INSULIN-RECEPTOR TYROSINE KINASE-ACTIVITY IS DECREASED IN ERYTHROCYTES FROM NONOBESE PATIENTS WITH NIDDM

We have examined insulin binding, and insulin receptor associated tyro sine kinase activity in detergent solubilized and Ricin II-agarose pur ified receptor preparations from erythrocytes of obese and non-obese s ubjects with normal glucose tolerance and non-obese patients with NIDD M. Insulin receptor activity, as assessed by [I-125 Tyr A(14)] insulin binding, was significantly lower in erythrocyte preparations from the obese group when compared with similar preparations from non-obese su bjects, 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, measure d in the absence (basal) and presence of insulin (0.3-3000 nM), was de creased in obese and NIDDM subjects with normal glucose tolerance and in patients with NIDDM. Insulin sensitivity, measured as the dose of i nsulin required for half-maximal activation of kinase activity, howeve r, 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 glucos e tolerance, but was reduced similar to 60% in the NIDDM group. These findings indicate that the functional behavior of insulin receptor-kin ase signaling system is markedly impaired in non-obese patients with N IDDM. Furthermore, the insulin receptor-tyrosine kinase defect (i.e. d ecrease in activity) observed in patients with NIDDM is probably relat ed to a reduction in coupling efficiency between insulin binding and t he activation of the receptor tyrosine kinase activity.