MAJOR CIRCADIAN VARIATIONS OF GLUCOSE-HOMEOSTASIS IN A PATIENT WITH RABSON-MENDENHALL-SYNDROME AND PRIMARY INSULIN-RESISTANCE DUE TO A MUTATION (CYS(284)-]TYR) IN THE INSULIN-RECEPTOR ALPHA-SUBUNIT

We have performed clinical, in vitro biochemical, and genetic studies of a patient with severe insulin resistance, considerable growth restr iction, and Rabson-Mendenhall syndrome (patient RM-3). The blood IGF-I level was undetectable in this patient, although the GH level was mod erately decreased. During the postprandial period, glycemia, ketonuria , and plasma glucagon were very elevated despite high doses of exogeno us insulin (glucose levels up to 30 mmol/L). Ln the postabsorptive sta te, blood glucose was normalized with small amounts of insulin; ketonu ria, and glucagon levels were reduced but remained supranormal. Erythr ocytes and cultured skin fibroblasts from the patient displayed a decr ease in cell surface insulin receptors (IRs). The ability of physiolog ic concentrations of insulin to stimulate metabolic processes was alte red in patient fibroblasts. Analysis of the LR gene by denaturing grad ient gel electrophoresis and direct sequencing showed a homozygous mis sense mutation in exon 3, replacing Cys(284) by Tyr in the alpha-subun it. In conclusion, marked primary insulin resistance was evidenced in patient cells as a result of a structural alteration in the LR alpha-s ubunit. The in vitro studies could not account alone for the in vivo m etabolic alterations because glucose homeostasis varied considerably d uring the day in the patient.