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
| Autor: | Kazuwa Nakao, Michio Noguchi, Junji Fujikura, Takeru Sakai, Mingming Zhao, Chihiro Ebihara, Yuji Yamamoto, Toru Kusakabe, Sachiko Yamamoto-Kataoka, Kiminori Hosoda, Nobuya Inagaki, Daisuke Aotani, Valentino Gumbilai, Megumi Aizawa-Abe, Ken Ebihara |
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| Rok vydání: | 2014 |
| Předmět: |
Leptin
Male medicine.medical_specialty Physiology Endocrinology Diabetes and Metabolism Type 2 diabetes Diet High-Fat Streptozocin Glucagon-Like Peptide 1 Physiology (medical) Internal medicine Insulin Secretion medicine Animals Hypoglycemic Agents Insulin Lipid deposition Insulin secretion Pancreas Triglycerides Adiposity Drug Implants Venoms business.industry digestive oral and skin physiology Drug Synergism High fat diet Overweight medicine.disease Streptozotocin Obesity Recombinant Proteins Mice Inbred C57BL Disease Models Animal Endocrinology Diabetes Mellitus Type 2 Hyperglycemia Exenatide Drug Therapy Combination Anti-Obesity Agents Peptides business hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 307:E712-E719 |
| ISSN: | 1522-1555 0193-1849 |
| DOI: | 10.1152/ajpendo.00272.2014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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