oxyntomodulin and Weight-Gain

The approval of once daily liraglutide, 3.0 mg, and once weekly semaglutide, 2.4 mg, for chronic weight management provides a novel effective strategy against obesity. The reliable models that might predict weight reducing potential at the individual level have not been identified yet. However, the coexistence of diabetes has been consistently related with less effective response than in people without this comorbidity. We aimed to review the efficacy of GLP-1 RAs approved for weight management in individuals with and without diabetes and discuss some potential mechanisms for consistently observed differences in efficacy between these two populations. The mean weight loss difference between GLP-1 RAs and placebo as add-on to lifestyle intervention in patients with diabetes was 4% to 6.2% compared to 6.1 to 17.4% in people without diabetes. Semaglutide compared to liraglutide resulted in greater weight loss. Some hypothetical explanations for the weaker anti-obesity response for both GLP-1 RAs in people with diabetes include the background medications that promote weight gain, the fear of hypoglycaemia inherently related to the treatment of diabetes, a decrease in glycosuria and subsequently less weight loss in diabetics, an altered microbiota in patients with obesity and diabetes and a genetic background that predispose to weight gain in patients with diabetes. Moreover, people with diabetes may have had obesity for longer and may be less adherent to exercise, which seems to potentiate the effects of GLP-1 RA. Emerging multimodal approaches combining peptides targeting receptors at different levels might therefore be of additional benefit particularly in patients with diabetes.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Weight Gain; Weight Loss

One of the effective and consistent ways to achieve glycaemic control for patients with type 2 diabetes mellitus (T2DM) is once-daily basal insulin. But it is also associated with adverse outcomes such as hypoglycaemia. Dulaglutide, a novel long-acting GLP-1 receptor agonist, may be a more suitable therapy. The present meta-analysis aims to assess the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide compared with insulin glargine for the treatment of T2DM.. We searched PubMed, Embase and Cochrane Library from inception to December 2020. Randomized clinical trials comparing dulaglutide with insulin glargine in adults with T2DM were included. Revman5.2 software was used for meta-analysis.. We included 5 studies with 3383 randomized participants. Compared with insulin glargine, dulaglutide 1.5 mg led to greater mean HbA1c reduction (MD = -0.33%, 95% CI = -0.52, -0.15) whereas dulaglutide 0.75 mg did not (MD = -0.21%, 95% CI = -0.43, 0.01). Body weight loss was seen with dulaglutide whereas weight gain was seen with insulin glargine. The risk of hypoglycaemia was lower in dulaglutide 0.75 mg and 1.5 mg groups than in insulin glargine group,whereas dulaglutide had a statistically higher gastrointestinal adverse events incidence than insulin glargine.. Compared with insulin glargine, dulaglutide may serve as an effective alternative to provide improvement in glycaemic control with weight loss and less hypoglycaemia in patients with T2DM. It may be a more suitable therapy instead of basal insulin.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Immunoglobulin Fc Fragments; Insulin Glargine; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Weight Gain; Weight Loss

To compare the effectiveness of dulaglutide 1.5 and 0.75 mg with active comparators and placebo with regard to a composite endpoint of glycated haemoglobin (HbA1c), weight and hypoglycaemia, using post hoc analyses.. A logistic regression analysis was performed on the intention-to-treat population, using data from the last observation carried forward, and the composite endpoint of HbA1c <7.0% (53 mmol/mol), no weight gain (≤0 kg) and no hypoglycaemia (glucose <3.0 mmol/l or severe hypoglycaemia) after 26 weeks for each trial in the AWARD programme separately.. At 26 weeks, within each study, 37-58% of patients on dulaglutide 1.5 mg, 27-49% of patients on dulaglutide 0.75 mg, and 9-61% of patients on active comparators achieved the composite endpoint. Significantly more patients reached the composite endpoint with dulaglutide 1.5 mg than with metformin, sitagliptin, exenatide twice daily or insulin glargine: odds ratio (OR) 1.5 [95% confidence interval (CI) 1.0, 2.2; p < 0.05], OR 4.5 (95% CI 3.0, 6.6; p < 0.001), OR 2.6 (95% CI 1.8, 3.7; p < 0.001) and OR 7.4 (95% CI 4.4, 12.6; p < 0.001), respectively, with no difference between dulaglutide 1.5 mg and liraglutide 1.8 mg. In addition, significantly more patients reached the composite endpoint with dulaglutide 0.75 mg than with sitagliptin or insulin glargine: OR 3.3 (95% CI 2.2, 4.8; p < 0.001) and OR 4.5 (95% CI 2.7, 7.8; p < 0.001), respectively.. Dulaglutide is an effective treatment option, resulting in a similar or greater proportion of patients reaching the HbA1c target of <7.0% (53 mmol/mol), without weight gain or hypoglycaemia compared with active comparators.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Male; Metformin; Middle Aged; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sitagliptin Phosphate; Treatment Outcome; Venoms; Weight Gain

Peptide YY (PYY) is a 36 amino acid, straight chain polypeptide, which is co-localized with GLP-1 in the L-type endocrine cells of the GI mucosa. PYY shares structural homology with neuropeptide Y (NPY) and pancreatic polypeptide (PP), and together form the Neuropeptide Y Family of Peptides, which is also called the Pancreatic Polypeptide-Fold Family of Peptides. PYY release is stimulated by intraluminal nutrients, including glucose, bile salts, lipids, short-chain fatty acids and amino acids. Regulatory peptides such as cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), gastrin and GLP-1 modulate PYY release. The proximal GI tract may also participate in the regulation of PYY release through vagal fibers. After release, dipeptidyl peptidase IV (DPP-IV; CD 26) cleaves the N-terminal tyrosine-proline residues forming PYY(3-36). PYY(1-36) represents about 60% and PYY(3-36) 40% of circulating PYY. PYY acts through Y-receptor subtypes: Y1, Y2, Y4 and Y5 in humans. PYY(1-36) shows high affinity to all four receptors while PYY(3-36) is a specific Y2 agonist. PYY inhibits many GI functions, including gastric acid secretion, gastric emptying, small bowel and colonic chloride secretion, mouth to cecum transit time, pancreatic exocrine secretion and pancreatic insulin secretion. PYY also promotes postprandial naturesis and elevates systolic and diastolic blood pressure. PYY(1-36) and PYY(3-36) cross the blood-brain barrier and participate in appetite and weight control regulation. PYY(1-36) acting through Y1- and Y5-receptors increases appetite and stimulates weight gain. PYY(3-36) acting through Y2-receptors on NPY-containing cells in the arcuate nucleus inhibits NPY release and, thereby, decreases appetite and promotes weight loss. PYY may play a primary role in the appetite suppression and weight loss observed after bariatric operations.

Topics: Adenosine Deaminase; Animals; Appetite; Arcuate Nucleus of Hypothalamus; Dipeptidyl Peptidase 4; Gastrointestinal Tract; Glucagon-Like Peptides; Glycoproteins; Humans; Kidney; Peptide Fragments; Peptide YY; Weight Gain

Rubino DM, Greenway FL, Khalid U, et al.

Topics: Adult; Diabetes Mellitus; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Liraglutide; Obesity; Overweight; Weight Gain; Weight Loss

To assess the effect of dulaglutide (DU) 1.5/0.75 mg in comparison with glimepiride (GLIM) or insulin glargine (GLAR) on the composite end-point in Chinese type 2 diabetes patients.. Post-hoc analyses of two randomized phase III trials (NCT01644500 and NCT01648582) were carried out using Fisher's exact test. The primary composite end-point was the number of patients reaching glycated hemoglobin (HbA1c) <7.0%, without weight gain and hypoglycemia. Secondary composite end-points included the number of patients reaching HbA1c <7.0% without weight gain and HbA1c <7.0% without hypoglycemia.. Data of 1,147 Chinese type 2 diabetes patients were analyzed (NCT01644500 = 556; NCT01648582 = 591). In each analyzed trial, 40-48% of patients received DU (1.5 mg), 30-39% of patients received DU (0.75 mg) and 15-20% of patients on active comparators (GLIM/GLAR) reached the primary composite end-point at week 26 (P < 0.001 for DU vs GLIM/GLAR). At 52 weeks, 26% of patients that received DU (1.5 mg), 23% of patients that received DU (0.75 mg) and 7% of patients that received GLAR attained the primary composite end-point (P < 0.001 for DU vs GLAR). A similar trend of results was found for secondary composite end-points.. Dulaglutide is found to be an effective therapeutic alternative for Chinese type 2 diabetes patients. Compared with GLIM/GLAR, significantly greater proportions of patients on DU attained the HbA1c target of <7.0% without weight gain or hypoglycemia.

Topics: Asian People; China; Diabetes Mellitus, Type 2; Endpoint Determination; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins; Weight Gain

To evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in patients with type 2 diabetes by subgroups of gender, duration of diabetes and baseline glycated haemoglobin (HbA1c) in the dulaglutide clinical development programme (AWARD-1 to -6 and -8 clinical trials).. Change in HbA1c was analysed by gender, duration of diabetes (<5, ≥5 years and <10, ≥10 years), and baseline HbA1c (<8.5%, ≥8.5%) in pooled and individual studies. Changes from baseline in weight, hypoglycaemia and gastrointestinal adverse events were evaluated for individual trials.. In the pooled analysis of patients treated with dulaglutide 1.5 mg at 6 months, the reductions in HbA1c from baseline were similar across gender (men: least squares [LS] mean -1.26% [95% confidence interval {CI} -1.36, -1.16]; women: LS mean -1.33% [95% CI -1.43, -1.24]) and among duration of diabetes subgroups (<5 years: LS mean -1.32% [95% CI -1.43, -1.22]; ≥5 and <10 years: LS mean -1.33% [95% CI -1.43, -1.22]; ≥10 years: -1.24% [95% CI -1.35, -1.14]). Patients with baseline HbA1c ≥8.5% had greater HbA1c reductions than patients with baseline HbA1c <8.5%, (≥8.5%: LS mean -1.86% [95% CI -1.97, -1.75]; <8.5%: LS mean -1.02% [95% CI -1.12, -0.93]). Reductions in fasting blood glucose (FBG) were consistent with HbA1c changes. Similar results were observed with dulaglutide 0.75 mg. In general, body weight changes were similar among duration of diabetes and in baseline HbA1c subgroups, respectively; women had a numerically greater weight loss or less weight gain than men with both dulaglutide doses. There was no clinically meaningful difference in hypoglycaemia trends by gender or duration of diabetes. Hypoglycaemia incidence and rate were generally lower in patients with baseline HbA1c ≥8.5% than in those with <8.5%, except for the AWARD-4 study (combination with mealtime insulin).. Across the AWARD studies, dulaglutide demonstrated significant improvements in glycaemic control irrespective of gender, duration of diabetes, or baseline HbA1c, with greater HbA1c and FBG reductions in patients with a higher baseline HbA1c. Dulaglutide was well tolerated, with a safety profile similar to other glucagon-like peptide-1 receptor agonists.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diarrhea; Drug Administration Schedule; Drug Therapy, Combination; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Male; Middle Aged; Nausea; Recombinant Fusion Proteins; Sex Characteristics; Vomiting; Weight Gain; Weight Loss

The aim of this study was to compare the effectiveness of semaglutide versus liraglutide for treating post-metabolic and bariatric surgery (MBS) weight recurrence.. A retrospective analysis of 207 adults with post-MBS weight recurrence treated with semaglutide 1.0 mg weekly (n = 115) or liraglutide 3.0 mg daily (n = 92) at an academic center from January 1, 2015, through April 1, 2021, was conducted. The primary end point was percentage body weight change at 12 months of treatment with regimens containing semaglutide or liraglutide.. The mean sample age was 55.2 years; mean BMI was 40.4 kg/m. These results show that treatment regimens including semaglutide 1.0 mg weekly lead to superior weight loss compared with liraglutide 3.0 mg daily for treating post-MBS weight recurrence, regardless of procedure type or the magnitude of weight recurrence.

Topics: Adult; Bariatric Surgery; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity, Morbid; Postoperative Period; Retrospective Studies; Treatment Outcome; Weight Gain; Weight Loss

About 20-25% of patients experience weight regain (WR) or insufficient weight loss (IWL) after bariatric metabolic surgery (BS). Therefore, we aimed to retrospectively assess the effectiveness of adjunct treatment with the GLP-1 receptor agonist semaglutide in non-diabetic patients with WR or IWL after BS.. Post-bariatric patients without type 2 diabetes (T2D) with WR or IWL (n = 44) were included in the analysis. The primary endpoint was weight loss 3 and 6 months after initiation of adjunct treatment. Secondary endpoints included change in BMI, HbA1c, lipid profile, hs-CRP, and liver enzymes.. Patients started semaglutide 64.7 ± 47.6 months (mean ± SD) after BS. At initiation of semaglutide, WR after post-bariatric weight nadir was 12.3 ± 14.4% (mean ± SD). Total weight loss during semaglutide treatment was - 6.0 ± 4.3% (mean ± SD, p < 0.001) after 3 months (3.2 months, IQR 3.0-3.5, n = 38) and - 10.3 ± 5.5% (mean ± SD, p < 0.001) after 6 months (5.8 months, IQR 5.8-6.4, n = 20). At 3 months, categorical weight loss was > 5% in 61% of patients, > 10% in 16% of patients, and > 15% in 2% of patients. Triglycerides (OR = 0.99; p < 0.05), ALT (OR = 0.87; p = 0.05), and AST (OR = 0.89; p < 0.05) at baseline were negatively associated with weight loss of at least 5% at 3 months' follow-up (p < 0.05).. Treatment options to manage post-bariatric excess weight (regain) are scarce. Our results imply a clear benefit of adjunct treatment with semaglutide in post-bariatric patients. However, these results need to be confirmed in a prospective randomized controlled trial to close the gap between lifestyle intervention and revision surgery in patients with IWL or WR after BS.

Topics: Bariatric Surgery; C-Reactive Protein; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Lipids; Obesity, Morbid; Prospective Studies; Retrospective Studies; Triglycerides; Weight Gain; Weight Loss

Once-weekly semaglutide 1 mg is a novel glucagon-like peptide 1 receptor agonist (GLP-1 RA) that, in the SUSTAIN clinical trials, has demonstrated greater reductions in glycated haemoglobin (HbA1c) and body weight than the other GLP-1 RAs exenatide extended-release (ER) 2 mg, dulaglutide 1.5 mg and liraglutide 1.2 mg. The aim of this analysis was to evaluate the relative cost of control of achieving treatment goals in people with type 2 diabetes (T2D) treated with once-weekly semaglutide versus exenatide ER, dulaglutide and liraglutide from a UK perspective.. Proportions of patients reaching HbA1c targets (< 7.0% and < 7.5%), weight loss targets (≥ 5% reduction in body weight) and composite endpoints (HbA1c < 7.0% without weight gain or hypoglycaemia; reduction in HbA1c of ≥ 1% and weight loss of ≥ 5%) were obtained from the SUSTAIN clinical trials. Annual per patient treatment costs were based on wholesale acquisition costs from July 2019 in the UK. Cost of control was calculated by plotting relative treatment costs against relative efficacy.. The annual per patient cost was similar for all GLP-1 RAs. Once-weekly semaglutide was superior to exenatide ER, dulaglutide and liraglutide in bringing patients to HbA1c and weight loss targets, and to composite endpoints. When looking at the composite endpoint of HbA1c < 7.0% without weight gain or hypoglycaemia, exenatide ER, dulaglutide and liraglutide were 50.0%, 21.6% and 51.3% less efficacious in achieving this, respectively, than once-weekly semaglutide. Consequently, the efficacy-to-cost ratios for once-weekly semaglutide were superior to all comparators in bringing patients to all endpoints.. The present study showed that once-weekly semaglutide offers superior cost of control versus exenatide ER, dulaglutide and liraglutide in terms of achieving clinically relevant, single and composite endpoints. Once-weekly semaglutide 1 mg would therefore represent good value for money in the UK setting.

Topics: Body Weight; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Male; Middle Aged; Recombinant Fusion Proteins; United Kingdom; Weight Gain

To evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects.. Data from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug-naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol-specified composite endpoint was the proportion of participants achieving HbA1c <53 mmol/mol (7.0%) at end of treatment (30 or 56 weeks) without weight gain and with no severe or blood glucose (BG)-confirmed symptomatic hypoglycaemia. A post hoc composite endpoint was the proportion of participants achieving the primary composite endpoint without moderate or severe GI adverse events (AEs).. Across the SUSTAIN trials 1 to 5, 3918 participants with T2D were randomized to once-weekly subcutaneous semaglutide 0.5 mg, 1.0 mg, or comparators (placebo, sitagliptin 100 mg, exenatide extended release 2.0 mg or insulin glargine). The proportion of participants achieving HbA1c <53 mmol/mol (7.0%) with no weight gain and no severe/BG-confirmed symptomatic hypoglycaemia was 47% to 66% (semaglutide 0.5 mg) and 57% to 74% (semaglutide 1.0 mg) vs 7% to 19% (placebo) and 16% to 29% (active comparators; all P < .0001). More participants achieved the primary composite endpoint with no moderate or severe GI AEs with semaglutide vs comparators (all P < .0001).. Semaglutide helped more people with T2D achieve HbA1c targets than did comparators in the SUSTAIN 1 to 5 trials, while avoiding unwanted outcomes such as weight gain, hypoglycaemia and GI side effects.

Topics: Adult; Aged; Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Gastrointestinal Diseases; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Retrospective Studies; Weight Gain

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.

Topics: Adipocytes; Animals; Antibodies; Diet; Drug Therapy, Combination; Feeding Behavior; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Immunoglobulin Fc Fragments; Insulin-Secreting Cells; Liraglutide; Mice, Obese; Obesity; Primates; Receptors, Gastrointestinal Hormone; Recombinant Fusion Proteins; Respiration; Weight Gain; Weight Loss

Oxyntomodulin (OXM) is a circulating gut hormone released post prandially from cells of the gastrointestinal mucosa. Given intracerebroventricularly to rats, it inhibits food intake and promotes weight loss. Here we report that peripheral (ip) administration of OXM dose-dependently inhibited both fast-induced and dark-phase food intake without delaying gastric emptying. Peripheral OXM administration also inhibited fasting plasma ghrelin. In addition, there was a significant increase in c-fos immunoreactivity, a marker of neuronal activation, in the arcuate nucleus (ARC). OXM injected directly into the ARC caused a potent and sustained reduction in refeeding after a fast. The anorectic actions of ip OXM were blocked by prior intra-ARC administration of the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin(9-39), suggesting that the ARC, lacking a complete blood-brain barrier, could be a potential site of action for circulating OXM. The actions of ip GLP-1, however, were not blocked by prior intra-ARC administration of exendin(9-39), indicating the potential existence of different OXM and GLP-1 pathways. Seven-day ip administration of OXM caused a reduction in the rate of body weight gain and adiposity. Circulating OXM may have a role in the regulation of food intake and body weight.

Topics: Animals; Appetite Depressants; Arcuate Nucleus of Hypothalamus; Darkness; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Fasting; Gastric Emptying; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Immunohistochemistry; Injections; Injections, Intraperitoneal; Male; Oxyntomodulin; Peptide Fragments; Peptide Hormones; Photoperiod; Protein Precursors; Rats; Rats, Wistar; Receptors, Glucagon; Weight Gain

The hypothesis tested in the present study is that dietary fructans are able to modulate gastrointestinal peptides involved in the control of food intake, namely glucagon-like peptide (GLP)-1 (7-36) amide and ghrelin. After 3 weeks of treatment with a standard diet (control) or the same diet enriched with 100 g fructans varying in their degrees of polymerization (oligofructose (OFS), Synergy 1 (Syn) or long chain inulin)/kg, male Wistar rats were deprived of food for 8 h before sample collection. Dietary energy intake throughout the experiment was significantly lower (P<0.05) in fructans-fed rats than in control rats, leading to a significant decrease (P<0.01) in epidydimal fat mass at the end of the treatment in OFS- and Syn-treated rats. GLP-1 (7-36) amide concentration in portal vein serum was higher in OFS- and Syn-fed than in control rats. Both GLP-1 (7-36) amide concentration and proglucagon mRNA concentrations were significantly greater (P<0.05) in the proximal colonic mucosa of fructans-fed rats v. controls. Normally active ghrelin concentration in plasma increases during food deprivation and rapidly falls during a meal. In the present study, after 8 h of food deprivation, active ghrelin in the plasma remained significantly lower (P<0.05) in OFS and Syn-fed than in control rats. These results are in accordance with the modifications of dietary intake and fat-mass development in short-chain fructans-treated rats and demonstrate the potential modulation of GLP-1 (7-36) amide and ghrelin by fermentable fibres such as fructans, which are rapidly and extensively fermented in the proximal part of the colon.

Topics: Animals; Appetite Regulation; Cecum; Colon; Diet; Eating; Energy Intake; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Inulin; Male; Organ Size; Peptide Fragments; Peptide Hormones; Proglucagon; Protein Precursors; Rats; Rats, Wistar; RNA, Messenger; Weight Gain

To investigate the effect of S 23521, a new glucagon-like peptide-1-(7-36) amide analogue, on food intake and body weight gain in obese rats, as well as on gene expression of several proteins involved in energy homeostasis.. Lean and diet-induced obese rats were treated with either S 23521 or vehicle. S 23521 was given either intraperitoneally (10 or 100 microg/kg) or subcutaneously (100 microg/kg) for 14 and 20 days, respectively. Because the low-dose treatment did not affect food intake and body weight, the subcutaneous treatment at high dose was selected to test the effect on selected end-points.. Treated obese rats significantly decreased their cumulative energy intake in relation to vehicle-treated counterparts (3401 +/- 65 vs. 3898 +/- 72 kcal/kg per 20 days; p < 0.05). Moreover, their body weight gain was reduced by 110%, adiposity was reduced by 20%, and plasma triglyceride levels were reduced by 38%. The treatment also improved glucose tolerance and insulin sensitivity of obese rats. Regarding gene expression, no changes in uncoupling protein-1, uncoupling protein-3, leptin, resistin, and peroxisome proliferator-activated receptor (PPAR)-gamma were observed.. S 23521 is an effective glucagon-like peptide-1-(7-36) amide analogue, which induced a decrease in energy intake, body weight, and adiposity in a rat model of diet-induced obesity. In addition, the treatment also improved glucose tolerance and insulin sensitivity of obese rats. These results strongly support S 23521 as a putative molecule for the treatment of obesity.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Obesity; Peptide Fragments; Random Allocation; Rats; Rats, Wistar; Time Factors; Weight Gain

Recent studies into the physiology of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have added stimulation of beta-cell growth, differentiation, and cell survival to well-documented, potent insulinotropic effects. Unfortunately, the therapeutic potential of these hormones is limited by their rapid enzymatic inactivation in vivo by dipeptidyl peptidase IV (DP IV). Inhibition of DP IV, so as to enhance circulating incretin levels, has proved effective in the treatment of type 2 diabetes both in humans and in animal models, stimulating improvements in glucose tolerance, insulin sensitivity, and beta-cell function. We hypothesized that enhancement of the cytoprotective and beta-cell regenerative effects of GIP and GLP-1 might extend the therapeutic potential of DP IV inhibitors to include type 1 diabetes. For testing this hypothesis, male Wistar rats, exposed to a single dose of streptozotocin (STZ; 50 mg/kg), were treated twice daily with the DP IV inhibitor P32/98 for 7 weeks. Relative to STZ-injected controls, P32/98-treated animals displayed increased weight gain (230%) and nutrient intake, decreased fed blood glucose ( approximately 26 vs. approximately 20 mmol/l, respectively), and a return of plasma insulin values toward normal (0.07 vs. 0.12 nmol/l, respectively). Marked improvements in oral glucose tolerance, suggesting enhanced insulin secretory capacity, were corroborated by pancreas perfusion and insulin content measurements that revealed two- to eightfold increases in both secretory function and insulin content after 7 weeks of treatment. Immunohistochemical analyses of pancreatic sections showed marked increases in the number of small islets (+35%) and total beta-cells (+120%) and in the islet beta-cell fraction (12% control vs. 24% treated) in the treated animals, suggesting that DP IV inhibitor treatment enhanced islet neogenesis, beta-cell survival, and insulin biosynthesis. In vitro studies using a beta-(INS-1) cell line showed a dose-dependent prevention of STZ-induced apoptotic cell-death by both GIP and GLP-1, supporting a role for the incretins in eliciting the in vivo results. These novel findings provide evidence to support the potential utility of DP IV inhibitors in the treatment of type 1 and possibly late-stage type 2 diabetes.

Topics: Animals; Blood Glucose; Cell Count; Cell Differentiation; Cell Division; Cell Survival; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Eating; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Tolerance Test; Immunohistochemistry; Insulin; Insulin Secretion; Islets of Langerhans; Lipids; Liver; Male; Peptide Fragments; Phosphoenolpyruvate Carboxykinase (GTP); Protease Inhibitors; Protein Precursors; Rats; Rats, Wistar; Weight Gain

Oxyntomodulin (OXM) is a product of proglucagon processing in the intestine and the central nervous system. We reported that intracerebroventricular (ICV) and intranuclear administration of OXM caused an inhibition of food intake in rats (Dakin CL, Gunn I, Small CJ, Edwards CM, Hay DL, Smith DM, Ghatei MA, and Bloom SR. Endocrinology 142: 4244-4250, 2001). In this study, we investigated the effect of twice-daily ICV administration of OXM, 1 nmol, for 7 days. A pair-fed control was included. These animals were restricted to the food intake of the OXM group but injected twice daily with saline. OXM-treated animals gained significantly less weight than either control group (day 8: OXM, 12.2 +/- 1.9 g vs. pair fed, 21.0 +/- 2.1 g; P < 0.005). OXM treatment caused a reduction in epididymal white adipose tissue (OXM, 1.13 +/- 0.03 g vs. pair fed, 1.29 +/- 0.04 g; P < 0.05) and interscapular brown adipose tissue (OXM, 0.15 +/- 0.01 g vs. pair fed, 0.18 +/- 0.01 g; P < 0.05) and increased core temperature compared with saline control, suggestive of enhanced energy expenditure. The food restriction-induced suppression in plasma TSH, seen in the pair-fed group, was prevented by OXM, potentially via increased release of hypothalamic TRH. In summary, ICV OXM causes reduced body weight gain and body adiposity following chronic administration.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Body Temperature; Cells, Cultured; Drug Administration Schedule; Eating; Glucagon-Like Peptides; Hypothalamus; Injections, Intraventricular; Male; Matched-Pair Analysis; Oxyntomodulin; Rats; Rats, Wistar; Thyrotropin; Weight Gain

Parenterally nourished preterm infants commonly receive minimal enteral feedings, the aim being to enhance intestinal function. Whether this regimen increases intestinal growth has not been established.. Our objective was to determine the minimal enteral nutrient intakes necessary to stimulate and to normalize neonatal intestinal growth.. Intestinal growth and cell proliferation were quantified in neonatal pigs given equal amounts of an elemental nutrient solution for 7 d. Different groups (n = 5-7 per group) received 0%, 10%, 20%, 40%, 60%, 80%, or 100% of total nutrient intake enterally, with the remainder given parenterally.. In the jejunum, wet weight, protein mass, and villus height were significantly greater at enteral intakes >40%. Stimulation of ileal protein mass required a higher enteral intake (60%). In both segments, abrupt increases in DNA mass, crypt depth, ornithine decarboxylase activity, and crypt cells in S-phase occurred between enteral intakes of 40% and 60%. Circulating concentrations of glucagon-like peptide-2 and peptide YY, but not gastrin, increased significantly between enteral intakes of 40% and 60% and closely paralleled indexes of cell proliferation.. The minimal enteral nutrient intake necessary to increase mucosal mass was 40% of total nutrient intake, whereas 60% enteral nutrition was necessary to sustain normal mucosal proliferation and growth. Our results imply that providing <40% of the total nutrient intake enterally does not have significant intestinal trophic effects.

Topics: Animals; Animals, Newborn; Cell Division; DNA; Enteral Nutrition; Food, Formulated; Gastrins; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Ileum; Intestines; Jejunum; Nutritional Requirements; Organ Size; Peptide YY; Peptides; Proteins; Swine; Weight Gain