Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians

Previous studies have demonstrated reduced in vivo insulin action in obese subjects compared with lean controls. However, little data is available on the relationship between degree of obesity and insulin action, and this relationship has not been shown to be independent of individual differences in maximal aerobic capacity. We studied 55 male Pima Indians and 35 male Caucasians with normal glucose tolerance. In vivo insulin action was measured using the hyperinsulinemic, euglycemic clamp technique at a plasma insulin concentration of approximately 100 microU/ml. Body composition was determined by densitometry, and maximal aerobic capacity was estimated using a graded exercise test. The results showed that degree of obesity was nonlinearly related to in vivo insulin action. In both Indians and Caucasians there was a significant decline in insulin action with increasing obesity up to a percent body fat of approximately 28-30%. Further increases in obesity in the Indians were not associated with significant changes in insulin action. Maximal aerobic capacity was positively linearly correlated with insulin action over the entire range of insulin action in both racial groups. Degree of obesity and maximal aerobic capacity were each independently associated with insulin action although these independent relationships were of marginal significance in the Caucasians. Surprisingly, individual differences in obesity and maximal aerobic capacity accounted for only half the variability observed in insulin action in these glucose tolerant subjects.

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Decreased muscle insulin receptor kinase correlates with insulin resistance in normoglycemic Pima Indians

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.2.e276 ◽

1997 ◽

Vol 273 (2) ◽

pp. E276-E283 ◽

Cited By ~ 5

Author(s):

J. F. Youngren ◽

I. D. Goldfine ◽

R. E. Pratley

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Body Fat ◽

Insulin Action ◽

Enzyme Linked Immunosorbent Assay ◽

Percent Body Fat ◽

Receptor Function ◽

Pima Indians ◽

Insulin Receptor Tyrosine Kinase

Defects in insulin receptor tyrosine kinase activity are present in insulin-resistant non-insulin-dependent diabetes mellitus patients and certain nondiabetic individuals, both lean and obese. However, the relationship between insulin receptor function, insulin action, and obesity is unclear. To address this issue, we have employed a new and highly sensitive enzyme-linked immunosorbent assay to measure in vitro insulin-stimulated autophosphorylation of immunocaptured muscle insulin receptors in a group of 25 normoglycemic Pima Indians. Insulin action, determined during two-step euglycemic insulin clamps, varied widely in these subjects. Maximal in vitro insulin stimulation of insulin receptor autophosphorylation strongly correlated with both low (Mlow)- and high (Mhigh)-dose insulin-stimulated glucose disposal (r = 0.62 and 0.51, P < 0.002 and 0.011, respectively). Insulin receptor autophosphorylation was inversely related to percent body fat (r = -0.52, P < 0.009). After control for percent body fat, receptor autophosphorylation remained correlated with Mlow (partial r = 0.49, P < 0.025). These data therefore suggest that defects in insulin receptor function are major contributors to insulin resistance in both lean and obese normoglycemic Pima Indians.

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