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 i nsulin response to glucose via an alteration of signal transduction pa thways, such as Ca2+ handling and the phosphoinositide pathway. In the present study the adenylyl cyclase pathway was examined in islets fro m 3 independent groups: normal rats, 4 weeks-vitamin D-3 deficient rat s 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 vit amin D-3 deficient rats could be restored in vitamin D-3 deficient isl ets 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(O H)(2)D-3 observed with or without DO-cyclic AMP was protein kinase A-d ependent, since the addition of omocinnamylamino)ethyl]-5-isoquinoline sulphonamide (H-89), a specific inhibitor of cyclic AMP-dependent prot ein kinases, decreased the insulin release of treated rats back to the level seen in vitamin D-3, deficient islets. 4 The low rate of insuli n 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 pa radoxically associated with a supranormal cyclic AMP content in the is lets. 5 This paradoxical increase in cyclic AMP observed in these cond itions could not be attributed to a lower total phosphodiesterase (PDE ) activity, although the portion of Ca2+-calmodulin-independent PDE wa s predominant in islets from vitamin D-3 deficient rats. 6 On the othe r hand, the higher cyclic AMP content of vitamin D-3 deficient islets could be related to an increase in glucagon-induced cyclic AMP synthes is in relation to the hyperglucagonaemia previously observed in vitami n D-3 deficient rats. Since higher concentrations of exogenous glucago n and higher endogenous cyclic AMP concentrations were required in vit ro to restore insulin release to normal values, the cyclic AMP-depende nt pathways that usually potentiate insulin secretion appeared to be l ess efficient in relation to an alteration in the post cyclic AMP effe ctor system. 7 1,25(OH)(2)D-3 exerted a stimulating effect on insulin release via protein kinase A activation but reduced the supranormal cy clic AMP synthesis, thus exerting a differential modulatory influence on biochemical disturbances in islets induced by vitamin D-3 deficienc y.