Melatonin protects against streptozotocin, but not interleukin-1beta-induced damage of rodent pancreatic beta-cells.
In the present study, we examined whether melatonin can protect rodent pancreatic islets against streptozotocin (STZ) and interleukin-1beta (IL-1beta)-induced suppression of beta-cell function. Formation of free radicals, DNA damage and extensive DNA repair leading to depletion of intracellular nicotinamide adenine dinucleotide (NAD) may mediate STZ toxicity. Activation of inducible nitric oxide synthase and nitric oxide (NO) formation may cause IL-1beta -induced beta-cell impairment. We also studied the effect of melatonin against STZ-induced hyperglycemia in C57BL/Ks mice. For in vitro studies, cultured rat islets were exposed to melatonin (100 microM-1 mM) 30 min prior to STZ (0.5 mM) or IL-1beta (25 U/mL) addition. After an additional 30 min incubation with STZ, islet function and NAD content were analyzed either acutely or after 18 hr of recovery in fresh culture medium. For IL-1beta experiments, islets were incubated for 48 hr with the cytokine before evaluation of islet function. We found that melatonin counteracted STZ-induced inhibition of glucose metabolism and insulin release in cultured rat islets after 18 hr of recovery. Moreover, NAD levels were higher in the melatonin-treated group at this time point. Melatonin had no effect on IL-1beta-induced islet inhibition of glucose oxidation or NO formation. Diabetes induced by STZ (140 mg/kg body weight; i.v.) was effectively prevented by administration of melatonin (100 mg/kg body weight; i.p.) 30 min before STZ injection. We conclude that the protective effects of melatonin against beta-cell damage may be related to interference with DNA damage and poly(ADP-ribose) polymerase (PARP) activation rather than through effects on NO generation pathways.
Andersson
A K
AK
Department of Medical Cell Biology, Uppsala University, Sweden. annika.andersson@medcellbiol.uu.se
Sandler
S
S
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000517:prevention & control*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D007328:Insulin / Q000378:metabolism; D007375:Interleukin-1 / Q000633:toxicity*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000633:toxicity
D016166:Free Radical Scavengers; D007328:Insulin; D007375:Interleukin-1; D009243:NAD; D009569:Nitric Oxide; D013311:Streptozocin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D011065:Poly(ADP-ribose) Polymerases; D005947:Glucose; D008550:Melatonin