Time-dependent effects of cholinergic stimulation on beta cell responsiveness

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Abstract
The effects of cholinergic stimulation on beta cell insulin secretory and phosphoinositide (PI) responses were determined in freshly isolated rat islets. Increasing the glucose level perifusing the islet from 5.6 to 8 mM was accompanied by a modest insulin secretory response. The further addition of 10 μM carbachol increased peak first- and second-phase responses by 2.6- and 6.8-fold, respectively. In the presence of 5.6 mM glucose, this low level (10 μM) of carbachol increased insulin release two-to three-fold, a response that was maintained for at least 60 min. In contrast to these acute stimulatory actions in the presence of glucose, chronic 3.5-h exposure of islets to 10 μM carbachol abolished beta cell insulin secretory responses to stimulation, with the combination of 8 mM glucose plus 10 μM carbachol. However, the further addition of 200 μM tolbutamide to these islets increased insulin secretory rates significantly. To establish the role of islet cell PI hydrolysis in these secretory responses, additional studies were conducted with islets whose PI pools were labeled with [3H]inositol. Acute exposure to 10 μM carbachol alone significantly increased inositol phosphate accumulation and the efflux of [3H]inositol, even in the absence of glucose. Including 10 μM carbachol during the labeling period with [3H]inositol resulted in significant impairments in subsequently measured inositol phosphate accumulation and [3H]inositol efflux responses to 8 mM glucose plus carbachol stimulation. Prior long-term exposure to 10 μM carbachol also induced heterologous desensitization: 20 mM glucose-stimulated insulin release and inositol phosphate accumulation were impaired in a parallel fashion. Chronic carbachol exposure had no deleterious effect on the usage of 8 or 20 mM glucose or on the insulin content of the islet. The acute stimulatory effects of carbachol on inositol phosphate accumulation as well as its inhibitory effect on 20 mM glucose-stimulated insulin release after prolonged exposure to the muscarinic agonist were significantly reduced by atropine. These findings demonstrate that changes in PI hydrolysis parallel those observed with insulin secretion and suggest that alterations in phospholipase C activation may account, at least in part, for the insulin secretory responses observed.

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