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

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 (M-low)- and high (M-high)-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 M-low (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.