SELECTIVE MUSCARINIC SENSITIVITY IN PERFUSED PANCREASES OF OBESE ZUCKER RATS

Insulin secretion was evaluated in response to the muscarinic agonist, bethanechol, and to the antagonist, atropine, in three-month-old fema le homozygous lean (Fa/Fa) and obese (fa/fa) Zucker rats, using an in vitro pancreas perfusion. Three doses of bethanechol were used (0.5, 5 or 50 muM). Bethanechol at 50 muM concentration had a significant pot entiating effect on glucose-induced insulin secretion in pancreata fro m both lean and obese rats. There was no effect of atropine (25 muM) o n insulin secretion in pancreata from either lean or obese rats. In an other study, the perfusate used contained glucose at 75, 125 or 200 mg /dl for the entire 60 min period. Perfusate, with or without bethanech ol (50 muM), was infused from 21-40 min, using a side-arm syringe. In general, bethanechol significantly increased insulin secretory rates i n both lean and obese rats. Since the pancreas of obese rats secretes more insulin to the same glucose concentration than the pancreas of le an rats, we compared changes in insulin release due to bethanechol in obese and lean rats having comparable basal insulin secretory rates du ring the 11-20 min period. To produce comparable insulin secretion, gl ucose levels in the perfusate were kept lower in the obese group (75 m g/dl). In the comparably secreting lean group, a glucose level of 200 mg/dl was required. We also compared changes in insulin secretory rate due to bethanechol stimulation between groups with comparable insulin secretory rates during the 21-40 min period in the control groups, i. e. 75 mg/dl glucose in the obese group vs. 125 mg/dl glucose in the le an group. In either experimental comparison, pancreata from obese rats showed greater changes in insulin secretory rates due to bethanechol than the pancreata from lean rats. The data reveal that there is no in trinsic cholinergic hyperactivity in the pancreata of obese rats. Howe ver, when the pancreas is stimulated to secrete insulin at similar rel ease rates, muscarinic receptor modulation in the pancreata from obese rats is hypersensitive to bethanechol. We speculate that this could p lay a role in the establishment of hyperinsulinemia in obese Zucker ra ts.