Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects.

Abstract

The objective of the study was to examine the potential differential effect of insulin and acipimox (both of which reduce free fatty acid [FFA] availability) on VLDL apolipoprotein (apo) B metabolism. We studied eight healthy men (age 40 +/- 4 years, BMI 25.8 +/- 0.9 kg/m2, plasma triglycerides 1.30 +/- 0.12 mmol/l) after an overnight fast (control study, n = 8), during inhibition of lipolysis with an antilipolytic agent, acipimox (n = 8), and under 8.5-h euglycemic-hyperinsulinemic conditions (n = 5). Plasma FFAs were similarly suppressed in the acipimox and insulin studies (approximately 70% suppression). 2H3-leucine was used to trace apo B kinetics in VLDL1 and VLDL2 subclasses (Svedberg flotation rates: 60-400 and 20-60), and a non-steady-state multicompartmental model was used to derive the kinetic constants. The mean rate of VLDL1 apo B production was 708 +/- 106 mg/day at the beginning and 602 +/- 140 mg/day at the end of the control study. Production of the lipoprotein decreased to 248 +/- 93 mg/day during the insulin study (P < 0.05 vs. control study) and to 375 +/- 92 mg/day (NS) during the acipimox study. Mean VLDL2 apo B production was significantly increased during the acipimox study (399 +/- 42 vs. 236 +/- 27 mg/day, acipimox vs. control, P < 0.05) but not during the insulin study (332 +/- 51 mg/day, NS). The fractional catabolic rates of VLDL1 and VLDL2 apo B were similar in all three studies. We conclude that acute lowering of FFAs does not change the overall production rate of VLDL particles, but there is a shift toward production of smaller and denser VLDL2 particles, and, thus, the amount of total VLDL particles secreted remained constant. Insulin acutely suppresses the total production rate of VLDL apo B by decreasing the production of large triglyceride-rich VLDL1 particles. Based on these findings, we postulate that insulin has a direct suppressive effect on the production of VLDL apo B in the liver, independent of the availability of FFAs.

Mathematical modelling of hepatic lipid metabolism

“…Stable isotope tracers have been used in conjunction with compartmental modelling to elucidate the kinetics of apoB (a key structural protein in lipoproteins) and triglyceride across VLDL subfractions simultaneously. Adiels' model [2] has proven to be a particularly useful tool in determining how physiological features impact VLDL size and dyslipidemia [4,3,39,38]. A more in-depth model of VLDL assembly has been proposed by Shorten and Upreti [50] in which the lipid composition of secreted VLDLs can be determined from uptake of individual free fatty acids after elongation and desaturation by liver enzymes.…”

Postprandial VLDL-triacylglycerol secretion is not suppressed in obese type 2 diabetic men

“…However, studies have also shown an association between liver fat content and the postprandial increase in ApoB-100 [28,29], indicating that endogenous VLDL-TAG secretion may also contribute to postprandial lipaemia in type 2 diabetes. Despite the wide range of different tracers and kinetic models employed to study VLDL-TAG kinetics, results in healthy individuals have convincingly shown that acute experimental hyperinsulinaemia decreases hepatic production of VLDL-ApoB [12,14,[30][31][32][33] and VLDL-TAG [10,12,14,30,31], primarily through suppression of VLDL 1 (rather than VLDL 2 ) production [12,32,33]. Insulin-mediated suppression of VLDL-TAG secretion may partly be attributed to diminished hepatic NEFA delivery secondary to suppression of adipose tissue lipolysis [34].…”

Significant improvement of apolipoprotein B-containing lipoprotein metabolism by insulin treatment in patients with non-insulin-dependent diabetes mellitus

“…Insulin interacts with hepatic apoB secretion by at least two mechanisms. In healthy subjects, euglycaemic hyperinsulinaemic clamp studies have shown that insulin suppresses the production of VLDL1 particles by decreasing the availability of free fatty acids to the liver and by exerting a direct suppressive effect on apoB production [22]. In Type II diabetic subjects, euglycaemic hyperinsulinaemic clamp studies yielded contradictory results, reporting either a twofold decrease of VLDL apoB production [23], or the inability of insulin to suppress VLDL1 production despite efficient suppression of serum non-esterified fatty acids and euglycaemic conditions [24].…”