Insulin and insulin-like growth factor-1 action on human skeletal muscle: Preferential effects of insulin-like growth factor-1 in type 2 diabetic subjects

Abstract

The metabolic actions of insulin and insulin-like growth factor-1 (IGF-1) were compared in cultured skeletal muscle cells from nondiabetic (ND) and type 2 diabetic subjects. Insulin stimulated glucose uptake with comparable sensitivity in ND (EC50 = 2.0 [plusmn] 0.7 nmol/L) and diabetic (1.3 [plusmn] 0.4) cells. IGF-1 sensitivity for uptake stimulation was similar in ND (EC50 = 0.30 [plusmn] 0.06 nmol/L) and type 2 cells (0.37 [plusmn] 0.01). In ND cells, insulin and IGF-1 were equally potent for stimulation of glucose uptake and glycogen synthase (GS) activity. However, in diabetic cells, maximal insulin stimulation of both responses was only half of the increases due to IGF-1. Final absolute activities after IGF-1 stimulation were still lower in diabetic cells compared with cells from ND subjects. Hormonal stimulation of Akt phosphorylation exhibited the same behavior as metabolic responses; comparable for insulin and IGF-1 in ND muscle, while IGF-1 was significantly more effective in diabetic cells. Both insulin receptor (IR) binding and receptor protein expression were similar in ND and diabetic cells. IGF-1 binding and receptor protein expression were not significantly different in diabetic compared with ND cells. The expression of IGF-binding proteins (IGFBP) 3, 5, and 6 were similar in ND and diabetic cells; IGFBP-4 was slightly, but significantly higher, in diabetic cells. While insulin and IGF-1 are equally effective on metabolic responses in ND muscle, diabetic muscle cells are markedly more resistant to insulin than IGF-1. The greater metabolic activity of IGF-1 in type 2 diabetic muscle may provide new insights into the mechanisms of insulin resistance in skeletal muscle.