Intravenous Glucose Acutely Stimulates Intestinal Lipoprotein Secretion in Healthy Humans

Abstract

Objective-Increased production of intestinal triglyceride-rich lipoproteins (TRLs) contributes to dyslipidemia and increased risk of atherosclerotic cardiovascular disease in insulin resistance and type 2 diabetes. We have previously demonstrated that enteral glucose enhances lipid-stimulated intestinal lipoprotein particle secretion. Here, we assessed whether glucose delivered systemically by intravenous infusion also enhances intestinal lipoprotein particle secretion in humans. Approach and Results-On 2 occasions, 4 to 6 weeks apart and in random order, 10 healthy men received a constant 15-hour intravenous infusion of either 20% glucose to induce hyperglycemia or normal saline as control. Production of TRL-apolipoprotein B48 (apoB48, primary outcomes) and apoB100 (secondary outcomes) was assessed during hourly liquid-mixed macronutrient formula ingestion with stable isotope enrichment and multicompartmental modeling, under pancreatic clamp conditions to limit perturbations in pancreatic hormones (insulin and glucagon) and growth hormone. Compared with saline infusion, glucose infusion induced both hyperglycemia and hyperinsulinemia, increased plasma triglyceride levels, and increased TRL-apoB48 concentration and production rate (P<0.05), without affecting TRLapoB48 fractional catabolic rate. No significant effect of hyperglycemia on TRL-apoB100 concentration and kinetic parameters was observed. Conclusions-Short-term intravenous infusion of glucose stimulates intestinal lipoprotein production. Hyperglycemia may contribute to intestinal lipoprotein overproduction in type 2 diabetes. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02607839.

Role of the Gut in Diabetic Dyslipidemia

“…Hyperglycemia itself may further enhance CM secretion in the diabetic state. In healthy, non-diabetic adults, we have shown enhanced apoB48 production in response to intraduodenal and intravenous glucose, and in response to intraduodenal fructose (55,56). Whether hyperglycemia in diabetes contributes directly to enhanced CM secretion is unknown.…”

Residual cardiovascular risk among people with diabetes

“…In addition, IR is associated with reduced hepatic clearance of TRL particles potentially due to free fatty acid mediated increase in apoCIII (which regulates TRL clearance) and competition between liver and gut TRL particles for clearance through common saturable pathways . In addition to IR, increased dietary and circulating glucose likely directly contribute to increased TRL production and reduced clearance, which is pertinent for patients with T2D …”

“…2,26,53 In addition to IR, increased dietary and circulating glucose likely directly contribute to increased TRL production and reduced clearance, which is pertinent for patients with T2D. [54][55][56]…”

Differential associations between plasma concentrations of insulin and glucose and intestinal expression of key genes involved in chylomicron metabolism

“…Previous studies have shown that plasma insulin inhibits chylomicron secretion (25), whereas it was recently demonstrated that plasma glucose stimulates chylomicron secretion (47). Conflicting observations regarding the intestinal expression of key genes involved in chylomicron assembly and secretion were, however, reported in humans, with IR exhibiting an overproduction of intestinal lipoproteins.…”

“…More specifically, we aimed to evaluate in a large sample of nondiabetic men displaying various degrees of IR the association between the plasma levels of insulin and glucose and the intestinal expression of sterol regulatory element-binding protein-1c (SREBP1c), FATP4, FABP2, DGATs, acetyl-CoA synthetase 1 (ACS1), ApoB, MTP, and SAR1B. We hypothesized that fasting intestinal expression of genes involved in chylomicron metabolism is inversely associated with insulin concentrations (21,27) and positively associated with plasma glucose levels (47).…”