Chronic sympathetic innervation of islets in transgenic mice results in differential desensitization of alpha-adrenergic inhibition of insulin secretion.

Abstract

The effects of chronic sympathetic hyperinnervation on pancreatic beta-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 beta-cells (1). The goal was to determine whether sympathetic hyperinnervation increased classic alpha-adrenergic inhibition of beta-cell insulin secretion or, in contrast, down-regulated beta-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 alpha-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 beta-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 alpha-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 alpha-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.