INSULIN-RECEPTOR TYROSINE-KINASE ACTIVITY IS ALTERED IN BOTH MUSCLE AND ADIPOSE-TISSUE FROM NONOBESE NORMOGLYCEMIC INSULIN-RESISTANT SUBJECTS

We performed i.v. insulin tolerance test in 30 non-obese (BMI < 30 mal e and < 28 female) nondiabetic (by oral glucose tolerance test) subjec ts and subdivided them into three groups of 10 subjects each, accordin g to their insulin sensitivity (K-itt values). Then we compared the ty rosine-kinase activity of immunopurified insulin receptors (using P-32 -ATP and poly-glu-tyr (4:1) from both muscle and adipose tissue in 7 o f the most insulin-sensitive and 7 of the most insulin-resistant subje cts. No difference was observed between the two groups in the basal (n o insulin) receptor tyrosine-kinase activity from both tissues. In con trast, tyrosine-kinase activity response to insulin was significantly higher (p < 0.05 by 2-way ANOVA test) in receptors from both tissues o f insulin-sensitive subjects. In addition, a decreased tyrosine-kinase sensitivity to insulin was observed in muscle, but not adipose, tissu e of insulin-resistant subjects (insulin ED(50) being 0.87 +/- 0.05 nm ol/l vs 2.03 +/- 0.07, p < 0.05 in insulin-sensitive and -resistant su bjects). Insulin ED(50) of muscle receptor tyrosine-kinase significant ly (p = 0.001) correlated to both K-itt values (r = -0.79) and plasma insulin values at 120 min during OGTT (r = +0.80). Insulin receptor co ntent, as assessed by radioimmunoassay, was similar in both muscle (7. 9 +/- 1.3 and 9.2 +/- 1.9 ng/mg protein) and adipose tissue (8.2 +/- 1 .3 and 7.5 +/- 1.4) of insulin-sensitive and -resistant subjects. Exon 11+ isoform of insulin receptor was similarly represented in muscle s pecimens from six insulin-sensitive (80 +/- 8% of total receptor conte nt) and six resistant (78 +/- 6%) subjects. In conclusion, a defective insulin stimulation of receptor tyrosine-kinase activity is present i n both muscle and adipose tissue of euglycaemic non-obese insulin-resi stant subjects. This defect is, therefore, an early event in the devel opment of insulin resistance.