Diabetes, Vol 44, Issue 7 802-809, Copyright © 1995 by American Diabetes Association

ARTICLES

Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting beta-cells

PL Rothenberg, LD Willison, J Simon and BA Wolf
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082, USA.

In the beta TC3 insulin-secreting beta-cell line, glucose rapidly induces the tyrosine phosphorylation of the 97-kDa insulin receptor beta-subunit. Phosphorylation is transient, with fourfold stimulation by 2 min and subsequent dephosphorylation to basal levels by 10-15 min. Elevating the extracellular KCl concentration equipotently initiates receptor phosphorylation. Preventing insulin secretion with 1 mumol/l epinephrine or by removing extracellular Ca2+ blocks the effect. In the absence of glucose-induced secretion, exogenous insulin also stimulated insulin receptor autophosphorylation transiently and with an ED50 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 indicated by IGF-I-induced receptor tyrosine phosphorylation (ED50 = 5 x 10(-9) mol/l) and also by detection of hybrid insulin/IGF-I receptor autophosphorylation at 10(-7) mol/l IGF-I. Both glucose and insulin stimulate 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, as determined by co-immunoprecipitation assays. These results demonstrate that in these beta-cells, glucose-induced insulin secretion activates the beta-cell surface insulin receptor tyrosine kinase and its intracellular signal transduction pathway, suggesting a new autocrine mechanism for the regulation of beta-cell function.
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