Nonalcoholic steatohepatitis (NASH) is a current health issue since the disease often leads to hepatocellular carcinoma; however, the pathogenesis of the disease has still not been fully elucidated. In this study, we investigated the pathophysiological changes observed in hepatic lesions in STAM mice, a novel NASH model. STAM mice, high fat-diet (HFD) fed mice, and streptozotocin (STZ) treated mice were prepared, and changes over time, such as biological parameters, mRNA expression, and histopathological findings, were evaluated once animal reached 5, 7, and 10 weeks of age. STZ mice presented with hyperglycemia and an increase in oxidative stress in immunohistochemical analyses of Hexanoyl-lysine: HEL from 5 weeks, with fibrosis in the liver also being observed from 5 weeks. HFD mice presented with hyperinsulinemia from 7 weeks and the slight hepatosteatosis was observed at 5 weeks, with changes significantly increasing until 10 weeks. STAM mice at 10 weeks showed significant hepatic changes, including hepatosteatosis, hypertrophic hepatocytes, and fibrosis, indicating pathological changes associated with NASH. These results suggested that the increase in oxidative stress with hyperglycemia triggered hepatic lesions in STAM mice, and insulin resistance promoted lesion formation with hepatic lipid accumulation. STAM mice may be a useful model for elucidating the pathogenesis of NASH with diabetes.

The onset and progression of type II diabetes is closely related to environmental factors, in particular dietary habit. Moreover, the environmental exposures very early in life can influence the risk for development of type II diabetes later in life. In this study, we investigated pathophysiological changes in the pups of maternal Spontaneously Diabetic Torii (SDT) rats that were fed a high-fat diet (HFD) throughout gestation and lactation. Maternal SDT rats were continued on HFD for 5 weeks, from day 8 of gestation to day 21 after birth, and biological analyses of the pups were performed from 2 to 22 weeks of age. Results of serum lipid levels in pups from dams fed HFD were higher than pups from dams fed a standard diet, and the onset of diabetes was significantly accelerated in pups from dams fed HFD. In pathological analyses, pups from dams fed HFD showed increases in liver weight and vacuolation of hepatic cells at 2 weeks of age. In conclusion, the metabolic disorder of lipids and glucose in SDT rats is closely related to the nutritional condition of dams during the periods of gestation and lactation.

Spontaneously Diabetic Torii (SDT) fatty rats, a new obese diabetic model, reportedly presented with features of non-alcoholic steatohepatitis (NASH) after 32 weeks of age. We tried to accelerate the onset of NASH in SDT fatty rats using dietary cholesterol loading and noticed changes in the blood choline level which is expected to be a NASH biomarker. Body weight and biochemical parameters were measured from 8 to 24 weeks of age. At 16, 20, 24 weeks, pathophysiological analysis of the livers were performed. Hepatic lipids, lipid peroxides, and the expression of mRNA related to triglyceride (TG) synthesis, inflammation, and fibrosis were evaluated at 24 weeks. Hepatic fibrosis was observed in SDT fatty rats fed cholesterol-enriched diets (SDT fatty-Cho) from 16 weeks. Furthermore, hepatic lipids and lipid peroxide were significantly higher in SDT fatty-Cho than SDT fatty rats fed normal diets at 24 weeks. Hepatic mRNA expression related to TG secretion decreased in SDT fatty-Cho, and the mRNA expression related to inflammation and fibrosis increased in SDT fatty-Cho at 24 weeks. Furthermore, SDT fatty-Cho presented with increased plasma choline, similar to human NASH. There were no significant changes in the effects of feeding a cholesterol-enriched diet in Sprague-Dawley rats. SDT fatty-Cho has the potential to become a valuable animal model for NASH associated with type 2 diabetes and obesity.

The Spontaneously Diabetic Torii (SDT) fatty rat is a new model for obese type 2 diabetes. The aim of the present study was to investigate the effect of 1/2 nephrectomy (Nx) on renal function and morphology and on blood pressure in SDT fatty rats. Male SDT fatty rats underwent 1/2 Nx or a sham operation (Sham). Subsequently, animals were studied with respect to renal function and histological alterations. Induction of 1/2 Nx in SDT fatty rats led to functional and morphological damage to the remnant kidney and to hypertension, which are considered main characteristics of chronic kidney disease, at a younger age compared with the sham group. In conclusion, the SDT fatty rat is useful in investigations to elucidate the pathogenesis of human diabetic nephropathy and in new drug discovery.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease, and some patients develop hepatic cirrhosis/carcinoma. Animal models play key roles in the development of new therapies for NASH. In this study, the pharmacological effects of metformin and pioglitazone were investigated in female Spontaneously Diabetic Torii (SDT) fatty rats to verify the utility of this model. The anti-diabetic drugs were administered to SDT fatty rats fed a cholesterol-enriched diet from 4 to 25 weeks, and changes in food intake, body weight, and blood chemistry parameters were evaluated every 4 weeks. The hepatic lipid content, mRNA expression in relation to lipid synthesis, inflammation, and fibrosis, and histopathological analyses were performed at 25 weeks. Pioglitazone improved hyperglycemia, hyperlipidemia, and abnormalities in hepatic parameters. The insulin levels were lower than those in the control rats before 16 weeks. Plasma glucose levels in the metformin-treated rats were lower than those in the control rats, and plasma alanine aminotransferase levels temporarily decreased. The lipid content and some mRNA expression in relation to fibrosis in the liver decreased with pioglitazone treatment, and the mRNA expression of microsomal triglyceride transfer protein increased. Hepatic fibrosis observed in the SDT fatty rats improved with pioglitazone treatment; however, the effect with metformin treatment was partial. These results in both drugs are in line with results in the human study, suggesting that the SDT fatty rat is useful for developing new anti-NASH drugs that show potential to regulate glucose/lipid metabolism.

G‐protein coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR119 agonist oleoylethanolamide is well known to enhance a glucose‐stimulated insulin secretion (GSIS) and glucagon‐like peptide‐1 (GLP‐1) secretion by elevating intracellular cAMP levels. In the present study, a glucose lowering effect of the GPR119 agonist, JTP‐109192 leading to improvement of insulin sensitivity was examined in Zucker Fatty (ZF) rats. We investigated the in vitro effects of JTP‐109192 on GSIS in the rat pancreatic β‐cell line (INS1E) cells and on GLP‐1 secretion in the murine enteroendocrine cell line (GLUTag) cells. We also investigated the effect of JTP‐109192 on GSIS in Sprague‐Dawley (SD) rats with single administration and its effect on glucose metabolism in ZF rats with repeated administration once daily for about 6 weeks. After repeated administration, the hyperinsulinaemic euglycaemic glucose clamp test was performed to evaluate insulin sensitivity. JTP‐109192 increased intracellular cAMP levels (EC50 value: 3.6 nmol/L) and enhanced GSIS in the INS1E cells and GLP‐1 secretion in GLUTag cells. In SD rats, a single administration of JTP‐109192 enhanced GSIS at high blood glucose levels. The repeated administrations in ZF rats improved glucose metabolism without lack of drug efficacy (tachyphylaxis) and increased glucose infusion rates due to improvement of insulin sensitivity.

G protein‐coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L‐cells is a potential therapeutic target for the treatment of type 2 diabetes. Previously, we have reported that the GPR119 agonist JTP‐109192 improves glucose metabolism with single and repeated administration. Conversely, overexpression of the Gpr119 gene reportedly regulates cholesterol transporter expression in animal models, and a natural GPR119 agonist, oleoylethanolamide (OEA), improves atherosclerosis. Therefore, improving dyslipidaemia is considered a possible feature of GPR119 agonists. In the present study, the lipid‐lowering effect of JTP‐109192 was examined in BALB/c background spontaneously hyperlipidaemic (SHL) mice with repeated administration, once daily for 12 weeks. On repeated administration, JTP‐109192 revealed a cholesterol‐lowering effect and improved atherosclerosis following histopathological examination. With further investigation, the cholesterol‐lowering effect and subsequent antiatherosclerotic effect of JTP‐109192 was attributed to changes in intestinal cholesterol metabolism gene expression. Based on these results, JTP‐109192 represents a new potential antihypercholesterolaemic agent for the treatment of dyslipidaemia.

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