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 pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) was investigated. Muscle biopsies from 13 patients with NIDDM and 10 control subjects at fasting serum insulin concentrations and approximately 1,000 pmol/l steady-state serum insulin during euglycemic hyperinsulinemic clamps were immediately frozen. The biopsies were then solubilized, and the receptors were immobilized to anti-insulin receptor antibody-coated microwells. 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 1,07 +/- 77 pmol/l in the NIDDM and control groups, respectively) had similar effects on receptor kinase activity in both study groups (12 +/- 1 to 42 +/- 5 and 12 +/- 2 to 47 +/- 5 amol P.fmol binding activity-1. min-1 in the NIDDM and control groups, respectively). Moreover, by selecting only the receptors that bound to anti-phosphotyrosine antibody, we found similar hyperinsulinemia-induced increases of this receptor fraction and its kinase activity in both study groups. In vitro activation of the immobilized receptors with 2 mmol/l ATP and insulin further increased their kinase activity to almost similar levels, independently of whether they had been previously stimulated in vivo or were from diabetic or nondiabetic subjects. Compared with this activity reached in vitro, the kinase activity obtained by in vivo stimulation at the clamp insulin concentration was only approximately 12%, because most receptors remained inactive and only a few reached almost the in vitro activation level.(ABSTRACT TRUNCATED AT 250 WORDS)
Klein
H H
HH
Department of Internal Medicine, Medizinische Universität zu Lübeck, Germany.
Vestergaard
H
H
Kotzke
G
G
Pedersen
O
O
D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology*; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values
D001786:Blood Glucose; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin