@misc{oai:niigata-u.repo.nii.ac.jp:00006071,
 author = {本橋, 雄},
 month = {Mar},
 note = {The prevalence of diabetes, obesity and metabolic syndrome is dramatically increasing in Western and developing countries. These metabolic diseases feature the visceral fat accumulation and the insulin resistance, which cause nonalcoholic fatty liver disease (NAFLD) in the liver. Furthermore, some NAFLD patients develop nonalcoholic steatohepatitis (NASH) featuring inflammation and fibrosis, cirrhosis and finally life-threatening hepatocellular carcinoma (Greenfield et al., 2008). In the eye, diabetic macular edema (DME) is a frequent finding associated with diabetic retinopathy and is a major factor contributing to visual disabilities. Many years of diabetes can cause damage to retinal blood vessels via some cytokines and chemokines including vascular endothelial growth factor (VEGF), retinal hyper-permeability and retinal thichening (Das, 2016). Although an intravitreal injection of anti-VEGF drugs has become standard of care for DME in the past 10 years, many patients must continue treatment, and 25% of DME patients do not respond to anti-VEGF treatment. To understand the complicated mechanism of NAFLD/NASH and DME, animal models can offer a source of important information. However, there are few animal models similar to human patients. Spontaneously diabetic torii Leprfa (SDT fatty) rat, established by introducing the fa allele of the Zucker fatty rat into SDT rat genome, is a new model of obese type 2 diabetes (Masuyama et al., 2004; Shinohara et al., 2000). The animals exhibit hyperphagia that leads to obesity associated with hyperglycemia, hyperinsulinemia, and hyperlipidemia at a young age compared with SDT rats. In the present study, we investigated whether SDT fatty rats had the biochemical parameters, and genetical and histological features as the NASH/NAFLD and DME models., [NASH/NAFLD] The female SDT fatty rats showed significantly increased body weight, serum glucose, triglyceride (TG), and total cholesterol (TC) levels compared with SD rats. The serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels in SDT fatty rats were significantly elevated at 8 weeks of age. Hepatic TG and free fatty acid contents were marked in SDT fatty rats from 8 to 32 weeks of age. The expression of lipogenic genes, such as sterol regulatory element binding protein (SREBP)-1c, fatty acid synthesis (FAS), and acetyl-CoA carboxylase (ACC) increased in SDT fatty rats at 8 weeks of age. The microsomal triglyceride transfer protein (MTP) mRNA levels, which were related to secretion of very low-density lipoprotein (VLDL), were decreased from 8 to 40 weeks of age. The mRNA levels of fibrotic genes, namely collagen type 1 and α-smooth muscle actin (SMA), tended to increase in SDT fatty rats compared with SD rats at 16 and 24 weeks of age. The liver histopathology was examined by Hematoxylin and eosin (HE) staining. Severe changes (3+) of the liver, including fatty and vacuolar changes, were observed in SDT fatty rats at 8 weeks of age. Moderate changes (1+-2+) of hypertrophy and very slight or slight changes in inflammation were also observed at 8 weeks of age. Moreover, moderate changes (2+) indicating fibrosis were observed at 32 weeks of age. Fibrosis was also confirmed by Sirius Red staining. Consistent with the HE staining, similar findings of fibrosis were observed in SDT fatty rats and no changes were observed in SD rats. Furthermore, ED1 and toluidin blue (TB) staining indicated increased macrophage and mast cell counts. Thus, blood parameters, gene analysis and histopathological analysis demonstrated the female SDT fatty rats were novel NAFLD/NASH animal models. We investigated pharamacological effects of fenofibrate on glucose and lipid metabolism in female SDT fatty rats. SDT fatty rats were given a regular powder diet or diets containing fenofibrate (30, 100 mg/kg) for 6 weeks, from 6 to 12 weeks of age. Fenofibrate treatment significantly reduced a blood glucose level at a dose of 100 mg/kg and tended to decrease hemoglobin A1c levels dose-dependently. Fenofibrate did not affect blood lipid levels, but blood ALT and AST concentrations decreased. Lipid contents in liver in fenofibrate treated group were significantly reduced and fenofibrate also ameliorated fatty liver in SDT fatty rats. To determine whether pioglitazone had the therapeutic effect on the female SDT fatty rats, the drug was given at 3, 10 mg/kg for 16 weeks, from 16 to 32 weeks of age. Although blood TG levels were decreased from 20 weeks of age, blood glucose and insulin levels did not improve. Pathological examination demonstrated pioglitazone could not improve fat accumulation in liver followed by inflammation and fibrosis., [DME] The male SDT fatty rats are known as severe diabetes animal models. In this study, the SDT fatty rats exhibited hyperglycemia, VEGF increase in vitreous humor, retinal vascular hyper-permeability and retinal thickening at 16 weeks of age. In particular, the layers between the retinal internal limiting membrane and the outer nuclear layer were thickened. These results imply the breakdown of the blood-retinal-barrier, which may be associated with the peak latencies of oscillatory potentials in electroretinograms (ERGs) at 16 weeks (Matsui et al., 2008). We evaluated the effects of phlorizin and pioglitazone known as glucose-lowering drugs on retinal lesions. Phlorizin treatment from 4 to 16 weeks of age improved hyperglycemia and normalized retinal thickness; however, the effect of pioglitazone on retinal thickness was not strong despite the normalization of hyperglycemia. Because edema, which is likely caused by renal sodium retention, is well recognized as a side effect of pioglitazone (Horita et al., 2015), the phenomenon that pioglitazone could not normalize the retinal thickness of SDT fatty rats despite plasma glucose normalization may have been derived from the deterioration of retinal edema similar to human DME patients. In summary, we confirmed that the female SDT fatty rats are suitable preclinical models for testing new therapeutic approaches in NASH/NAFLD and the male SDT fatty rats in DME., 学位の種類: 博士（農学）. 報告番号: 甲第4478号. 学位記番号: 新大院博（農）甲第181号. 学位授与年月日: 平成30年3月23日, 新大院博（農）甲第181号},
 title = {肥満2型糖尿病モデルSDT fattyラットを用いた非アルコール性脂肪肝炎および糖尿病黄斑浮腫に関する解析},
 year = {2018}
}