2型糖尿病モデルラット(SDTラット)における免疫異常の病態解析に関する研究

• Material Type: 博士論文
• Title: 2型糖尿病モデルラット(SDTラット)における免疫異常の病態解析に関する研究
• Author/Editor: 小林, 和真
• Author Heading: 小林, 和真
• Publication Date: 2022-03-23
• Publication Date (W3CDTF): 2022-03-23
• Degree grantor/type: 新潟大学
• Date Granted: 2022-03-23
• Date Granted (W3CDTF): 2022-03-23
• Dissertation Number: 甲第5061号
• Degree Type: 博士（農学）
• Conferring No. (Dissertation): 甲第5061号
• Text Language Code: jpn
• Target Audience: 一般
• Note (General): Type 2 diabetes (T2D) is a polygenic disorder characterized by insulin deficiency and insulin resistance. High-calorie intake and sedentary lifestyles have resulted in an increased number of patients with this disorder worldwide. Type 1 diabetes (T1D) is considered a cell-mediated autoimmune disease, and T2D to be a non-autoimmune metabolic disorder. However, some patients with T2D have been identified with autoimmune abnormalities, such as islet autoantibodies and islet-reactive T cells associated with severe β-cell dysfunction. Although the prevalence of islet autoimmunity in T2D patients is unknown, it has been estimated to be approximately 30% using islet autoantibodies as a biomarker. The involvement of autoimmunity in T2D may be more significant than it is considered. Besides autoimmunity, the involvement of immunity and inflammation is often discussed in relation to obesity, but there are several uncertainties, and therapeutic interventions targeting them have not been realized. Understanding the pathophysiology of T2D and evaluating the efficacy of the drug are very important in developing new therapeutic agents. However, there are few reports investigating immune abnormalities in the T2D animal models. Spontaneously Diabetic Torii (SDT) rats are a non-obese T2D model, and it is known that there is a sex difference in the onset of diabetes, but little is known about the involvement of immune disorders in the pathophysiology of diabetes. In this study, we examined immune abnormalities in SDT rats, using immune cell subsets analysis by multicolor flow cytometry and pharmacological analysis by the immunomodulator. The diabetic etiology in SDT rats was also examined to see if this is a useful model for the development of new therapeutic agents for T2D patients with immune abnormalities. Firstly, we investigated immune abnormalities and sex differences in SDT rats. Immune cell subsets 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. On the other hand, female SDT rats which are the model of impaired glucose tolerance (IGT) showed immune abnormalities such as a higher weight of spleen and lymph nodes and a higher number of lymphocytes (T cells in particular) in the blood, spleen, and lymph nodes similar to male SDT rats. Hence, female SDT rats may be useful in studying the involvement of immune abnormalities in IGT. Secondly, we investigated the preventive and therapeutic effect of fingolimod (FTY720), the sphingosine-1-phosphate (S1P) receptor modulator, in male SDT rats. The S1P receptor modulator regulates lymphocyte trafficking, resulting in its depletion from circulation which ultimately causes immunosuppression. First, FTY720 (0.3 mg/kg p.o.) was administered for 12 weeks to SDT rats from 5 to 17 weeks of age to investigate the preventive effect. Based on our findings, FTY720 could suppress the incidence of diabetes in SDT rats. Further, glucose intolerance was improved in FTY720 treated-SDT rats at 14 weeks of age. Based on the hematological and histological analyses performed at 17 to 18 weeks of age, a decrease in lymphocytes and monocytes in the peripheral blood and a decrease in lymphocyte and atrophy in the spleen occurred in the FTY720-treated SDT rats. Furthermore, the pancreatic changes, such as inflammation, atrophy, and fibrosis in islets observed in SDT rats were improved by FTY720 treatment. These findings suggest that the immunomodulatory effects of FTY720 reduced the pancreatic lesion in SDT rats, thereby demonstrating its preventive effect against diabetes. Next, FTY720 was administered for 18 weeks to SDT rats with diabetes from 18 to 36 weeks of age to investigate the therapeutic effect. Administration of FTY720 showed a decrease in lymphocytes such as CD4+T cells, CD8+T cells, and B cells in the blood and spleen, but no effect on blood glucose level and insulin concentration was observed. The reason for this is that therapeutic administration did not show a sufficient decrease in monocytes in the blood and spleen, or that the pancreatic β-cell damage progressed severely and insulin secretion sufficient to normalize blood glucose levels was not restored. These results suggest that lymphocyte- and monocyte-mediated immune system abnormalities are involved in the progression of diabetes in SDT rats and that the S1P modulator is useful for the treatment of T2D with immune abnormalities. On the other hand, it was suggested that therapeutic intervention is needed to correct the immune abnormalities in T2D patients before the pancreatic lesion progresses severely. In conclusion, we found that male SDT rats may be a beneficial model of T2D involved in especially monocyte/macrophage-mediated immune disorders, and female SDT rats may be a useful model of studying the association between IGT and lymphocytes. Further research will help elucidate the pathophysiology of T2D with immune abnormalities and develop new therapeutic agents.; 新大院博(農)第221号
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• Date Accepted (W3CDTF): 2022-08-08T06:02:54+09:00
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• Periodical Title (URI): http://hdl.handle.net/10191/0002000622; https://niigata-u.repo.nii.ac.jp/records/2000622
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