Assessment of hepatic insulin action in obese type 2 diabetic patients

Defects in hepatic insulin action in type 2 diabetes and its possible under lying mechanisms were assessed in euglycemic-hyperinsulinemic clamp studies , using improved tracer methods (constant specific activity technique). Ten obese diabetic patients (age 54 years, BMI 29 +/- 0.5 kg/m(2)) and ten mat ched control subjects were studied at baseline (after an overnight fast) an d during insulin infusions of 20- and 40-m.U.m(-2).min(-1). In the diabetic patients, plasma. glucose levels were normalized overnight before the stud ies by low-dose insulin infusion. Hepatic sinusoidal insulin levels were es timated, and plasma levels of free fatty acids (FFAs) and glucagon were det ermined to assess the direct and indirect effects of insulin on hepatic glu cose production (HGP) in type 2 diabetes. Baseline rates of HGP (86 +/- 3 v s. 76 +/- 3 mg.m(-2).min(-1), P < 0.05) were slightly elevated in the diabe tic patients compared with control subjects, despite much higher hepatic si nusoidal insulin levels (26 <plus/minus> 3 vs. 12 +/- 2 mU/l, P < 0.001). C onsequently, a marked defect in the direct (hepatic) effect of insulin on H GP appeared to be present at low insulin levels. However, in response to a small increase in baseline hepatic sinusoidal insulin levels of 11 mU/l (26 <plus/minus> 3 to 37 +/- 3 mU/l, P < 0.05) in the 20-mU clamp, a marked su ppression of HGP was observed in the diabetic patients (86 <plus/minus> 3 t o 32 +/- 5 mg.m(-2).min(-1), P < 0.001), despite only minimal changes in FF As (0.33 <plus/minus> 0.05 to 0.25 +/- 0.05 mmol/l, NS) and glucagon (14 +/ - 1 to 11 +/- 2 pmol/l, P < 0.05) levels, suggesting that the impairment in the direct effect of insulin can be overcome by a small increase in insuli n levels. Compared with control subjects, suppression of HGP in the diabeti c patients was slightly impaired in the 20-mU clamp (32 <plus/minus> 5 vs. 22 +/- 4 mg.m(-2).min(-1) P < 0.05) but not in the 40-mU clamp (25 <plus/mi nus> 2 vs. 21 +/- 3 mg.m(-2).min(-1), NS). In the 20-mU clamp, hepatic sinu soidal insulin levels in the diabetic patients mere comparable with control subjects (37 +/- 3 vs. 36 +/- 3 mU/l, NS), whereas both FFA and glucagon l evels mere higher (i.e,, less suppressed) and correlated with the rates of HGP (R = 0.71, P < 0.02; and R = 0.69, P < 0.05, respectively). Thus, at th is insulin level impaired indirect (extrahepatic) effects of insulin seemed to prevail. In conclusion, hepatic insulin resistance is present in obese type 2 diabetic patients but is of quantitative significance only at low ph ysiological insulin levels. Defects in both the direct and the indirect eff ects of insulin on HGP appear to contribute to this resistance.