Pm. Bourlon et al., MODULATORY ROLE OF 1,25-DIHYDROXYVITAMIN-D-3 ON PANCREATIC-ISLET INSULIN RELEASE VIA THE CYCLIC-AMP PATHWAY IN THE RAT, British Journal of Pharmacology, 121(4), 1997, pp. 751-758
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.