title: Progressive decline in insulin levels in Rabson-Mendenhall syndrome.
abstract: Mutations in the insulin receptor gene cause the severe insulin-resistant syndromes leprechaunism and Rabson-Mendenhall syndrome, whose metabolic features include fasting hypoglycemia, post-prandial hyperglycemia, and extremely elevated insulin levels. Patients with Rabson-Mendenhall syndrome have a protracted course and eventually develop ketoacidosis. To determine the mechanism causing this progression and the paradoxical fasting hypoglycemia, we conducted a retrospective study in a patient with Rabson-Mendenhall syndrome, who was a compound heterozygous for two missense mutations affecting the kinase domain of the insulin receptor beta-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 and, at 6 yr of age, by constant ketoacidosis. Urinary organic acids during ketoacidosis resembled those of patients with type 1 diabetes. Plasma glucose levels increased (r2 = 0.31; P < 0.01), whereas insulin levels decreased with age (r2 = 0.51; P < 0.01). During periods ofhypoglycemia and hyperglycemia (0-1 yr of age), constant hyperglycemia (3-4 yr of age), and hyperglycemia with ketoacidosis (6-7 yr of age), insulin levels were significantly correlated with plasma glucose levels (P < 0.05). However, the slope of the regression and the predicted insulin level at zero glucose decreased with increasing age. When insulin levels were normalized for the plasma glucose concentrations, an exponential decrease in the insulin/glucose ratio was observed (r2 = 0.92; P < 0.01), with most of the decline occurring before 2 yr of age. These results indicate that the paradoxical fasting hypoglycemia of patients with Rabson-Mendenhall syndrome is associated with severely increased levels of circulating insulin and that the progression of this disease is due to a decline in insulin levels.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: N
authors.initials: N
authors.lastname: Longo
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Pasquali
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D002648:Child; D016883:Diabetic Ketoacidosis / Q000209:etiology; D006801:Humans; D007328:Insulin / Q000097:blood*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics*; D013577:Syndrome
chemical_list: D001786:Blood Glucose; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin