title: 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: 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.
authors.affiliation: Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan; Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Takeru
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; kusakabe@kuhp.kyoto-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Kusakabe
authors.affiliation: Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan; and.
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aotani
authors.affiliation: Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamamoto-Kataoka
authors.affiliation: Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Valentino Milton Junior
authors.initials: VM
authors.lastname: Gumbilai
authors.affiliation: Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ebihara
authors.affiliation: Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan; and.
authors.forename: Megumi
authors.initials: M
authors.lastname: Aizawa-Abe
authors.affiliation: Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Michio
authors.initials: M
authors.lastname: Noguchi
authors.affiliation: Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Junji
authors.initials: J
authors.lastname: Fujikura
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Human Health Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hosoda
authors.affiliation: Department of Diabetes, Endocrinology, and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan;
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004343:Drug Implants; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D050177:Overweight / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D013311:Streptozocin; D014280:Triglycerides / Q000378:metabolism; D014688:Venoms / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D019440:Anti-Obesity Agents; D004343:Drug Implants; D007004:Hypoglycemic Agents; D007328:Insulin; D020738:Leptin; D010455:Peptides; D011994:Recombinant Proteins; D014280:Triglycerides; D014688:Venoms; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: combination; drug therapy; insulin secretion