W09.200 Insulin resistance is associated with increased VLDL triglyceride and VLDL apoC-III production

Insulin regulates hepatic VLDL production by activation of phosphatidylinositide 3-kinase (PI3-kinase) which decreases apo B available for lipid assembly. The current study evaluated the dependence of the VLDL apolipoprotein B (apo B) pathway on PI3-kinase activity in vivo. VLDL production was examined in B100 only, apo B mRNA editing catalytic subunit 1 ( apobec-1 −/−) mice, using the Triton WR 1339 method. Glucose injection suppressed VLDL triglyceride production by 28% in male and by 32% in female mice compared with saline-injected controls. When wortmannin was injected to inhibit PI3-kinase, VLDL triglyceride production was increased by 52% in males and by 89% in females, and VLDL B100 levels paralleled triglyceride changes. Pulse-chase experiments in primary mouse hepatocytes showed that wortmannin increased net freshly synthesized B100 availability by >35%. To test whether physiological insulin resistance produced equivalent effects to wortmannin, we studied male apobec-1 −/− mice who became hyperlipidemic on being fed a fructose-enriched diet. Fructose-fed apobec-1 −/− mice had significantly higher VLDL triglyceride and B100 production rates compared with chow-fed mice, and rates were refractile to glucose or wortmannin. Hepatic VLDL triglyceride and B100 production in wortmannin-injected chow-fed mice equaled that observed in fructose-fed mice. Together, results suggest in vivo and in vitro that wortmannin-sensitive PI3-kinases maintain a basal level of VLDL suppression that is sensitive to changes in activation and that can increase VLDL production when PI3-kinase is inhibited to levels similar to those induced by insulin resistance.

Download Full-text

Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00374.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. E920-E927 ◽

Cited By ~ 62

Author(s):

Morten B. Krag ◽

Lars C. Gormsen ◽

ZengKui Guo ◽

Jens S. Christiansen ◽

Michael D. Jensen ◽

...

Keyword(s):

Insulin Resistance ◽

Growth Hormone ◽

Future Research ◽

Double Blind ◽

Triglyceride Content ◽

Intramuscular Triglyceride ◽

Rebound Increase ◽

The Impact ◽

Vldl Triglyceride

The ability of growth hormone (GH) to stimulate lipolysis and cause insulin resistance in skeletal muscle may be causally linked, but the mechanisms remain obscure. We investigated the impact of GH on the turnover of FFA and VLDL-TG, intramuscular triglyceride content (IMTG), and insulin sensitivity (euglycemic clamp) in nine healthy men in a randomized double-blind placebo-controlled crossover study after 8 days treatment with (A) Placebo + Placebo, (B) GH (2 mg daily) + Placebo, and (C) GH (2 mg daily) + Acipimox (250 mg × 3 daily). In the basal state, GH (B) increased FFA levels ( P < 0.05), palmitate turnover ( P < 0.05), and lipid oxidation ( P = 0.05), but VLDL-TG kinetics were unaffected. Administration of acipimox (C) suppressed basal lipolysis but did not influence VLDL-TG kinetics. In the basal state, IMTG content increased after GH (B; P = 0.03). Insulin resistance was induced by GH irrespective of concomitant acipimox ( P < 0.001). The turnover of FFA and VLDL-TG was suppressed by hyperinsulinemia during placebo and GH, whereas coadministration of acipimox induced a rebound increase FFA turnover and VLDL-TG clearance. We conclude that these results show that GH-induced insulin resistance is associated with increased IMTG and unaltered VLDL-TG kinetics; we hypothesize that fat oxidation in muscle tissue is an important primary effect of GH and that circulating FFA rather than VLDL-TG constitute the major source for this process; and the role of IMTG in the development of GH-induced insulin resistance merits future research.

Download Full-text