Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans.
To investigate the relationship of insulin receptor kinase with insulin resistance in humans, we studied insulin-sensitive tyrosine kinase activity in muscle biopsies taken from 20 Pima Indians [14 nondiabetics, 6 with non-insulin-dependent mellitus (NIDDM)] during euglycemic clamps, at insulin concentrations of approximately 68 microU/ml (low dose) and approximately 1,170 microU/ml (high dose). In the nondiabetics, the low dose, insulin-induced kinase activation in vivo was 1.5-fold the activity in the fasting state (P less than 0.05), whereas in the diabetics, the kinase activity actually decreased by 40% relative to fasting (P less than 0.05). The difference in delta-kinase in vivo was significant (P less than 0.01) between the two groups. Similarly, the kinase activation in vitro in response to 1 nM insulin was lower in diabetic subjects compared with nondiabetics (P less than 0.01). These data indicate that, in NIDDM, both in vitro and in vivo insulin-stimulated tyrosine kinase activity is impaired. Among nondiabetics, the kinase sensitivity to insulin, calculated as the ratio of the kinase activity at 1 nM insulin in vitro to the kinase activity at 100 nM insulin, was positively correlated with plasma insulin concentrations 2 h after an oral glucose load (r = 0.69, P less than 0.01). Thus, in nondiabetic subjects with insulin resistance, insulin activation of the kinase is not reduced, but the kinase sensitivity to insulin increases with increasing plasma insulin levels. Therefore, the site of insulin resistance in nondiabetic subjects is distal to the insulin receptor kinase. Furthermore, it is possible that circulating insulin, by increasing the kinase sensitivity to insulin, is a determinant of the receptor kinase activity.
Nyomba
B L
BL
Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016.
Ossowski
V M
VM
Bogardus
C
C
Mott
D M
DM
D000328:Adult; D001130:Arizona; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology; D015309:Glucose Clamp Technique; D006801:Humans; D007198:Indians, North American; D007328:Insulin / Q000494:pharmacology*; D007332:Insulin Infusion Systems; D007333:Insulin Resistance; D007700:Kinetics; D008297:Male; D009132:Muscles / Q000201:enzymology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D012016:Reference Values
D001786:Blood Glucose; D007328:Insulin; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin