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

Abstract

restores the insulinotropic effect of exenatide in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet. Am J Physiol Endocrinol Metab 307: E712-E719, 2014. First published August 26, 2014; doi:10.1152/ajpendo.00272.2014.-Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair ␤-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 ␤-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 g·kg Ϫ1 ·day Ϫ1 ) and/or exenatide (20 g·kg Ϫ1 ·day Ϫ1 ) for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and highfat 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. drug therapy; combination; insulin secretion LEPTIN, AN ADIPOCYTE-DERIVED hormone, has therapeutic potential for treating diabetes and obesity (7, 13 19, 27, 32, 34). In our previous clinical trial in patients with lipodystrophy (6), we confirmed the therapeutic usefulness of leptin as a glucose-lowering agent, and it was first approved for the treatment of lipodystrophy in Japan in March 2013. Given these glucoregulatory effects of leptin, we and others have reported the therapeutic usefulness of leptin for various forms of diabetes, including type 2 diabetes, in rodent models (20,23,26,28,47). The glucoregulatory effects of leptin are associated with the reduction of ectopic lipid deposition, which increases with progression of obesity (36,39,46). The reduction of ectopic lipid deposition in the liver and skeletal muscle could improve insulin sensitivity (42). In the pancreas, the reduction of ectopic lipid deposition could improve ␤-cell function ...

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