incretins and Weight-Gain

Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the theory that GIP is obesogenic, limiting interest in developing GIPR agonists to treat type 2 diabetes. A resurgence of GIP research has occurred in the last five years, reinvigorating interest in this peptide. Two independent approaches have emerged for treating obesity, one promoting GIPR agonism and the other antagonism. In this report, evidence supporting both cases is discussed and hypotheses are presented to reconcile this apparent paradox.. This review presents evidence to support targeting GIPR to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR using both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R.. There is substantial evidence to support that GIPR agonism and antagonism can positively impact body weight. The long-standing theory that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight; however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required to understand how modulating this system impacts metabolic homeostasis.

Topics: Adipose Tissue; Animals; Body Weight; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Mice; Mice, Knockout; Obesity; Weight Gain

Review available data on adjunctive therapies for type 1 diabetes (T1D), with a special focus on newer antihyperglycemic agents.. Published data on hypoglycemia, obesity, mortality, and goal attainment in T1D were reviewed to determine unmet therapeutic needs. PubMed databases and abstracts from recent diabetes meetings were searched using the term "type 1 diabetes" and the available and investigational sodium-glucose cotransporter (SGLT) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 inhibitors, and metformin.. The majority of patients with T1D do not meet glycated hemoglobin (A1C) goals established by major diabetes organizations. Hypoglycemia risks and a rising incidence of obesity and metabolic syndrome featured in the T1D population limit optimal use of intensive insulin therapy. Noninsulin antihyperglycemic agents may enable T1D patients to achieve target A1C levels using lower insulin doses, which may reduce the risk of hypoglycemia. In pilot studies, the SGLT2 inhibitor dapagliflozin and the GLP-1 receptor agonist liraglutide reduced blood glucose, weight, and insulin dose in patients with T1D. Phase 2 studies with the SGLT2 inhibitor empagliflozin and the dual SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in A1C, weight, and glucose variability without an increased incidence of hypoglycemia.. Newer antihyperglycemic agents, particularly GLP-1 agonists, SGLT2 inhibitors, and dual SGLT1 and SGLT2 inhibitors, show promise as adjunctive treatment for T1D that may help patients achieve better glucose control without weight gain or increased hypoglycemia.

Topics: Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Drug Therapy, Combination; Drugs, Investigational; Humans; Hypoglycemic Agents; Incretins; Insulin; Sodium-Glucose Transport Proteins; Weight Gain

To review the current literature for the efficacy and safety of available treatments for type 2 diabetes (T2DM) in the pediatric population.. A search from January 1990 to April 2016 was conducted using PubMed and clinicaltrials.gov using the search terms diabetes mellitus, type 2; adolescent; child; and pediatric Bibliographies of chosen articles were reviewed.. Relevant articles and preliminary data from clinical trials on metformin, insulin, sulfonylureas, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and α-glucosidase inhibitors for the treatment of pediatric T2DM were reviewed. Studies included randomized controlled, observational, and open-label designs.. Metformin, studied in 4 of the reviewed trials, and premixed insulin appear to be safe and effective in pediatric patients with T2DM. TZDs were well tolerated and yielded favorable results, but may have limited applicability. A sulfonylurea had favorable hemoglobin A1C reduction, but was associated with significant weight gain. Studies of incretin-based agents also showed favorable results in the pediatric population but have limited safety and efficacy data. Several trials for other agents are reported on clinicaltrials.gov with unpublished results, but no statistical analyses are reported.. Metformin and insulin remain the mainstay of treatment for T2DM in pediatric patients. More robust studies are needed to assist in the provision of evidence-based guidance for the treatment of T2DM in youth.

Topics: Adolescent; Child; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Metformin; Sulfonylurea Compounds; Thiazolidinediones; Weight Gain

Recently, incretin-based therapy was introduced for the treatment of type 2 diabetes (T2D). In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin) play an increasing role in the management of T2D.. An extensive literature search was performed to analyze the pharmacological characteristics of DPP-4i and their clinical implications.. DPP-4i present significant pharmacokinetic differences. They also differ in chemical structure, in the interaction with distinct subsites of the enzyme and in different levels of selectivity and potency of enzyme inhibition. Moreover, disparities in the effects on glycated hemoglobin, glucagon-like peptide-1 and glucagon levels and on glucose variability have been observed. However, indirect comparisons indicate that all DPP-4i have a similar safety and efficacy profiles. DPP-4i are preferred in overweight/obese and elderly patients because of the advantages of minimal or no influence on weight gain and low risk of hypoglycemia. For the same reasons, DPP-4i can be safely combined with insulin. However, currently cardiovascular outcomes related to DPP-4i are widely debated and the available evidence is controversial. Today, long-term studies are still in progress and upcoming results will allow us to better define the strengths and limits of this therapeutic class.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Weight Gain

To review the recent work on potential mechanisms underlying a paradoxical positive association between the consumption of non-nutritive sweeteners (NNS) and weight gain.. Several potential mechanisms, not mutually exclusive, are hypothesized. First, by dissociating sweetness from calories, NNS could interfere with physiological responses that control homeostasis. Second, by changing the intestinal environment, NNS could affect the microbiota and in turn trigger inflammatory processes that are associated with metabolic disorders. Third, by interacting with novel sweet-taste receptors discovered in the gut, NNS could affect glucose absorptive capacity and glucose homeostasis. The latter mechanism that has received the most attention recently. Some animal studies, but not all, found that NNS activate gut sweet-taste pathways that control incretin release and upregulate glucose transporters. Human studies found that, at least for healthy fasted individuals, the sole interaction of NNS with sweet-taste gut receptors is insufficient to elicit incretin responses. The reasons for discrepancy between different studies are unknown but could be related to the species of mammal tested and the dose of NNS used.. Whether NNS are metabolically inactive, as previously assumed, is unclear. Further research on the potential effects of NNS on human metabolism is warranted.

Topics: Energy Intake; Energy Metabolism; Glucose; Glucose Metabolism Disorders; Homeostasis; Humans; Incretins; Metagenome; Nutritive Value; Sweetening Agents; Taste; Up-Regulation; Weight Gain

Patients with type 2 diabetes, approximately 85% of whom are overweight or obese, often have an increased incidence of cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia. Both type 2 diabetes and obesity are independent risk factors for CVD. Unfortunately, many therapies aimed at maintaining and improving glucose control are associated with weight gain. Among the older antidiabetes agents, most, including the insulin secretagogues and sensitizers, can lead to weight gain, except for metformin, which is weight-neutral. Among the newer agents, the dipeptidyl peptidase-4 inhibitors generally are weight-neutral in addition to lowering glucose, while the glucagon-like peptide-1 receptor agonists lead to weight reduction. Patients with type 2 diabetes are at an increased risk for both diabetes- and CV-related outcomes, and weight reduction is an important component of diabetes management. Weight gain in patients with type 2 diabetes can contribute to patient frustration and may negatively impact their compliance to therapeutic regimens. The selection of antidiabetes agents that not only improve glucose control but reduce or have a neutral effect on weight with beneficial effects on lipids are ideal options for managing patients with type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Exenatide; Glucagon-Like Peptide 1; Health Knowledge, Attitudes, Practice; Humans; Hypoglycemic Agents; Incretins; Motivation; Obesity; Patient Compliance; Peptides; Risk Management; Self Care; Venoms; Weight Gain

One of the challenges facing health care providers in the treatment of patients with type 2 diabetes mellitus is maintaining the balance between achieving hemoglobin A(1c) targets while simultaneously minimizing adverse events-most notably hypoglycemia and weight gain-that may negatively affect adherence to therapy and thus treatment outcomes. Incretin-based treatments, such as glucagon-like peptide-1 (GLP-1)-receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are the newest class of therapies for the management of patients with type 2 diabetes. Data from clinical trials in which liraglutide, exenatide, saxagliptin, or sitagliptin were employed as monotherapy or added to ongoing antidiabetic treatment indicate that the incretin-based therapies have very low risk for the development of hypoglycemia and either decrease body weight (GLP-1-receptor agonists) or are weight neutral (DPP-4 inhibitors). Decreased risk for hypoglycemia and weight gain may improve adherence. Avoiding weight gain, which is commonly associated with older oral antidiabetic agents and some insulins, also has the potential to decrease the risk for cardiovascular disease. Future pharmacoeconomic studies may demonstrate translation of these benefits into good cost-effectiveness for these therapies.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Incretins; Patient Compliance; Randomized Controlled Trials as Topic; Weight Gain

The vast majority of patients with type 2 diabetes are overweight or obese. Lifestyle intervention to lose weight is recommended in most diabetic patients to improve glycaemic control and reduce associated risk factors for microvascular and macrovascular complications. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors, although achieving this level of weight reduction remains difficult for many patients. Complicating the matter, many agents used to target hyperglycaemia are associated with weight gain, making management of overweight or obese patients with type 2 diabetes quite challenging. Incretin-based therapies with the new classes of glucagon-like peptide-1 mimetics (e.g. exenatide, liraglutide) and dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g. sitagliptin, vildagliptin) may be of particular value in the treatment of overweight/obese type 2 diabetic patients because of their efficacy in improving glycaemic control and their favourable or neutral effects on body weight. In addition, DPP-4 inhibitors have a low risk for causing hypoglycaemia, undesirable gastrointestinal effects, or other prominent adverse effects that might limit their use. These classes of drugs hold promise for the treatment of type 2 diabetes, alone or in combination with other classes of antidiabetic agents.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Obesity; Overweight; Weight Gain

Topics: Anti-Obesity Agents; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Combinations; Drug Monitoring; Drug Resistance, Multiple; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Metformin; Obesity; Overweight; Weight Gain; Weight Loss

We have previously reported that once-weekly albiglutide was noninferior to thrice-daily lispro for glycemic lowering, with decreased weight and risk of hypoglycemia, in patients inadequately controlled on basal insulin over 26 weeks. Findings after 52 weeks reveal similar responses to albiglutide as an add-on to insulin glargine.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Incretins; Insulin Glargine; Insulin Lispro; Meals; Risk; Weight Gain; Weight Loss

Metformin monotherapy is recommended as initial treatment of type 2 diabetes. The selection of optimal second-line therapy that is often necessary due to the progressive nature of the disease is still a subject of ongoing discussions.. The aim of the international EDGE (Effectiveness of Diabetes control with vildaGliptin and vildagliptin/mEtformin) study was to prospectively compare the efficacy and safety of vildagliptin vs other oral antidiabetic agents in patients with type 2 diabetes not adequately controlled on monotherapy in a real-life clinical setting. In this paper, we present the data of patients participating in the EDGE study in the Czech Republic.. Patients with type 2 diabetes not adequately controlled on monotherapy were enrolled into the study, and randomised into either the vildagliptin arm or control arm with another OAD at the discretion of the treating physician. Patients with the addition of other incretin-based medications were not enrolled into the study. The efficiency was evaluated as a proportion of patients reaching the combined endpoint of decreasing HbA1c> 3 mmol/mol without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects during the 12 months of treatment.. 654 patients were enrolled into the study in the Czech Republic. The mean age of the patients when enrolled into the study (vildagliptin group vs control group) was 59.5 ± 10.6 vs 63.7 ± 8.5 years, mean body mass index was 32.4 ± 5.7 vs 31.7 ± 6.5 kg/m2, mean HbA1c was 62 ± 12 vs 64 ± 11 mmol/mol. The probability of reaching the combined primary endpoint (calculated using a binary logistic regression model to calculate the odds ratios with 95% confidence intervals) was higher for vildagliptin regardless of baseline HbA1c or type of medication added in the control group. Primary endpoint was reached by 60.6 % of patients in the vildagliptin group vs 51.3 % of patients in the control group, odds ratio 1.46 (1.06, 1.99); p< 0.019. The proportion of patients reaching secondary endpoint (HbA1c< 54 mmol/mol without hypoglycemic event or weight gain 3 % with baseline glycated hemoglobin > 54 mmol/mol was higher for vildagliptin 45.7 % vs 31.4 % in the control arm, odds ratio 1.84 (1.26, 2.68), p< 0.001. The rate of adverse events was comparable in both groups.. In a real-life clinical set-ting, the percentage of patients reaching the combined endpoint of decreasing HbA1c> 3 mmol/mol, without hypoglycaemia, peripheral oedema or treatment termination due to gastrointestinal side effects was higher after the addition of vildagliptin as compared to other antidiabetic agents with comparable rate of side effects.

Topics: Adamantane; Adult; Aged; Cohort Studies; Czech Republic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Male; Metformin; Middle Aged; Nitriles; Prospective Studies; Pyrrolidines; Vildagliptin; Weight Gain

Topics: Animals; Carbohydrates; Diabetes Mellitus, Type 2; Humans; Incretins; Mice; Parasympathetic Nervous System; Weight Gain

Glucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and adiposity in the context of nutrient excess. Interrupting GIPR signaling also enhances the sensitivity of the receptor for the other incretin peptide, glucagon-like peptide 1 (GLP-1). The role of GLP-1 compensation in loss of GIPR signaling to protect against obesity has not been directly tested.. We blocked the GIPR and GLP-1R with specific antibodies, alone and in combination, in healthy and diet-induced obese (DIO) mice. The primary outcome measure of these interventions was the effect on body weight and composition.. Antagonism of either the GIPR or GLP-1R system reduced food intake and weight gain during high-fat feeding and enhanced sensitivity to the alternative incretin signaling system. Combined antagonism of both GIPR and GLP-1R produced additive effects to mitigate DIO. Acute pharmacological studies using GIPR and GLP-1R agonists demonstrated both peptides reduced food intake, which was prevented by co-administration of the respective antagonists.. Disruption of either axis of the incretin system protects against diet-induced obesity in mice. However, combined antagonism of both GIPR and GLP-1R produced additional protection against diet-induced obesity, suggesting additional factors beyond compensation by the complementary incretin axis. While antagonizing the GLP-1 system decreases weight gain, GLP-1R agonists are used clinically to target obesity. Hence, the phenotype arising from loss of function of GLP-1R does not implicate GLP-1 as an obesogenic hormone. By extension, caution is warranted in labeling GIP as an obesogenic hormone based on loss-of-function studies.

Topics: Animals; Anti-Obesity Agents; Diet, High-Fat; Incretins; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Weight Gain

Dietary polyphenols including anthocyanins target multiple organs.. We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G).. Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2).. In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and β-klotho (>3-fold, P < 0.05).. Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21.

Topics: Animals; Anthocyanins; Diet, High-Fat; Dietary Fats; Fibroblast Growth Factors; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucose Intolerance; Glucosides; Incretins; Leptin; Liver; Male; Mice; Random Allocation; Weight Gain; Weight Loss

Our main goal is to study the effects on the carbohydrate metabolism. Thus, we designed various experimental surgical models on healthy non-obese Wistar rats to reproduce several conditions. In this sense, we report a new experimental model. It is well known that bariatric surgery has important effects on the control of Type 2 Diabetes Mellitus. The underlying reasons are yet unknown, although the different theories focused in the release of different hormones after the pass of the nutrients through the tract. These released hormones have opposite effects that come together in a balanced glycemic metabolism.. After bariatric surgical techniques, the modified anatomy resulted in an imbalance of the secreted hormones. Wistar rats were randomized in two groups Sham and surgical group. Our model consisted on the transposition of the terminal ileum right after the pylorus. Weight gain, food intake, and basal glycemia were measured weekly.. We did not obtain significant differences between both groups for these functional variables.. This technique involved an early pass of the bolus through the ileum. The change on the luminal pH, along with the lack of enzymes to absorb the content, or the changes in the release of several hormones must be variables to the study. The mortality rate was assumable considering it was an experimental model on animals.. Crear un nuevo modelo quirúrgico experimental en ratas Wistar sanas no obesas para estudiar los efectos del metabolismo glucídico. Es bien sabido que las técnicas de cirugía bariátrica tienen un efecto importante sobre la resolución de la diabetes mellitus tipo 2. Se han invocado diferentes hipótesis, algunas centradas en el papel que tienen distintas hormonas secretadas por el propio tubo digestivo tras el paso de los nutrientes a su través, pero las razones últimas subyacentes permanecen desconocidas. El efecto contrapuesto de dichas hormonas consigue un efecto de control glucémico. El desequilibrio hormonal tras las alteraciones anatómicas de las cirugías bariátricas podría estar en la base de dicha mejora del metabolismo glucídico final.. Las ratas fueron operadas en dos grupos (control quirúrgico y experimental) y se procedió a disponerles el íleon anastomosado al antro pilórico, previo al esfínter pilórico. Medimos distintos parámetros funcionales (ganancia de peso, ingesta y glucemias semanales).. No obtuvimos diferencias significativas en la evolución de estos parámetros.. Este modelo será útil para nuestro propósito de estudiar el íleon, en su componente secretor de enterohormonas, cuando el paso de los nutrientes se produzca tempranamente. La mortalidad fue asumible, dada la innovación técnica realizada.

Topics: Anastomosis, Surgical; Animals; Bariatric Surgery; Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Duodenum; Eating; Gastrointestinal Transit; Ileum; Incretins; Male; Models, Animal; Pylorus; Random Allocation; Rats; Rats, Wistar; Weight Gain

Topics: Bariatric Surgery; Binge-Eating Disorder; Craniopharyngioma; Humans; Hypothalamic Diseases; Incretins; Liraglutide; Male; Neurosurgical Procedures; Obesity; Pituitary Neoplasms; Postoperative Complications; Satiety Response; Treatment Failure; Weight Gain; Young Adult

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.

Topics: Adaptor Proteins, Signal Transducing; Animals; Binding, Competitive; Cytokine Receptor gp130; Cytokines; Diabetes Mellitus, Type 2; Drug Design; Fatty Liver; Glucose Tolerance Test; Humans; Hyperglycemia; Immunoglobulin G; Incretins; Interleukin-6; Male; Mice; Muscle, Skeletal; Obesity; Pancreas; Phosphoproteins; Protein Engineering; Receptors, Interleukin-6; Recombinant Fusion Proteins; Signal Transduction; Transcription Factors; Weight Gain; YAP-Signaling Proteins

To study the effect of different daily doses of pioglitazone on glycemic control and weight gain in newly-diagnosed type 2 diabetes mellitus (DM) patients.. Chart reviews were performed of recently-diagnosed (<24 months) type 2 DM patients receiving oral therapy including pioglitazone. Patients were excluded if they had heart disease, liver dysfunction or renal insufficiency; or were being treated with insulin or the incretin drugs. Patients had received 7.5 mg/day (Group A), 15 mg/day (Group B) or 30 mg/day (Group C) of pioglitazone. Characteristics including demographics, weight, body mass index and glycated hemoglobin (HbA1c) were recorded at baseline and at six months.. At the end of six months, there was significant weight gain in all groups from baseline (P<0.01). Weight gain was greatest in Group C (2.72 kg; SD=2.97), intermediate in Group B (1.62 kg; SD=2.91) and least in Group A (0.88 kg; SD=2.77). The difference was statistically significant between Groups A and C; and Groups B and C; but not between Groups A and B. There was no difference between HbA1c lowering in the three groups (P>0.05). Dose correlated with weight gain (r=0.254; P<0.001) but not with HbA1c reduction (r=0.012; P=0.85). There was no correlation between HbA1c reduction and BMI increase (r = -0.024; P=0.72).. The glycemic effect of pioglitazone is preserved even at lower doses, while the propensity to cause weight gain increases with dose. We suggest that low-dose pioglitazone (7.5 mg/day) should be the preferred dose at which to initiate therapy in recently-diagnosed patients. Pioglitazone is an extremely useful agent in the treatment of type 2 diabetes mellitus (DM) through its actions on alleviating insulin resistance.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Monitoring; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; India; Insulin; Male; Middle Aged; Pioglitazone; Retrospective Studies; Thiazolidinediones; Treatment Outcome; Weight Gain

We reported recently that after a nutritional growth retardation, rats showed significant weight gain, central fat accumulation, dyslipidemia, and β-cell dysfunction during a catch-up growth (CUG) phase. Here, we investigated whether glucagon-like peptide-1 (GLP-1) ameliorated the rapid weight gain, central fat deposition, and β-cell dysfunction during the CUG in rats. Sixty-four male Sprague Dawley rats were stratified into four groups including normal control group, CUG group, catch-up growth with liraglutide treatment group, and catch-up growth with liraglutide and exendin 9-39 treatment group. Energy intake, body weight, and body length were monitored. Fat mass percentage was analyzed by dual energy X-ray absorptiometry scan. Plasma triglyceride and non-esterified fatty acid were measured. The β-cell mass was analyzed by morphometric analysis and signaling molecules were examined by Western blot and real-time PCR. Insulin secretion capability was evaluated by hyperglycemic clamp test. Liraglutide prevented weight gain and improved lipid and glucose metabolism in rats under CUG conditions, which were associated with reduced fasting insulin levels and improved glucose-stimulated insulin secretion. Improved β-cell function is found to be associated with increased β-cell replication as determined by β-cell density and insulin-Ki67 dual staining. Furthermore, liraglutide increased islet pancreatic duodenal homeobox-1 (Pdx-1) and B-cell lymphoma-2 transcript and protein expression, and reduced Procaspase-3 transcript and Caspase-3 p11 subunit protein expression, suggesting that expression of Pdx-1 and reduction of apoptosis may be the mechanisms involved. The therapeutic effects were attenuated in rats co-administered with exendin 9-39, suggesting a GLP-1 receptor-dependent mechanism. These studies revealed that incretin therapy effectively prevented fast weight gain and β-cell dysfunction in rats under conditions of nutrition restriction followed by nutrition excess, which is in part due to enhanced functional β-cell mass and insulin secretory capacity.

Topics: Animals; Caloric Restriction; Cell Proliferation; Cell Survival; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Homeodomain Proteins; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Liraglutide; Male; Models, Animal; Obesity, Abdominal; Rats; Rats, Sprague-Dawley; Trans-Activators; Triglycerides; Up-Regulation; Weight Gain

Glucagon-like peptide 1-based therapies, collectively described as incretins, produce glycemic benefits in the treatment of type 2 diabetes. Recent publications raised concern for a potential increased risk of pancreatitis and pancreatic cancer with incretins based in part on findings from a small number of rodents. However, extensive toxicology assessments in a substantial number of animals dosed up to 2 years at high multiples of human exposure do not support these concerns. We hypothesized that the lesions being attributed to incretins are commonly observed background findings and endeavored to characterize the incidence of spontaneous pancreatic lesions in three rat strains (Sprague-Dawley [S-D] rats, Zucker diabetic fatty [ZDF] rats, and rats expressing human islet amyloid polypeptide [HIP]; n = 36/group) on a normal or high-fat diet over 4 months. Pancreatic findings in all groups included focal exocrine degeneration, atrophy, inflammation, ductular cell proliferation, and/or observations in large pancreatic ducts similar to those described in the literature, with an incidence of exocrine atrophy/inflammation seen in S-D (42-72%), HIP (39%), and ZDF (6%) rats. These data indicate that the pancreatic findings attributed to incretins are common background findings, observed without drug treatment and independent of diet or glycemic status, suggesting a need to exercise caution when interpreting the relevance of some recent reports regarding human safety.

Topics: Animals; Diabetes Mellitus; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Incretins; Pancreas; Pancreatic Diseases; Pancreatitis; Rats; Rats, Sprague-Dawley; Rats, Zucker; Weight Gain

Real-world data on emerging combination approaches for type 2 diabetes mellitus (T2DM) management are limited. The objective of the current study was to document the characteristics and clinical outcomes of patients with T2DM initiating prandial insulin or a glucagon-like peptide-1 (GLP-1) receptor agonist while on basal insulin.. This was a retrospective analysis of an electronic medical records database of patients with T2DM managed in a community practice setting in the United States. The main outcome measures were glycated hemoglobin (HbA1c), body weight, hypoglycemia, and health care resource utilization at baseline and at 6-month and 1-year follow-up.. A total of 33 810 patients were included in the study: 31 848 on prandial insulin and 1962 on a GLP-1 receptor agonist. At baseline there were significant differences in mean age (60 vs 56 years), mean Charlson Comorbidity Index score (1.1 vs 0.7), mean HbA1c (8.8% vs 8.4%), and mean body weight (99 vs 112 kg) between the prandial insulin and GLP-1 receptor agonist groups, respectively (P < 0.001 for each). After matching for baseline differences, significant and similar changes from baseline were observed between the prandial insulin and the GLP-1 receptor agonist groups during follow-up at the 6 months/1 year post-index date for HbA1c (-0.45/-0.60% vs -0.44/-0.58%, respectively; P = 0.907/0.723 between groups). Body weight changes between the groups were significantly different at 6 months/1 year (+1.7/-1.7 vs -0.9/-3.7 kg; P < 0.001). Hypoglycemia incidence and health care resource utilization were significantly greater in the prandial insulin versus GLP-1 receptor agonist group.. The results of this real-world analysis of patients with T2DM adding a GLP-1 receptor agonist or prandial insulin to basal insulin suggest an association between adding a GLP-1 receptor agonist with similar glycemic control, greater reduction in body weight, lower hypoglycemia incidence, and lower health care utilization compared with adding prandial insulin.

Topics: Aged; Community Health Services; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Therapy, Combination; Endocrinology; Family Practice; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Male; Middle Aged; Retrospective Studies; United States; Weight Gain

Topics: Blood Glucose; Clinical Trials as Topic; Congresses as Topic; Consensus; Diabetes Mellitus; Diabetic Angiopathies; Humans; Hypertension; Incretins; Obesity; Weight Gain

(1) When type 2 diabetes is inadequately controlled with oral antidiabetic therapy, one option is to add subcutaneous insulin injections (or to accept less stringent glycaemic control). However, since the effects of adding insulin have only been evaluated in the short-term, effects on long-term clinical outcomes remain unknown. (2) Exenatide, a drug belonging to a new pharmacological class (incretin analogues), is marketed as a subcutaneously administered adjunct to inadequately effective oral antidiabetic therapy in adults with type 2 diabetes. (3) Three placebo-controlled trials lasting 7 months showed that adding exenatide to metformin and/or a glucose-lowering sulphonylurea yielded an HbA1c level of 7% or less in about 40% of patients treated with exenatide 10 micrograms twice a day, versus about 10% of patients on placebo. The potential impact of exenatide on morbidity and mortality is not known. (4) In two trials versus insulin glargine and in one trial versus insulin aspart (+ isophane insulin), exenatide was as effective as the various insulins in controlling HbA1c levels. (5) During clinical trials, patients receiving exenatide lost an average of about 2 kg after 6 months, while insulin was associated with a weight gain of about 2 kg. (6) There was a similar incidence of hypoglycaemia with exenatide and insulin. In patients treated with exenatide, concomitant use of glucose-lowering sulphonylurea increases the risk of hypoglycaemia. (7) More than half of patients on exenatide experienced nausea, versus fewer than 10% of patients on insulin glargine. (8) The long-term consequences of the presence of antiexenatide antibodies on the effectiveness of treatment are not known. (9) Exenatide is administered in two subcutaneous injections a day, at fixed doses. Insulin is administered in one or several injections a day, at doses adjusted to self-monitored blood glucose levels. (10) Adding insulin rather than exenatide is a better option in general when oral antidiabetic therapy fails in patients with type 2 diabetes, as we have more experience with insulin and there is no evidence of important advantages with exenatide. The latter should be reserved for situations in which weight gain is a major problem.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Metformin; Overweight; Peptides; Sulfonylurea Compounds; Venoms; Weight Gain; Weight Loss