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.

Biological Pharmacological Research Laboratories Takatsuki Research Center Central Pharmaceutical Research Institute Japan Tobacco Inc 1 1 Osaka Japan

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Brooks-Worrell BM, Reichow JL, Goel A, Ismail H, Palmer JP. Identification of autoantibody-negative autoimmune type 2 diabetic patients. Diabetes Care. 2011;34:168–173. doi: 10.2337/dc10-0579. PubMed DOI PMC

Brooks-Worrell B, Narla R, Palmer JP. Islet autoimmunity in phenotypic type 2 diabetes patients. Diabetes Obes Metab. 2013;15(Suppl 3):137–140. doi: 10.1111/dom.12167. PubMed DOI PMC

Tsai S, Clemente-Casares X, Revelo XS, Winer S, Winer DA. Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases? Diabetes. 2015;64:1886–1897. doi: 10.2337/db14-1488. PubMed DOI

Gao X, Sun W, Wang Y, Zhang Y, Li R, Huang J, Yang Y. Prevalence of positive islet autoantibody in type 2 diabetes patients: a cross-sectional study in a Chinese community. Endocr Connect. 2019;8:1493–1502. doi: 10.1530/EC-19-0379. PubMed DOI PMC

Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–281. doi: 10.1016/j.diabres.2018.02.023. PubMed DOI

Clark JB, Palmer CJ, Shaw WN. The diabetic Zucker fatty rat. Proc Soc Exp Biol Med. 1983;173:68–75. doi: 10.3181/00379727-173-41611. PubMed DOI

Tsuchitani M, Saegusa T, Narama I, Nishikawa T, Gonda T. A new diabetic strain of rat (WBN/Kob) Lab Anim. 1985;19:200–07. doi: 10.1258/002367785780893575. PubMed DOI

Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 1992;41:1422–1428. doi: 10.2337/diab.41.11.1422. PubMed DOI

Sasase T, Ohta T, Ogawa N, Miyajima K, Ito M, Yamamoto H, Morinaga H, Matsushita M. Preventive effects of glycaemic control on ocular complications of Spontaneously Diabetic Torii rat. Diabetes Obes Metab. 2006;8:501–507. doi: 10.1111/j.1463-1326.2005.00535.x. PubMed DOI

Ohta T, Matsui K, Miyajima K, Sasase T, Masuyama T, Shoda T, Koizumi H, Shinohara M, Matsushita M. Effect of insulin therapy on renal changes in Spontaneously Diabetic Torii rats. Exp Anim. 2007;56:355–362. doi: 10.1538/expanim.56.355. PubMed DOI

Masuyama T, Komeda K, Hara A, Noda M, Shinohara M, Oikawa T, Kanazawa Y, Taniguchi K. Chronological characterization of diabetes development in male Spontaneously Diabetic Torii rats. Biochem Biophys Res Commun. 2004;314:870–77. doi: 10.1016/j.bbrc.2003.12.180. PubMed DOI

Matsui K, Oda T, Nishizawa E, Sano R, Yamamoto H, Fukuda S, Sasase T, Miyajima K, Ueda N, Ishii Y, Ohta T, Matsushita M. Pancreatic function of Spontaneously Diabetic Torii rats in pre-diabetic stage. Exp Anim. 2009;58:363–374. doi: 10.1538/expanim.58.363. PubMed DOI

Mukai E, Ohta T, Kawamura H, Lee EY, Morita A, Sasase T, Miyajima K, Inagaki N, Iwanaga T, Miki T. Enhanced vascular endothelial growth factor signaling in islets contributes to beta cell injury and consequential diabetes in Spontaneously Diabetic Torii rats. Diabetes Res Clin Pract. 2014;106:303–311. doi: 10.1016/j.diabres.2014.08.023. PubMed DOI

Inokuchi C, Ueda H, Hamaguchi T, Miyagawa J, Shinohara M, Okamura H, Namba M. Role of macrophages in the development of pancreatic islet injury in Spontaneously Diabetic Torii rats. Exp Anim. 2009;58:383–394. doi: 10.1538/expanim.58.383. PubMed DOI

Kobayashi K, Sasase T, Ishii Y, Katsuda Y, Miyajima K, Yamada T, Ohta T. The sphingosine-1-phosphate receptor modulator, FTY720, prevents the incidence of diabetes in Spontaneously Diabetic Torii rats. Clin Exp Pharmacol Physiol. 2021;48:869–876. doi: 10.1111/1440-1681.13405. PubMed DOI

Shinohara M, Masuyama T, Shoda T, Takahashi T, Katsuda Y, Komeda K, Kuroki M, Kakehashi A, Kanazawa Y. A new spontaneously diabetic non-obese Torii rat strain with severe ocular complications. Int J Exp Diabetes Res. 2000;1:89–100. doi: 10.1155/edr.2000.89. PubMed DOI PMC

Barnett-Vanes A, Sharrock A, Birrell MA, Rankin S. A single 9-colour flow cytometric method to characterise major leukocyte populations in the Rat: Validation in a model of LPS-induced pulmonary inflammation. PLoS One. 2016;11:e0142520. doi: 10.1371/journal.pone.0142520. PubMed DOI PMC

Ginhoux F, Jung S. Monocytes and macrophages: Developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014;14:392–404. doi: 10.1038/nri3671. PubMed DOI

Passlick B, Flieger D, Ziegler-Heitbrock HW. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood. 1989;74:2527–2534. doi: 10.1182/blood.V74.7.2527.2527. PubMed DOI

Ahuja V, Miller SE, Howell DN. Identification of two subpopulations of rat monocytes expressing disparate molecular forms and quantities of CD43. Cell Immunol. 1995;163:59–69. doi: 10.1006/cimm.1995.1099. PubMed DOI

Strauss-Ayali D, Conrad SM, Mosser DM. Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol. 2007;82:244–252. doi: 10.1189/jlb.0307191. PubMed DOI

Narasimhan PB, Marcovecchio P, Hamers AAJ, Hedrick CC. Nonclassical monocytes in health and disease. Annu Rev Immunol. 2019;37:439–456. doi: 10.1146/annurev-immunol-042617-053119. PubMed DOI

Kakehashi A, Inoda S, Mameuda C, Kuroki M, Jono T, Nagai R, Horiuchi S, Kawakami M, Kanazawa Y. Relationship among VEGF, VEGF receptor, AGEs, and macrophages in proliferative diabetic retinopathy. Diabetes Res Clin Pract. 2008;79:438–445. doi: 10.1016/j.diabres.2007.10.018. PubMed DOI

Klessens CQF, Zandbergen M, Wolterbeek R, Bruijn JA, Rabelink TJ, Bajema IM, DHT IJ. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant. 2017;32:1322–1329. doi: 10.1093/ndt/gfw260. PubMed DOI

Shinohara M, Oikawa T, Sato K, Kanazawa Y. Effect of oophorectomy and estrogen administration on diabetic pathogenesis in female Spontaneously Diabetic Torii rats. Open Diab J. 2011;4:96–100. doi: 10.2174/1876524601104010096. DOI

Prochazka M, Premdas FH, Leiter EH, Lipson LG. Estrone treatment dissociates primary versus secondary consequences of “diabetes” (db) gene expression in mice. Diabetes. 1986;35:725–728. doi: 10.2337/diab.35.6.725. PubMed DOI

Kon H, Saegusa T, Tsuchitani M, Narama I. [Effect of gonadectomy on the onset of diabetic syndrome in the female WBN/Kob rats. Jikken Dobutsu. 1988;37:429–435. doi: 10.1538/expanim1978.37.4_429. PubMed DOI

Shi K, Mizuno A, Sano T, Ishida K, Shima K. Sexual difference in the incidence of diabetes mellitus in Otsuka-Long-Evans-Tokushima-Fatty rats: Effects of castration and sex hormone replacement on its incidence. (Article in Japanese) Metabolism. 1994;43:1214–1220. doi: 10.1016/0026-0495(94)90213-5. PubMed DOI

Trenti A, Tedesco S, Boscaro C, Trevisi L, Bolego C, Cignarella A. Estrogen, angiogenesis, immunity and cell metabolism: Solving the puzzle. Int J Mol Sci. 2018;19:859. doi: 10.3390/ijms19030859. PubMed DOI PMC

Frazier-Jessen MR, Kovacs EJ. Estrogen modulation of JE/monocyte chemoattractant protein-1 mRNA expression in murine macrophages. J Immunol. 1995;154:1838–1845. PubMed

Lambert KC, Curran EM, Judy BM, Lubahn DB, Estes DM. Estrogen receptor-alpha deficiency promotes increased TNF-alpha secretion and bacterial killing by murine macrophages in response to microbial stimuli in vitro. J Leukoc Biol. 2004;75:1166–1172. doi: 10.1189/jlb.1103589. PubMed DOI

Friedrich EB, Clever YP, Wassmann S, Hess C, Nickenig G. 17Beta-estradiol inhibits monocyte adhesion via down-regulation of Rac1 GTPase. J Mol Cell Cardiol. 2006;40:87–95. doi: 10.1016/j.yjmcc.2005.10.007. PubMed DOI

Blasko E, Haskell CA, Leung S, Gualtieri G, Halks-Miller M, Mahmoudi M, Dennis MK, Prossnitz ER, Karpus WJ, Horuk R. Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis. J Neuroimmunol. 2009;214:67–77. doi: 10.1016/j.jneuroim.2009.06.023. PubMed DOI PMC

Sellau J, Groneberg M, Fehling H, Thye T, Hoenow S, Marggraff C, Weskamm M, Hansen C, Stanelle-Bertram S, Kuehl S, Noll J, Wolf V, Metwally NG, Hagen SH, Dorn C, Wernecke J, Ittrich H, Tannich E, Jacobs T, Bruchhaus I, Altfeld M, Lotter H. Androgens predispose males to monocyte-mediated immunopathology by inducing the expression of leukocyte recruitment factor CXCL1. Nat Commun. 2020;11:3459. doi: 10.1038/s41467-020-17260-y. PubMed DOI PMC

De Paoli M, Zakharia A, Werstuck GH. The role of estrogen in insulin resistance: A review of clinical and preclinical data. Am J Pathol. 2021;191:1490–498. doi: 10.1016/j.ajpath.2021.05.011. PubMed DOI

Shinohara M, Oikawa T, Sato K, Kanazawa Y. Glucose intolerance and hyperlipidemia prior to diabetes onset in female Spontaneously Diabetic Torii (SDT) rats. Exp Diabesity Res. 2004;5:253–256. doi: 10.1080/15438600490898609. PubMed DOI PMC

Xia C, Rao X, Zhong J. Role of T lymphocytes in type 2 diabetes and diabetes-associated inflammation. J Diabetes Res. 2017;2017:6494795. doi: 10.1155/2017/6494795. PubMed DOI PMC

Ford ES. Leukocyte count, erythrocyte sedimentation rate, and diabetes incidence in a national sample of US adults. Am J Epidemiol. 2002;155:57–64. doi: 10.1093/aje/155.1.57. PubMed DOI

Menart-Houtermans B, Rutter R, Nowotny B, Rosenbauer J, Koliaki C, Kahl S, Simon MC, Szendroedi J, Schloot NC, Roden M German Diabetes Study Group. Leukocyte profiles differ between type 1 and type 2 diabetes and are associated with metabolic phenotypes: Results from the German Diabetes Study (GDS) Diabetes Care. 2014;37:2326–2333. doi: 10.2337/dc14-0316. PubMed DOI

Louet JF, LeMay C, Mauvais-Jarvis F. Antidiabetic actions of estrogen: insight from human and genetic mouse models. Curr Atheroscler Rep. 2004;6:180–85. doi: 10.1007/s11883-004-0030-9. PubMed DOI

Margolis KL, Bonds DE, Rodabough RJ, Tinker L, Phillips LS, Allen C, Bassford T, Burke G, Torrens J, Howard BV Women’s Health Initiative I. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: Results from the Women’s Health Initiative Hormone Trial. Diabetologia. 2004;47:1175–1187. doi: 10.1007/s00125-004-1448-x. PubMed DOI

Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310:1353–1368. doi: 10.1001/jama.2013.278040. PubMed DOI PMC

Ben-Hur H, Mor G, Insler V, Blickstein I, Amir-Zaltsman Y, Sharp A, Globerson A, Kohen F. Menopause is associated with a significant increase in blood monocyte number and a relative decrease in the expression of estrogen receptors in human peripheral monocytes. Am J Reprod Immunol. 1995;34:363–369. doi: 10.1111/j.1600-0897.1995.tb00965.x. PubMed DOI

Serological markers of intestinal barrier impairment do not correlate with duration of diabetes and glycated hemoglobin in adult patients with type 1 and type 2 diabetes mellitus