Role of adrenoceptors in vitro and in vivo in the effects of lithium on blood glucose levels and insulin secretion in the rat.

1. Pretreatment of rats with the non-selective alpha-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 lithium-induced hyperglycaemia and inhibition of insulin secretion. 2. The lithium-induced effects were reversibly blocked by pretreatment of rats with the alpha 2-adrenoceptor antagonist yohimbine or a combination of yohimbine and the non-selective beta-receptor antagonist propranolol, whereas the alpha 1-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 alpha 2-adrenoceptors.

Dihydroergotamine, but not naloxone, counteracts lithium as an inhibitor of glucose-induced insulin release in isolated rat islets in vitro.

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.

Blocking effect of naloxone, dihydroergotamine and adrenalectomy in lithium-induced hyperglycaemia and glucose intolerance in the rat.

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.

Incorporation of (U-14C)-glucose into glycogen in normal rat pancreatic islets.

The incorporation of glucose into glycogen was determined in pancreatic islets isolated from normal rats and incubated with glucose (5 or 20 mM) and compounds known to affect glycogen metabolism in other tissues. Incubation of pancreatic islets with glucose (20 mM) induced a marked increase in radioactive glycogen. Exposure to epinephrine in the presence of glucose (20 mM) slightly increased incorporation of glucose into glycogen. In contrast the incorporation of glucose into glycogen was not affected when isolated islets were exposed to glucagon or insulin, whereas anti-insulin serum in the incubation medium decreased radioactive glycogen formation.

"Big big" gastrin release by the isolated islets of Langerhans incubated in vitro.

The immunoreactive form of gastrin released by the islets and some of the characteristics of this release have been studied. This gastrin released by the islets in the present experiments corresponds to what has been named "Big Big" gastrin in serum of patients with the Zollinger-Ellison syndrome, in normal human serum and in extracts of proximal jejunum. Most of the "Big Big" gastrin released from the islets corresponds to spontaneous release.

Insulin components released by the normal and subtotal degranulated perifused islets of Langerhans of the rat.

The insulin components released from normal and tolbutamide treated islets of the rat were studied in a perifusion system. The treated islets showed diminished quantities of insulin secreted as compared to the controls and an increase in the proportions of "big insulin" secreted during the second phase of this release. On the other hand, the main component of insulin released during the first phase was "little insulin". These studies confirm that the subtotally degranulated islets are less efficient than the controls in producing insulin release.

Fine structure of the A and D cells of the rabbit endocrine pancreas in vivo and incubated in vitro. I. Mechanism of secretion of the A cells.

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 which A 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.