ELEVATION OF SERUM-INSULIN CONCENTRATION DURING EUGLYCEMIC HYPERINSULINEMIC CLAMP STUDIES LEADS TO SIMILAR ACTIVATION OF INSULIN-RECEPTOR KINASE IN SKELETAL-MUSCLE OF SUBJECTS WITH AND WITHOUT NIDDM

The role of skeletal muscle insulin receptor kinase in the pathogenesi s of non-insulin-dependent diabetes mellitus (NIDDM) was investigated, Muscle biopsies hom 13 patients with NIDDM and 10 control subjects at fasting serum insulin concentrations and similar to 1,000 pmol/l stea dy-state serum insulin during euglycemic hyperinsulinemic clamps were immediately frozen, The biopsies were then solubilized, and the recept ors were immobilized to antiinsulin receptor antibody-coated microwell s, Receptor kinase and binding activities were consecutively measured in these wells, The increase in serum insulin concentration (73 +/- 14 to 1,004 +/- 83 and 45 +/- 7 to 1,070 +/- 77 pmol/l in the NIDDM and control groups, respectively) had similar effects on receptor kinase a ctivity in both study groups (12 +/- to 42 +/- 5 and 12 +/- 2 to 47 +/ - 5 fmol P . fmol binding activity(-1) min(-1) in the NIDDM and contro l groups, respectively), Moreover, by selecting only the receptors tha t bound to anti-phosphotyrosine antibody, we found similar hyperinsuli nemia-induced increases of this receptor fraction and its kinase activ ity in both study groups. In vitro activation of the immobilized recep tors with 2 mmol/l ATP and insulin further increased their kinase acti vity to almost similar levels, independently of whether they had been previously stimulated in vivo or were from diabetic or nondiabetic sub jects, Compared with this activity reached in vitro, the kinase activi ty obtained by in vivo stimulation at the clamp insulin concentration was only similar to 12%, because most receptors remained inactive and only a few reached almost the in vitro activation level, Our data sugg est I) that 1,000 pmol/l serum insulin activates only a small fraction of insulin receptors in intact muscle and 2) that NIDDM is not associ ated with impaired insulin activation of insulin receptor kinase in sk eletal muscle, at least not when euglycemia is maintained.