Role of the Gut in Diabetic Dyslipidemia

Abstract

Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and impaired clearance of liver-derived very-low-density lipoproteins and gut-derived chylomicrons (CMs) contribute to hypertriglyceridemia and elevated atherogenic remnant lipoproteins. Although ingested fat is the major stimulus of CM secretion, intestinal lipid handling and ultimately CM secretory rate is determined by numerous additional regulatory inputs including nutrients, hormones and neural signals that fine tune CM secretion during fasted and fed states. Insulin resistance and T2D represent perturbed metabolic states in which intestinal sensitivity to key regulatory hormones such as insulin, leptin and glucagon-like peptide-1 (GLP-1) may be altered, contributing to increased CM secretion. In this review, we describe the evidence from human and animal models demonstrating increased CM secretion in insulin resistance and T2D and discuss the molecular mechanisms underlying these effects. Several novel compounds are in various stages of preclinical and clinical investigation to modulate intestinal CM synthesis and secretion. Their efficacy, safety and therapeutic utility are discussed. Similarly, the effects of currently approved lipid modulating therapies such as statins, ezetimibe, fibrates, and PCSK9 inhibitors on intestinal CM production are discussed. The intricacies of intestinal CM production are an active area of research that may yield novel therapies to prevent atherosclerotic CVD in insulin resistance and T2D.

Keywords: Enteroendocrine; chylomicron; diabetes; intestine; lipoprotein.

Figure 1

Intestinal lipoprotein overproduction in diabetes and potential therapeutic targets. The following are potential therapeutic targets, as discussed in the text. (1) Dietary triglycerides (TG) are hydrolyzed in the intestinal lumen by pancreatic lipases which can be inhibited to reduce fatty acid (FA) and monoacylglycerol (MAG) availability for absorption. (2) Fatty acyl-CoA (FACoA) are progressively re-esterified into TG by monoacylglycerol acyltransferase (MGAT) and diacylglycerol acyltransferase (DGAT) (3) Microsomal triglyceride transfer protein (MTP) is a crucial enzyme for lipidation of nascent apoB48 and the pre-chylomicron (CM) particle (4) The cholesterol transporter Niemann-Pick C1-like-1 (NPC1L1) is a rate limiting step in cholesterol absorption. Cholesteryl esters are an important component of CM particles. (5) Antagonism of sodium-glucose cotransporter-1 (SGLT1) is in development as a diabetes therapy to attenuate glucose absorption which may modify CM secretion. (6) Fibrates are approved lipid-lowering treatments that agonize peroxisome proliferator-activated alpha (PPARα). Whether fibrates markedly lower CM secretion is under investigation. (7) Glucagon-like peptide-1 (GLP-1) suppresses CM secretion. GLP-1 analogs and inhibitors of the GLP-1-degrading enzyme DPP-IV are available diabetes therapies that acutely inhibit CM secretion in healthy humans. Glucagon-like peptide-2 (GLP-2) has been shown to acutely stimulate intestinal CM release in human and rodent models, however antagonistic therapies have not yet been examined as a therapy to decrease CM secretion. (8) Circulating CMs and liver-derived very-low density lipoproteins (VLDL) are delipidated by lipoprotein lipase (LPL) at peripheral tissues. Angiopoietin-like peptides (ANGPTL) 3,4 and 8 negatively regulate LPL and their effects on CMs is under investigation. (9) Hepatic clearance of CM remnants (CM-R) and low-density lipoprotein cholesterol (LDL-c) is mediated in part by the LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PSCK9) negatively regulates LDLR and is also highly expressed in the small intestine. Monoclonal antibodies against PCSK9 effectively lower LDL-c; however, PCSK9 inhibition in healthy humans had no impact on postprandial TG or apoB48 kinetics. (10) Statins are well-described inhibitors of HMGCoA reductase that effectively reduce cholesterol synthesis. Statin therapy reduces circulating apoB48 and CM-TG by increasing CM clearance, and perhaps decreasing CM secretion.