Chronic Sympathetic Innervation of Islets in Transgenic Mice Results in Differential Desensitization of α-Adrenergic Inhibition of Insulin Secretion
- 128 Downloads
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.
KeywordsInsulin Secretion Insulin Release Hypothalamic Lesion Inhibit Insulin Secretion Enhance Insulin Secretion
Unable to display preview. Download preview PDF.
- 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
- 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
- 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.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
- 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
- 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
- 28.A.E. Boyd, 1988, Sulfonylurea receptors, ion channels and fruit flies, Diabetes 37:847–850.Google Scholar
- 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
- 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
- 47.N.G. Morgan, 1987, Regulation of insulin secretion by α2-adrenergic agonists, TIPS 8:369–370.Google Scholar
- 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.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.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
- 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