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

Abstract

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 H 2 O 2 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.

The Role of Bilirubin in Diabetes, Metabolic Syndrome, and Cardiovascular Diseases

“…Markers of diabetes, such as fasting blood glucose and HbA1c levels were much less pronounced in Gunn rats; on the other hand, insulin secretion by the pancreatic islets was preserved in hyperbilirubinemic animals. In addition, concentrations as low as 1.7 μmol/L bilirubin prevented streptozocin-induced apoptosis in rat insulinoma cell culture; significantly supporting the in vivo data (Fu et al, 2010). …”

“…Additionally, expression of NADPH oxidase was markedly attenuated in the kidneys of diabetic Gunn rats, who also exhibited complete inhibition of mesangial expansion when compared to normobilirubinemic diabetic controls (Fujii et al, 2010). Consistent with this data, Korean researchers reported substantial resistance of hyperbilirubinemic Gunn rats to developing diabetes after intraperitoneal exposure to streptozocin, compared to their normobilirubinemic littermates (Fu et al, 2010). Markers of diabetes, such as fasting blood glucose and HbA1c levels were much less pronounced in Gunn rats; on the other hand, insulin secretion by the pancreatic islets was preserved in hyperbilirubinemic animals.…”

Endothelial Cells Derived from the Blood-Brain Barrier and Islets of Langerhans Differ in their Response to the Effects of Bilirubin on Oxidative Stress Under Hyperglycemic Conditions

“…These disparate responses suggest that hyperglycemia might compromise the function of the BBB during hyperbilirubinemia, while islets of Langerhans are more resistant to hyperbilirubinemia, and thus may preserve their insulin secreting capacity in response to hyperglycemia. Interestingly, hyperbilirubinemic Gunn rats do not develop diabetes in response to streptozotocin exposure, as compared to normobilirubinemic animals (Fu et al, 2010). Moreover, insulin secretion by the pancreatic islets was preserved in these hyperbilirubinemic animals.…”

Induction of Protective Genes Leads to Islet Survival and Function

“…This protective effect of bilirubin leads to reduced β -cell destruction after transplantation, reduced macrophages infiltration, and decreased expression of MCP-1, BID, caspase-3, -8, and -9, TNF- α , iNOS, Fas, TRAIL-R, and CXCL10 in the graft after allogeneic transplantation [84]. The therapeutic potential of bilirubin is further corroborated by data reported in Gunn rats (genetically predisposed to high bilirubin levels) rendered diabetic by streptozotocin administration in which the typical hyperbilirubinemia represents a “natural” protection to oxidative stress [85]. …”