incretins and Metabolic-Syndrome

Equine insulin dysregulation (ID) comprises amplified insulin responses to oral carbohydrates or insulin resistance, or both, which leads to sustained or periodic hyperinsulinaemia. Hyperinsulinaemia is important in horses because of its clear association with laminitis risk, and the gravity of this common sequela justifies the need for a better understanding of insulin and glucose homoeostasis in this species. Post-prandial hyperinsulinaemia is the more commonly identified component of ID and is diagnosed using tests that include an assessment of the gastrointestinal tract (GIT). There are several factors present in the GIT that either directly, or indirectly, enhance insulin secretion from the endocrine pancreas, and these factors are collectively referred to as the enteroinsular axis (EIA). A role for key components of the EIA, such as the incretin peptides glucagon-like peptide-1 and 2, in the pathophysiology of ID has been investigated in horses. By comparison, the function (and even existence) of many EIA peptides of potential importance, such as glicentin and oxyntomodulin, remains unexplored. The incretins that have been examined all increase insulin responses to oral carbohydrate through one or more mechanisms. This review presents what is known about the EIA in horses, and discusses how it might contribute to ID, then compares this to current understanding derived from the extensive studies undertaken in other species. Future directions for research are discussed and knowledge gaps that should be prioritised are suggested.

Topics: Animals; Glucose; Horse Diseases; Horses; Hyperinsulinism; Incretins; Insulin; Insulin Resistance; Metabolic Syndrome

The prevalence of nonalcoholic liver disease (NAFLD) is increasing worldwide in conjunction with the epidemic increase in obesity and metabolic risk factors. Consequently, NAFLD has become a leading indication for liver transplantation. Although genetic factors play an important role in the pathogenesis of NAFLD, detrimental lifestyle trends favoring a calorically unrestricted diet rich in carbohydrates and unsaturated fat, prolonged sedentary periods or limited physical activity have major metabolic implications. In aggregate these physiological dysregulations constitute the main risk factors for the metabolic syndrome and NAFLD. The cornerstone of the treatment of NAFLD, is lifestyle changes, including modifications to diet and physical activity, to reduce body weight and liver fat, however adherence is notoriously poor and the epidemic of NAFLD continues to grow unimpeded. In the face of this unmet clinical need, the pharmacologic therapy of NAFLD has been expanding as the varied mechanistic pathways of NAFLD are elucidated. Beyond these approaches to treating NAFLD, the prevention of other liver diseases is additionally important. Chief among these is alcoholic liver disease, and heavy use is detrimental irrespective of underlying NAFLD. However, the impact of mild to moderate alcohol use in patients with mild or nonadvanced forms NAFLD is undefined. This article summarizes the results of the International Liver Transplantation Society consensus meeting on NAFLD in liver transplantation. It describes the available evidence and provides consensus guidance on the lifestyle and pharmacologic therapies of NAFLD, and the consensus position on alcohol use in patients with NAFLD.

Topics: Alcohol Drinking; Antioxidants; Bariatric Surgery; Comorbidity; Consensus Development Conferences as Topic; Diet, Carbohydrate Loading; Exercise; Healthy Lifestyle; Humans; Hypoglycemic Agents; Incretins; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Transplantation; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Obesity; Patient Compliance; Practice Guidelines as Topic; Prevalence; Risk Factors; Weight Loss

In recent years, many studies have related gut microbiome to development of highly prevalent diseases such as type 2 diabetes and obesity. Obesity itself is associated to changes in the composition of gut microbiome, with a trend to an overgrowth of microorganisms more efficiently obtaining energy from diet. There are several mechanisms that relate microbiota to the onset of insulin resistance and diabetes, including changes in bowel permeability, endotoxemia, interaction with bile acids, changes in the proportion of brown adipose tissue, and effects associated to use of drugs like metformin. Currently, use of pro and prebiotics and other new techniques such as gut microbiota transplant, or even antibiotic therapy, has been postulated to be useful tools to modulate the development of obesity and insulin resistance through the diet.

Topics: Adipose Tissue, Brown; Bacterial Physiological Phenomena; Butyrates; Diabetes Mellitus, Type 2; Disease Susceptibility; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Humans; Incretins; Insulin Resistance; Insulin-Secreting Cells; Metabolic Syndrome; Microbiota; Obesity; Prebiotics; Probiotics; Species Specificity

Adipose tissue is an endocrine organ that secretes a number of hormones and metabolically active substances that impact energy metabolism and insulin sensitivity. These inflammatory markers are collectively referred to as adipocytokines, or adipokines. Adipose tissue's functional capacity and metabolic activity vary among individuals, thus partly explaining the incomplete overlap between obesity and the metabolic syndrome. The functional failure of adipose tissues results in changed energy delivery and impaired glucose consumption, triggering self-regulatory mechanisms to maintain homeostasis. Antihyperglycemic, hypolipidemic, antiobesity, and angiotensin II receptor blocker drugs influence adipokine levels in different ways. However, clinical data are still scarce and the clinical relevance of these effects needs to be fully determined.

Topics: Adipokines; Adipose Tissue; Animals; Anti-Obesity Agents; Azetidines; Ezetimibe; Fibric Acids; Glucose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Insulin; Insulin Resistance; Lipids; Lipoproteins; Metabolic Syndrome; Metformin; Niacin; Thiazolidinediones

The metabolic syndrome (MetS) is associated with a higher risk for both, type 2 diabetes mellitus and cardiovascular disease. The cornerstone of treatment is lifestyle modification, encompassing weight reduction and physical exercise. However, pharmacotherapy is usually also required to achieve the recommended target values for the various components of the MetS, such as hypertension, dysglycemia and dyslipidemia. Regarding lipid treatment, statins are the main therapeutic agents while in blood pressure control a significant amount of pathophysiological and clinical evidence would suggest the use, as first line agents, of ACE inhibitors or angiotensin receptor blockers. Metformin seems to be the drug of choice for dysglycemia, specially since recent evidence questions the safety of thiazolidinediones. New drugs, targeting multiple components of the MetS, are under development but no data are currently available regarding their long-term efficacy and safety profile. In general, a multifactorial approach is recommended to decrease cardiovascular risk in patients with the MetS.

Topics: Acarbose; Cardiovascular Diseases; Drug Combinations; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Hypolipidemic Agents; Incretins; Insulin; Metabolic Syndrome; Metformin; Risk Reduction Behavior; Thiazolidinediones

Incretin peptides are a group of gastrointestinal hormones that play a prominent role in the regulation of glucose metabolism. Incretin-based therapies (IBTs) have recently emerged as an important treatment option for patients with type 2 diabetes mellitus (T2DM). These pharmaceutical agents may be specially well suited for patients who are overweight or obese with primarily post-meal glucose peaks, and in whom traditional first-line oral agents have failed to maintain adequate glycemic control. There are 2 classes of IBTs: the dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide 1 (GLP-1) receptor agonists. The ultimate effect of both types of agents is to augment GLP-1 signaling, which results in enhanced glucose-dependent insulin secretion, inhibition of glucagon secretion and decreased appetite. This leads to improved regulation of glucose homeostasis accompanied by either no increase in body weight (with DPP-4 inhibitors) or a reduction (with GLP-1 receptor agonists). GLP-1 inhibits food intake and the increased GLP-1 response may contribute as a satiety signal. Although data regarding the effect of GLP-1 agonists and DPP-4 inhibitors on levels of peptides involved in the regulation of food intake in T2DM are few, an indirect effect of IBT on weight loss is possible (e.g. Exendin-4 induces adiponectin secretion in vitro). Results from animal models indicate reduction of food intake and body weight by GLP-1 agonists, but follow-up studies are required. A growing amount of evidence suggests that these peptides may also impact the cardiovascular system, including beneficial effects on myocardial cells, lipid profiles and blood pressure as well as reduced markers of systemic inflammation and improved endothelial dysfunction. The potential role of these agents in improving components of the metabolic syndrome and retardation of atherosclerosis needs to be fully elucidated. Although IBTs are currently recommended only for use in the early treatment of T2DM, the 'non-glycemic' actions of these drugs may have far reaching therapeutic implications. It is hoped that future studies will elucidate their potential strengths and weaknesses for use in various metabolic conditions.

Topics: Animals; Atherosclerosis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Incretins; Inflammation; Lipoproteins; Metabolic Syndrome

Psoriasis is a chronic inflammatory skin disease with a global prevalence of 2-3%. In recent years it has been established that patients with psoriasis carry an increased risk of type 2 diabetes, but the underlying pathophysiological mechanisms remain unclear. The association is most likely due to a combination of shared genes, immunoinflammatory mechanisms and a number of diabetes risk factors in patients with psoriasis. The current review summarises the evidence in the field and calls for attention on diabetes risk assessment, preventive measures and treatment in patients with psoriasis.

Topics: Alcohol Drinking; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucocorticoids; Humans; Incretins; Metabolic Syndrome; Obesity; Psoriasis; Risk Factors; Smoking

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

Incretin hormones are peptides that are secreted from endocrine cell of gastrointestinal tract after nutrient ingestion and stimulate insulin secretion. Glucosodependent Insulinotropic Peptide--GIP is released from K-cells of duodenum and proximal jejunum, recently GIP synthesis has been proved in pancreatic alpha cells. Besides the incretin effect causes GIP increased lipogenesis and decreased lipolysis in fat tissue, increased bone formation and decreased resorption and has protective and proliferative effect on CNS neurons. Both GIP agonists (to treat diabetes) and antagonist (to treat obesity) are being studied. Another incretin hormone is derived in intestinal I-cells by posttranslational processing of proglucagon--glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). GLP-1 stimulates insuline production and inhibits glucagon secretion, exerts proliferative and antiapoptotic effect on beta-cells. Via receptors on vagal nerve and central mechanisms decreases food intake and decreases body weight. By deceleration of gastric emptying it attenuates increases in meal-associated blood glucose levels. It exerts cardioprotective effects. GLP-1 receptors have been proved in liver recently but decreased liver glucose production and increased glucose uptake by liver and muscle are mediated indirectly by altering insulin and glucagons levels. GLP-2 stimulates enterocytes proliferation, up-regulates intestinal nutrient transport, improves intestinal barrier function, and inhibits gastric and intestinal motility. GLP-2 also reduces bone resorption.

Topics: Gastrointestinal Tract; Humans; Incretins; Metabolic Syndrome

Incretin therapy includes treatment with incretin analogues (exenatid and liraglutid) and so called incretin enhancers (gliptins and DPP-4 inhibitors respectively--sitagliptin, vildagliptin, saxagliptin, linagliptin). In patients with type 2 diabetes, this novel antidiabetic treatment usually leads to successful reduction in fasting as well as postprandial glycaemia and glycosylated haemoglobin. At the same time, it importantly improves all components of metabolic syndrome (dyslipidemia, hypertension, systemic inflammation). Incretin analogues also reduce body weight while DPP-4 inhibitors are weight-neutral. Both groups of drugs are expected to have positive cardiovascular effects, although it is not clear whether these are likely to be direct or indirect, i.e. facilitated by improved compensation of metabolic syndrome components.

Topics: Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Humans; Incretins; Metabolic Syndrome

Topics: Glucagon-Like Peptides; Humans; Incretins; Metabolic Syndrome

Rates of type 2 diabetes, obesity and their associated detrimental cardiovascular effects are rapidly increasing. Despite the availability of several treatment options for type 2 diabetes and the use of intensive regimens combining several antidiabetic drugs, less than one-half of all patients reach a target glycosylated hemoglobin level of less than 7%. Disease progression due to ongoing deterioration of pancreatic islet cell health and beta-cell function is likely responsible. Therefore, there is a need to identify new pharmacological compounds that may not only treat hyperglycemia, but may also correct impaired glucose homeostasis and preserve endogenous beta-cell function. Identification and characterization of the incretin system and its effect on glucose homeostasis have resulted in the development of new antidiabetic agents that target these concerns. The current review examines the incretin effect and the pharmacological agents that have been developed based on the understanding of this physiological system. The influence of incretins on the cardiovascular system beyond the proatherogenic effect of type 2 diabetes will also be discussed.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Incretins; Metabolic Syndrome

A link between diabetes mellitus (DM) and heart failure (HF) has been well-recognized for more than a century. HF is also closely linked to abnormal glucose regulation (AGR) and insulin resistance (IR) in patients without DM and, similarly, these conditions commonly coexist. In epidemiological studies, each condition appears to predict the other. The prevalence of AGR/IR in HF patients without DM is significantly underrecognized and, as yet, the optimal method for screening for these abnormalities in the outpatient setting is unclear.. The purpose of this review is to overview the prevalence and prognostic impact of AGR and IR in HF patients without DM and discuss potential pathophysiological pathways that link these conditions with HF. The severity of glucose intolerance in patients with HF correlates with functional and clinical severity of HF and is an independent predictor of an adverse outcome. It is thought that changes in cardiac metabolism, including a switch from glucose metabolism toward fatty acid metabolism, may in part contribute to the pathophysiological processes associated with HF patients with AGR/IR.. We discuss how pharmacological targeting of metabolic pathways in the myocardium of these patients with HF may represent novel therapeutic strategies in these at-risk patients.

Topics: Blood Glucose; Fatty Acids; Glucose Intolerance; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Insulin Resistance; Metabolic Syndrome; Metformin; Myocardium; Prognosis; Risk Factors; Treatment Outcome

Many data are available on the epidemiology of type 2 diabetes in France (ENTRED 2007, DIABASIS 2008). It is currently estimated that 2.2 million people (3.8% of the population) have type 2 diabetes, with a higher prevalence among those with lower socioeconomic status. Ninety-five per cent of patients are over 45 years of age, 52% are male, 71% are overweight, 54% have hypertension, 18% have elevated LDL cholesterol, 19% have elevated triglyceride levels, and 13% are smokers. The main complications are cardiac (16.7%), retinal (16.6%), and renal disorders (elevated plasma creatinine in 19%), and foot ulcers (9.9%). HbA1c values exceed 7% in 41% of cases. Most patients are treated by general practitioners (93%), while 20% are followed by a diabetologist. Education is provided more often by hospital diabetologists (71%) than by general practitioners (11%). Nine out of ten patients are treated with oral antidiabetic drugs, consisting of metformin (62%), sulfonylurea (50%), glitazones (13%), glinides (8%), and alpha glucosidase inhibitors (8%), usually alone (43%) or in dual-agent combinations (29%). Insulin is prescribed to 17% of patients, an average of 13.8 years after initial diagnosis. Three-quarters of patients are prescribed antihypertensives, 47% statins and 40% antiplatelet drugs. One-third of patients are poorly adherent to their treatment and three-quarters experience adverse effects. Only one-quarter of patients follow dietary measures. The estimated annual per-patient cost of type 2 diabetes is 5400 euros, a sum that is fully reimbursed in 89% of cases. Patient management in France started to improve markedly in 2001 (ENTRED 2001), with more attention being paid to risk factors, and more widespread use of antihypertensive drugs, statins and antiplatelet agents. If the dramatic increase in the incidence of type 2 diabetes is to be reversed, patients at risk must be identified and managed earlier. In particular, plasma glucose levels must be determined regularly in all people over 45 years of age and in all subjects at risk of diabetes. Management of hyperglycemia and other risk factors must be more aggressive and adapted to disease progression. Patient follow-up must be improved, taking in account the entire healthcare infrastructure, and especially structures involved in the treatment of obesity and diabetes.

Topics: Adult; Aged; Bariatric Surgery; Combined Modality Therapy; Comorbidity; Cost of Illness; Diabetes Mellitus, Type 2; Diet, Diabetic; Exercise Therapy; Female; France; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidence; Incretins; Male; Metabolic Syndrome; Middle Aged; Obesity; Patient Compliance; Risk Factors; Socioeconomic Factors

Treatment of type 2 diabetes (T2DM) is based on lifestyle changes and oral antidiabetic agents or insulin. The UKPDS study has confirmed metformin (Met) as the initial monotherapy. Accordingly, Met is widely regarded as the first drug of choice for most patients with T2DM. Safety and efficacy of sulphonylureas (SU) have been confirmed by several clinical trials. Recently, thiazolidinediones (TZD) have addressed some aspects of insulin-resistance that characterized several T2DM patients. However, SU and TZD are associated with various side effects that limit their use in many patients. New agents have been recently developed which potentiate the activity of the incretin (GLP1). GLP1, a gut hormone secreted in response to meal ingestion, is rapidly degraded by dipeptidylpeptidase-4 (DPP-4). GLP1 enhances insulin secretion and inhibits glucagon secretion in a glucose-dependent manner, delays gastric emptying and, in animal studies, preserves beta-cell mass by reducing apoptosis and stimulates of beta-cell proliferation. GLP1 levels are abnormally low in T2DM patients. Two classes of agents based on GLP1 have been launched: DPP-4 inhibitors and DPP-4 resistant GLP1 analogues. Randomized studies confirmed their efficacy to improve glycemic control in T2DM patients. Orally administered DPP-4 inhibitors reduce HbA1c by 0.5-1.1%, without hypoglycaemic events and no weight gain. The sub-cutaneous injected GLP1 analogues (exenatide and liraglutide) show larger reductions in HbA1c by 0.8-1.7% and weight loss but are associated with gastrointestinal side effects contributing to a significant treatment interruption. Several studies support the use of DPP-4 inhibitors in combination with Met as a promising second line treatment.

Topics: Administration, Oral; Diabetes Mellitus, Type 2; Glucagon; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Metabolic Syndrome; Metformin; Piperidines; Pyrazoles; Rimonabant; Safety; Sulfonylurea Compounds; Thiazolidinediones

In recent years new pharmacological agents have emerged, which enable us to widen the spectrum of diabetes management based on clear pathophysiological concepts. One should first of all mention the DPP4-inhibitors and the incretin mimetics, which have the potential of restoring the incretin effect in patients with type 2 diabetes mellitus. Moreover, it has been shown that the agent rimonabant, which was first used in order to achieve weight reduction, also contributed to the significant improvement of metabolic syndrome's parameters. Recent studies have shown that the dual alpha/gamma-PPAR-agonists have serious adverse effects. The thiazolidinediones (glitazones) significantly improve insulin sensitivity, diminish fat accumulation in the liver and increase circulating levels of adiponectin. Various adverse effects of glitazones have been described in recent studies. In the near future one should await the discovery of more oral antidiabetic agents acting through modulation of important enzymes in glucose metabolism and transport pathways.

Topics: Adverse Drug Reaction Reporting Systems; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Fractures, Spontaneous; Humans; Hypoglycemic Agents; Incretins; Male; Metabolic Syndrome; PPAR alpha; PPAR gamma; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

Full-fat dairy milk may protect against cardiometabolic disorders, due to the milk fat globule membrane (MFGM), through anti-inflammatory and gut-health-promoting activities. We hypothesized that a MFGM-enriched milk beverage (MEB) would alleviate metabolic endotoxemia in metabolic syndrome (MetS) persons by improving gut barrier function and glucose tolerance. In a randomized crossover trial, MetS persons consumed for two-week period a controlled diet with MEB (2.3 g/d milk phospholipids) or a comparator beverage (COMP) formulated with soy phospholipid and palm/coconut oil. They then provided fasting blood and completed a high-fat/high-carbohydrate test meal challenge for evaluating postprandial metabolism and intestinal permeability. Participants had no adverse effects and achieved high compliance, and there were no between-trial differences in dietary intakes. Compared with COMP, fasting endotoxin, glucose, incretins, and triglyceride were unaffected by MEB. The meal challenge increased postprandial endotoxin, triglyceride, and incretins, but were unaffected by MEB. Insulin sensitivity; fecal calprotectin, myeloperoxidase, and short-chain fatty acids; and small intestinal and colonic permeability were also unaffected by MEB. This short-term study demonstrates that controlled administration of MEB in MetS persons does not affect gut barrier function, glucose tolerance, and other cardiometabolic health biomarkers, which contradicts observational evidence that full-fat milk heightens cardiometabolic risk. Registered at ClinicalTrials.gov (NCT03860584).

Topics: Adult; Animals; Biomarkers; Cardiovascular Diseases; Cross-Over Studies; Endotoxemia; Endotoxins; Glucose; Humans; Incretins; Lecithins; Metabolic Syndrome; Milk; Phospholipids; Triglycerides

Liraglutide, a GLP-1 analogue, exerts several beneficial non-glycemic effects in patients with type-2 diabetes (T2DM), such as those on body weight, blood pressure, plasma lipids and inflammation markers. However, the effects of liraglutide on cardiovascular (CV) risk markers in subjects with the metabolic syndrome (MetS) are still largely unknown. We herein explored its effects on various cardio-metabolic risk markers of the MetS in subjects with T2DM.. We performed an 18-month prospective, real-world study. All subjects had T2DM and the MetS based on the AHA/NHLBI criteria. Subjects with a history of a major CV event were excluded. One hundred-twenty-one subjects (71 men and 50 women; mean age: 62 ± 9 years) with T2DM and the MetS, who were naïve to incretin-based therapies and treated with metformin only, were included. Liraglutide (1.2 mg/day) was added to metformin (1500-3000 mg/day) for the entire study. Fasting plasma samples for metabolic parameters were collected and carotid-intima media thickness (cIMT) was assessed by B-mode real-time ultrasound at baseline and every 6 months thereafter.. There was a significant reduction in waist circumference, body mass index, fasting glycemia, HbA1c, total- and LDL-cholesterol, triglycerides, and cIMT during the 18-month follow-up. Correlation analysis showed a significant association between changes in cIMT and triglycerides (r = 0.362; p < 0.0001). The MetS prevalence significantly reduced during the study, and the 26% of subjects no longer fulfilled the criteria for the MetS after 18 months.. Liraglutide improves cardio-metabolic risk factors in subjects with the MetS in a real-world study. Trial Registration ClinicalTrials.gov: NCT01715428.

Topics: Aged; Biomarkers; Carotid Artery Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Echocardiography, Doppler, Color; Female; Humans; Hypoglycemic Agents; Incretins; Italy; Liraglutide; Male; Metabolic Syndrome; Metformin; Middle Aged; Predictive Value of Tests; Prevalence; Prospective Studies; Risk Factors; Treatment Outcome

We hypothesize that type 2 diabetic patients with different phenotypes may show different response to incretin-based therapies. Therefore, we tested whether the presence of metabolic syndrome (MS) influences glycemic response to these drugs. We prospectively followed 211 patients, treated with the GLP-1 analog exenatide (n = 102) or a DPP-4 inhibitor (n = 109) for at least 4 months. Treatment was decided on clinical grounds. We collected baseline data (age, sex, BMI, waist, systolic and diastolic blood pressure, lipid profile, data on diabetic complications and concomitant treatment) and HbA1c at subsequent visits. Patients were divided into groups according to the presence/absence of MS. Compared to patients on exenatide, patients on DPP-4 inhibitors were older and had lower BMI, waist, diastolic blood pressure, fasting plasma glucose, and HbA1c. At means of baseline values, HbA1c reduction was similar in patients treated with exenatide or DPP-4 inhibitors. Patients on exenatide showed significantly higher HbA1c reduction if they had MS (-1.55 ± 0.22%; n = 88) than if they had not (-0.34 ± 0.18%; P = 0.002). Conversely, patients on DPP-4 inhibitors showed significantly lower HbA1c reduction if they had MS (-0.60 ± 0.12%; n = 73) than if they had not (-1.50 ± 0.24%; P < 0.001). Type of MS definition (ATP-III, IDF or WHO) poorly influenced these trends. The interaction between type of therapy (exenatide vs. DPP-4 inhibitors) and MS remained significant after adjusting for age, baseline HbA1c, BMI, and concomitant medications. In conclusion, the presence of MS appears to modify the response to incretin-based therapies. Given the non-randomized nature of this study, these data need to be replicated.

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Male; Metabolic Syndrome; Middle Aged; Nitriles; Peptides; Prognosis; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms; Vildagliptin

Survivors of pediatric hematopoietic stem cell transplantation (HSCT) have increased risk of developing metabolic syndrome (MetS), but the mechanisms are poorly understood.. We aimed to test the hypothesis that insufficient secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) plays a pathogenetic role in HSCT survivors with MetS.. This cross-sectional cohort study, conducted at the Danish national referral center for HSCT, studied 42 male HSCT survivors (median age 28.9 years) for a median 21.2 years from HSCT, along with 15 age- and sex-matched healthy controls. Main outcome measures were glucose metabolism and incretin hormones (by oral glucose tolerance test [OGTT]) and MetS criteria. The hypothesis was formulated before data collection.. GLP-1, GIP, and glucagon during an OGTT were similar in patients and controls, with no overall difference between survivors with (24%) and without MetS. However, fasting glucagon was significantly higher in patients with hypertriglyceridemia (mean difference [MD]: 6.1 pmol/L; 95% CI, 1.5-10.8; P = 0.01), and correlated with HDL (MD: 4.7 mmol/L; 95% CI, -0.6 to 9.9; P = 0.08), android-gynoid ratio (correlation coefficient [r] = 0.6, P = 0.0001) and waist-hip ratio (r = 0.5, P = 0.002). A similar pattern was seen for GIP, correlating positively with triglyceride (MD: 60%; 95% CI, 44-82; P = 0.002). GIP levels were significantly increased in patients treated with total body irradiation (TBI) (MD: 165%; 95% CI, 118-230; P = 0.004), which was found to be a significant risk factor for MetS.. This study demonstrates an altered production of incretin hormones in HSCT survivors previously treated with TBI, developing dyslipidemia and abdominal adiposity.

Topics: Adult; Blood Glucose; Child; Cross-Sectional Studies; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Hematopoietic Stem Cell Transplantation; Humans; Incretins; Insulin; Male; Metabolic Syndrome; Survivors

Incretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Lipids; Metabolic Syndrome; Receptors, Gastrointestinal Hormone; Treatment Outcome

The oral glucose test (OGT) is a useful tool for diagnosing insulin dysregulation (ID) and is somewhat repeatable in ponies under consistent management. This study aimed to determine whether the insulin and incretin responses to an OGT in ponies differed after short-term access to fertilised pasture, compared to unfertilised pasture, by using a randomised, repeated measures study design. Sixteen mixed-breed ponies were classified as severely insulin-dysregulated (SD; post-prandial insulin ≥80 μIU/mL) or not severely insulin-dysregulated (NSD; post-prandial insulin < 80 μIU/mL) using an OGT prior to the study. The ponies accessed pasture that was fertilised, or unfertilised, for 5 days (4 h/day, with supplemental hay provided at 0.7% bodyweight), with a 10 day period between phases. An OGT was performed after each phase. Glucose, insulin, active glucagon-like peptide-1 (aGLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured in post-prandial blood samples.. The volume of fertilised pasture was five-fold greater than unfertilised pasture, with % non-structural carbohydrates (NSC) similar between all forages. Consuming fertilised pasture increased (P = 0.018) the serum insulin response to an OGT, compared to grazing unfertilised pasture. A limitation of the study was that pasture intake was unable to be quantified. Insulin responses were greater in SD, compared to NSD, ponies (P < 0.001) and remained well above the test cut-off at all times. A subset of ponies, initially screened as NSD, became (more) insulin-dysregulated after pasture access. Further, aGLP-1 was a significant predictor of insulin concentration in this cohort.. Whereas some insulin-dysregulated ponies were comparatively resistant to dietary intervention, others showed markedly different OGT responses following subtle changes in their forage-based diet. This implies that mild/early ID might be unmasked by dietary change, and that dietary management is important in these ponies. However, dietary management alone may not be adequate for all cases of ID.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Cross-Over Studies; Diet; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Horse Diseases; Horses; Hyperinsulinism; Incretins; Insulin; Metabolic Syndrome; Peptide Fragments; Queensland; Random Allocation

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

Metabolic syndrome increases the risk of cardiovascular disease. Recently glucagon-like peptide 1 (GLP-1) agonists proved to be effective in preventing cardiovascular disease (CVD) in patients with type 2 diabetes. We investigated the association of blood incretin levels with metabolic syndrome in patients with type 2 diabetes.. This is a cross-sectional study involving 334 people with type 2 diabetes. Intact GLP-1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 min after ingestion of a standard mixed meal. Metabolic syndrome was diagnosed based on the criteria of the International Diabetes Federation.. Two hundred twenty-five (69%) of the subjects have metabolic syndrome. The fasting iGLP-1 level was no different between groups. Thirty-min postprandial iGLP-1 was non-significantly lower in the subjects who had metabolic syndrome. Incremental iGLP-1 (ΔiGLP-1, the difference between 30-min postmeal and fasting iGLP-1 levels) was significantly lower in those with metabolic syndrome. There were no significant differences in fasting iGIP, postprandial iGIP, and ΔiGIP between groups. The ΔiGLP-1, but not ΔiGIP levels decreased significantly as the number of metabolic syndrome components increased. In hierarchical logistic regression analysis, the ΔiGLP-1 level was found to be a significant contributor to metabolic syndrome even after adjusting for other covariates.. Taken together, the iGLP-1 increment in the 30 min after meal ingestion is inversely associated with metabolic syndrome in patients with type 2 diabetes. This suggests that postmeal iGLP-1 increment could be useful in assessing cardiovascular risk in type 2 diabetes.

Topics: Aged; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Male; Metabolic Syndrome; Middle Aged; Postprandial Period; Risk

To compare the effect of different hypoglycemic drugs on laboratory and ultrasonographic markers of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes not controlled on metformin alone.. Prospective study of diabetic patients treated with metformin in combination with gliclazide, pioglitazone, sitagliptin, exenatide, or liraglutide. NAFLD was assessed by abdominal ultrasound and NAFLD fibrosis score was calculated at baseline and 6 months.. Fifty-eight patients completed 6 months of follow-up: 15 received gliclazide, 13 pioglitazone, 15 sitagliptin, 7 exenatide, and 8 liraglutide. NAFLD affected 57.8% of patients at baseline, and its ultrasonographic course varied depending on changes in weight (P=.009) and waist circumference (P=.012). The proportions of patients who experienced ultrasonographic improvement in the different treatment groups were: 33.3% with gliclazide, 37.5% with pioglitazone, 45.5% with sitagliptin, 80% with exenatide, and 33% with liraglutide (P=.28).. Qualitative ultrasonographic NAFLD improvement in diabetic patients treated with metformin in combination with other hypoglycemic drugs is associated to change over time in weight and waist circumference. Long-term clinical trials are needed to assess whether incretin therapies result in better liver outcomes than other hypoglycemic therapies.

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Gliclazide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Lipids; Liraglutide; Liver Function Tests; Male; Metabolic Syndrome; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptides; Pilot Projects; Pioglitazone; Prospective Studies; Sitagliptin Phosphate; Thiazolidinediones; Venoms; Waist Circumference

Topics: Anti-Obesity Agents; Comorbidity; Female; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Male; Metabolic Syndrome; Obesity; Treatment Outcome; Weight Loss

The incretin system has been shown to stimulate insulin secretion in a glucose dependent manner and currently fosters considerable hope for the treatment of diabetes. Recently, we have shown that the dipeptidylpeptidase-4 (DPP4) gene, which is responsible for incretin inactivation, was overexpressed in omental adipose tissue of obese men with the metabolic syndrome, compared to men not characterized by this condition. Since the cardiovascular disease (CVD) risk profile shows substantial inter-individual variability in obesity, this study aimed at verifying whether DPP4 polymorphisms contribute to explain such a difference. In the first step of this multi-stage study, seven tagging SNPs were genotyped in a sample of 576 obese (BMI>40 kg/m(2)) individuals and tested for their association with blood pressure and lipids, as well as diabetes-related phenotypes. Then, in an additional sample of 572 obese individuals (stage 2), SNPs showing trends (P<0.10) for an association in the first sample were genotyped and reanalyzed. Logistic regressions were used to compute odds ratio for obesity-related metabolic complications. In sample 1, homozygotes for rs17848915 and rs7608798 minor alleles were at lower risk of hyperglycemia/diabetes (P=0.002) and elevated plasma triglyceride levels (P=0.030) respectively, whereas rs1558957 heterozygotes were at higher risk to have high plasma triglyceride (P=0.040), HDL- (P=0.021), LDL- (P=0.001) and total-cholesterol (P=0.003) levels. However, none of these associations was consistently replicated in stage 2. This first comprehensive genetic analysis does not support the notion that DPP4 polymorphisms could modulate the CVD risk profile among obese patients.

Topics: Adipose Tissue; Cardiovascular Diseases; Diastole; Dipeptidyl Peptidase 4; Exons; Female; Humans; Incretins; Linkage Disequilibrium; Lipids; Lipoproteins; Male; Metabolic Syndrome; Obesity, Morbid; Polymorphism, Genetic; Quebec; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors

Obesity has reached epidemic proportions in the USA with a nearly fourfold rise in the prevalence of childhood obesity. There are many possible etiologies of obesity as the adipose tissue plays a significant, complex role in the physiology of fuel metabolism and hormone regulation. The development of obesity represents a pathophysiologic increase in fat mass in which multiple metabolic pathways are deranged. The consequences of these metabolic derangements, including insulin resistance and inflammation, are reflected in obesity-related comorbidities and can be seen in the setting of pediatric obesity. Obese adolescents demonstrate increased rates of early maturation, orthopedic growth abnormalities, diabetes mellitus, obstructive sleep apnea, hypertension, steatosis, and polycystic ovarian syndrome, placing this group of children at risk for long-term health problems and reduced quality of life. Given the negative short- and long-term impact of obesity on children, careful attention should be paid to the unique health issues of this "at-risk" population with both prevention and early intervention strategies.

Topics: Adipocytes; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Adolescent; Animals; Body Mass Index; Diabetes Mellitus; Evidence-Based Medicine; Female; Humans; Hypercholesterolemia; Hypertension; Incretins; Metabolic Syndrome; Obesity; Ohio; Polycystic Ovary Syndrome; Prevalence; Quality of Life; Risk Factors; Sleep Apnea, Obstructive