Advertisement

Chronic Sympathetic Innervation of Islets in Transgenic Mice Results in Differential Desensitization of α-Adrenergic Inhibition of Insulin Secretion

  • Gerold M. Grodsky
  • Yan Hui Ma
  • Robert H. Edwards
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 426)

Summary

The effects of chronic sympathetic hyperinnervation on pancreatic β-cell insulin secretion were investigated utilizing the in vitro perfused pancreas from transgenic mice. These mice exhibit islet hyperinnervation of sympathetic neurons resulting from overexpression of nerve growth factor in their β-cells (1). The goal was to determine whether sympathetic hyperinnervation increased classic α-adrenergic inhibition of β-cell insulin secretion or, in contrast, down-regulated β-cell sensitivity to adrenergic input resulting in enhanced insulin secretion.

Both fasting and fed blood sugars and pancreatic insulin content were normal in the transgenics. Response of the transgenic perfused pancreas to low glucose (7 mM) was primarily first phase and normal whereas high glucose (22 mM) caused enhanced, rather than reduced, insulin secretion of both first and second phases. The α-antagonist, phentolamine, caused a six-fold increase in glucose-stimulated insulin secretion from the control pancreas, an effect that was blunted for the transgenic pancreas. A similarly blunted response to phentolamine occurred when this agent was superimposed on a combined glucose-forskolin stimulus. (The positive effect on insulin secretion by phentolamine in normal β-cell preparations has arguably been ascribed to non-specific ionic effects.) Therefore, as a test of possible changes in the ATP regulated K+ channel or the linked Ca++ channels, glyburide was perfused during glucose stimulation. Insulin secretion in response to glyburide was increased two fold in the control pancreas. However, with the transgenic pancreas, in contrast to the enhanced response to glucose, the effect of glyburide was almost completely inhibited. It is concluded that: 1) chronic adrenergic hyperinnervation results in enhanced glucose-stimulated insulin secretion by desensitization of a major α-adrenergic inhibitory site(s); and 2) adrenergic hyperinnervation acts directly or indirectly on ion flux to partially inhibit insulin release, an effect which is not desensitized. Since down-regulation of a single α-adrenergic receptor would be expected to desensitize both phenomena the observed differential desensitization indicates that different post receptor events or more than one adrenergic receptor are involved.

Keywords

Insulin Secretion Insulin Release Hypothalamic Lesion Inhibit Insulin Secretion Enhance Insulin Secretion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    R.H. Edwards, W.J. Rutter, D. Hanahan, 1989, Directed expression of NGF to pancreatic β cells in transgenic mice leads to selective hyperinnervation of the islets, Cell 58:161–170.PubMedCrossRefGoogle Scholar
  2. 2.
    H.G. Coore, P.J. Randle, 1964, Regulation of insulin secretion studied with pieces of rabbit pancreas incubated in vitro, Biochem J 93:66–78.PubMedGoogle Scholar
  3. 3.
    E. Cerasi, S. Efendic, R. Luft, 1969, Role of adrenergic receptors in glucose-induced insulin secretion in man, Lancet ii:301–302.CrossRefGoogle Scholar
  4. 4.
    F. Rohner-Jearenaud, B. Jeanrenaud, 1980, Consequences of ventromedical hypothalamic lesions upon insulin and glucagon secretion by subsequently isolated perfused pancreas in the rat, J Clin Invest, 65:902–910.CrossRefGoogle Scholar
  5. 5.
    P.H. Smith, S.C. Woods, D Porte, 1979, Control of the endocrine pancreas by the autonomic nervous system and related neural factors. In: “Integrative Functions of the Autonomic Nervous System,” C.M. Brooks, K. Koizumi, A Sato, eds, Elsevier/North-Holland, Amsterdam, Netherlands, 84–97.Google Scholar
  6. 6.
    P. Rorsman, K. Bokvist, C. Ammala, P. Arkhammar, P.-O. Berggren, O. Larsson, K. Wahlander, 1991, Activation by adrenaline of a low-conductance G protein-dependent K+ channel in mouse pancreatic B cells, Nature, 349:77–79.PubMedCrossRefGoogle Scholar
  7. 7.
    T. Nakaki, T. Nakadate, K. Ishii, R. Kato, 1981, Postsynaptic alpha-2 adrenergic receptors in isolated rat islets of langerhans: inhibition of insulin release and cyclic 3′,5′-adenosine monophosphate accumulation, J Pharmacol Exp Ther 216:607–612.PubMedGoogle Scholar
  8. 8.
    H.H. Keahey, A.E. Boyd III, D.L. Kunze, 1990, G protein-dependent modification of calcium currents in clonal pancreatic β-cells, J Physiol 257:C1171–C1176.Google Scholar
  9. 9.
    D. Porte, 1969, Sympathetic regulation of insulin secretion, Arch Intern Med 123:252–260.PubMedCrossRefGoogle Scholar
  10. 10.
    R.P. Robertson, J.B. Halter, D. Porte, 1976, A role for a-adrenergic receptors in abnormal insulin secretion in diabetes mellitus, J Clin Invest 57:791–795.PubMedCrossRefGoogle Scholar
  11. 11.
    L.A. Campfield, F.J. Smith, 1983, Alteration of islet neurotransmitter sensitivity following ventromedial hypothalamic lesion, Am J Physiol 244:R635–R640.PubMedGoogle Scholar
  12. 12.
    M.C. Michel, P.A. Insel, 1989, Are there multiple imidazoline binding sites?, TIPS 10:342–344.PubMedGoogle Scholar
  13. 13.
    G.M. Grodsky, 1989, A new phase in insulin secretion. How will it contribute to our understanding of B-cell function?, Diabetes 38:673–678.PubMedCrossRefGoogle Scholar
  14. 14.
    G.M. Grodsky, J.L. Bolaffi, 1992, Desensitization of the insulin-secreting beta cells, J Cell Biochem 48:3–11.PubMedCrossRefGoogle Scholar
  15. 15.
    G.G. Weir, J.L. Leahy, S. Bonner-Weir, 1986, Experimental reduction of β-cell mass: implications for the pathogenesis of diabetes, Diabetes Metab Rev 2:125–161.PubMedCrossRefGoogle Scholar
  16. 16.
    W.P. Hausdorff, M.G. Caron, R.J. Lefkowitz, 1990, Turning off the signal: desensitization of β-adrenergic receptor function, FASEB J 4:2881–2888.PubMedGoogle Scholar
  17. 17.
    G.M. Grodsky, R. Fanska, 1974, The in vitro perfused pancreas. In “Methods in Enzymology,” J.G. Hardman, B.W. O’Malley, eds., Academic Press, New York, 363–372.Google Scholar
  18. 18.
    G.M. Grodsky, A. Heldt, 1984, Methods for the in vitro perfusion of the pancreas., In “Methods in Diabetes Research,” J. Lamer, S.L. Pohl, eds., Wiley and Sons, New York, 137–146.Google Scholar
  19. 19.
    G.M. Grodsky, C.T. Peng, 1959, Extractable insulin measured by immunochemical assay: effect of tolbutamide, Proc Soc Exp Biol and Med 101:100–103.CrossRefGoogle Scholar
  20. 20.
    G.M. Grodsky, F. Schmidt-Formby, 1985, Kinetic and quantitative relationships between insulin release and 65Zn efflux from perifused islets, Endocrinology 117:704–710.PubMedCrossRefGoogle Scholar
  21. 21.
    M.D.L. O’Connor, H. Landahl, G.M. Grodsky, 1990, Comparison of storage-and signal-limited models of pancreatic insulin secretion, Am J Physiol 238:R378–R389.Google Scholar
  22. 22.
    G.M. Grodsky, 1972, Threshold distribution hypothesis for packet storage of insulin and its mathematical modeling, J Clin Invest 51:2047–2059.PubMedCrossRefGoogle Scholar
  23. 23.
    G.M. Grodsky, Y.H. Ma, B. Cullen, N. Sarvetnick, 1992, Effect on insulin production sorting and secretion by major histocompatibility complex class II gene expression in the pancreatic β cell of transgenic mice, Endocrinology 131:933–938.PubMedCrossRefGoogle Scholar
  24. 24.
    S. Lenzen, 1979, Insulin secretion by isolated perfused rat and mouse pancreas, Am J Physiol 236:E391–E400.PubMedGoogle Scholar
  25. 25.
    O. Berglund, 1987, Lack of glucose-induced priming of insulin release in the perfused mouse pancreas, J Endocrinol 114:185–189.PubMedCrossRefGoogle Scholar
  26. 26.
    A. Schulz, A. Hasselblatt, 1989, An insulin-releasing property of imidazoline derivatives is not limited to compounds that block α-adrenoceptors, Naunym-Schmiedebergs Arch Pharmacol 340:321–327.Google Scholar
  27. 27.
    T.D. Plant, J.C. Henquin, 1990, Phentolamine and yohimbine inhibit ATP-sensitive K+ channels in mouse pancreatic β-cells, Br J Pharmacol 101:115–120.PubMedCrossRefGoogle Scholar
  28. 28.
    A.E. Boyd, 1988, Sulfonylurea receptors, ion channels and fruit flies, Diabetes 37:847–850.Google Scholar
  29. 29.
    I. Niki, J.L. Nicks, S.J. Aschroft, 1990, The beta cell glibenclamide receptor is an ADP-binding protein, Biochem J 268:713–718.PubMedGoogle Scholar
  30. 30.
    J.L. Bolaffi, G. Rodd, Y.H. Ma, G.M. Grodsky, 1990, Effect of glucagon or somatostatin on desensitized insulin secretion, Endocrinology 126:1750–1775.PubMedCrossRefGoogle Scholar
  31. 31.
    J.L. Bolaffi, G.G. Rodd, Y.H. Ma, D. Bright, G.M. Grodsky, 1991, The role of Ca++-related events in glucose-stimulated desensitization of insulin secretion, Endocrinology 129:2131–2138.PubMedCrossRefGoogle Scholar
  32. 32.
    W.H. Hsu, H. Xiang, A.S. Rajan, A.E. Boyd, 1991, Activation of α2-adrenergic receptors decreases Ca2+ influx to inhibit insulin secretion in a hamster β-cell line: An action mediated by a guanosine triphosphate-binding protein, Endocrinology 128:958–964.PubMedCrossRefGoogle Scholar
  33. 33.
    S. Ullrich, C.B. Wollheim, 1988, GTP-dependent inhibition of insulin secretion by epinephrine in permeabilized RINm5F cells, J Biol Chem 263:8615–8620.PubMedGoogle Scholar
  34. 34.
    C.B. Wollheim, M. Kikuchi, A.E. Renold, G.W.G. Sharp, 1977, Somatostatin-and epinephrine-induced modification of 45Ca++ fluxes in insulin release in rat pancreatic islets maintained in tissue culture, J Clin Invest 60:1165–1173.PubMedCrossRefGoogle Scholar
  35. 35.
    S. Ullrich, C.B. Wollheim, 1985, Expression of both α-and α2-adrenoceptors in an insulin secreting cell line: Parallel studies of cytosolic free Ca++ and insulin release, Mol Pharmacol 28:100–106.PubMedGoogle Scholar
  36. 36.
    A. Robinovitch, E. Cerasi, G.W.G. Sharp, 1978, Adenosine 3′,5′-monophosphate-dependent and independent inhibitory effects of epinephrine on insulin release in rat pancreatic islets, Endocrinology 102:1733–1740.Google Scholar
  37. 37.
    S.J. Persaud, P.M. Jones, S.L. Howell, 1993, Activation of protein kinase C partially alleviates noradrenaline inhibition of insulin secretion, Biochem J 289:497–501.PubMedGoogle Scholar
  38. 38.
    S. Santana de Sa, R. Ferrer, E. Rojas, I. Atwater, 1983, Effects of adrenaline and noradrenaline on glucose-induced electrical activity of mouse pancreatic β cell, J Physiol 68:247–258.Google Scholar
  39. 39.
    G. Drews, A. Debuyser, M. Henquin, J.C. Henquin, 1990, Galanin and epinephrine act on distinct receptors to inhibit insulin release by the same mechanisms including an increase in K+ permeability of the B-cell membrane, Endocrinology 126:1646–1653.PubMedCrossRefGoogle Scholar
  40. 40.
    W.H. Hsu, H. Xiang, A.S. Rajan, A.E. Boyd III, 1991, Activation of α2-adrenergic receptors decreases Ca2+ influx to inhibit insulin secretion in a hamster β-cell line: An action mediated by a guanosine triphosphate-binding protein, Endocrinology 128:958–964.PubMedCrossRefGoogle Scholar
  41. 41.
    L. Siconolfi-Baez, M.A. Banerji, H.E. Lebovitz, 1990, Characterization and significance of sulfonylurea receptors, Diabetes Care 13:2–8.PubMedGoogle Scholar
  42. 42.
    H. Schmid-Antomarchi, J. DeWeille, M. Fosset, M. Lazdunski, 1987, The receptor for antidiabetic sulfonylureas controls the activity of the ATP-modulated K+ channel in insulin-secreting cells, J Biol Chem 262: 15840–15844.PubMedGoogle Scholar
  43. 43.
    C.-G. Ostenson, A.G. Cattaneo, J.C. Doxey, S. Efendic, 1989, a-adrenoceptors and insulin release from pancreatic islets of normal and diabetic rats, Am J Physiol 257 (Endocrinol Metab 20):E439–E443.PubMedGoogle Scholar
  44. 44.
    G. Koh, Y. Seino, K. Tsuda, S. Nishi, H. Ishida, J. Takeda, H. Fukumoto, T. Taminato, H. Imura, 1992, Effect of the α2-blocker DG-5128 on insulin and somatostatin release from the isolated perfused rat pancreas, Life Sciences 40:1113–1118.CrossRefGoogle Scholar
  45. 45.
    G.M. Grodsky, J.L. Bolaffi, 1992, Desensitization of insulin-secreting beta cells, J of Cellular Biochem 48:3–11.CrossRefGoogle Scholar
  46. 46.
    W.S. Zawalich, K.A. Zawalich, G.I. Shulman, L. Rossetti, 1990, Chronic in vivo hyperglycemia impairs phosphoinositide hydrolysis and insulin release in isolated perfused rat islets, Endocrinology 126:253–260.PubMedCrossRefGoogle Scholar
  47. 47.
    N.G. Morgan, 1987, Regulation of insulin secretion by α2-adrenergic agonists, TIPS 8:369–370.Google Scholar
  48. 48.
    C.M. Fraser, S. Arakawa, W.R. McCombie, J.C. Venter, 1989, Cloning, Sequence analysis, and permanent expression of a human α2-adrenergic receptor in chinese hamster overy cells, J of Biol Chem 264:11754–11761.Google Scholar
  49. 49.
    H.R. Bourne, A.L. DeFranco, 1989, Signal transduction and intercellular messengers. In “Oncogenes and the Molecular Origins of Cancer,” R. Weinberg, M. Wigler, eds., Cold Spring Harbor Laboratory Press, 97-124.Google Scholar
  50. 50.
    A. Schmidt, J. Hescheler, S. Offermanns, K. Spicher, K.-D. Hinsch, F.-J. Klinz, J. Codina, L. Birnbaumer, H. Gausepohl, R. Frank, G. Schultz, W. Rosenthal, 1991, Involvement of pertussis toxin-sensitive G-proteins in the hormonal inhibition of dihydropyridine-sensitive Ca2+ currents in an insulin-secretion cell line (RINm5F), J of Biol Chem 266:18025–18033.Google Scholar
  51. 51.
    J.L. Benivic, M. Bouvier, M.G. Caron, R.J. Lefkowitz, 1988, Regulation of adenyl cyclase-coupled β-adrenergic receptors, Ann Rev Cell Biol 4:405–428.CrossRefGoogle Scholar
  52. 52.
    J. Garthwaite, 1990, Nitric oxide synthesis linked to activation of excitatory neurotransmitter receptors in the brain. In “Nitric Oxide from L-Arginine: A Bioregulatory System,” Excerpta Medica, New York, 115–137.Google Scholar
  53. 53.
    L. Birnbaumer, J. Abramowitz, A. Yatani, K. Okabe, R. Matterà, R. Graff, J. Sanford, J. Codina, A.M. Brown, 1990, Roles of G Proteins in Coupling of Receptors to Ionic Channels and Other Effector Systems, Biochem and Molecular Biology 25:225–244.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Gerold M. Grodsky
    • 1
  • Yan Hui Ma
    • 1
  • Robert H. Edwards
    • 2
  1. 1.Metabolic Research Unit, HSW 1157University of California, San FranciscoSan FranciscoUSA
  2. 2.Department of NeurologyUCLA School of MedicineLos AngelesUSA

Personalised recommendations