The combined inducible nitric oxide synthase inhibitor and free radical scavenger guanidinoethyldisulfide prevents multiple low-dose streptozotocin-induced diabetes in vivo and interleukin-1beta-induced suppression of islet insulin secretion in vitro.
Inhibition of inducible nitric oxide synthase has been shown to be antiinflammatory in a variety of disease states. Type I diabetes is an autoimmune disease resulting from the specific destruction of the insulin-producing pancreatic beta cells. Here we demonstrate that guanidinoethyldisulfide (GED), a combined inducible nitric oxide synthase inhibitor and peroxynitrite/reactive oxygen species scavenger reduces the hyperglycemia and incidence of type I diabetes induced in mice by multiple low-dose streptozotocin treatment. GED treatment (10 and 30 mg/kg/d) protected against the decrease in pancreatic insulin content as well as completely attenuating the increased pancreatic oxidative stress as determined by tissue levels of malondialdehyde. GED treatment also decreased neutrophil infiltration into the pancreas and reduced pancreatic levels of the chemokine MIP-1alpha and the proinflammatory cytokines IL-1 and IL-12. We hypothesize that GED exerts these latter effects by protecting beta cells from destruction reducing autoantigen release and decreasing the autoimmune response. In vitro GED treatment of isolated rat islets of Langerhans protected glucose-stimulated insulin secretion from inhibition by IL-1beta. In conclusion, inhibiting formation and/or scavenging reactive nitrogen or oxygen species with GED protects against development of diabetes in vivo and isolated pancreatic islets of Langerhans from cytokine inhibitory effects in vitro.
Mabley
Jon G
JG
Inotek Pharmaceuticals Corp., Beverly, Massachusetts, USA.
Southan
Gary J
GJ
Salzman
Andrew L
AL
Szabó
Csaba
C
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D013311:Streptozocin / Q000008:administration & dosage
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D007328:Insulin; D007375:Interleukin-1; C014363:bis(2-guanidinoethyl)disulfide; 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