Progressive decline in insulin levels in Rabson-Mendenhall syndrome

Mutations in the insulin receptor gene cause the severe insulin-resistant s yndromes leprechaunism and Rabson-Mendenhall syndrome, whose metabolic feat ures include Easting hypoglycemia, postprandial hyperglycemia, and extremel y elevated insulin levels. Patients with Rabson-Mendenhall syndrome have a protracted course and eventually develop ketoacidosis. To determine the mec hanism causing this progression and the paradoxical fasting hypoglycemia, w e conducted a retrospective study in a patient with Rabson-Mendenhall syndr ome, who was a compound heterozygous for two missense mutations affecting t he kinase domain of the insulin receptor p-subunit (I1115T and R1131W). At birth, the patient had fasting hypoglycemia and postprandial hyperglycemia. This was followed at approximately 3 yr of age by constant hyperglycemia a nd, at 6 yr of age, by constant ketoacidosis. Urinary organic acids during ketoacidosis resembled those of patients with type 1 diabetes. Plasma gluco se levels increased (r(2) = 0.31; P < 0.01), whereas insulin levels decreas ed with age (r(2) =0.51; P < 0.01). During periods of hypoglycemia and hype rglycemia (0-1 yr of age), constant hyperglycemia (3-4 yr of age), and hype rglycemia with ketoacidosis (6-7 yr of age), insulin levels were significan tly correlated with plasma glucose levels (P < 0.05). However, the slope of the regression and the predicted insulin level at zero glucose decreased w ith increasing age. When insulin levels were normalized for the plasma gluc ose concentrations, an exponential decrease in the insulin/glucose ratio wa s observed (r(2) = 0.92; P < 0.01), with most of the decline occurring befo re 2 yr of age. These results indicate that the paradoxical fasting hypogly cemia of patients with Rabson-Mendenhall syndrome is associated with severe ly increased levels of circulating insulin and that the progression of this disease is due to a decline in insulin levels.