Decreased insulin responsiveness of glucose uptake in cultured human skeletal muscle cells from insulin-resistant nondiabetic relatives of type 2 diabetic families

To investigate the contribution of inherited biochemical defects to the per ipheral insulin resistance of type 2 diabetes, we studied cultured skeletal muscle from 10 insulin-resistant nondiabetic first-degree relatives of typ e 2 diabetic families and 6 control subjects. Insulin stimulation of glucos e uptake and glycogen synthesis was maximal in myoblasts. Insulin-stimulate d glucose uptake (fold-stimulation over basal uptake) was decreased in rela tive compared with control myoblasts at 0.001 mu mol/l (0.93 +/- 0.05 [mean +/- SE] vs. 1.15 +/- 0.06, P < 0.05) and 0.1 mu mol/l (1.38 +/- 0.10 vs. 1 .69 +/- 0.08, P = 0.025) insulin. Insulin responsiveness was markedly impai red in 5 of the relative myoblast cultures, and in 4 of these, there was an associated increase in basal glucose uptake (76.7 +/- 7.0 vs. 47.4 +/- 5.5 pmol . min(-1) . mg(-1) protein, relative vs. control; P < 0.02). Expressi on of insulin receptor substrate 1, phosphatidylinositol 3-kinase, protein kinase B, and glycogen synthase was normal in the relative cultures with im paired insulin responsiveness. Glycogen synthesis was also normal in the re lative cultures. We conclude that the persistence of impaired insulin respo nsiveness in some of the relative cultures supports the role of inherited f actors in the insulin resistance of type 2 diabetes and that the associatio n with increased basal glucose uptake suggests that the 2 abnormalities may be linked.