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 restriction, and Rabson-Mendenhall syndrome (patient RM-3). The blood IGF-I level was undetectable in this patient, although the GH level was moderately decreased. During the postprandial period, glycemia, ketonuria, and plasma glucagon were very elevated despite high doses of exogenous insulin (glucose levels up to 30 mmol/L). Ln the postabsorptive state, blood glucose was normalized with small amounts of insulin; ketonuria, and glucagon levels were reduced but remained supranormal. Erythrocytes and cultured skin fibroblasts from the patient displayed a decrease in cell surface insulin receptors (IRs). The ability of physiologic concentrations of insulin to stimulate metabolic processes was altered in patient fibroblasts. Analysis of the LR gene by denaturing gradient gel electrophoresis and direct sequencing showed a homozygous missense mutation in exon 3, replacing Cys(284) by Tyr in the alpha-subunit. In conclusion, marked primary insulin resistance was evidenced in patient cells as a result of a structural alteration in the LR alpha-subunit. The in vitro studies could not account alone for the in vivo metabolic alterations because glucose homeostasis varied considerably during the day in the patient.