Glucose-Induced Insulin Receptor Tyrosine Phosphorylation in Insulin-Secreting β-Cells

In the βTC3 insulin-secreting β-cell line, glucose rapidly induces the tyrosine phosphorylation of the 97-kDa insulin receptor β-subunit. Phosphorylation is transient, with fourfold stimulation by 2 min and subsequent dephosphorylation to basal levels by 10–15 min. Elevating the extracellular KC1 concentration equipotently initiates receptor phosphorylation. Preventing insulin secretion with 1 μmol/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 × 10−9 mol/1. In addition, functional insulin-like growth factor I (IGF-I) receptors are also expressed by these β-cells, as indicated by IGF-I-induced receptor tyrosine phosphorylation (ED50 = 5 × 10−9 mol/1) and also by detection of hybrid insulin/IGF-I receptor autophosphorylation at 10−7 mol/1 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 α-subunit of the phosphatidylinositol-3-kinase, as determined by co-immunoprecipitation assays. These results demonstrate that in these β-cells, glucose-induced insulin secretion activates the β-cell surface insulin receptor tyrosine kinase and its intracellular signal transduction pathway, suggesting a new autocrine mechanism for the regulation of β-cell function.

[1]  D. Accili,et al.  Insulin Resistance or Insulin Deficiency: Which Is the Primary Cause of NIDDM? , 1994, Diabetes.

[2]  R. Sorenson,et al.  Effect of tyrosine kinase inhibitors on islets of Langerhans: evidence for tyrosine kinases in the regulation of insulin secretion. , 1994, Endocrinology.

[3]  R. Duan,et al.  Multiple inhibitory effects of genistein on stimulus-secretion coupling in rat pancreatic acini. , 1994, The American journal of physiology.

[4]  C. Kahn,et al.  The insulin signaling system. , 1994, The Journal of biological chemistry.

[5]  I. Trowbridge.  Dynamin, SH3 domains and endocytosis , 1993, Current Biology.

[6]  I. Campbell,et al.  The GTPase dynamin binds to and is activated by a subset of SH3 domains , 1993, Cell.

[7]  K. Takegawa,et al.  Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. , 1993, Science.

[8]  C. W. Garner,et al.  Insulin stimulates the degradation of IRS-1 in 3T3-L1 adipocytes. , 1993, Biochemical and biophysical research communications.

[9]  I. Godsland,et al.  Role of glucose and insulin resistance in development of type 2 diabetes mellitus , 1992, The Lancet.

[10]  J. Glenney.  Tyrosine-phosphorylated proteins: mediators of signal transduction from the tyrosine kinases. , 1992, Biochimica et biophysica acta.

[11]  S. Jacobs,et al.  Insulin/IGF‐I receptor hybrids: A mechanism for increasing receptor diversity , 1992, Journal of cellular biochemistry.

[12]  B. Goldstein.  Protein‐Tyrosine phosphatases and the regulation of insulin action , 1992, Journal of cellular biochemistry.

[13]  E. Van Obberghen,et al.  Interaction between heterologous receptor tyrosine kinases , 1991, FEBS letters.

[14]  M. Beukers,et al.  Insulin‐Like Growth Factor Receptors , 1991, Acta paediatrica Scandinavica. Supplement.

[15]  M. J. MacDonald,et al.  Elusive Proximal Signals of β-Cells for Insulin Secretion , 1990, Diabetes.

[16]  S. Efrat,et al.  Regulation of Insulin Secretion from β-Cell Lines Derived from Transgenic Mice Insulinomas Resembles that of Normal β-Cells* , 1990 .

[17]  R. Mooney,et al.  Phosphorylation of the insulin receptor in permeabilized adipocytes is coupled to a rapid dephosphorylation reaction. , 1989, The Journal of biological chemistry.

[18]  D. Hanahan,et al.  Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[19]  F M Matschinsky,et al.  Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. , 1987, Physiological reviews.

[20]  R. Eaton,et al.  Insulin Suppresses Its Own Secretion In Vivo , 1987, Diabetes.

[21]  K. Polonsky,et al.  Lack of direct inhibition of insulin secretion by exogenous insulin in the canine pancreas. , 1986, The Journal of clinical investigation.

[22]  D. Morgan,et al.  Mapping surface structures of the human insulin receptor with monoclonal antibodies: localization of main immunogenic regions to the receptor kinase domain. , 1986, Biochemistry.

[23]  C. Kahn,et al.  Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells , 1985, Nature.

[24]  J. Shafer,et al.  Inhibition of the activation and catalytic activity of insulin receptor kinase by zinc and other divalent metal ions. , 1985, The Journal of biological chemistry.

[25]  J. Olefsky,et al.  Modulation of insulin secretion by insulin and glucose in type II diabetes mellitus. , 1985, The Journal of clinical endocrinology and metabolism.

[26]  P. H. Seeburg,et al.  Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes , 1985, Nature.

[27]  P. Cuatrecasas,et al.  Somatomedin-C stimulates the phosphorylation of the beta-subunit of its own receptor. , 1983, The Journal of biological chemistry.

[28]  L. Orci,et al.  Quantitative electron microscopic autoradiography of insulin, glucagon, and somatostatin binding sites on islets. , 1982, Science.

[29]  C. Kahn,et al.  Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system , 1982, Nature.

[30]  K. Shima,et al.  Failure of exogenous insulin to inhibit C-peptide release from the perfused rat pancreas. , 1980, Endocrinologia japonica.

[31]  E. Verspohl,et al.  Evidence for presence of insulin receptors in rat islets of Langerhans. , 1980, The Journal of clinical investigation.

[32]  U. Keller,et al.  Inhibition of Insulin Secretion by Exogenous Insulin in Normal Man as Demonstrated by C-peptide Assay , 1978, Diabetes.

[33]  E. Verspohl,et al.  Pyridine nucleotides in pancreatic islets during inhibition of insulin release by exogenous insulin. , 1976, Endocrinology.

[34]  C. Kahn,et al.  Quantitative aspects of the insulin-receptor interaction in liver plasma membranes. , 1974, The Journal of biological chemistry.

[35]  P. Cuatrecasas.  Properties of the insulin receptor of isolated fat cell membranes. , 1971, The Journal of biological chemistry.

[36]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[37]  P. Lacy,et al.  Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas , 1967, Diabetes.

[38]  L. Cheatham.  3-Kinase Activation IsRequired forInsulin Stimulation ofpp7OS6Kinase, DNA Synthesis, and Glucose Transporter Translocation , 1994 .

[39]  H. Towbin,et al.  Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. 1979. , 1992, Biotechnology.

[40]  E. Verspohl,et al.  Indirect evidence for short-loop negative feedback of insulin secretion in the rat. , 1991, The Journal of endocrinology.

[41]  J. Avruch,et al.  Insulin Regulation of Protein Phosphorylation , 1990 .

[42]  M. Rechler,et al.  The nature and regulation of the receptors for insulin-like growth factors. , 1985, Annual review of physiology.