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Control of insulin secretion from the perfused rat pancreas : effects of acetylcholine and a somatostatin analog, SMS 201-995 Verchere, Cameron Bruce


The effect of varying concentrations of glucose or the gastrointestinal hormones, gastric inhibitory polypeptide (GIP) and somatostatin (SS-14), on the in vitro immunoreactive insulin (IRI) response to the parasympathetic neurotransmitter, acetylcholine (ACh) was investigated. The isolated, vascularly perfused rat pancreas was used in all experiments. Acetylcholine (1.0 µM) did not stimulate IRI secretion in the presence of 2.2 mM glucose. However, in the presence of 4.4, 6.6, or 8.9 mM glucose, ACh (1.0 µM) potently stimulated IRI secretion (approximately fourfold). At a higher glucose concentration (17.8 mM), the IRI response to ACh was reduced. GIP also potentiated the IRI response to 1.0 µM ACh. This potentiation was most marked in the presence of 1.0 nM GIP, whereas the effect of concomitant infusion of 0.2 nM GIP and 1.0 µM ACh was only slightly greater than additive. SS-14 potently inhibited ACh-stimulated IRI secretion. These results demonstrated the glucose dependency of cholinergically stimulated IRI secretion, and that physiological levels of glucose and GIP increased B-cell sensitivity to cholinergic stimulation. It was suggested that the parasympathetic stimulation of IRI secretion associated with food intake could be affected by postprandial increases in glucose, GIP, and SS-14. The idea that endogenously released somatostatin may have influenced glucose or GIP-stimulated IRI secretion was not supported by the present experiments, since neither glucose (8.9 mM) nor GIP (2.0 nM) were found to have a significant effect on the release of pancreatic somatostatin-like immunoreactivity (SLI). Both atropine (1.0 µM) and hexamethonlum (100 µM) inhibited the IRI response to ACh. This suggested that the parasympathetic stimulation of IRI secretion was mediated not only by muscarinic receptors on the B-cell, but also by nicotinic receptors on intrapancreatic ganglia. Neither atropine nor hexamethonlum had a significant effect on glucose- or GIP-stimulated IRI secretion, indicating that the IRI response to these stimuli was not mediated by cholinergic receptors. Both SS-14 and the synthetic somatostatin analog SMS 201-995 (SMS; Sandostatin®) inhibited IRI secretion stimulated by 8.9 mM glucose, 2.0 nM GIP, or 1;.0 µM ACh, but not 17.8 mM glucose. The most potent inhibition by both SS-14 and SMS was observed in the presence of the weakest IRI stimuli (8.9 mM glucose and 1.0 µM ACh). These results suggested that the inhibitory effects of somatostatin on the B-cell could be overcome by the presence of strong stimuli. In addition, the inhibitory effects of the native hormone and the analog were found to be approximately equipotent (weight basis), indicating that the increased potency of SMS previously observed in vivo was due to its longer half-life in plasma, and not due to a more potent direct effect on the B-cell.

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