A role for glucagon-like peptide-1 in the central regulation of feeding

AimsTo examine the efficacy and safety of once‐weekly dulaglutide monotherapy (0.75 mg) compared with placebo and once‐daily liraglutide (0.9 mg) in Japanese patients with type 2 diabetes.MethodsThis was a phase III, 52‐week (26‐week primary endpoint), randomized, double‐blind, placebo‐controlled, open‐label comparator (liraglutide) trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70) who were aged ≥20 years. Patients and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the superiority of dulaglutide versus placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the full analysis set.ResultsAt 26 weeks, once‐weekly dulaglutide was superior to placebo and non‐inferior to once‐daily liraglutide for HbA1c change from baseline [least squares mean difference: dulaglutide vs placebo −1.57% (95% confidence interval −1.79 to −1.35); dulaglutide vs liraglutide −0.10% (95% confidence interval −0.27 to 0.07)]. The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension and decreased appetite; only decreased appetite was different between the dulaglutide and liraglutide groups [dulaglutide, n = 2 (0.7%); liraglutide, n = 8 (5.8%); p = 0.003]. Nine (1.8%) patients experienced hypoglycaemia [dulaglutide, n = 6 (2.1%); liraglutide, n = 2 (1.5%); placebo, n = 1 (1.4%)], with no event being severe.ConclusionsIn Japanese patients with type 2 diabetes, once‐weekly dulaglutide (0.75 mg) was superior to placebo and non‐inferior to once‐daily liraglutide (0.9 mg) for reduction in HbA1c at 26 weeks. Dulaglutide was safe and well tolerated.

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“…GLP‐1 enhances glucose‐dependent secretion of insulin 2, 3, inhibits glucagon secretion 4, slows gastric emptying 5 and reduces food intake 6, 7.…”

Section: Introductionmentioning

confidence: 99%

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

Miyagawa

Odawara

Takamura

et al. 2015

Diabetes Obesity Metabolism

175

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“…[15][16][17] More recently, exenatide has been found to promote pancreatic b-cell proliferation and islet cell neogenesis in both animal and in vitro studies. 18,19 In addition to its role in glycemic control, GLP-1 is a shortterm regulator of food intake, [20][21][22] an effect mediated via central GLP-1 receptors. 22,23 Agents with actions similar to GLP-1, particularly those resistant to degradation by DPPIV, may be potential therapeutic agents in the treatment of obesity.…”

Section: Introductionmentioning

confidence: 99%

“…18,19 In addition to its role in glycemic control, GLP-1 is a shortterm regulator of food intake, [20][21][22] an effect mediated via central GLP-1 receptors. 22,23 Agents with actions similar to GLP-1, particularly those resistant to degradation by DPPIV, may be potential therapeutic agents in the treatment of obesity. 24 Exenatide reduces food intake in rodents following either central [25][26][27] or peripheral 18,27-31 administration, and repeated or chronic exposure reduces body weight.…”

Section: Introductionmentioning

confidence: 99%

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Mack¹,

Moore²,

Jodka³

et al. 2006

Int J Obes

129

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Background: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. Objective: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. Methods and results: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 mg/kg/ day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 mg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 mg/kg/day (Po0.05). Decreased body weight gain was associated with a significant decrease in fat mass (Po0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (Po0.05). Exenatide at 10 mg/kg significantly reduced food intake (Po0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. Conclusion: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

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“…This peptide and its long-acting receptor agonist, exendin-4 [9], possess a variety of actions that are protective against diabetes and that are mediated at the level of the beta cell, as well as in peripheral tissues. These include stimulation of glucose-dependent insulin secretion [10,11], and inhibition of glucagon release [11,12], gastric emptying [12,13] and food intake [14,15]. Recent data show that the actions of GLP-1 that protect against diabetes also include the enhancement of beta cell mass in rodents, through inhibition of beta cell apoptosis, and stimulation of beta cell proliferation and islet neogenesis [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

et al. 2005

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Aims/hypothesis: The gut hormone glucagonlike peptide-1 (GLP-1) decreases beta cell apoptosis in a protein kinase B (PKB)-dependent fashion, and increases islet cell mass and function in vivo. In contrast, cytokines induce beta cell apoptosis, leading to decreased islet mass and type 1 diabetes. In the present study we used rat INS-1E beta cells and primary rat islet cells to examine the potential role of PKB as a mediator of the effect of GLP-1 on cytokine-induced apoptosis. Methods: Cell viability was determined by MTTassay, and apoptosis and necrosis by Hoechst 33342-propidium iodide staining. Immunoblot analysis was used to detect changes in protein expression, including active (phosphorylated) and total PKB, phosphorylated and total glycogen synthase kinase-3β, activated caspase-3 and inducible nitric oxide synthase. Reactive oxygen species were determined by 1,7-dichlorofluorescein (DCF) analysis, and mutant forms of PKB were introduced into cells using adenoviral vectors. Results: Incubation of INS-1E cells with cytokines (IL-1β, TNF-α and interferon-γ; 10-50 ng/ml) for 18 h significantly decreased cell viability (by 44%, p<0.001), cell proliferation (by 80%, p<0.001), and activation of PKB (by 67%, p<0.001). Pre-treatment with exendin-4 (10 −7 mol/l), a long-acting GLP-1 receptor agonist, partially protected the cells against cytokine-induced toxicity (p<0.01) in association with a reduction in cytokine-induced inhibition of PKB phosphorylation (p<0.05). Exendin-4 pre-treatment did not change cell proliferation. Cytokine treatment increased apoptosis (by 156%, p<0.05) and necrosis (from undetectable to 2.6% of cells). These increases were both reduced by pre-treatment with exendin-4 (p<0.05-0.01). Furthermore, cytokine-induced apoptosis and necrosis were significantly increased in cells infected with kinase-dead PKB (p<0.05), and the protective effect of exendin-4 on both parameters was fully abolished in these cells. Similar changes were observed in primary islet cells. In parallel with these changes, exendin-4 decreased the cytokine-induced activation of caspase-3 (by 46%, p<0.05), and decreased levels of inducible nitric oxide synthase (by 71%, p<0.05) and reactive oxygen species (by 27%, p< 0.05). Conclusions/interpretation: The results of our study indicate that GLP-1 plays a protective role against cytokineinduced apoptosis and necrosis in beta cells through a PKB-dependent signalling pathway.

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A role for glucagon-like peptide-1 in the central regulation of feeding

Cited by 1,743 publications

References 21 publications

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

Once‐weekly glucagon‐like peptide‐1 receptor agonist dulaglutide is non‐inferior to once‐daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26‐week randomized phase III study

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B

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