Modulatory role of 1,25 dihydroxyvitamin D 3 on pancreatic islet insulin release via the cyclic AMP pathway in the rat

Previous studies have shown that vitamin D 3 deficiency impairs the insulin response to glucose via an alteration of signal transduction pathways, such as Ca 2+ handling and the phosphoinositide pathway. In the present study the adenylyl cyclase pathway was examined in islets from 3 independent groups: normal rats, 4 weeks‐vitamin D 3 deficient rats and one week‐1,25 dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) treated rats. We found that the very low rate of insulin release observed in vitamin D 3 deficient rats could be restored in vitamin D 3 deficient islets only with high concentrations of dioctanoyl‐cyclic AMP (DO‐cyclic AMP), whereas 1,25(OH) 2 D 3 improved the sensitivity of the islets to this exogenous cyclic AMP analogue. The beneficial effect of 1,25(OH) 2 D 3 observed with or without DO‐cyclic AMP was protein kinase A‐dependent, since the addition of N‐[2‐(p‐bromocinnamylamino) ethyl]‐5‐isoquinolinesulphonamide (H‐89), a specific inhibitor of cyclic AMP‐dependent protein kinases, decreased the insulin release of treated rats back to the level seen in vitamin D 3 deficient islets. The low rate of insulin release could not be consistently related to an alteration in cyclic AMP content of the islets. Indeed, low insulin response to a barium + theophylline stimulus observed in vitamin D 3 deficient islets was paradoxically associated with a supranormal cyclic AMP content in the islets. This paradoxical increase in cyclic AMP observed in these conditions could not be attributed to a lower total phosphodiesterase (PDE) activity, although the portion of Ca 2+ ‐calmodulin‐independent PDE was predominant in islets from vitamin D 3 deficient rats. On the other hand, the higher cyclic AMP content of vitamin D 3 deficient islets could be related to an increase in glucagon‐induced cyclic AMP synthesis in relation to the hyperglucagonaemia previously observed in vitamin D 3 deficient rats. Since higher concentrations of exogenous glucagon and higher endogenous cyclic AMP concentrations were required in vitro to restore insulin release to normal values, the cyclic AMP‐dependent pathways that usually potentiate insulin secretion appeared to be less efficient in relation to an alteration in the post cyclic AMP effector system. 1,25(OH) 2 D 3 exerted a stimulating effect on insulin release via protein kinase A activation but reduced the supranormal cyclic AMP synthesis, thus exerting a differential modulatory influence on biochemical disturbances in islets induced by vitamin D 3 deficiency.British Journal of Pharmacology (1997) 121 , 751–758; doi: 10.1038/sj.bjp.0701204