Investigation of pharmacological responses to anti-diabetic drugs in female Spontaneously Diabetic Torii (SDT) fatty rats, a new nonalcoholic steatohepatitis (NASH) model

Abstract

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.

Analysis of haemodynamics and angiogenic response to ischaemia in the obese type 2 diabetic model Spontaneously Diabetic Torii Leprfa (SDT fatty) rats

“…Spontaneously Diabetic Torii Lepr fa (SDT fatty) rats were established by transferring the fa allele of the Zucker fatty rat into the genome of the nonobese SDT rat. The SDT fatty rat shows hyperphagia, obesity, hyperglycaemia, and dyslipidaemia, so it can be considered a new model for obese type 2 diabetes . However, the details of the haemodynamics in SDT fatty rats remain uncertain.…”

“…Therefore, in nonclinical studies, it is very important to evaluate the efficacy of drugs in a PAD model based on metabolic syndrome animals. Masuyama et al reported that SDT fatty rats develop obesity, hyperglycaemia, and dyslipidaemia at a young age due to the transfer of the fa allele from the Zucker fatty rat to the genome of the nonobese SDT rat . In this study, we found that hindlimb blood flow was significantly lower and the plasma NOx level was significantly higher in the SDT fatty rats compared with the SD rats.…”

“…This number for the SDT fatty rats was significantly less than that for the SD rats ( Figure 3D, E). [8][9][10] In this study, we found that hindlimb blood flow was significantly lower and the plasma NOx level was significantly higher in the SDT fatty rats compared with the SD rats. These results suggest that ROS production in the SDT fatty rats increased because of metabolic disorders such as hyperglycaemia and hyperlipidaemia.…”

“…The SDT fatty rat shows hyperphagia, obesity, hyperglycaemia, and dyslipidaemia, so it can be considered a new model for obese type 2 diabetes. [8][9][10] However, the details of the haemodynamics in SDT fatty rats remain uncertain. In this study, we investigated the usefulness of the SDT fatty rat as a new PAD animal model.…”

Spontaneously Diabetic Torii (SDT) Fatty Rat, a Novel Animal Model of Type 2 Diabetes Mellitus, Shows Blunted Circadian Rhythms and Melatonin Secretion

“…Circadian rhythms are known to be affected by food-taking behavior [ 26 , 27 ]. As our previous studies have revealed that SDT fatty rats show hyperphagia [ 28 , 29 ], this feature may underlie the deficits of circadian rhythm in the SDT fatty rats. Although there is no data on the food intake pattern of SDT fatty rats, the relatively higher SLA during the light phase may reflect the food-taking behavior.…”