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

1 Previous studies have shown that vitamin D, deficiency impairs the insulin response to glucose via an alteration of signal transduction pathways, such as Ca2+ 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. 2 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. 3 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. 4 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. 5 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 Ca2+-calmodulin-independent PDE was predominant in islets from vitamin D-3 deficient rats. 6 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. 7 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.