Tissue specificity of insulin resistance in humans: fat in the liver rather than muscle is associated with features of the metabolic syndrome

Aims/hypothesis The aim of this study was to investigate whether intrahepatic and intramyocellular fat are related to insulin resistance in these respective tissues or to the metabolic syndrome. Methods Hepatic (insulin 1.8 pmol kg(-1) min(-1) combined with [3-H-3]glucose) and muscle (insulin 6.0 pmol kg(-1)min(-1)) insulin sensitivity were measured on separate occasions in 45 non-diabetic men (age 42 +/- 1 years, BMI 26.2 +/- 0.6 kg/m(2)) using the euglycaemic-hyperinsulinaemic clamp. Liver fat and intramyocellular lipid (IMCL) were measured by proton magnetic resonance spectroscopy and body composition by magnetic resonance imaging. We also determined fasting serum insulin and adiponectin concentrations, components of the metabolic syndrome and maximal oxygen consumption. Results In participants with high [median 12.0% (interquartile range 5.7-18.5%)] vs low [2.0% (1.0-2.0%)] liver fat, fasting serum triacylglycerols (1.6 +/- 0.2 vs 1.0 +/- 0.1 mmol/l, p=0.002) and fasting serum insulin (55 +/- 4 vs 32 +/- 2 pmol/l, p < 0.0001) were increased and serum HDL-cholesterol (1.26 +/- 0.1 vs 1.48 +/- 0.1 mmol/l, p=0.02) and fasting serum adiponectin (9.5 +/- 1.2 vs 12.2 +/- 1.2 mu g/ml, p=0.05) decreased. In participants with high [19.5% (16.0-26.0%)] vs low [5.0% (2.3-7.5%)] IMCL, these parameters were comparable. Liver fat was higher in participants with [10.5% (3.0-18.0%)] than in those without [2.0% (1.5-6.0%), p=0.010] the metabolic syndrome, even independently of obesity, while IMCL was comparable. Insulin suppression of glucose rate of appearance and serum NEFA was significantly impaired in the high liver fat group. Conclusions/interpretation Fat accumulation in the liver rather than in skeletal muscle is associated with features of the metabolic syndrome, i.e. increased fasting serum triacylglycerols and decreased fasting serum HDL-cholesterol, as well as with hyperinsulinaemia and low adiponectin.