Type 2 diabetes (T2D) is believed to be a non-autoimmune metabolic disorder. However, there are increasing reports that some T2D patients have immune abnormalities. In addition, it is known that there are sex differences in the onset of diabetes and immune responses in humans. Spontaneously Diabetic Torii (SDT) rats, a non-obese T2D model, also have sex differences in the onset of diabetes, but the involvement of immune abnormalities in diabetes is unknown. In this study, we investigated immune abnormalities in SDT rats. Immune cell subset analysis was performed in male and female SDT rats and control Sprague-Dawley (SD) rats at 5, 11, and 17 weeks of age. Male and female SDT rats had swelling of the spleen and lymph nodes and a higher number of T cells and B cells in the blood, spleen, and lymph nodes than SD rats. Only male SDT rats developed diabetes at 17 weeks of age, and the number of classical and non-classical monocytes in the blood and spleen of male SDT rats was higher than that in male SD rats and female SDT rats that did not develop diabetes. Most of these findings were observed before the onset of diabetes (~11 weeks of age), suggesting that classical and non-classical monocytes may contribute to the development of diabetes in male SDT rats. In conclusion, SDT rats may be a useful T2D model involved in immune abnormalities, and further research will help elucidate the pathophysiology of T2D with immune abnormalities and develop new therapeutic agents.
Diabetic nephropathy, included in diabetic kidney disease (DKD), is the primary disease leading to end-stage renal disease (ESRD) or dialysis treatment, accounting for more than 40 % of all patients with ESRD or receiving dialysis. Developing new therapeutics to prevent the transition to ESRD or dialysis treatment requires an understanding of the pathophysiology of DKD and an appropriate animal model for drug efficacy studies. In this study, we investigated the pathophysiology of diabetic kidney disease with type 2 diabetes in uninephrectomized db/db mice. In addition, the nephrectomized db/db mice from 10 weeks to 42 weeks were used to assess the efficacy of longterm administration of the angiotensin-II–receptor antagonist losartan. The blood and urinary biochemical parameters and the blood pressure which is a main pharmacological endpoint of the losartan therapy, were periodically measured. And at the end, histopathological analysis was performed. Uninephrectomized db/db mice clearly developed obesity and hyperglycemia from young age. Furthermore, they showed renal pathophysiological changes, such as increased urinary albumin-creatinine ratio (UACR) (the peak value 3104±986 in 40-week-old mice), glomerular hypertrophy and increased fibrotic areas in the tubulointerstitial tubules. The blood pressure in the losartan group was significantly low compared to the normotensive Vehicle group. However, as expected, Losartan suppressed the increase in UACR (829±500) indicating the medication was sufficient, but the histopathological abnormalities including tubular interstitial fibrosis did not improve. These results suggest that the uninephrectomized db/db mice are useful as an animal model of the severe DKD indicated by the comparison of the efficacy of losartan in this model with the efficacy of losartan in clinical practice.