Intestinal Lipoprotein Secretion: Incretin-Based Physiology and Pharmacology Beyond Glucose.

Abstract

The incretin axis, mostly glucagon-like peptide 1 (GLP-1), is a well-acknowledged and -applied science of glucose homeostasis. Importantly, modifying this physiology with GLP-1 receptor (GLP-1R) agonists or inhibiting the enzymatic breakdown of GLP-1 with dipeptidyl peptidase-4 (DPP-4) inhibitors experienced increasing success in achieving glycemic control in patients with type 2 diabetes (T2D) (1). Yet, the role of gut peptides on lipid and lipoprotein metabolism has been relatively unnoticed, and the favorable changes in fasting and nonfasting lipids with incretin-directed pharmacotherapy may be an important pathway to promote cardiovascular health beyond glucose lowering alone (2). The most typical lipid and lipoprotein disorder in T2D is hypertriglyceridemia with a reduced plasma level of HDL cholesterol, mechanisms related to increased VLDL triglyceride (TG) production and secretion, and reduced clearance of TG-rich particles by lipoprotein lipase (3). Moreover, increases in postprandial lipid excursion in patients with T2D are also seen, an alteration related to similar mechanisms in the setting of chylomicron assembly and secretion by the intestine. Herein is where the evolving science of incretins is worthy of attention. In this issue of Diabetes , the Perspective by Xiao et al. (4) is timely and state of the art. As documented by the authors, treatment of patients with T2D with GLP-1R agonists has variable reductions in fasting TG, an effect typically more pronounced with GLP-1R agonists than DPP-4 inhibitors. A reduction mediated by GLP-1R agonists and/or DPP-4 inhibitors in postprandial …