Effects of acute hyperglucagonemia on hepatic and intestinal lipoprotein production and clearance in healthy humans

Abstract

Objective: The metabolism of hepatic- and intestinally derived lipoproteins is regulated in a complex fashion by nutrients, hormones, and neurologic and other factors. Recent studies in animal models suggest an important role for glucagon acting via the glucagon receptor in regulating hepatic triglyceride (TG) secretion. Here we examined the direct effects of glucagon on regulation of hepatic and intestinal lipoprotein metabolism in humans.

Research design and methods: Eight healthy men underwent two studies each, in random order, 4-6 weeks apart in which de novo lipogenesis, kinetics of larger VLDL1 TG, and kinetics of VLDL1 and smaller VLDL2 apolipoprotein (apo)B100 and B48 were studied using established stable isotope enrichment methods. Subjects were studied in the constant fed state under conditions of a pancreatic clamp (with infusion of somatostatin, insulin, and growth hormone) at either basal glucagon (BG study, 64.5 ± 2.1 pg/mL) or hyperglucagonemia (high glucagon [HG] study, 183.2 ± 5.1 pg/mL).

Results: There were no significant differences in plasma concentration of VLDL1 or VLDL2 TG, apoB100 or apoB48 between BG and HG studies. There was, however, lower (P < 0.05) VLDL1 apoB100 fractional catabolic rate (-39%) and production rate (-30%) in HG versus BG, but no difference in de novo lipogenesis or TG turnover, and glucagon had no effect on intestinal (B48-containing) lipoprotein metabolism.

Conclusions: Glucagon acutely regulates hepatic but not intestinal lipoprotein particle metabolism in humans both by decreasing hepatic lipoprotein particle production as well as by inhibiting particle clearance, with no net effect on particle concentration.

FIG. 1.

Study protocol (A) and plasma concentrations of glucose (B), insulin (C), and glucagon (D) over the time course of the study. A constant infusion of sodium 1-¹³C-acetate was started at 3 p.m. on the day before the kinetics study. A mixed meal was provided that day at 5 p.m., after which the subject fasted. At 4 a.m. the next day subjects started to ingest identical hourly, then half hourly, volumes of a liquid high fat nutritional supplement to maintain a constant fed state. At 7 a.m., i.e., 3 h after starting to ingest the formula, a pancreatic clamp was started with infusion of somatostatin, insulin, growth hormone, and glucagon, the latter to achieve either BG (□) or HG (♦) plasma concentrations. At 10 a.m. (referred to as time 0 for the lipoprotein kinetic study), i.e., 3 h after starting the pancreatic clamp, a bolus of [1,1,2,3,3-²H₅]-glycerol (d5-glycerol) was administered and a primed, constant infusion of l-[5,5,5-²H₃]-leucine (d3-leucine) was started and continued for 10 h (A). Plasma glucose (B) and insulin (C) concentrations were similar in BG and HG studies, whereas glucagon (D) was approximately threefold higher in HG vs. BG. *P < 0.0001 HG vs. BG.

FIG. 2.

Plasma TG (A), plasma FFA (B), VLDL1-TG (C), and VLDL2-TG (D) over the time course of the lipoprotein kinetic study in subjects receiving either BG (□) or HG (♦) infusion rate during pancreatic clamp. N = 8. P = NS HG vs. BG for all parameters.

FIG. 3.

VLDL1 apoB48 (A), VLDL1 apoB100 (B), VLDL2 apoB48 (C), and VLDL2 apoB100 (D) over the time course of the lipoprotein kinetic study in subjects receiving either BG (□) or HG (♦) infusion rate during pancreatic clamp. Conc, concentration. N = 8. P = NS HG vs. BG for all parameters.

FIG. 4.

Effect of acute hyperglucagonemia on VLDL apoB FCR (A and C) and PR (B and D) in subjects receiving either BG (white bar) or HG (hatched bar) infusion rate during pancreatic clamp. N = 8. The only significant differences were a lower FCR and PR for VLDL1-apoB100 in HG vs. BG. *P < 0.05 HG vs. BG.

FIG. 5.

Effect of acute hyperglucagonemia on de novo lipogenesis (A), VLDL1-TG FCR (B), and PR (C) in subjects receiving either BG (white bar) or HG (hatched bar) infusion rate during pancreatic clamp. VLDL apoB FCR and PR are shown. %DN V1-C16:0, percentage of newly synthesized palmitate in VLDL1-TG. There were no significant differences for any of the parameters illustrated.