Interrelationship of changes in islet nicotine adeninedinucleotide, insulin secretion, and cell viability induced by interleukin-1 beta.
Complete loss of pancreatic insulin function in insulin-dependent diabetes is thought to be due to an autoimmune cytokine-mediated destruction of the beta-cell. The effects of several classes of agents on interleukin-1 beta (IL-1 beta)-induced suppression of insulin secretion, beta-cell NAD levels, and beta-cell viability were examined. After overnight incubation of isolated rat islets with 15 U/ml IL-1 beta and 11 mM glucose, sequential hourly insulin secretory responses to the same glucose concentration, 22 mM glucose, and 22 mM glucose plus forskolin were severely inhibited to 10-37% of the control value. Islet NAD levels were also sharply reduced to 43% of the control value after 24-h exposure to IL-1 beta, but not after 1 or 3 h, demonstrating the same time course as that for inhibition of insulin secretion. Exposure to IL-1 beta also decreased islet cell viability measured as trypan blue exclusion. Only 1 mM N-methyl arginine, an inhibitor of nitric oxide synthase, completely protected all three parameters of beta-cell function from damage by IL-1 beta. Nicotinamide and thymidine prevented the IL-1 beta-induced loss of cell viability and suppression of NAD, but had no effect on sustaining insulin secretion. Antioxidants, steroids, and several neuropeptides also did not prevent inhibition or restore the secretory response. Thus, the loss of the secretory response appears to be more narrowly restricted to nitric oxide radical damage induced by exposure to IL-1B.
Bolaffi
J L
JL
Metabolic Research Unit, University of California, San Francisco 94143.
Rodd
G G
GG
Wang
J
J
Grodsky
G M
GM
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D004399:Dynorphins / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D008297:Male; D009243:NAD / Q000378:metabolism*; D009536:Niacinamide / Q000494:pharmacology; D019001:Nitric Oxide Synthase; D011341:Probucol / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D014810:Vitamin E / Q000494:pharmacology; D001615:beta-Endorphin / Q000494:pharmacology; D019323:omega-N-Methylarginine
D007328:Insulin; D007375:Interleukin-1; D009243:NAD; D001127:Arginine Vasopressin; D014810:Vitamin E; D005576:Colforsin; D009536:Niacinamide; D019323:omega-N-Methylarginine; D011374:Progesterone; D001615:beta-Endorphin; D004399:Dynorphins; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D005947:Glucose; D011341:Probucol; D003345:Corticosterone