Hormone

Insulin secretion in response to acetylcholine receptor activation by carbachol in insulin resistance induced by 12 weeks of high-fat diet in C57BL/6J mice is exaggerated. To study whether this persists after a longer period of time and also involves other non-glucose stimuli, we fed C57BL/6J mice a high-fat diet for 24 weeks. Both hyperinsulinemia (341 +/- 33 vs. 148 +/- 15 pmol/l) and slight hyperglycemia (7.8 +/- 0.2 vs. 6.1 +/- 0.1 mmol/l) were evident at this time point. The insulinotropic response to high dose carbachol (0.53 micromol/kg; 3403 +/- 377 vs. 1595 +/- 429 pmol/l), to the glucose analogue, 2-deoxyglucose (6 mmol/kg; 2014 +/- 315 vs. 1167 +/- 200 pmol/l), to cholecystokinin-8 (15.9 nmol/kg; 499 +/- 93 vs. 119 +/- 40 pmol/l) and to glucagon-like peptide-1 (32 nmol/kg; 307 +/- 86 vs. 71 +/- 9 pmol/l), were all exaggerated in mice given high-fat diet. In contrast, the insulin response to glucose was impaired. This shows that insulin resistance is accompanied by a general islet supersensitivity to non-glucose stimuli, which persists over a long period of time.

Topics: Animals; Antimetabolites; Blood Glucose; Body Weight; Carbachol; Deoxyglucose; Diet; Female; Glucagon; Glucagon-Like Peptide 1; Glucose; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Mice; Mice, Inbred C57BL; Muscarinic Agonists; Peptide Fragments; Protein Precursors; Sincalide; Stimulation, Chemical

Administration of the truncated glucagon-like peptide 1 (GLP-1) has been considered for treatment of noninsulin-dependent diabetes mellitus (NIDDM). We studied its antidiabetogenic mechanism by examining its influences on islet function and peripheral insulin sensitivity in six subjects (aged 56-74 yr) with well-controlled NIDDM. Islet function was evaluated with arginine stimulation at three plasma glucose levels (fasting, 14 mmol/L, and > 28 mmol/L). GLP-1 (1.5 pmol/kg per min iv) increased serum insulin levels at fasting glucose (P = 0.028), at 14 mmol/L glucose (P = 0.028), and at 28 mmol/L glucose (P = 0.028). The acute insulin response (AIR) to 5 g iv arginine was increased by GLP-1 at 14 mmol/L glucose (P = 0.028), and the slopeAIR, i.e., the glucose potentiation of insulin secretion, was markedly increased by GLP-1 (P = 0.028). Plasma glucagon levels were reduced by GLP-1 (P = 0.028), and arginine-stimulated glucagon secretion (AGR) was inhibited by GLP-1 at 14 (P = 0.046) and 28 mmol/L glucose (P = 0.028). Glucose-induced inhibition of arginine-stimulated glucagon secretion (slopeAGR) was not significantly affected by GLP-1. In contrast, GLP-1 did not affect the low insulin sensitivity during a hyperinsulinemic, euglycemic clamp. Thus, GLP-1 improves islet dysfunction in diabetes, mainly by increasing the glucose-induced potentiation of insulin secretion. In contrast, the peptide does not seem to improve insulin resistance in NIDDM.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Peptides