Insulin resistance in congenital adrenal hyperplasia is compensated for by reduced insulin clearance.

Context Congenital Adrenal Hyperplasia (CAH) patients have potential normal longevity. However, a greater risk for cardiovascular disease has been reported. Insulin resistance and hyperinsulinemia have been described in CAH patients, whereas the prevalence of overt type 2 diabetes is not higher in CAH than in normal population. Objective To examine the contributions of insulin secretion and of hepatic insulin clearance to compensatory hyperinsulinemia in young insulin resistant adults with classic CAH due to 21-hydroxylase deficiency (21-OHD). Design Cross-sectional. Setting University outpatient clinics. Participants Fifty-one participants: 21 controls, and 30 CAH (15 virilizing and 15 salt-wasting phenotypes), female/male (33/18), age [mean (SD)]: 24.0 (3.6) years, BMI: 24.6 (4.9) kg/m 2 with normal glucose tolerance, were submitted to a hyperglycemic clamp study. Main outcome measures Insulin sensitivity, beta cell function and hepatic insulin clearance using appropriate modeling. Results We found an increased insulin resistance in 21-OHD. The systemic hyperinsulinemia (posthepatic insulin delivery) was elevated in CAH patients. No increases were observed in insulin secretory rate (beta-cell function) in the first-phase or during the hyperglycemic clamp. The increase in insulin concentrations was totally due to a ˜33% reduction in insulin clearance. Conclusions 21-OHD non-obese subjects have reduced insulin sensitivity, and beta cell response unable to compensate for the insulin resistance, probably due to overexposure to glucocorticoids. The compensatory hyperinsulinemia is most related with reduced hepatic insulin clearance. The exclusive adaptation of the liver acts as a gating mechanism to regulate the access of insulin to insulin-sensitive tissues to maintain glucose homeostasis.