title: Long-term effects of nicotinamide-induced inhibition of poly(adenosine diphosphate-ribose) polymerase activity in rat pancreatic islets exposed to interleukin-1 beta.
abstract: Nicotinamide (NIC) is presently extensively studied as a potential agent that might prevent the development of insulin-dependent diabetes mellitus. This study aimed to examine the consequence of exposing isolated rat pancreatic islets to various concentrations of NIC (0, 0.5, 1.0, 5.0, 10, and 25 mM) over a prolonged period (6 days) in tissue culture and also to assess the efficacy of NIC to counteract interleukin-1 beta (IL-1; 25 U/ml)-induced beta-cell dysfunction. Except for a 30-40% increase at 5.0 mM NIC, the insulin content of islets was not affected by NIC. Also, the islet DNA content remained essentially unchanged. The insulin accumulation in the culture medium declined at 5-25 mM NIC between days 4-6. The insulin release in response to 16.7 mM glucose on day 6 was enhanced after culture with the addition of 0.5 mM NIC, but 25 mM NIC caused a strong inhibition of insulin secretion. However, neither the (pro)insulin nor the total protein biosynthesis rate of the islets was affected by NIC. A significant inhibition of the islet poly(ADP-ribose) polymerase activity by 40-80% was observed at 5-25 mM NIC. IL-1 was then tested together with 1.0 and 10 mM NIC. The islet DNA content was markedly reduced in all groups treated with IL-1, as was the medium insulin accumulation. Moreover, NIC failed to prevent IL-1 induced impairment of islet insulin release on day 6. The cytokine induced a very pronounced and sustained increase in the medium nitrite accumulation, and NIC could not influence this elevation. Thus, these data show that prolonged exposure to elevated NIC levels impaired the function of rat beta-cells, and NIC failed to counteract IL-1 actions. Whether these events are mimicked in the ongoing clinical trials with NIC remain to be established.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Reddy
authors.forename: N
authors.initials: N
authors.lastname: Salari-Lak
authors.forename: S
authors.initials: S
authors.lastname: Sandler
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009536:Niacinamide / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D007328:Insulin; D007375:Interleukin-1; D010716:Phosphatidylinositols; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D004247:DNA; D005947:Glucose