Increased VLDL-Triglyceride Secretion Precedes Impaired Control of Endogenous Glucose Production in Obese, Normoglycemic Men

Abstract

OBJECTIVE To assess basal and insulin-mediated VLDL-triglyceride (TG) kinetics and the relationship between VLDL-TG secretion and hepatic insulin resistance assessed by endogenous glucose production (EGP) in obese and lean men. RESEARCH DESIGN AND METHODS A total of 12 normoglycemic, obese (waist-to-hip ratio >0.9, BMI >30 kg/m2) and 12 lean (BMI 20–25 kg/m2) age-matched men were included. Ex vivo–labeled [1-14C]VLDL-TGs and [3-3H]glucose were infused postabsorptively and during a hyperinsulinemic-euglycemic clamp to determine VLDL-TG kinetics and EGP. Body composition was determined by dual X-ray absorptiometry and computed tomography scanning. Energy expenditure and substrate oxidation rates were measured by indirect calorimetry. RESULTS Basal VLDL-TG secretion rates were increased in obese compared with lean men (1.25 ± 0.34 vs. 0.86 ± 0.34 μmol/kg fat-free mass [FFM]/min; P = 0.011), whereas there was no difference in clearance rates (150 ± 56 vs. 162 ± 77 mL/min; P = NS), resulting in greater VLDL-TG concentrations (0.74 ± 0.40 vs. 0.38 ± 0.20 mmol/L; P = 0.011). The absolute insulin-mediated suppression of VLDL-TG secretion was similar in the groups. However, the percentage reduction (−36 ± 18 vs. −54 ± 10%; P = 0.008) and achieved VLDL-TG secretion rates (0.76 ± 0.20 vs. 0.41 ± 0.19 μmol/kg FFM/min; P < 0.001) were impaired in obese men. Furthermore, clearance rates decreased significantly in obese men, but there was no significant change in lean men (−17 ± 18 vs. 7 ± 20%; P = 0.007), resulting in less percentage reduction of VLDL-TG concentrations in obese men (−22 ± 20 vs. −56 ± 11%; P < 0.001). Insulin-suppressed EGP was similar (0.4 [0.0-0.8] vs. 0.1 [0.0-1.2] mg/kg FFM/min (median [range]); P = NS), and the percentage reduction was equivalent (−80% [57–98] vs. −98% [49–100], P = NS). Insulin-mediated glucose disposal was significantly reduced in obese men. CONCLUSIONS Basal VLDL-TG secretion rates are increased in normoglycemic but insulin-resistant, obese men, resulting in hypertriglyceridemia. Insulin-mediated suppression of EGP is preserved in obese men, whereas suppression of VLDL-TG secretion is less pronounced in obese men. Compared with EGP, the inability to achieve suppression of VLDL-TG secretions to a level similar to control subjects during hyperinsulinemia seems to be an early manifestation in male obesity.