Exenatide, a Glucagon-like Peptide Receptor Agonist, Acutely Inhibits Intestinal Lipoprotein Production in Healthy Humans

Dyslipidemia is a prominent feature of insulin resistance and type 2 diabetes mellitus, playing an important role in the etiology of cardiovascular disease in these conditions. An important component of the typical dyslipidemia of type 2 diabetes mellitus is elevated triglycerides (TG). We and others have demonstrated in animal models that, in insulinresistant states, triglyceride-rich lipoprotein (TRL); (apolipoprotein [apo] B-100–containing lipoproteins in the liver and apoB-48–containing lipoproteins in the intestine) production is increased. We have also demonstrated in humans that TRL production is regulated by several factors, including circulating free fatty acid (FFA) and pancreatic hormones (insulin and glucagon). Understanding the regulation of TRL production and strategies in ameliorating TRL overproduction in insulin resistance may lead to new therapies to treat dyslipidemia and prevent cardiovascular disease. The identification and characterization of intestinally derived incretins, including glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide, have led to the development and clinical use of incretin-based therapies for type 2 diabetes mellitus. GLP-1, through its receptor (GLP-1R), executes multiple physiological functions including enhancing glucose-stimulated insulin secretion by pancreatic -cells, inducing -cell proliferation, and inhibiting -cell apoptosis (the latter shown in animal models and in vitro but not directly in humans). GLP-1 also slows gastric emptying, inhibits glucose-dependent glucagon secretion, and promotes satiety. The incretins are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). GLP-1 receptor agonists, such as the GLP-1 mimetic exenatide, and DPP-4 inhibitors have proven efficacy in treating type 2 diabetes mellitus. Aside from their primary effects on glucose homeostasis, recent clinical studies also suggest their potential role in ameliorating hyperlipidemia. Because of the known effects of GLP-1 on satiety and weight gain, the exact mechanism of GLP-1R modulation on lipid homeostasis remains poorly defined from Exenatide, a Glucagon-like Peptide Receptor Agonist, Acutely Inhibits Intestinal Lipoprotein Production in Healthy Humans