Neural control of pancreatic polypeptide (PP) release has not been previously investigated in the mouse. In addition, it is not known to what extent increased glucagon secretion during hypoglycemia in mice is neurally mediated vs. an effect of hypoglycemia to directly stimulate glucagon secretion at the level of the islet. Feeding or the cholinergic agonist carbachol increased plasma PP levels in conscious mice (+74 +/- 18 pg/ml vs. fasted mice and +141 +/- 17 pg/ml vs. control, respectively). Neuroglucopenia induced by 2-deoxy-D-glucose or insulin-induced hypoglycemia also increased plasma PP (+79 +/- 18 and +89 +/- 11 pg/ml vs. control, respectively). These increases were abolished by hexamethonium and reduced by atropine methylnitrate (atropine). Hypoglycemia-induced hyperglucagonemia (+1,243 +/- 275 pg/ml) was reduced to 31 +/- 7% of control by atropine (+382 +/- 85 pg/ml), to 48 +/- 9% of control by combined adrenergic blockade (+601 +/- 112 pg/ml), and nearly abolished by atropine plus combined blockade (+143 +/- 41 pg/ml; 11 +/- 3% of control) or hexamethonium (+151 +/- 38 pg/ml; 12 +/- 3% of control). We conclude the following in the mouse. 1) Feeding or cholinergic agonists increase plasma PP. 2) During neuroglucopenia or hypoglycemia, plasma PP is increased via nicotinic and muscarinic mechanisms. 3) The glucagon response to hypoglycemia is predominantly the result of autonomic activation and is mediated by both muscarinic and adrenergic mechanisms.
Both the parasympathetic and sympathoadrenal inputs to the pancreas can stimulate glucagon release and are activated during hypoglycemia. However, blockade of only one branch of the autonomic nervous system may not reduce hypoglycemia-induced glucagon secretion, because the unblocked neural input is sufficient to mediate the glucagon response, ie, the neural inputs are redundant. Therefore, to determine if parasympathetic and sympathoadrenal activation redundantly mediate increased glucagon secretion during hypoglycemia, insulin was administered to conscious rats pretreated with a muscarinic antagonist (methylatropine, n = 7), combined alpha- and beta-adrenergic receptor blockade (tolazoline + propranolol, n = 5) or adrenergic blockade + methylatropine (n = 7). Insulin administration produced similar hypoglycemia in control and antagonist-treated rats (25 to 32 mg/dL). In control rats (n = 9), plasma immunoreactive glucagon (IRG) increased from a baseline level of 125 +/- 11 to 1,102 +/- 102 pg/mL during hypoglycemia (delta IRG = +977 +/- 98 pg/mL, P < .0005). The plasma IRG response was not significantly altered either by methylatropine (delta IRG = +677 +/- 141 pg/mL) or by adrenergic blockade (delta IRG = +1,374 +/- 314 pg/mL). However, the IRG response to hypoglycemia was reduced to 25% of the control value by the combination of adrenergic blockade + methylatropine (delta IRG = +250 +/- 83 pg/mL, P < .01 v control rats). These results suggest that the plasma glucagon response to hypoglycemia in conscious rats is predominantly the result of autonomic neural activation, and is redundantly mediated by the parasympathetic and sympathoadrenal divisions of the autonomic nervous system.
The secretion of both glucagon and insulin by the isolated perfused rat pancreas was significantly stimulated by 10−7 M PGH2. Experiments to show that the stimulated secretion was mediated by conversion of PGH2 to TXA2 or TXB2 revealed no correlation between the amount of secretion and the amount of thromboxane formed. Conversion of PGH2 with a crude platelet thromboxane synthase preparation caused a progressive loss of ability to secrete insulin, whereas the capacity to stimulate release of glucagon remained at about one-half the maximal level. This relatively stable and selective secretogogue action on the α-cells appeared to be due to the formation of PGD2 by the platelet preparation. Direct administration of PGD2 confirmed this interpretation and showed clearly that this prostaglandin is a potent secretagogue for glucagon with little activity in stimulating the release of insulin. Our results have shown high and relatively equal stimulation of secretion by α- and β-cells with exogenous PGE2, PGF2α, and PGH2, little or no secretion by either cell type with TXA2, TXB2, or PGI2, and a unique selective stimulatory action of PGD2 upon the α-cell.
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