Multiple low dose streptozotocin-induced diabetes as a model for studying autoimmune diabetes in humans

Ivan Koprivica , Suzana Stanisavljević , Dragica Mićanović , Ivana Stojanović , Đorđe Miljković

Animal Models and Experimental Medicine ›› 2025, Vol. 8 ›› Issue (9) : 1539 -1551.

PDF
Animal Models and Experimental Medicine ›› 2025, Vol. 8 ›› Issue (9) : 1539 -1551. DOI: 10.1002/ame2.70050
REVIEW

Multiple low dose streptozotocin-induced diabetes as a model for studying autoimmune diabetes in humans

Author information +
History +
PDF

Abstract

The autoimmune response directed against pancreatic β cells is the most essential pathogenic process in type 1 diabetes (T1D) in humans. Spontaneous animal models of T1D greatly contribute to our understanding of the disease pathogenesis and therapeutic options. Amongst many disease models, a significant proportion of T1D research is performed on multiple low dose streptozotocin induced diabetes in experimental animals, in parallel. Here, we discuss advantages of this model for contemporary T1D research. Additionally, challenges and perspectives for further improvement of the model are presented.

Keywords

animal model / autoimmunity / streptozotocin / type 1 diabetes

Cite this article

Download citation ▾
Ivan Koprivica, Suzana Stanisavljević, Dragica Mićanović, Ivana Stojanović, Đorđe Miljković. Multiple low dose streptozotocin-induced diabetes as a model for studying autoimmune diabetes in humans. Animal Models and Experimental Medicine, 2025, 8(9): 1539-1551 DOI:10.1002/ame2.70050

登录浏览全文

4963

注册一个新账户 忘记密码

References

[1]

American Diabetes Association Professional Practice Committee. 2. Classification and diagnosis of diabetes: standards of medical Care in Diabetes-2022. Diabetes Care. 2022; 45(Suppl 1): S17-S38.

[2]

den Hollander NHM, Roep BO. From disease and patient heterogeneity to precision medicine in type 1 diabetes. Front Med (Lausanne). 2022; 9: 932086.

[3]

Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem. 2011; 57(2): 176-185.

[4]

Lebastchi J, Herold KC. Immunologic and metabolic biomarkers of β-cell destruction in the diagnosis of type 1 diabetes. Cold Spring Harb Perspect Med. 2012; 2(6): a007708.

[5]

Purcell AW, Sechi S, DiLorenzo TP. The evolving landscape of autoantigen discovery and characterization in type 1 diabetes. Diabetes. 2019; 68(5): 879-886.

[6]

Kawasaki E. Anti-islet autoantibodies in type 1 diabetes. Int J Mol Sci. 2023; 24(12): 10012.

[7]

King AJ. The use of animal models in diabetes research. Br J Pharmacol. 2012; 166(3): 877-894.

[8]

Athmuri DN, Shiekh PA. Experimental diabetic animal models to study diabetes and diabetic complications. MethodsX. 2023; 11: 102474.

[9]

Mordes JP, Bortell R, Blankenhorn EP, Rossini AA, Greiner DL. Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J. 2004; 45(3): 278-291.

[10]

Like AA, Guberski DL, Butler L. Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats. Diabetes. 1991; 40(2): 259-262.

[11]

Acharjee S, Ghosh B, Al-Dhubiab BE, Nair AB. Understanding type 1 diabetes: etiology and models. Can J Diabetes. 2013; 37(4): 269-276.

[12]

Zipris D, Greiner DL, Malkani S, Whalen B, Mordes JP, Rossini AA. Cytokine gene expression in islets and thyroids of BB rats. IFN-gamma and IL-12p40 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats. J Immunol. 1996; 156(3): 1315-1321.

[13]

Ramanathan S, Poussier P. BB rat lyp mutation and type 1 diabetes. Immunol Rev. 2001; 184: 161-171.

[14]

Lenzen S, Tiedge M, Elsner M, et al. The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus. Diabetologia. 2001; 44(9): 1189-1196.

[15]

Jörns A, Günther A, Hedrich HJ, Wedekind D, Tiedge M, Lenzen S. Immune cell infiltration, cytokine expression, and beta-cell apoptosis during the development of type 1 diabetes in the spontaneously diabetic LEW.1AR1/Ztm-iddm rat. Diabetes. 2005; 54(7): 2041-2052.

[16]

Jörns A, Kubat B, Tiedge M, et al. Pathology of the pancreas and other organs in the diabetic LEW.1AR1/Ztm- iddm rat, a new model of spontaneous insulin-dependent diabetes mellitus. Virchows Arch. 2004; 444(2): 183-189.

[17]

Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu. 1980; 29(1): 1-13.

[18]

Lampeter EF, Signore A, Gale EA, Pozzilli P. Lessons from the NOD mouse for the pathogenesis and immunotherapy of human type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1989; 32(10): 703-708.

[19]

Kikutani H, Makino S. The murine autoimmune diabetes model: NOD and related strains. Adv Immunol. 1992; 51: 285-322.

[20]

Jun HS, Yoon CS, Zbytnuik L, van Rooijen N, Yoon JW. The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Exp Med. 1999; 189(2): 347-358.

[21]

Yang Y, Santamaria P. Lessons on autoimmune diabetes from animal models. Clin Sci (Lond). 2006; 110(6): 627-639.

[22]

Todd JA, Aitman TJ, Cornall RJ, et al. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature. 1991; 351(6327): 542-547.

[23]

Aubin AM, Lombard-Vadnais F, Collin R, Aliesky HA, McLachlan SM, Lesage S. The NOD mouse beyond autoimmune diabetes. Front Immunol. 2022; 13: 874769.

[24]

Wen L, Ley RE, Volchkov PY, et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature. 2008; 455(7216): 1109-1113.

[25]

Leiter EH, Schile A. Genetic and pharmacologic models for type 1 diabetes. Curr Protoc Mouse Biol. 2013; 3(1): 9-19.

[26]

Drel VR, Pacher P, Stavniichuk R, et al. Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice. Int J Mol Med. 2011; 28(4): 629-635.

[27]

Riahi Y, Israeli T, Yeroslaviz R, et al. Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse. elife. 2018; 7: e38472.

[28]

Yoon JW, McClintock PR, Bachurski CJ, Longstreth JD, Notkins AL. Virus-induced diabetes mellitus. No evidence for immune mechanisms in the destruction of beta-cells by the D-variant of encephalomyocarditis virus. Diabetes. 1985; 34(9): 922-925.

[29]

Guberski DL, Thomas VA, Shek WR, et al. Induction of type I diabetes by Kilham's rat virus in diabetes-resistant BB/Wor rats. Science. 1991; 254(5034): 1010-1013.

[30]

Filippi CM, von Herrath MG. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: viruses, autoimmunity and immunoregulation. Clin Exp Immunol. 2010; 160(1): 113-119.

[31]

Gvazava IG, Rogovaya OS, Borisov MA, Vorotelyak EA, Vasiliev AV. Pathogenesis of type 1 diabetes mellitus and rodent experimental models. Acta Nat. 2018; 10(1): 24-33.

[32]

Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia. 2008; 51(2): 216-226.

[33]

Federiuk IF, Casey HM, Quinn MJ, Wood MD, Ward WK. Induction of type-1 diabetes mellitus in laboratory rats by use of alloxan: route of administration, pitfalls, and insulin treatment. Comp Med. 2004; 54(3): 252-257.

[34]

Patterson E, Marques TM, O'Sullivan O, et al. Streptozotocin-induced type-1-diabetes disease onset in Sprague-Dawley rats is associated with an altered intestinal microbiota composition and decreased diversity. Microbiology (Reading). 2015; 161(Pt 1): 182-193.

[35]

Mathavan S, Chen-Tan N, Arfuso F, Al-Salami H. A comprehensive study of novel microcapsules incorporating gliclazide and a permeation enhancing bile acid: hypoglycemic effect in an animal model of Type-1 diabetes. Drug Deliv. 2016; 23(8): 2869-2880.

[36]

Vavra JJ, Deboer C, Dietz A, Hanka LJ, Sokolski WT. Streptozotocin, a new antibacterial antibiotic. Antibiot Annu. 1959-1960; 7: 230-235.

[37]

Lewis C, Barbiers AR. Streptozotocin, a new antibiotic. In vitro and in vivo evaluation. Antibiot Annu. 1959-1960; 7: 247-254.

[38]

Agarwal MK. Streptozotocin: mechanisms of action: proceedings of a workshop held on 21 June 1980, Washington, DC. FEBS Lett. 1980; 120(1): 1-3.

[39]

Capdevila J, Ducreux M, García Carbonero R, et al. Streptozotocin, 1982-2022: forty years from the FDA's approval to treat pancreatic neuroendocrine tumors. Neuroendocrinology. 2022; 112(12): 1155-1167.

[40]

Like AA, Rossini AA. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science. 1976; 193(4251): 415-417.

[41]

Rossini AA, Like AA, Chick WL, Appel MC, Cahill GF. Studies of streptozotocin-induced insulitis and diabetes. Proc Natl Acad Sci USA. 1977; 74(6): 2485-2489.

[42]

Kiesel U, Freytag G, Biener J, Kolb H. Transfer of experimental autoimmune insulitis by spleen cells in mice. Diabetologia. 1980; 19(6): 516-520.

[43]

Kiesel U, Greulich B, Moumé CM, Kolb H. Induction of experimental autoimmune diabetes by low-dose streptozotocin treatment in genetically resistant mice. Immunol Lett. 1981; 3(4): 227-230.

[44]

Fontaine DA, Davis DB. Attention to background strain is essential for metabolic research: C57BL/6 and the international knockout mouse consortium. Diabetes. 2016; 65(1): 25-33.

[45]

Papaccio G, Mezzogiorno V. Morphological aspects of glucagon and somatostatin islet cells in diabetic bio breeding and low-dose streptozocin-treated Wistar rats. Pancreas. 1989; 4(3): 289-294.

[46]

Lukic ML, Al-Sharif R, Mostarica M, Bahr G, Behbehani K. Immunological basis of the strain differences in susceptibility to low-dose streptozotocin-induced diabetes in rats. In: Imhof BA, Berrih-Aknin S, Ezine S, eds. Lymphatic Tissues and In Vivo Immune Responses. Marcel Dekker; 1991: 643-647.

[47]

Ghasemi A, Jeddi S. Streptozotocin as a tool for induction of rat models of diabetes: a practical guide. EXCLI J. 2023; 22: 274-294.

[48]

Karabatas LM, Pastorale C, de Bruno LF, et al. Early manifestations in multiple-low-dose streptozotocin-induced diabetes in mice. Pancreas. 2005; 30(4): 318-324.

[49]

Jonić N, Koprivica I, Kyrkou SG, et al. Novel AHR ligand AGT-5 ameliorates type 1 diabetes in mice through regulatory cell activation in the early phase of the disease. Front Immunol. 2024; 15: 1454156.

[50]

Saadane A, Lessieur EM, Du Y, Liu H, Kern TS. Successful induction of diabetes in mice demonstrates no gender difference in development of early diabetic retinopathy. PLoS One. 2020; 15(9): e0238727.

[51]

Stosic-Grujicic S, Dimitrijevic M, Bartlett R. Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes. Clin Exp Immunol. 1999; 117(1): 44-50.

[52]

Grisé KN, Olver TD, McDonald MW, et al. High intensity aerobic exercise training improves deficits of cardiovascular autonomic function in a rat model of type 1 diabetes mellitus with moderate hyperglycemia. J Diabetes Res. 2016; 2016: 8164518.

[53]

Stosić-Grujicić S, Maksimović D, Badovinac V, et al. Antidiabetogenic effect of pentoxifylline is associated with systemic and target tissue modulation of cytokines and nitric oxide production. J Autoimmun. 2001; 16(1): 47-58.

[54]

Hahn M, van Krieken PP, Nord C, et al. Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes. Commun Biol. 2020; 3(1): 541.

[55]

Kantwerk-Funke G, Burkart V, Kolb H. Low dose streptozotocin causes stimulation of the immune system and of anti-islet cytotoxicity in mice. Clin Exp Immunol. 1991; 86(2): 266-270.

[56]

Kim YT, Steinberg C. Immunologic studies on the induction of diabetes in experimental animals. Cellular basis for the induction of diabetes by streptozotocin. Diabetes. 1984; 33(8): 771-777.

[57]

McGinty JW, Marré ML, Bajzik V, Piganelli JD, James EA. T cell epitopes and post-translationally modified epitopes in type 1 diabetes. Curr Diab Rep. 2015; 15(11): 90.

[58]

Luo Z, Soläng C, Mejia-Cordova M, et al. Kinetics of immune cell responses in the multiple low-dose streptozotocin mouse model of type 1 diabetes. FASEB Bioadv. 2019; 1(9): 538-549.

[59]

Lin M, Yin N, Murphy B, et al. Immune cell-derived c3 is required for autoimmune diabetes induced by multiple low doses of streptozotocin. Diabetes. 2010; 59(9): 2247-2252.

[60]

Elliott JI, Dewchand H, Altmann DM. Streptozotocin-induced diabetes in mice lacking alphabeta T cells. Clin Exp Immunol. 1997; 109(1): 116-120.

[61]

De George DJ, Ge T, Krishnamurthy B, Kay TWH, Thomas HE. Inflammation versus regulation: how interferon-gamma contributes to type 1 diabetes pathogenesis. Front Cell Dev Biol. 2023; 11: 1205590.

[62]

Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol. 2012; 3: 51.

[63]

Yu H, Paiva R, Flavell RA. Harnessing the power of regulatory T-cells to control autoimmune diabetes: overview and perspective. Immunology. 2018; 153(2): 161-170.

[64]

Nikolic I, Saksida T, Mangano K, et al. Pharmacological application of carbon monoxide ameliorates islet-directed autoimmunity in mice via anti-inflammatory and anti-apoptotic effects. Diabetologia. 2014; 57(5): 980-990.

[65]

Vujicic M, Saksida T, Mostarica Stojkovic M, Djedovic N, Stojanovic I, Stosic-Grujicic S. Protective effects of carbonyl iron against multiple low-dose streptozotocin-induced diabetes in rodents. J Cell Physiol. 2018; 233(6): 4990-5001.

[66]

Koprivica I, Vujičić M, Gajić D, Saksida T, Stojanović I. Ethyl pyruvate stimulates regulatory T cells and ameliorates type 1 diabetes development in mice. Front Immunol. 2019; 9: 3130.

[67]

Koprivica I, Gajic D, Saksida T, et al. Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice. Eur J Pharmacol. 2019; 864: 172721.

[68]

Koprivica I, Jonić N, Diamantis D, et al. Phenethyl ester of rosmarinic acid attenuates autoimmune responses during type 1 diabetes development in mice. Life Sci. 2022; 288: 120184.

[69]

Elias D, Prigozin H, Polak N, Rapoport M, Lohse AW, Cohen IR. Autoimmune diabetes induced by the beta-cell toxin STZ. Immunity to the 60-kDa heat shock protein and to insulin. Diabetes. 1994; 43(8): 992-998.

[70]

Wei L, Lu Y, He S, et al. Induction of diabetes with signs of autoimmunity in primates by the injection of multiple-low-dose streptozotocin. Biochem Biophys Res Commun. 2011; 412(2): 373-378.

[71]

Lucier J, Mathias PM, Doerr C. Type 1 diabetes (nursing). StatPearls [Internet]. StatPearls Publishing; 2024.

[72]

Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017; 40(1): 136-154.

[73]

Yang K, Wang Y, Li YW, et al. Progress in the treatment of diabetic peripheral neuropathy. Biomed Pharmacother. 2022; 148: 112717.

[74]

Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005; 293(2): 217-228.

[75]

Singh A, Raghav A, Shiekh PA, Kumar A. Transplantation of engineered exosomes derived from bone marrow mesenchymal stromal cells ameliorate diabetic peripheral neuropathy under electrical stimulation. Bioact Mater. 2021; 6(8): 2231-2249.

[76]

Sullivan KA, Hayes JM, Wiggin TD, et al. Mouse models of diabetic neuropathy. Neurobiol Dis. 2007; 28(3): 276-285.

[77]

Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: distinct or continuum? Indian J Endocrinol Metab. 2016; 20(4): 546-551.

[78]

Qu C, Tan X, Hu Q, et al. A systematic review of astragaloside IV effects on animal models of diabetes mellitus and its complications. Heliyon. 2024; 10(5): e26863.

[79]

Samsu N. Diabetic nephropathy: challenges in pathogenesis, diagnosis, and treatment. Biomed Res Int. 2021; 2021(1): 1497449.

[80]

Wang ZS, Xiong F, Xie XH, Chen D, Pan JH, Cheng L. Astragaloside IV attenuates proteinuria in streptozotocin-induced diabetic nephropathy via the inhibition of endoplasmic reticulum stress. BMC Nephrol. 2015; 16: 44.

[81]

Rossi C, Marzano V, Consalvo A, et al. Proteomic and metabolomic characterization of streptozotocin-induced diabetic nephropathy in TIMP3-deficient mice. Acta Diabetol. 2018; 55(2): 121-129.

[82]

Greenhalgh DG. Wound healing and diabetes mellitus. Clin Plast Surg. 2003; 30(1): 37-45.

[83]

Yang H, Song L, Sun B, et al. Modulation of macrophages by a paeoniflorin-loaded hyaluronic acid-based hydrogel promotes diabetic wound healing. Mater Today Bio. 2021; 12: 100139.

[84]

Huyan T, Fan L, Zheng ZY, et al. ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway. Acta Pharmacol Sin. 2024; 45: 1477-1491.

[85]

Chen S, Li Y, Song W, et al. Insulin eye drops improve corneal wound healing in STZ-induced diabetic mice by regulating corneal inflammation and neuropeptide release. BMC Ophthalmol. 2024; 24(1): 155.

[86]

Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci USA. 2011; 108(28): 11548-11553.

[87]

Hamilton SE, Badovinac VP, Beura LK, et al. New insights into the immune system using dirty mice. J Immunol. 2020; 205(1): 3-11.

[88]

Limoges MA, Cloutier M, Nandi M, Ilangumaran S, Ramanathan S. The GIMAP family proteins: an incomplete puzzle. Front Immunol. 2021; 12: 679739.

[89]

Lenzen S, Arndt T, Elsner M, Wedekind D, Jörns A. Rat models of human type 1 diabetes. Methods Mol Biol. 2020; 2128: 69-85.

[90]

Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001; 50(6): 537-546.

[91]

Li Z, Zhao L, Sandler S, Karlsson FA. Expression of pancreatic islet MHC class I, insulin, and ICA 512 tyrosine phosphatase in low-dose streptozotocin-induced diabetes in mice. J Histochem Cytochem. 2000; 48(6): 761-767.

[92]

Hässler S, Peltonen L, Sandler S, Winqvist O. Aire deficiency causes increased susceptibility to streptozotocin-induced murine type 1 diabetes. Scand J Immunol. 2008; 67(6): 569-580.

[93]

Nakayama M, Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005; 435(7039): 220-223.

[94]

Elso CM, Scott NA, Mariana L, et al. Replacing murine insulin 1 with human insulin protects NOD mice from diabetes. PLoS One. 2019; 14(12): e0225021.

[95]

Ben-Nun A, Wekerle H, Cohen IR. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol. 1981; 11(3): 195-199.

[96]

Bartholomäus I, Kawakami N, Odoardi F, et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature. 2009; 462(7269): 94-98.

[97]

Kawakami N, Nägerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flügel A. Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J Exp Med. 2005; 201(11): 1805-1814.

[98]

Lodygin D, Odoardi F, Schläger C, et al. A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity. Nat Med. 2013; 19(6): 784-790.

[99]

Abuqwider J, Corrado A, Scidà G, et al. Gut microbiome and blood glucose control in type 1 diabetes: a systematic review. Front Endocrinol (Lausanne). 2023; 14: 1265696.

[100]

Costa FR, Françozo MC, de Oliveira GG, et al. Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset. J Exp Med. 2016; 213(7): 1223-1239.

[101]

Nopparat J, Khuituan P, Peerakietkhajorn S, Teanpaisan R. Probiotics of Lacticaseibacillus paracasei SD1 and Lacticaseibacillus rhamnosus SD11 attenuate inflammation and β-cell death in streptozotocin-induced type 1 diabetic mice. PLoS One. 2023; 18(4): e0284303.

[102]

Saksida T, Paunović V, Koprivica I, et al. Development of type 1 diabetes in mice is associated with a decrease in IL-2-producing ILC3 and FoxP3+ Treg in the small intestine. Molecules. 2023; 28(8): 3366.

[103]

Berer K, Gerdes LA, Cekanaviciute E, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci USA. 2017; 114(40): 10719-10724.

[104]

Al Nabhani Z, Eberl G. Imprinting of the immune system by the microbiota early in life. Mucosal Immunol. 2020; 13(2): 183-189.

[105]

Fujimoto K, Miyaoka D, Uematsu S. Characterization of the human gut virome in metabolic and autoimmune diseases. Inflamm Regen. 2022; 42(1): 32.

[106]

Hosang L, Canals RC, van der Flier FJ, et al. The lung microbiome regulates brain autoimmunity. Nature. 2022; 603(7899): 138-144.

[107]

Jaakkola I, Jalkanen S, Hänninen A. Diabetogenic T cells are primed both in pancreatic and gut-associated lymph nodes in NOD mice. Eur J Immunol. 2003; 33(12): 3255-3264.

[108]

Chakir H, Lefebvre DE, Wang H, Caraher E, Scott FW. Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats. Diabetologia. 2005; 48(8): 1576-1584.

[109]

Jacob N, Jaiswal S, Maheshwari D, et al. Butyrate induced Tregs are capable of migration from the GALT to the pancreas to restore immunological tolerance during type-1 diabetes. Sci Rep. 2020; 10(1): 19120.

[110]

Yu H, Gagliani N, Ishigame H, et al. Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development. Proc Natl Acad Sci USA. 2017; 114(39): 10443-10448.

[111]

Stojanović I, Saksida T, Miljković Đ, Pejnović N. Modulation of intestinal ILC3 for the treatment of type 1 diabetes. Front Immunol. 2021; 12: 653560.

[112]

Lazarević M, Stegnjaić G, Jevtić B, et al. Increased regulatory activity of intestinal innate lymphoid cells type 3 (ILC3) prevents experimental autoimmune encephalomyelitis severity. J Neuroinflammation. 2024; 21(1): 26.

[113]

Kiesel U, Kolb H. Low-dose streptozotocin-induced autoimmune diabetes is under the genetic control of the major histocompatibility complex in mice. Diabetologia. 1982; 23(1): 69-71.

[114]

Jederström G, Gråsjö , Nordin A, Sjöholm I, Andersson A. Blood glucose-lowering activity of a hyaluronan-insulin complex after oral administration to rats with diabetes. Diabetes Technol Ther. 2005; 7(6): 948-957.

[115]

Kargar C, Ktorza A. Anatomical versus functional beta-cell mass in experimental diabetes. Diabetes Obes Metab. 2008; 10(Suppl 4): 43-53.

[116]

Kiesel U, Falkenberg FW, Kolb H. Genetic control of low-dose streptozotocin-induced autoimmune diabetes in mice. J Immunol. 1983; 130(4): 1719-1722.

[117]

Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin N Am. 2010; 39(3): 481-497.

[118]

Rossini AA, Williams RM, Appel MC, Like AA. Sex differences in the multiple-dose streptozotocin model of diabetes. Endocrinology. 1978; 103(4): 1518-1520.

[119]

Kim B, Kim YY, Nguyen PTT, Nam H, Suh JG. Sex differences in glucose metabolism of streptozotocin-induced diabetes inbred mice (C57BL/6J). Appl Biol Chem. 2020; 63: 59.

[120]

Wilcox NS, Rui J, Hebrok M, Herold KC. Life and death of β cells in type 1 diabetes: a comprehensive review. J Autoimmun. 2016; 71: 51-58.

[121]

Morgan NG. Insulitis in human type 1 diabetes: lessons from an enigmatic lesion. Eur J Endocrinol. 2024; 190(1): R1-R9.

[122]

Lukić ML, Stosić-Grujicić S, Shahin A. Effector mechanisms in low-dose streptozotocin-induced diabetes. Dev Immunol. 1998; 6(1-2): 119-128.

[123]

Davanso MR, Crisma AR, Braga TT, et al. Macrophage inflammatory state in type 1 diabetes: triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid. Clin Sci (Lond). 2021; 135(1): 19-34.

[124]

Obeagu EI, Obeagu GU. Type 1 diabetes mellitus: roles of neutrophils in the pathogenesis. Medicine (Baltimore). 2023; 102(50): e36245.

[125]

Huang J, Xiao Y, Xu A, Zhou Z. Neutrophils in type 1 diabetes. J Diabetes Investig. 2016; 7(5): 652-663.

[126]

Petrelli A, Popp SK, Fukuda R, Parish CR, Bosi E, Simeonovic CJ. The contribution of neutrophils and NETs to the development of type 1 diabetes. Front Immunol. 2022; 13: 930553.

[127]

Valle A, Giamporcaro GM, Scavini M, et al. Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Diabetes. 2013; 62(6): 2072-2077.

[128]

Nabi AH, Islam LN, Rahman MM, Biswas KB. Polymorphonuclear neutrophil dysfunctions in streptozotocin-induced type 1 diabetic rats. J Biochem Mol Biol. 2005; 38(6): 661-667.

[129]

Uno S, Imagawa A, Okita K, et al. Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-alpha in patients with recent-onset type 1 diabetes. Diabetologia. 2007; 50(3): 596-601.

[130]

Pugliese A. Autoreactive T cells in type 1 diabetes. J Clin Invest. 2017; 127(8): 2881-2891.

[131]

Yue M, He X, Min X, et al. The role of islet autoantigen-specific T cells in the onset and treatment of type 1 diabetes mellitus. Front Immunol. 2024; 15: 1462384.

[132]

Burrack AL, Martinov T, Fife BT. T cell-mediated Beta cell destruction: autoimmunity and Alloimmunity in the context of type 1 diabetes. Front Endocrinol (Lausanne). 2017; 8: 343.

[133]

Roep BO. The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure. Diabetologia. 2003; 46(3): 305-321.

[134]

Goyal SN, Reddy NM, Patil KR, et al. Challenges and issues with streptozotocin-induced diabetes - a clinically relevant animal model to understand the diabetes pathogenesis and evaluate therapeutics. Chem Biol Interact. 2016; 244: 49-63.

[135]

Singh K, Kadesjö E, Lindroos J, Sandler S, Thorvaldson L. Functional impairment of regulatory T cell in multiple low dose streptozotocin induced murine diabetes (P3099). J Immunol. 2013; 190(Supplement_1): 43.11.

[136]

Hull CM, Peakman M, Tree TIM. Regulatory T cell dysfunction in type 1 diabetes: what's broken and how can we fix it? Diabetologia. 2017; 60(10): 1839-1850.

[137]

Zhu BT. Pathogenic mechanism of autoimmune diabetes mellitus in humans: potential role of Streptozotocin-induced selective autoimmunity against human islet β-cells. Cells. 2022; 11(3): 492.

[138]

Eizirik DL, Darville MI. Beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes. Diabetes. 2001; 50(Suppl 1): S64-S69.

[139]

Brady V. Management of immunotherapy-induced type 1 diabetes. Crit Care Nurs Clin North Am. 2025; 37(1): 93-102.

[140]

Stojanovic I, Dimitrijevic M, Vives-Pi M, et al. Cell-based tolerogenic therapy, experience from animal models of multiple sclerosis, type 1 diabetes and rheumatoid arthritis. Curr Pharm Des. 2017; 23(18): 2623-2643.

[141]

Zheng P, Li Z, Zhou Z. Gut microbiome in type 1 diabetes: a comprehensive review. Diabetes Metab Res Rev. 2018; 34(7): e3043.

[142]

Fu H, Vuononvirta J, Fanti S, et al. The glucose transporter 2 regulates CD8+ T cell function via environment sensing. Nat Metab. 2023; 5(11): 1969-1985.

[143]

Queiroz LAD, Assis JB, Guimarães JPT, et al. Endangered lymphocytes: the effects of Alloxan and Streptozotocin on immune cells in type 1 induced diabetes. Mediat Inflamm. 2021; 2021: 9940009.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.

AI Summary AI Mindmap
PDF

20

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/