Insulin receptor tyrosine-kinase activity is altered in both muscle and adipose tissue from non-obese normoglycaemic insulin-resistant subjects

Summary We performed i. v. insulin tolerance test in 30 non-obese (BMI < 30 male and < 28 female) non-diabetic (by oral glucose tolerance test) subjects and subdivided them into three groups of 10 subjects each, according to their insulin sensitivity (K_itt values). Then we compared the tyrosine-kinase activity of immunopurified insulin receptors (using ³²P-ATP and poly-glu-tyr (4 : 1) from both muscle and adipose tissue in 7 of the most insulin-sensitive and 7 of the most insulin-resistant subjects. No difference was observed between the two groups in the basal (no insulin) receptor tyrosine-kinase activity from both tissues. In contrast, tyrosine-kinase activity response to insulin was significantly higher (p < 0.05 by 2-way ANOVA test) in receptors from both tissues of insulin-sensitive subjects. In addition, a decreased tyrosine-kinase sensitivity to insulin was observed in muscle, but not adipose, tissue of insulin-resistant subjects (insulin ED₅₀ being 0.87 ± 0.05 nmol/l vs 2.03 ± 0.07, p < 0.05 in insulin-sensitive and -resistant subjects). Insulin ED₅₀ of muscle receptor tyrosine-kinase significantly (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 content, 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 specimens from six insulin-sensitive (80 ± 8 % of total receptor content) and six resistant (78 ± 6 %) subjects. In conclusion, a defective insulin stimulation of receptor tyrosine-kinase activity is present in both muscle and adipose tissue of euglycaemic non-obese insulin-resistant subjects. This defect is, therefore, an early event in the development of insulin resistance. [Diabetologia (1995) 38: 55–61] Received: 14 January 1994 and in revised form: 14 June 1994