Sitagliptin, a DPP-4 inhibitor, acutely inhibits intestinal lipoprotein particle secretion in healthy humans

Abstract

The dipeptidyl peptidase-4 inhibitor sitagliptin, an antidiabetic agent, which lowers blood glucose levels, also reduces postprandial lipid excursion after a mixed meal. The underlying mechanism of this effect, however, is not clear. This study examined the production and clearance of triglyceride-rich lipoprotein particles from the liver and intestine in healthy volunteers in response to a single oral dose of sitagliptin. Using stable isotope tracer techniques and with control of pancreatic hormone levels, the kinetics of lipoprotein particles of intestinal and hepatic origin were measured. Compared with placebo, sitagliptin decreased intestinal lipoprotein concentration by inhibiting particle production, independent of changes in pancreatic hormones, and circulating levels of glucose and free fatty acids. Fractional clearance of particles of both intestinal and hepatic origin, and production of particles of hepatic origin, were not affected. This pleiotropic effect of sitagliptin may explain the reduction in postprandial lipemia seen in clinical trials of this agent and may provide metabolic benefits beyond lowering of glucose levels.

Figure 1

A: Schematic representation of the experimental design. Hourly ingestion of a liquid formula was started at 4:00 a.m. to achieve a constant fed state. A pancreatic clamp (with infusion of somatostatin, insulin, glucagon, and growth hormone) was started 3 h later. Two hours into the pancreatic clamp, sitagliptin (100 mg) or placebo was administered orally, and a primed, constant infusion of d3-leucine was started. Frequent blood samples were drawn for isolation of TRL fractions, gel separation of apoB-100 and apoB-48, and gas chromatography–mass spectrometry quantification of stable isotopic enrichment. B: Compartmental model for estimating TRL apoB-100 and apoB-48 FCRs. The model consists of 1) a plasma amino acid (PAA; leucine) precursor pool, 2) a delay compartment, and 3) a plasma TRL compartment. Plasma TG (C), TRL TG (D), TRL apoB-100 (E), and TRL apoB-48 (F) concentrations during the kinetic study. The “fasting” sample was taken after a 14-h overnight fast the day prior to the study. Open diamond, placebo; solid squares, sitagliptin; PAA, plasma amino acids; conc, concentration. *P < 0.05, sitagliptin vs. placebo.

Figure 2

TRL apoB-100 pool size (A), TTR time course (B), FCR (C), and PR (D) after sitagliptin (SIT) (100 mg) or placebo treatment during a pancreatic clamp. White bars, placebo; hatched bars, sitagliptin; open diamond, placebo; solid squares, sitagliptin.

Figure 3

TRL apoB-48 pool size (A), TTR time course (B), FCR (C), and PR (D) after sitagliptin (SIT) (100 mg) or placebo treatment during a pancreatic clamp. White bars, placebo; hatched bars, sitagliptin; open diamond, placebo; solid squares, sitagliptin. *P < 0.05, vs. placebo.