Insulin action and hepatic glucose cycling in Cushing's syndrome

Abstract

OBJECTIVE: Although it is well established that hypercortisolism causes insulin resistance, the mechanisms responsible for impaired insulin action in Cushing's syndrome are unclear. This study investigated the contribution of the glucose/glucose‐6‐phosphate substrate cycle (G/G6P). PATIENTS: Eight patients with Cushing's syndrome and seven control subjects were studied. All had normal fasting plasma glucose. DESIGN: Insulin action was assessed using the euglycaemic glucose clamp at insulin infusion rates of 0.4 and 2.0 mU/kg/min combined with a simultaneous infusion of [2 3 H]‐ and [6 3‐H]‐glucose. Glucose/ glucose‐6‐phosphate cycle activity was calculated as the difference in glucose turnover rates determined separately for [2 3 H]‐ and [6 3 H]‐glucose by selective enzymatic detritiation. MEASUREMENTS AND RESULTS: Exogenous glucose infusion rates required to maintain euglycaemia were significantly lower in Cushing's patients compared to controls, during the 0.4 mU/kg/min (7.8±1.2 vs 15.7±0.5 μmol/kg/min, P<0.001) and the 2.0 mU/kg/min insulin infusions (26.2±2.8 vs 51.5±3.5 μmol/kg/min, P<0.001). Endogenous glucose production was similar in both groups in the postabsorptive state (10.2±0.3 vs 10.8±0.4 μmol/kg/min, P=0.50) and suppressed to a similar degree during hyperinsulinaemia. G/G6P cycle activity was markedly increased in the Cushing's group in the postabsorptive state (5.4±1.1 vs 2.0±0.5 μmol/kg/min, P=0.028) and during the 0.4 mU/kg/min (3.2±0.6 vs 1.2±0.4 μmol/kg/min, P=0.014) and 2.0 mU/kg/min insulin infusions (3.3±0.8 vs 1.1±0.5 μmol/kg/min, P=0.049). CONCLUSIONS: Patients with Cushing's syndrome show marked peripheral insulin resistance and enhanced hepatic G/G6P cycle activity. In the fasting state increased glucose/glucose‐6‐phosphate cycle activity may be a protective mechanism limiting hyperglycaemia. During hyperinsulinaemia G/G6P cycle activity was increased but insulin resistance was predominantly due to reduced peripheral glucose uptake.