Hyperbilirubinemia Reduces the Streptozotocin-Induced Pancreatic Damage through Attenuating the Oxidative Stress in the Gunn Rat

Hyperbilirubinemia Reduces the Streptozotocin-Induced Pancreatic Damage through Attenuating the Oxidative Stress in the Gunn Rat

YAN YAN FU,^1,2 KYUNG JA KANG,² JUNG MYUNG AHN,¹ HAE-RYOUNG KIM,³ KI YOUNG NA,^1,2 DONG-WAN CHAE,^1,2,4 SUHNGGWON KIM^1,2,4,5 and HO JUN CHIN^1,2,4,5

¹Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
²Department of Internal Medicine, Seoul National University Bundang Hospital, Seong-nam, Korea
³Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
⁴Renal Institute, Clinical Research Center, Seoul National University Hospital, Seoul, Korea
⁵Department of Immunology, Seoul National University Postgraduate School, Seoul, Korea

Oxidative stress is an important pathogenic factor in diabetes. Bilirubin may serve a cytoprotective function as an anti-oxidant. The Gunn rat lacks the enzyme uridine-diphosphate glucuronosyltransferase that is responsible for conjugation of bilirubin, exhibiting elevation of plasma bilirubin. We examined the effect of hyperbilirubinemia on the pancreatic damage caused by streptozotocin (STZ) in the Gunn rat. Male Wistar rats and male Gunn rats were treated with STZ (WS and GS groups, respectively) or vehicle (WC and GC groups, respectively). All 5 rats in the WS group developed diabetes, defined as fasting blood glucose 300 mg/dL or more, at 3 days, whereas only 2 of the 5 GS rats became diabetic at 7 days after STZ injection. Without insulin supplement at 7 days after STZ injection, the WS group displayed higher levels of fasting blood glucose (510.3 ± 50.3 vs. 236.4 ± 42.5 mg/dL, p = 0.003) and HbA1c (5.0 ± 0.1 vs. 3.9 ± 0.1, p = 0.001), compared to those of GS group. In Wistar rats, STZ induced apoptosis of the pancreatic islet cells, accompanied with activation of NADPH oxidase and increased production of reactive oxygen species and nitric oxide, but not in Gunn rats. Moreover, in a rat insulinoma cell line (RIN-m5F), pre-treatment with bilirubin (0.1 mg/dL) decreased cell death and apoptosis caused by STZ, and also reduced H₂O₂ production. Considering the protective effect of hyperbilirubinemia against STZ-induced injury, we postulate that bilirubin could be a potential therapeutic modality for oxidative stress of pancreas islets.

keywords —— bilirubin; streptozotocin; NADPH oxidase; reactive oxygen species; diabetes

===============================

Tohoku J. Exp. Med., 2010, 222, 265-273

Correspondence: Ho Jun Chin, M.D., Ph.D., 12303 Seoul National University Bundang Hospital, Gumidong 300 Bundang-Gu, Seong-nam, Kyeong-Ki Do, 463-707, Republic of Korea.

e-mail: mednep@snubh.org