Interleukin 1 beta induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases.
Substantial in vitro evidence suggests that nitric oxide may be a major mediator of interleukin 1 (IL-1) induced pancreatic beta-cell inhibition and destruction in the initial events leading to insulin-dependent diabetes mellitus. Using NG-nitro-L-arginine methyl ester, an inhibitor of both the constitutive and the cytokine inducible forms of nitric oxide synthase, and aminoguanidine, a preferential inhibitor of the inducible form of nitric oxide synthase, we investigated the impact of inhibiting nitric oxide production on food-intake, body weight and temperature, blood glucose, plasma insulin, glucagon, corticosterone and leukocyte- and differential-counts in normal rats injected once daily for 5 days with interleukin 1 beta (IL-1 beta) (0.8 microgram/rat = 4.0 micrograms/kg). Inhibition of both the constitutive and the inducible forms of nitric oxide synthase prevented IL-1 beta-induced fever, hyperglycaemia, hypoinsulinemia, and hyperglucagonemia, and partially prevented lymphopenia and neutrophilia, but had no effect on IL-1 beta-induced anorexia and changes in plasma corticosterone. Preferential inhibition of the inducible form of nitric oxide synthase using two daily injections of 5 mg/rat of aminoguanidine prevented IL-1 beta-induced hyperglycaemia and hypoinsulinaemia, and slightly reduced the pyrogenicity of IL-1 on 3 out of 5 days. Higher doses of aminoguanidine (100 mg/rat) prevented lymphopenia and neutrophilia. We conclude that nitric oxide produced by the inducible form of nitric oxide synthase, mediates the IL-1 beta-induced inhibition of insulin release and that the effect of IL-1 beta on temperature, pancreatic alpha-cells, and leukocyte differential counts seems to be mediated by nitric oxide produced by the constitutive form of nitric oxide synthase.
Reimers
J I
JI
Steno Diabetes Center, Gentofte, Denmark.
Bjerre
U
U
Mandrup-Poulsen
T
T
Nerup
J
J
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects / Q000276:immunology; D003345:Corticosterone / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced* / Q000201:enzymology; D005934:Glucagon / Q000097:blood; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000097:blood; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D051381:Rats; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects / Q000276:immunology
D001786:Blood Glucose; D006146:Guanidines; D007328:Insulin; D007375:Interleukin-1; D007527:Isoenzymes; D011994:Recombinant Proteins; D009569:Nitric Oxide; D005934:Glucagon; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D003345:Corticosterone