Insulin-Receptor Tyrosine Kinase Activity is Decreased in Erythrocytes from Non-Obese Patients with NIDDM

Abstract

We have examined insulin binding, and insulin receptor associated tyrosine kinase activity in detergent solubilized and Ricin II-agarose purified receptor preparations from erythrocytes of obese and non-obese subjects with normal glucose tolerance and non-obese patients with NIDDM. Insulin receptor activity, as assessed by [125I Tyr A14] insulin binding, was significantly lower in erythrocyte preparations from the obese group when compared with similar preparations from non-obese subjects, with either normal glucose tolerance or NIDDM. The affinity of the receptor for insulin, however, was reduced in both obese subjects and patients with NIDDM as compared to non-obese subjects with normal glucose tolerance. Insulin receptor tyrosine kinase activity, measured in the absence (basal) and presence of insulin (0.3-3000 nM), was decreased in obese and NIDDM subjects with normal glucose tolerance and in patients with NIDDM. Insulin sensitivity, measured as the dose of insulin required for half-maximal activation of kinase activity, however, was comparable among three groups. In contrast, insulin-stimulated tyrosine kinase activity, when normalized to insulin binding activity, was unchanged in both non-obese and obese subjects with normal glucose tolerance, but was reduced approximately 60% in the NIDDM group. These findings indicate that the functional behavior of insulin receptor-kinase signaling system is markedly impaired in non-obese patients with NIDDM. Furthermore, the insulin receptor-tyrosine kinase defect (i.e. decrease in activity) observed in patients with NIDDM is probably related to a reduction in coupling efficiency between insulin binding and the activation of the receptor tyrosine kinase activity.