Effect of long- and short-term treatments with pravastatin on diabetes mellitus and pancreatic fibrosis in the Otsuka-Long-Evans-Tokushima fatty rat.
OBJECTIVE
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.


METHODS
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.


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-beta1 mRNA in the pancreas. In contrast, after a short-term treatment with pravastatin, these parameters markedly deteriorated after its cessation.


CONCLUSIONS
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.
Otani
M
M
Department of Gastroenterology and Metabolism, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Yamamoto
M
M
Harada
M
M
Otsuki
M
M
D052436:Adipose Tissue, White / Q000187:drug effects / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005355:Fibrosis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D017035:Pravastatin / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D009195:Peroxidase; D013482:Superoxide Dismutase; D017035:Pravastatin