ROLE OF HUMAN SKELETAL-MUSCLE INSULIN-RECEPTOR KINASE IN THE IN-VIVO INSULIN-RESISTANCE OF NONINSULIN-DEPENDENT DIABETES-MELLITUS AND OBESITY

被引:98
作者
NOLAN, JJ
FREIDENBERG, G
HENRY, R
REICHART, D
OLEFSKY, JM
机构
[1] VET ADM MED CTR 111G, SAN DIEGO, CA 92161 USA
[2] UNIV CALIF SAN DIEGO, DEPT MED, LA JOLLA, CA 92093 USA
[3] UNIV CALIF SAN DIEGO, DEPT PEDIAT, LA JOLLA, CA 92093 USA
[4] UNIV INDIANAPOLIS, DEPT PEDIAT, INDIANAPOLIS, IN 46202 USA
关键词
D O I
10.1210/jc.78.2.471
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
To assess the role of insulin receptor (IR) tyrosine kinase in human insulin resistance, we examined the kinase activity of IR of skeletal muscle biopsies from eight lean and five obese nondiabetics and six obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). Biopsies were taken during euglycemic clamps at insulin infusion rates of 0, 40, 120, and 1200 mU/m(2).min. IRs were immobilized on insulin agarose beads, and autophosphorylation and histone 2B phosphorylation were measured. Phosphatase and protease inhibitors preserved the in vivo phosphorylation state of the IRs. Glucose disposal rates (GDR) were reduced according to insulin dose by 23-30% in the obese (P < 0.05) and 43-64% in the NIDDM subjects (P < 0.0005). IR autophosphorylation was increased up to 9-fold in controls and was reduced (P = 0.04) in NIDDM compared to obese subjects. Histone-2B kinase was increased up to 6-fold in controls and was reduced by 50% in NIDDM. Kinase values by both methods were similar in lean and obese controls. In vivo stimulation of kinase was well correlated to the increase in GDR, as was the decrement in kinase in NIDDM to the decrement in GDR. These results suggest that defects in muscle IR kinase are significant in the in vivo insulin resistance of NIDDM, but not that of obesity.
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页码:471 / 477
页数:7
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