The incretin receptors for GLP-1 and GIP are essential for the sustained metabolic actions of vildagliptin in mice

Abstract

Objective: DPP4 inhibitors (DPP-4i) lower blood glucose in diabetic subjects however the mechanism of action through which these agents improve glucose homeostasis remains incompletely understood. Although GLP-1 and GIP represent important targets for DPP4 activity, whether additional substrates are important for the glucose-lowering actions of DPP4 inhibitors remains uncertain.

Research Design and Methods: We examined the efficacy of continuous vildagliptin administration in wildtype (WT) and dual incretin receptor knockout (DIRKO) mice after 8 weeks of a high fat (HF)-diet.

Results: Vildagliptin had no significant effect on food intake, energy expenditure, body composition, body weight gain or insulin sensitivity in WT or DIRKO mice. However glycemic excursion after oral glucose challenge was significantly reduced in WT but not in DIRKO mice after vildagliptin treatment. Moreover, vildagliptin increased levels of glucose-stimulated plasma insulin, and reduced levels of cholesterol and triglycerides in WT but not in DIRKO mice. Vildagliptin treatment reduced the hepatic expression of genes important for cholesterol synthesis and fatty acid oxidation, including Phospho-mevalonate kinase (Mvk), Acyl-Coenzyme Dehydrogenase medium chain (Acadm), Mevalonate (diphospho)decarboxylase (Mvd), and Acyl-CoA Synthetase (Acsl1) in WT but not in DIRKO mice. However, vildagliptin also reduced levels of hepatic mRNA transcripts for Farnesyl di-phosphate transferase (Fdft1), Acetyl Co-enzyme A Acyltransferase 1 (Acaa1) and Carnitine palmitoyl transferase 1 (Cpt 1) in DIRKO mice. No direct effect of GLP-1R agonists was detected on cholesterol or triglyceride synthesis and secretion in WT hepatocytes.

Conclusions: These findings illustrate that although GLP-1 and GIP receptors represent the dominant molecular mechanisms for transducing the glucoregulatory actions of DPP4 inhibitors, prolonged DPP4 inhibition modulates the expression of genes important for lipid metabolism independent of incretin receptor action in vivo.