Effect of long‐ and short‐term treatments with pravastatin on diabetes mellitus and pancreatic fibrosis in the Otsuka–Long–Evans–Tokushima Fatty rat

Background and purpose: The effects of statins on diabetes mellitus (DM) are controversial, and their effects on pancreatic fibrosis are poorly defined. We investigated the effect of long‐ and short‐term treatments with pravastatin on the development of DM and pancreatic fibrosis in DM‐prone Otsuka–Long–Evans–Tokushima Fatty (OLETF) rats. Experimental approach: Male OLETF rats were divided into four groups at 12 weeks of age. The first group received a standard rat diet until the end of the experimental period at age 80 weeks. The second group was given a diet containing 0.05% pravastatin from 12 weeks of age, before the onset of DM and pancreatic fibrosis, and the third group was given the same pravastatin diet from 28 weeks of age, after the onset of DM and pancreatic fibrosis, until age 80 weeks. The fourth group received the same pravastatin diet only for 16 weeks, from 12 to 28 weeks of age, and switched to a standard diet. Progressions of DM and pancreatic fibrosis were evaluated. Key results: Long‐term treatments with pravastatin, either from 12 or 28 weeks of age, decreased serum glucose concentration and fibrotic area, elevated superoxide dismutase activity and down‐regulated transforming growth factor‐β1 mRNA in the pancreas. In contrast, after a short‐term treatment with pravastatin, these parameters markedly deteriorated after its cessation. Conclusions and implications: The results suggest that long‐term treatment with pravastatin improves DM and pancreatic fibrosis via anti‐oxidative and anti‐fibrotic properties, whereas cessation of pravastatin abolishes these beneficial effects, and accelerates DM and pancreatic fibrosis.