Impaired insulin action in the liver, but not in adipose tissue or muscle, is a distinct metabolic feature of impaired fasting glucose in obese humans

AIM: Elevated basal endogenous glucose production (EGP), impaired suppression of EGP by insulin and reduced insulin-stimulated glucose disposal are cornerstones of the pathogenesis of hyperglycemia in patients with type 2 diabetes. We aimed to determine the contribution of these processes to impaired fasting glucose (IFG) levels in obese non-diabetic adults. METHODS: We included 131 obese non-diabetic adults with normal fasting glucose levels (NFG; fasting glucose <5.6mmol/L; 62 men, 25 women; mean±SEM age 49±1years; median (IQR) BMI 36 (34-41) kg/m(2)) or IFG (fasting glucose 5.6-6.9mmol/L; 35 men, 9 women; age 53±1years; BMI 36 (34-42) kg/m(2)) and studied basal EGP and hepatic, adipose tissue and peripheral insulin sensitivity by two-step euglycemic hyperinsulinemic clamp studies with [6,6-(2)H2]glucose infusion. RESULTS: Compared to equally obese adults with NFG, individuals with IFG did not differ in basal EGP (9.1±0.2 vs 9.8±0.3μmolkg(-1)min(-1), p=0.082), insulin-mediated suppression of circulating free fatty acid levels (75±1 vs 72±3%, p=0.240) and insulin-stimulated glucose disposal (26.6±1.0 vs 25.2±1.5μmolkg(-1)min(-1), p=0.441). Insulin-mediated suppression of EGP (68±2 vs 55±3%, p