The IR1152 mutant insulin receptor selectively impairs insulin action in skeletal muscle but not in liver

In patients harboring the IR1152 mutant insulin receptor, hepatic glucose p roduction was normally suppressed by insulin. Hepatocytes without the insul in receptor gene and expressing IR1152 (Hep(MUT)) also showed normal insuli n suppression of glucose production and full insulin response of glycogen s ynthase. In contrast, expression of the IR1152 mutant in skeletal muscle ma ximally increased glucose uptake and storage, preventing further insulin st imulation. IRS-1 phosphorylation was normally stimulated by insulin in both intact Hep(MUT) and L6 skeletal muscle cells expressing the IR1152 mutant (L6(MUT)). At variance, IRS-2 phosphorylation exhibited high basal levels w ith no further insulin-dependent increase in L6(MUT) but almost normal phos phorylation, both basal and insulin-stimulated, in the Hep(MUT) cells. In v itro, IR1152 mutant preparations from both the L6(MUT) and the Hep(MUT) cel ls exhibited increased basal and no insulin-stimulated phosphorylation of I RS-2 immobilized from either muscle or liver cells. IR1152 internalization in liver and muscle cells closely paralleled the ability of this mutant to phosphorylate IRS-2 in vivo in these cells. Block of receptor internalizati on (wild-type and mutant) in the liver and muscle cells also inhibited IRS- 2, but not IRS-1, phosphorylation. Thus, the mechanisms controlling insulin receptor internalization differ in liver and skeletal muscle cells and may enable IR1152 to control glucose metabolism selectively in liver. In both cell types, receptor internalization seems necessary for IRS-2 but not IRS- 1 phosphorylation.