Probucol preserves pancreatic β-cell function through reduction of oxidative stress in type 2 diabetes

Abstract 

Oxidative stress is induced under diabetic conditions and causes various forms of tissue damage in patients with diabetes. Recently, pancreatic β-cells have emerged as a putative target of oxidative stress-induced tissue damage and this seems to explain in part the progressive deterioration of β-cell function in type 2 diabetes. As a step toward clinical trial of antioxidant for type 2 diabetes, we investigated the possible anti-diabetic effects of probucol, an antioxidant widely used as an anti-hyperlipidemic agent, on preservation of β-cell function in diabetic C57BL/KsJ-db/db mice. Probucol-containing diet was given to mice from 6 to 16 weeks of age. Immunostaining for oxidative stress markers such as 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1 revealed that probucol treatment decreased reactive oxygen species (ROS) in pancreatic islets of diabetic animals. Oxidative stress is known to enhance apoptosis of β-cells and to suppress insulin biosynthesis, but probucol treatment led to preservation of β-cell mass and the insulin content. According to intraperitoneal glucose tolerance tests, the probucol treatment preserved glucose-stimulated insulin secretion and improved glucose tolerance at 10 and 16 weeks: insulin, 280±82 vs. 914±238 pmol/l (120 min, at 16 weeks; P<0.05); glucose, 44.6±2.4 vs. 35.2±2.6 mmol/l (120 min, at 16 weeks; P<0.05). Thus, our present observations demonstrate the potential usefulness of probucol for treatment of type 2 diabetes.

Keywords:  Probucol, Glucose toxicity, Glucotoxicity, Oxidative stress, Antioxidant