Sensitivity to Acute Insulin-Mediated Suppression of Plasma Free Fatty Acids Is Not a Determinant of Fasting VLDL Triglyceride Secretion in Healthy Humans
- 1Department of Medicine, Division of Endocrinology, University of Toronto, and the Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
- 2Department of Internal Medicine and Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri
Abstract
One important mechanism whereby obesity-associated insulin resistance leads to VLDL overproduction is thought to be by the increased flux of free fatty acids (FFAs) from extrahepatic tissues to liver, which arises as a direct consequence of impaired insulin action in adipose tissue and skeletal muscle. The aim of the present study was to address whether direct measures of peripheral tissue insulin sensitivity with regard to FFAs and glucose in the fasting state are good predictors of postabsorptive VLDL triglyceride secretion rate (VLDL-TG ASR) in humans, independent of obesity. Eighteen healthy control subjects, after an overnight fast, underwent three studies 3 weeks apart, in random order. Study 1: VLDL-TG levels, fractional clearance rate (per h), and VLDL-TG ASR were determined after an intravenous bolus of [1,1,2,3,3-2H5] glycerol. Study 2: Insulin sensitivity (SI), acute insulin response (AIR), and acute C-peptide response to glucose were assessed by frequently sampled intravenous glucose tolerance test using the minimal model approach. Study 3: Insulin-mediated suppression of plasma FFAs (k) and insulin clearance were assessed in response to a low-dose stepwise intravenous insulin infusion. BMI (R2 = 0.54), AIR, and fasting insulin levels were positively and SI negatively correlated with VLDL-TG ASR, but there was no significant association with plasma FFAs or k. Only BMI remained significantly associated with VLDL-TG ASR in multivariate analysis. The best multivariate model for VLDL-TG ASR (R2 = 0.61, P = 0.0008) included BMI (P = 0.0008) and SI (P = 0.12, inversely correlated). VLDL-TG secretion is predicted by BMI, independently of direct measures of insulin sensitivity. The sensitivity to insulin’s acute suppressive effect on plasma FFA levels during fasting is not an important determinant of postabsorptive VLDL-TG secretion in humans.
Footnotes
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Address correspondence and reprint requests to Dr. Gary Lewis, The Toronto General Hospital, 200 Elizabeth St., Room EN 11-229, Toronto, ON, Canada M5G 2C4. E-mail: gary.lewis{at}uhn.on.ca.
Received for publication 28 June 2001 and accepted in revised form 27 February 2002.
ACR, acute C-peptide response; AIR, acute insulin response; apoB, apolipoprotein B; Clins, plasma insulin clearance rate; CV, coefficient of variation; FCR, fractional clearance rate; FFA, free fatty acid; GC/MS, gas chromatography/mass spectrometry; ISR, insulin secretion rate; IV, intravenous; k, insulin-mediated suppression of plasma FFAs; mFSIVGTT, insulin-modified frequently-sampled intravenous glucose tolerance test; Ra, insulin appearance rate; SI, insulin sensitivity index; TG, triglyceride; VLDL-TG ASR, VLDL-TG secretion rate.
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