Fat Accumulation in the Liver Is Associated with Defects in Insulin Suppression of Glucose Production and Serum Free Fatty Acids Independent of Obesity in Normal Men

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Abstract
We determined whether interindividual variation in hepatic insulin sensitivity could be attributed to variation in liver fat content (LFAT) independent of obesity. We recruited 30 healthy nondiabetic men whose LFAT (determined by proton spectroscopy); intraabdominal, sc, and total (determined by magnetic resonance imaging) fat; and insulin sensitivity of endogenous glucose rate of production (Ra) and suppression of serum FFA (euglycemic insulin clamp combined with (3-3H)glucose (0 -300 min); insulin infusion rate, 0.3 mU/ kgmin, 120 -300 min) were measured. The men were divided into groups of low (mean SD, 1.7 0.2%) and high (10.5 2.0%) LFAT based on their median fat content. The low and high LFAT groups were comparable with respect to age (44 2 vs. 42 2 yr), body mass index (25 1 vs. 26 1 kg/m2), waist to hip ratio (0.953 0.013 vs. 0.953 0.013), maximal oxygen uptake (35.6 1.5 vs. 33.5 1.5 ml/kgmin), and intraabdomi- nal, sc, and total fat. The high compared with the low LFAT group had several features of insulin resistance, including fasting hyperinsulinemia (7.3 0.6 vs. 5.3 0.6 mU/liter; P < 0.02, high vs. low LFAT) hypertriglyceridemia (1.4 0.2 vs. 0.9 0.1 mmol/liter; P < 0.02), a low high density lipoprotein (HDL) cholesterol concentration (1.4 0.1 vs. 1.6 0.1 mmol/ liter; P < 0.05), and a higher ambulatory 24-h systolic blood pressure (130 3 vs. 122 3m m Hg;P < 0.05). Basal glucose Ra and serum FFA were comparable between the groups, whereas insulin suppression of glucose Ra (51 8 vs. 20 12 mg/m2min during 240 -300 min (P < 0.05) or 55 7 vs. 85 12% below basal (P < 0.05, high vs. low LFAT)) and of serum FFA (299 33 vs. 212 13 mol/liter; 240 -300 min; P < 0.02) were impaired in the high compared with the low LFAT group. Insulin stimulation of glucose Rd were comparable in the men with high LFAT (141 12 mg/m2min) and those with low LFAT (156 14 mg/m2min; P NS). Fat accumulation in the liver is, independent of body mass index and intraabdominal and overall obesity, characterized by several features of insulin resistance in normal weight and moderately overweight subjects. (J Clin Endocrinol Metab 87: 3023-3028, 2002)

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