Increased Liver Fat, Impaired Insulin Clearance, and Hepatic and Adipose Tissue Insulin Resistance in Type 2 Diabetes

Background & Aims: Liver fat is increased in type 2 diabetes. We determined whether it is associated with impaired insulin clearance and to what extent insulin resistance, impaired insulin clearance, or secretion contribute to fasting hyperinsulinemia. We also examined whether insulin suppression of serum free fatty acid (FFA) correlates with liver fat. Methods: We compared 68 type 2 diabetic patients and age-, gender-, and body mass index (BMI)-matched nondiabetic subjects. Liver fat was determined by ¹H-MRS, body composition by magnetic resonance imaging, and insulin clearance and action on hepatic glucose production (HGP), glucose uptake, and serum FFA by the euglycemic insulin clamp technique (insulin 0.3 mU/kg·min) combined with infusion of [3-³H]glucose. Results: Liver fat was 54% higher and insulin clearance 24% lower in type 2 diabetic patients than nondiabetic subjects. The percent suppression of both HGP and serum FFA by insulin were comparable, but serum insulin concentrations were significantly higher (34 mU/L [interquartile range, 30–39 mU/L] vs 25 mU/L [interquartile range, 22–30 mU/L]; P < .0001) in the type 2 diabetic than the nondiabetic subjects. When this difference was taken into account, both hepatic and adipose tissue insulin sensitivity were impaired in the type 2 diabetic subjects. Liver fat correlated with insulin clearance (r = −0.41; P = .001), and hepatic (r = 0.46; P = .0001) and adipose tissue (r = 0.55; P < .0001) insulin sensitivity. Hepatic but not peripheral insulin sensitivity was independently associated with liver fat content. Insulin clearance and secretion were independent determinants of fasting serum insulin. Conclusions: We conclude that increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance characterize type 2 diabetic patients.

Abbreviations used in this paper: ALT, alanine aminotransferase, AST, aspartate aminotransferase, BP, blood pressure, BMI, body mass index, CVD, cardiovascular disease, FFA, free fatty acid, FFM, fat free mass, fP, fasting plasma, fS, fasting serum, HbA_1c, glycosylated hemoglobin A_1c, HDL, high density lipoprotein, HGP, hepatic glucose production, HOMA-IR, homeostatic model assessment of insulin resistance, IA, intraabdominal, LDL, low density lipoprotein, MCR, metabolic clearance rate, MRI, magnetic resonance imaging, NAFLD, nonalcoholic fatty liver disease, QUICKI, quantitative insulin sensitivity check index, R_a, rate of appearance, R_d, rate of disappearance, S, serum, SA, specific activity, SC, subcutaneous, TG, triglycerides, VLDL, very-low-density lipoprotein