GLUCOSE-INDUCED INSULIN-RECEPTOR TYROSINE PHOSPHORYLATION IN INSULIN-SECRETING BETA-CELLS

In the beta TC3 insulin-secreting beta-cell line, glucose rapidly indu ces the tyrosine phosphorylation of the 97-kDa insulin receptor beta-s ubunit. Phosphorylation is transient, with fourfold stimulation by 2 m in and subsequent dephosphorylation to basal levels by 10-15 min. Elev ating the extracellular KCl concentration equipotently initiates recep tor phosphorylation. Preventing insulin secretion with 1 mu mol/l epin ephrine or by removing extracellular Ca2+ blocks the effect. In the ab sence of glucose-induced secretion, exogenous insulin also stimulated insulin receptor autophosphorylation transiently and with an ED(50) of 4 x 10(-9) mol/l. In addition, functional insulin-like growth factor I(IGF-I) receptors are also expressed by these beta-cells, as indicate d by IGF-I-induced receptor tyrosine phosphorylation (ED(50) 5 x 10(-9 ) mol/l) and also by detection of hybrid insulin/IGF-I receptor autoph osphorylation at 10(-7) mol/l IGF-I. Both glucose and insulin stimulat e the tyrosine phosphorylation of the insulin receptor substrate (IRS) IRS-1 and increase by two- to fivefold the rapid association of IRS-1 with the 85-kDa alpha-subunit of the phosphatidylinositol-3-kinase, a s determined by co-immunoprecipitation assays. These results demonstra te that in these beta-cells, glucose-induced insulin secretion activat es the beta-cell surface insulin receptor tyrosine kinase and its intr acellular signal transduction pathway, suggesting a new autocrine mech anism for the regulation of beta-cell function.