Effects of Acute Hyperinsulinemia on VLDL Triglyceride and VLDL ApoB Production in Normal Weight and Obese Individuals

Abstract

The effects of short-term hyperinsulinemia on the production of both VLDL triglyceride and VLDL apoB were determined semiquantitatively before and during a 6-h euglycemic hyperinsulinemic clamp (40 mU.m-2 x min-1) in 17 women (8 chronically hyperinsulinemic obese, BMI = 35.7 kg/m2; 9 normal weight, BMI = 22.5 kg/m2). During acute hyperinsulinemia, plasma FFA decreased by approximately 95% within 1 h in both groups. VLDL triglyceride production decreased 66% in the control subjects (P = 0.0003) and 67% in obese subjects (P = 0.0003). ApoB production decreased 53% in control subjects (P = 0.03) but only 8% in obese (NS). Plasma triglycerides decreased by 40% from baseline in control subjects (P < 0.0001) but only by 10% in obese subjects (P = NS). Despite the similar decrease in triglyceride and apoB production in control subjects, VLDL particle size (triglyceride-to-apoB ratio) decreased with hyperinsulinemia (P = 0.003). In obese subjects, despite a decrease in triglyceride production similar to that in control subjects but no change in apoB production, VLDL size did not change appreciably. Acute hyperinsulinemia in humans: 1) suppresses plasma FFA equally in control and obese subjects at this high dose of insulin; 2) inhibits VLDL triglyceride production equally in control and obese subjects, perhaps secondary to the decrease in FFA; 3) inhibits VLDL apoB production in control but less so in obese subjects, suggesting that obese subjects may be resistant to this effect of insulin; 4) decreases plasma triglyceride and VLDL particle size in control subjects, reflecting either stimulation of LPL activity or a greater relative decrease in triglyceride to apoB production; and 5) does not decrease plasma triglyceride or VLDL size in obese subjects to the same extent as it does in control subjects. Thus, the insulin resistance of obesity affects some but not all aspects of VLDL metabolism.

Normal metabolism of apolipoprotein B100-containing lipoproteins despite qualitative abnormalities in type 1 diabetic men

“…This hypothesis is supported by the results of in vitro studies demonstrating that hepatocytes are able to secrete apoB-containing lipoproteins with variable triglyceride contents, depending on the intracellular availability of triglycerides [16]. Moreover, in humans, we know from simultaneous kinetic studies of VLDL triglycerides and apoB100 that variations in VLDL triglycerides and apoB production rates are not directly related [20,21]. The reasons for the decreased production rate of VLDL triglycerides in type 1 diabetic patients treated with subcutaneous insulin are not fully understood.…”

Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM

“…VLDL1 was modelled as a short delipidation chain in line with previously published systems [17] and a remnant compartment was included for subjects who required it to obtain a good fit. The default was to set k 8,6 to zero. Similarly, in most patients k 0,7 was not required and this was set to zero for baseline and clamp studies.…”

“…If k 6,5 decreases with time in the non-steady-state situation k 0,5 compensates for this and allows k 9,5 to remain constant. To reduce the number of unknowns a number of dependent constants were defined k 7,6 = k 9,7 ; k 0,8 = k 8,6 ; k 10,9 = k 0,10 . The equation permitting the decrease in k 6,5 , the VLDL1 apo B input, with time is given.…”

“…Data on the suppression of VLDL production by insulin in insulin resistant states are controversial. Lewis et al [6] showed an impaired suppression of VLDL apo B production in obese subjects while Cummings et al [9] did not find any defect in the ability of insulin to suppress VLDL apo B production in patients with NIDDM.…”

“…A majority of studies indicate that the elevation of plasma triglycerides in NIDDM result from an overproduction of VLDL triglyceride [2,3] and apo B [4,5] but it is unclear and a matter of controversy whether the increased production of VLDL particles is driven by a direct effect of hyperinsulinaemia or is a consequence of defective suppression of VLDL production by insulin [1]. In healthy subjects acute insulin administration suppresses VLDL apo B production [6][7][8]. Data on the suppression of VLDL production by insulin in insulin resistant states are controversial.…”