The direct effect of lithium administration on plasma glucose levels and glucose-induced insulin release, and the role of opioid and amine systems in these effects were examined in rats. Naloxone, an opiate antagonist, and dihydroergotamine, an alpha-adrenergic blocking agent, reversed the hyperglycaemia as well as the inhibition of glucose-stimulated insulin release induced by lithium. In adrenalectomized rats, administration of lithium induced hypoglycaemia and not hyperglycaemia as in the intact rats. The results suggest that the interaction of secreted endorphins with the sympathetic nervous system is the likely cause of the hyperglycaemia and the inhibition of the glucose-stimulated insulin release induced by lithium.

The cytological changes observed in the A and D cells of rabbit endocrine pancreas incubated in a medium containing 0.6 mg/ml or 3 mg/ml of glucose are described. These cells showed no changes in their fine structure nor any signs of degranulation. When the A cells were incubated in a medium without glucose, they released A granules and synthesized new hormone. The way in whichA granules are eliminated is compared to that following insulinic hypoglycemia in the animal in vivo. In both cases, the mechanism of secretion involves margination, emiocytosis of the entire granule, and formation of microvilli, in contrast to previously reported observations (9). The D cells showed no alteration of their fine structure after incubation with different concentrations of glucose in the medium. Only very rarely could we observe morphological changes which were suggestive of emiocytosis of the entire D granule.

Lithium exerts an inhibitory effect on glucose-induced insulin release. Lithium (5 mmol/l) added 30 min prior to glucose stimulation or together with glucose (16.7 mmol/l) failed to affect first phase, but reduced second phase glucose-induced insulin release by 35%. Similar results were obtained when islets isolated from rats following long-term oral lithium treatment were perifused with glucose (16.7 mmol/l). The inhibitory effect of lithium was counteracted by pretreatment of the rats with the alpha-adrenergic blocking agent dihydroergotamine, whereas the opiate antagonist naloxone had no apparent effect on lithium-induced inhibition of glucose-stimulated insulin release.

1 Pretreatment of rats with the non-selective a-adrenoceptor antagonist dihydroergotamine counteracts the inhibition of glucose-induced insulin secretion caused by lithium both in vitro and in vivo. The present study was therefore carried out to specify further which type of adrenoceptor is involved in lithiuminduced hyperglycaemia and inhibition of insulin secretion. 2 The lithium-induced effects were reversibly blocked by pretreatment of rats with the a2-adrenoceptor antagonist yohimbine or a combination of yohimbine and the non-selectivefl-receptor antagonist propranolol, whereas the a,-receptor antagonist prazosin and propranolol alone were ineffective in blocking these effects. 3 These findings suggest that the effects of lithium on plasma glucose and insulin levels are mediated mainly by the stimulation of a2-adrenoceptors.