Abstract
ObjectiveIn addition to improve glucose intolerance, recent studies suggest that glucagon-like peptide-1 (GLP-1) receptor agonism also decreases triglyceride (TG) levels. The aim of this study was to evaluate the effect of GLP-1 receptor agonism on very-low-density lipoprotein (VLDL)-TG production and liver TG metabolism.Experimental ApproachThe GLP-1 peptide analogues CNTO3649 and exendin-4 were continuously administered subcutaneously to high fat diet-fed APOE*3-Leiden transgenic mice. After 4 weeks, hepatic VLDL production, lipid content, and expression profiles of selected genes involved in lipid metabolism were determined.ResultsCNTO3649 and exendin-4 reduced fasting plasma glucose (up to −30% and −28% respectively) and insulin (−43% and −65% respectively). In addition, these agents reduced VLDL-TG production (−36% and −54% respectively) and VLDL-apoB production (−36% and −43% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. Moreover, they markedly decreased hepatic content of TG (−39% and −55% respectively), cholesterol (−30% and −55% respectively), and phospholipids (−23% and −36% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, Fasn, Dgat1) and apoB synthesis (Apob).ConclusionGLP-1 receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus.
Highlights
Type 2 diabetes mellitus (T2DM) has become a major metabolic disorder in both developed and developing countries, with impaired glucose tolerance and insulin resistance as hallmarks [1,2]
These agents reduced very-low-density lipoprotein (VLDL)-TG production (236% and 254% respectively) and VLDLapoB production (236% and 243% respectively), indicating reduced production of VLDL particles rather than reduced lipidation of apoB. They markedly decreased hepatic content of TG (239% and 255% respectively), cholesterol (230% and 255% respectively), and phospholipids (223% and 236% respectively), accompanied by down-regulation of expression of genes involved in hepatic lipogenesis (Srebp-1c, FA synthase (Fasn), Dgat1) and apoB synthesis (Apob)
glucagon-like peptide-1 (GLP-1) receptor agonism reduces VLDL production and hepatic steatosis in addition to an improvement of glycemic control. These data suggest that GLP-receptor agonists could reduce hepatic steatosis and ameliorate dyslipidemia in patients with type 2 diabetes mellitus
Summary
Type 2 diabetes mellitus (T2DM) has become a major metabolic disorder in both developed and developing countries, with impaired glucose tolerance and insulin resistance as hallmarks [1,2]. GLP-1 is released in response to food intake to stimulate glucose-dependent insulin secretion by the pancreas [4,6]. GLP-1 exerts multiple other effects, including inhibition of food intake [7], slowing gastric emptying [8], and inhibition of glucagon secretion [9]. Therapeutic application of GLP-1 is hampered due to its short circulating halflife (,2 minutes), because it is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) that is widely expressed in endothelium and intestinal mucosa [10]. Pharmaceutical GLP-1 analogues that are resistant to inactivation by DPP-4 have been developed with an improved pharmacokinetic profile related to a longer half-life, of which exenatide
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