Defective insulin receptors in Rabson-Mendenhall syndrome cause complete peripheral insulin resistance but minimal hepatic insulin response remains.

Abstract

In Rabson-Mendenhall syndrome, severe insulin resistance is caused by defective insulin receptors. The patient studied lacks insulin receptor binding due to a truncation mutation of one allele and a point mutation of the other allele of the insulin receptor alpha-subunit. He developed pulmonary hypertension and cor pulmonale, and was considered for organ transplantation. A trial of prednisone 1.2 mg/kg/d was initiated to determine if he could tolerate immunosuppressive therapy without deterioration of his pre-existing, difficult to control diabetes mellitus. Insulin responsiveness was measured prior to and after 4 d of glucocorticoid administration ('Before GC' and 'After GC') using the hyperinsulinemic glucose clamp and stable isotope tracer dilution techniques. After a 12-h fast and 24 h of intravenous insulin, a primed continuous infusion of 6,6-(2)H(2)-glucose was administered during a 2-h tracer equilibration period followed by a 2-h insulin-deficient period, and a 2-h hyperinsulinemic glucose clamp period during which insulin was infused at 7 u/kg/h. Blood glucose concentrations during the basal periods, while no insulin was infused, were 245+/-7 and 138+/-8 mg/dL in the studies Before GC and After GC, respectively. During both hyperinsulinemic glucose clamp periods, the blood glucose was 171+/-1 and 167+/-5 mg/dL, respectively. Hepatic glucose production (HGP) was higher during the basal period Before GC than during the same period After GC (7.86+/-0.23 vs. 5.31+/-0.19 mg/kg/min). HGP rate was suppressed by insulin to 1.48+/-0.45 mg/kg/min Before GC, but was not suppressed After GC (4.19+/-0.81 mg/kg/min). The hyperinsulinemic glucose clamp did not increase the glucose utilization rate nor the glucose clearance rate over basal in either Before GC or After GC, indicating complete peripheral insulin resistance. In summary, the liver showed some response to insulin in the absence of insulin receptors but the peripheral tissues had no response to insulin. Glucocorticoids worsened insulin resistance in the liver in this patient.