title: Impact of alogliptin and pioglitazone on lipid metabolism in islets of prediabetic and diabetic Zucker Diabetic Fatty rats.
abstract: Prolonged exposure of pancreatic beta (β) cells to elevated glucose and free fatty acids (FFA) as occurs in type 2 diabetes results in loss of β cell function and survival. In Zucker Diabetic Fatty (ZDF) rats, β cell failure is associated with increased triacylglyceride (TAG) synthesis and disruption of the glycerolipid/FFA (GL/FFA) cycle, a critical arm of glucose-stimulated insulin secretion (GSIS). The aim of this study was to determine the impact of activation of PPARγ and increased incretin action via dipeptidyl-peptidase inhibition using pioglitazone and/or alogliptin, respectively, on islet lipid metabolism in prediabetic and diabetic ZDF rats. Transition of control prediabetic ZDF rats to diabetes was associated with reduced plasma insulin levels, reduced islet insulin content and GSIS, reduced stearoyl-CoA desaturase 2 (SCD 2) expression, and increased islet TAG, diacylglyceride (DAG) and ceramides species containing saturated FA. Treatment of prediabetic ZDF rats with a combination of pioglitazone and alogliptin, but not individually, prevented the transition to diabetes and was associated with marked lowering of islet TAG and DAG levels. Pioglitazone and alogliptin, however, did not restore SCD2 expression, the degree of FA saturation in TAG, DAG or ceramides, islet insulin content, or lower ceramide levels. These findings are consistent with activation of PPARγ and increased incretin action working in concert to restore GL/FFA cycle in β cells of ZDF rats. Restoration of the GL/FFA cycle without correcting islet FA desaturation, production of islet ceramides, and/or insulin sensitivity, however, may place these islets at risk for β cell failure.
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: ycai7@uncc.edu.
authors: Ying
authors: Y
authors: Cai
authors: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: lydictod@msu.edu.
authors: Todd A
authors: TA
authors: Lydic
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: tturkette@gmail.com.
authors: Thomas
authors: T
authors: Turkette
authors: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA; Department of Chemistry, Michigan State University, East Lansing, MI 48824 USA. Electronic address: reid@chemistry.msu.edu.
authors: Gavin E
authors: GE
authors: Reid
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. Electronic address: olsonla@msu.edu.
authors: L Karl
authors: LK
authors: Olson
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000502:physiology; D008297:Male; D000077205:Pioglitazone; D010880:Piperidines / Q000008:administration & dosage*; D011236:Prediabetic State / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000008:administration & dosage*; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D010880:Piperidines; D045162:Thiazolidinediones; D014498:Uracil; C520853:alogliptin; D000077205:Pioglitazone
keywords: Diacylglyceride; Dipeptidyl-peptidase 4 (DPP-4); Insulin secretion; Lipotoxicity; Peroxisome proliferator-activated receptor γ (PPARγ); Triacylglyceride