Spatial distribution and temporal onset of NF-kB activation and inducible nitric oxide synthase within pancreatic islets in the pre-diabetic stage of genetic, diabetic-prone BB rats: attenuation by drug intervention decreases inflammatory cell infiltration and incidence of diabetes.
OBJECTIVE
To document in vivo immunolocalization and activation of nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) expression in prediabetic stages of diabetes mellitus.


METHODS
Genetic, diabetic-prone or diabetic-resistant BB rats (total = 189).


METHODS
Various doses of an oral dithiocarbamate derivative, NOX-700, or cyclosporine (2.5 mg/kg) starting at 30 or 60 days of age.


METHODS
Immunohistochemistry, electrophoretic mobility shift assays, plasma glucose.


RESULTS
NF-kappaB and iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not normoglycemic, diabetic-resistant rats. Immunostaining for NF-kappaB and iNOS was largely confined to islets and occurred in diabetic-prone rats prior to overt hyperglycemia. NOX-700 decreased cell infiltration, delayed the onset of disease and decreased the incidence of hyperglycemia to levels achieved by immunosuppressant therapy. NOX-700 also decreased the intensity of immunoreactive NF-kappaB and iNOS within pancreatic islets.


CONCLUSIONS
These studies support a role of NF-kB and iNOS in diabetogenesis in vivo.
Pieper
C M
CM
Division of Transplant Surgery, Medical College of Wisconsin, Froedtert Memorial Hospital, West Wisconsin Avenue, Milwaukee, WI 53226, USA. gmpieper@mcw.edu
Roza
A M
AM
Henderson
J D
JD
Zhu
Y-R
YR
Lai
C-S
CS
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism* / Q000517:prevention & control; D004334:Drug Administration Schedule; D004586:Electrophoresis; D020022:Genetic Predisposition to Disease; D006943:Hyperglycemia / Q000473:pathology; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D011236:Prediabetic State / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011913:Rats, Inbred BB; D013859:Thiocarbamates / Q000008:administration & dosage; D013997:Time Factors; D014018:Tissue Distribution
D016328:NF-kappa B; C488980:NOX 700; D013859:Thiocarbamates; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat