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

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Physiology and Pathophysiology of the Islets of Langerhans

Part of the book series: Advances in Experimental Medicine and Biology ((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.

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Authors and Affiliations

  1. Metabolic Research Unit, HSW 1157, University of California, San Francisco, 3rd and Parnassus, San Francisco, California, 94143, USA

    Gerold M. Grodsky & Yan Hui Ma

  2. Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, California, 90024-1769, USA

    Robert H. Edwards

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  1. Gerold M. Grodsky
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  2. Yan Hui Ma
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  3. Robert H. Edwards
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  1. Miguel Hernandez University, Alicante, Spain

    Bernat Soria

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Grodsky, G.M., Ma, Y.H., Edwards, R.H. (1997). Chronic Sympathetic Innervation of Islets in Transgenic Mice Results in Differential Desensitization of α-Adrenergic Inhibition of Insulin Secretion. In: Soria, B. (eds) Physiology and Pathophysiology of the Islets of Langerhans. Advances in Experimental Medicine and Biology, vol 426. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1819-2_17

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  • DOI: https://doi.org/10.1007/978-1-4899-1819-2_17

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