Research Article| Volume 54, ISSUE 5, P619-627, May 2005

Synthetic protease inhibitor camostat prevents and reverses dyslipidemia, insulin secretory defects, and histological abnormalities of the pancreas in genetically obese and diabetic rats



      Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes, lacks the expression of cholecystokinin-1 receptor mRNA and exhibits inflammation and degeneration of the pancreas and eventually develops insulinopenic diabetes. Protease inhibitors are known to modulate inflammatory response and fibrosis as well as inhibit proteases activity.


      To examine the effects of long-term treatment with camostat, a synthetic protease inhibitor, on metabolic and histopathological changes in the islets of OLETF rats.


      OLETF rats were fed either camostat-containing food (200 mg/100 g) from 12 or 28 weeks of age to 72 weeks of age, or fed standard rat diet.


      Camostat-fed rats gained less weight or lost weight, although they consumed more food than the control rat when food intake was adjusted for body weight. Camostat reduced visceral adipose depots and fasting serum concentrations of triglyceride, free fatty acids, cholesterol, glucose, and insulin. Pancreatic insulin content in camostat-treated rats was significantly higher than in control rats. Immunohistochemistry revealed marked suppression of expressions of tumor necrosis factor α, interleukin 1β, interleukin 6, and α-smooth muscle actin in the islets of camostat-treated rats, compared with control rats. Histologically, disruption of the islets and pancreatic fibrosis were noted in control rats but not in camostat-fed rats.


      Our findings suggest that camostat prevents and reverses obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia and markedly inhibits inflammation, fibrosis, and disruption of the islets in the genetically obese diabetic OLETF rats.
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