Leptin restores the insulinotropic effect of exenatide in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet

Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair β-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired β-cell function. In this study, we e...

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Published in:	American journal of physiology: endocrinology and metabolism Vol. 307; no. 8; p. E712
Main Authors:	Sakai, Takeru, Kusakabe, Toru, Ebihara, Ken, Aotani, Daisuke, Yamamoto-Kataoka, Sachiko, Zhao, Mingming, Gumbilai, Valentino Milton Junior, Ebihara, Chihiro, Aizawa-Abe, Megumi, Yamamoto, Yuji, Noguchi, Michio, Fujikura, Junji, Hosoda, Kiminori, Inagaki, Nobuya, Nakao, Kazuwa
Format:	Journal Article
Language:	English
Published:	United States 15-10-2014
Subjects:	Adiposity - drug effects Animals Anti-Obesity Agents - administration & dosage Anti-Obesity Agents - therapeutic use Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Diet, High-Fat - adverse effects Disease Models, Animal Drug Implants Drug Synergism Drug Therapy, Combination Exenatide Glucagon-Like Peptide 1 - agonists Glucagon-Like Peptide 1 - metabolism Hyperglycemia - prevention & control Hypoglycemic Agents - administration & dosage Hypoglycemic Agents - therapeutic use Insulin - metabolism Insulin Secretion Leptin - administration & dosage Leptin - genetics Leptin - therapeutic use Male Mice, Inbred C57BL Overweight - complications Overweight - drug therapy Overweight - etiology Overweight - metabolism Pancreas - drug effects Pancreas - metabolism Peptides - administration & dosage Peptides - therapeutic use Recombinant Proteins - administration & dosage Recombinant Proteins - genetics Recombinant Proteins - therapeutic use Streptozocin Triglycerides - metabolism Venoms - administration & dosage Venoms - therapeutic use drug therapy insulin secretion combination
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Summary:	Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair β-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired β-cell function. In this study, we examined whether leptin could restore the efficacy of exenatide, a GLP-1 receptor agonist, in type 2 diabetes with increased adiposity. We chronically administered leptin (500 μg·kg⁻¹·day⁻¹) and/or exenatide (20 μg·kg⁻¹·day⁻¹) for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet (STZ/HFD mice). The STZ/HFD mice exhibited hyperglycemia, overweight, increased pancreatic triglyceride level, and reduced glucose-stimulated insulin secretion (GSIS); moreover, the insulinotropic effect of exenatide was reduced. However, leptin significantly reduced pancreatic triglyceride level, and adding leptin to exenatide (LEP/EX) remarkably enhanced GSIS. These results suggested that the leptin treatment restored the insulinotropic effect of exenatide in the mice. In addition, LEP/EX reduced food intake, body weight, and triglyceride levels in the skeletal muscle and liver, and corrected hyperglycemia to a greater extent than either monotherapy. The pair-feeding experiment indicated that the marked reduction of pancreatic triglyceride level and enhancement of GSIS by LEP/EX occurred via mechanisms other than calorie restriction. These results suggest that leptin treatment may restore the insulinotropic effect of exenatide associated with the reduction of pancreatic lipid deposition in type 2 diabetes with increased adiposity. Combination therapy with leptin and exenatide could be an effective treatment for patients with type 2 diabetes with increased adiposity.
ISSN:	1522-1555
DOI:	10.1152/ajpendo.00272.2014