DECREASED TYROSINE KINASE-ACTIVITY IN PARTIALLY PURIFIED INSULIN-RECEPTORS FROM MUSCLE OF YOUNG, NONOBESE 1ST DEGREE RELATIVES OF PATIENTS WITH TYPE-2(NON-INSULIN-DEPENDENT) DIABETES-MELLITUS

Recently, we demonstrated insulin resistance due to reduced glucose st orage in young relatives of Type 2 diabetic patients. To investigate w hether this was associated with a defective insulin receptor kinase, w e studied ten of these young (27 +/- 1 years old) non-obese glucose to lerant first degree relatives of patients with Type 2 diabetes and eig ht matched control subjects with no family history of diabetes. Insuli n sensitivity was assessed by a hyperinsulinaemic, euglycaemic clamp. Insulin receptors were partially purified from muscle biopsies obtaine d in the basal and the insulin-stimulated state during the clamp. Insu lin binding capacity was decreased by 28 % in the relatives (p < 0.05) in the basal biopsy. Tyrosine kinase activity in the receptor prepara tion was decreased by 50 % in both basal and insulin-stimulated biopsi es from the relatives. After stimulation with insulin ''in vitro'', ki nase activity was reduced in the relatives in basal (p < 0.005) and in sulin-stimulated (p < 0.01) biopsies and also when expressed per insul in binding capacity (p almost-equal-to 0.05). Insulin stimulation of n on-oxidative glucose metabolism correlated with ''in vitro'' insulin-s timulated tyrosine kinase activity (r = 0.61, p < 0.01) and also when expressed per binding capacity (r = 0.53, p < 0.025). We suggest that the marked defect in tyrosine kinase activity in partially purified in sulin receptors from skeletal muscle is an early event in the developm ent of insulin resistance and contributes to the pathophysiology of Ty pe 2 diabetes.