Animal Models of Diabetes and Complications for Studying Disease Mechanisms

Asli San Dagli Gul, OKAN ARIHAN

  • OKAN ARIHAN: HACETTEPE ÜNİVERSİTESİ
  • Year : 2025
  • Vol : 41
  • Issue : 2
  •  Page : 99-109
ABSTRACT
This review aims to examine the use and effectiveness of animal models in understanding the pathophysiology and complications of diabetes. This review includes an analysis of recent literature investigating diabetes-related complications in animal models. Only English-language articles were included, with the majority published after 2018. Chemical models such as Alloxan and Streptozotocin (STZ) effectively induce diabetes; however, they may cause toxicity and systemic side effects. While Alloxan triggers Type 1 diabetes through β-cell toxicity, STZ is preferred for modeling both Type 1 and Type 2 diabetes. Genetic models, such as NOD mice simulating autoimmune diabetes or db/db mice developing obesity-induced diabetes, provide advantages in studying the genetic aspects of the disease. However, these models have drawbacks, including high costs and complexity. Surgical approaches offer valuable insights into insulin secretion and pancreatic function, but their invasive nature and potential physiological differences pose limitations. Most models demonstrate that oxidative stress and inflammation associated with diabetes lead to complications such as nephropathy, retinopathy, neuropathy, and cardiovascular diseases. Specifically, diabetic nephropathy is characterized by podocyte damage, proteinuria, and changes in glomerular filtration, while diabetic retinopathy models show vascular alterations and vision loss. Diabetic neuropathy results in sensory and motor function loss, whereas cardiovascular complications are linked to arterial stiffness, hypertension, and heart failure. Selecting the appropriate model is crucial for evaluating diabetes progression and its complications. However, each model has its unique advantages and limitations. Chemical agents offer a fast and cost-effective approach, while genetic models provide a more physiologically relevant but expensive and technically complex alternative. This review may guide researchers in selecting the most suitable animal model for diabetes studies and contribute to the development of new therapeutic strategies.
Keywords: Diabetes, Complications, Animal Model, STZ, Alloxan
Cite this Article As : Dagli Gul AS, Arihan O. Animal Models of Diabetes and Complications for Studying Disease Mechanisms. Selcuk Med J 2025;41(2): 99-109

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Conflict of interest : The authors declare that they have no conflict of interest.
This article is published under the CC BY-NC 4.0 license.
Selcuk Medical Journal
2025, Vol. 41 (2)
ISSN: 1017-6616
E-ISSN: 2149-8059
Received : , Accepted : , Published Online :

References

  1. 1. Schleicher E, Gerdes C, Petersmann A, et al. Definition, classification, and diagnosis of diabetes mellitus. Exp Clin Endocrinol Diabetes. 2022;130(S 01):S1-S8. doi: 10.1055/a-1624-2897
  2. 2. Sweeting A, Wong J, Murphy HR, et al. A clinical update on gestational diabetes mellitus. Endocr Rev. 2022;43(5):763-793. doi: 10.1210/endrev/bnac003
  3. 3. Stožer A, Paradiž Leitgeb E, Pohorec V, et al. The role of cAMP in beta cell stimulus–secretion and intercellular coupling. Cells. 2021;10(7):1658. doi: 10.3390/cells10071658
  4. 4. Mears D. Regulation of insulin secretion in islets of Langerhans by Ca²⁺ channels. J Membr Biol. 2004;200:57-66. doi: 10.1007/s00232-004-0692-9
  5. 5. de Souza AH, Tang J, Yadev AK, et al. Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets. Sci Rep. 2020;10(1):2823. 3. doi: 10.1038/s41598-020-59799-2
  6. 6. Robertson RP. Glucagon and Insulin Overview: An Odd Couple's History and Physiology. J Endocrinol. 2023; pJOE-22. doi: 10.1530/JOE-22-0224
  7. 7. Huang W, Wu T, Xie C, et al. Sensing Intra-and Extra-Cellular Ca²⁺ in the Islet of Langerhans. Adv Funct Mater. 2022;32(3):2106020. doi: 10.1002/adfm.202106020
  8. 8. Rygiel KA, Elkins JM. Recent advances in the structural biology of tyrosine kinases. Curr Opin Struct Biol. 2023;82:102665. doi: 10.1016/j.sbi.2023.102665
  9. 9. Lin J, Selicharová I, Mitrová K, et al. Targeting the insulin receptor with hormone and peptide dimers. J Pept Sci. 2023;29(4):e3461. doi: 10.1002/psc.3461
  10. 10. Hall C, Yu H, Choi E. Insulin receptor endocytosis in the pathophysiology of insulin resistance. Exp Mol Med. 2020;52(6):911-920. doi: 10.1038/s12276-020-0456-3
  11. 11. Sulaiman MK. Diabetic nephropathy: recent advances in pathophysiology and challenges in dietary management. Diabetol Metab Syndr. 2019;11:1-5. doi: 10.1186/s13098-019-0403-4
  12. 12. Jensen TS, Karlsson P, Gylfadottir SS, et al. Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management. Brain. 2021;144(6):1632-1645. doi: 10.1093/brain/awab079
  13. 13. Yang P, Feng J, Peng Q, et al. Advanced glycation end products: potential mechanism and therapeutic target in cardiovascular complications under diabetes. Oxid Med Cell Longev. 2019;2019:9570616. doi: 10.1155/2019/9570616
  14. 14. Chang M, Nguyen TT. Strategy for treatment of infected diabetic foot ulcers. Acc Chem Res. 2021;54(5):1080-1093. doi: 10.1021/acs.accounts.0c00864
  15. 15. Schneider DJ. Diabetes and thrombosis. In: Diabetes and cardiovascular disease. Springer; 2023:99-127. doi: 10.1007/978-3-031-13177-6_5
  16. 16. Kottaisamy CPD, Raj DS, Prasanth Kumar V, et al. Experimental animal models for diabetes and its related complications—a review. Lab Anim Res. 2021;37(1):1-14. doi: 10.1186/s42826-021-00101-4
  17. 17. Rees D, Alcolado J. Animal models of diabetes mellitus. Diabet Med. 2005;22(4):359-370. doi: 10.1111/j.1464-5491.2005.01499.x
  18. 18. Eulálio JMR, Ferreira ML, Silva PC, et al. Laparoscopic Pancreatectomy in Rats: The Development of an Experimental Model. J Invest Surg. 2022;35(4):776-782. doi: 10.1080/08941939.2021.1946220
  19. 19. Masiello P. Animal models of type 2 diabetes with reduced pancreatic β-cell mass. The international journal of biochemistry & cell biology. 2006;38(5-6):873-893. doi: 10.1016/j.biocel.2005.09.007
  20. 20. Case RM. Is the rat pancreas an appropriate model of the human pancreas? Pancreatology. 2006;6(3):180-190. doi: 10.1159/000091849
  21. 21. Tsuchitani M, Sato J, Kokoshima H. A comparison of the anatomical structure of the pancreas in experimental animals. J Toxicol Pathol. 2016;29(3):147-154. doi: 10.1293/tox.2016-0016
  22. 22. King AJ. The use of animal models in diabetes research. Br J Pharmacol. 2012;166(3):877-894. doi: 10.1111/j.1476-5381.2012.01911.x
  23. 23. Qamar F, Sultana S, Sharma M. Animal models for induction of diabetes and its complications. J Diabetes Metab Disord. 2023:1-8. doi: 10.1007/s40200-023-01277-3
  24. 24. Algul S, Ozcelik O. Comprehensive review of animal models in diabetes research using chemical agents. Lab Anim. 2025; p. 00236772241296199. doi: 10.1177/00236772241296199
  25. 25. Zhao ZS, Khan S, O'Brien PJ. The prevention of ferric nitrilotriacetate-induced nephro-and hepatotoxicity by methylenedioxybenzene antioxidants. Chem. Biol. Interact. 1997; 108(1-2): p. 107-118. doi: 10.1016/S0009-2797(97)00103-8.
  26. 26. Wright PH. The production of experimental diabetes by means of insulin antibodies. Am J Med. 1961 Dec; 31:892-900. doi: 10.1016/0002-9343(61)90031-6.
  27. 27. Maqbool M, Dar MA, Gani I, Mir SA. Animal models in diabetes mellitus: an overview. J Drug Deliv Ther. 2019;9(1-s):472-475. doi: 10.22270/jddt.v9i1-s.2351
  28. 28. Lenzen S. The mechanisms of alloxan-and streptozotocin-induced diabetes. Diabetologia. 2008;51(2):216-226. doi: 10.1007/s00125-007-0886-7
  29. 29. Tiedge M, Richter T, Lenzen S. Importance of cysteine residues for the stability and catalytic activity of human pancreatic beta cell glucokinase. Arch Biochem Biophys. 2000;375(2):251-260. doi: 10.1006/abbi.1999.1666
  30. 30. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001;50(6):537-546. doi: 10.33549/physiolres.933247
  31. 31. Katoh M, Sakurai K, Fujimoto Y. Alloxan radical-induced generation of reactive oxygen species in the reaction system of alloxan with ascorbate. Yakugaku Zasshi: J Pharm Soc Jpn. 2002;122(10):831-839. doi: 10.1248/yakushi.122.831
  32. 32. Aba PE, Edeh MN. Age Susceptibility of Wistar Rats to Alloxan-Induced Diabetes: A Paradox. Not Sci Biol. 2019;11(2). doi: 10.15835/nsb11210438
  33. 33. Mostafavinia A, Amini A, Ghorishi SK, et al. The effects of dosage and the routes of administrations of streptozotocin and alloxan on induction rate of type 1 diabetes mellitus and mortality rate in rats. Lab Anim Res. 2016;32:160-165. doi: 10.5625/lar.2016.32.3.160
  34. 34. Zhang M, Lv X-Y, Li J, et al. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. J Diabetes Res. 2008:704045. doi: 10.1155/2008/704045
  35. 35. Singaram S, Lawrence RS et al. Studies on the biosynthesıs of the antibıotic streptozotocin (streptozocin) by streptomyces achromogenes var. streptozoticus. J. Antibiot. 1979;32(4):379-385. doi: 10.7164/antibiotics.32.379
  36. 36. Siedlecka D, Micał W. Streptozotocin - an antibiotic used to induce diabetes on experimental animals. J educ helath sport. 2020;10(9):906-909. doi.org/10.12775/JEHS.2020.10.09.110
  37. 37. Broder LE, Carter SK. Pancreatic islet cell carcinoma: II. Results of therapy with streptozotocin in 52 patients. Ann Intern Med. 1973;79(1):108-118. doi: 10.7326/0003-4819-79-1-108
  38. 38. Ghasemi A, Jeddi S. Streptozotocin as a tool for induction of rat models of diabetes: A practical guide. EXCLI Journal. 2023;22:274. doi: 10.17179/excli2022-5720
  39. 39. McNeill JH. Experimental models of diabetes. Routledge; 2018. ISBN: 0-8493-1667-7
  40. 40. Wu J, Yan L-J. Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2015:181-188. doi: 10.2147/DMSO.S82272
  41. 41. Ghasemi A, Norouzirad R. Type 2 diabetes: an updated overview. Critical Reviews™ in Oncogenesis. 2019;24(3). doi: 10.1615/CritRevOncog.2019030976
  42. 42. Yan L-J. The nicotinamide/streptozotocin rodent model of type 2 diabetes: Renal pathophysiology and redox imbalance features. Biomolecules. 2022;12(9):1225. doi: 10.3390/biom12091225
  43. 43. Junod A, Lambert AE, Stauffacher W, et al. Diabetogenic action of streptozotocin: relationship of dose to metabolic response. The Journal of Clinical Investigation. 1969;48(11):2129-2139. doi: 10.1172/JCI106180
  44. 44. Furman BL. Streptozotocin-induced diabetic models in mice and rats. Current Protocols. 2021;1(4):e78. doi: 10.1002/cpz1.78
  45. 45. Elamin N, Fadlalla I, Omer S, et al. Histopathological alteration in STZ-nicotinamide diabetic rats, a complication of diabetes or a toxicity of STZ. Int J Diabetes Clin Res. 2018;5(3):1-8. doi: 10.23937/2377-3634/1410091
  46. 46. Gilbert ER, Fu Z, Liu D. Development of a nongenetic mouse model of type 2 diabetes. J Diabetes Res. 2011;2011(1):416254. doi: 10.1155/2011/416254
  47. 47. Qinna NA, Badwan AA. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats. Drug Des Devel Ther. 2015:2515-2525. doi: 10.2147/DDDT.S79885
  48. 48. Wszola M, Klak M, Kosowska A, et al. Streptozotocin-induced diabetes in a mouse model (BALB/c) is not an effective model for research on transplantation procedures in the treatment of type 1 diabetes. Biomedicines. 2021;9(12):1790. doi: 10.3390/biomedicines9121790
  49. 49. Wang-Fischer Y, Garyantes T. Improving the reliability and utility of streptozotocin-induced rat diabetic model. J Diabetes Res. 2018;2018(1):8054073. doi: 10.1155/2018/8054073
  50. 50. Kleinert M, Clemmensen C, Hofmann SM, et al. Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol. 2018;14(3):140-162. doi: 10.1038/nrendo.2017.161
  51. 51. González P, Lozano P, Ros G, et al. Hyperglycemia and oxidative stress: An integral, updated and critical overview of their metabolic interconnections. Int J Mol Sci. 2023;24(11):9352. doi: 10.3390/ijms24119352
  52. 52. Vianello E, Beltrami AP, Aleksova A, et al. The advanced glycation end-products (AGE)–receptor for AGE system (RAGE): An inflammatory pathway linking obesity and cardiovascular diseases. Int J Mol Sci. 2025;26(8):3707. doi: 10.3390/ijms26083707
  53. 53. Xiao Q, Wang D, Li D, et al. Protein kinase C: A potential therapeutic target for endothelial dysfunction in diabetes. J Diabetes Complications. 2023;37(9):108565. doi: 10.1016/j.jdiacomp.2023.108565
  54. 54. Tigchelaar C, van Zuylen ML, Hulst AH, et al. Elevated cerebrospinal fluid glucose levels and diabetes mellitus are associated with activation of the neurotoxic polyol pathway. Diabetologia. 2022;65(6):1098-1107. doi: 10.1007/s00125-022-05693-7
  55. 55. Dissanayake WC, Oh JK, Sorrenson B, et al. Glucose regulates expression of pro-inflammatory genes, IL-1β and IL-12, through a mechanism involving hexosamine biosynthesis pathway-dependent regulation of α-E catenin. Biosci Rep. 2021;41(7):BSR20211066. doi: 10.1042/BSR20211066
  56. 56. Dong An, Tan B, Yu DY, et al. Differentiating microaneurysm pathophysiology in diabetic retinopathy through objective analysis of capillary nonperfusion, inflammation, and pericytes. Diabetes. 2022;71(4):733-746. doi: 10.2337/db21-0737
  57. 57. Dahlin LB. The dynamics of nerve degeneration and regeneration in a healthy milieu and in diabetes. Int J Mol Sci. 2023;24(20):15241. doi: 10.3390/ijms242015241
  58. 58. Zakir M, Ahuja N, Surksha M, et al. Cardiovascular complications of diabetes: From microvascular to macrovascular pathways. Cureus. 2023;15(9):e45835. doi: 10.7759/cureus.45835
  59. 59. Maruhashi T, Higashi Y. Pathophysiological association between diabetes mellitus and endothelial dysfunction. Antioxidants (Basel). 2021;10(8):1306. doi: 10.3390/antiox10081306
  60. 60. Ren Q, Yu S, Zeng H, et al. The role of PTEN in puromycin aminonucleoside-induced podocyte injury. Int J Med Sci. 2022;19(9):1451-1459. doi: 10.7150/ijms.72988
  61. 61. Ye LX, Huang HH, Zhang SH, et al. Lu JS, Cao DX, Wu DD, Chi PW, Hong LH, Wu MX, Xu Y, Yu CX. Streptozotocin-induced hyperglycemia affects the pharmacokinetics of koumine and its anti-allodynic action in a rat model of diabetic neuropathic pain. Front Pharmacol. 2021;12:640318. doi: 10.3389/fphar.2021.640318
  62. 62. Prandi FR, Evangelista I, Sergi D, et al. Mechanisms of cardiac dysfunction in diabetic cardiomyopathy: molecular abnormalities and phenotypical variants. Heart Fail Rev. 2023;28(2):597-606. doi: 10.1007/s10741-021-10200-y
  63. 63. Hu T, Yue J, Tang Q, et al. The effect of quercetin on diabetic nephropathy (DN): A systematic review and meta-analysis of animal studies. Food Funct. 2022;13(9):4789-4803. doi: 10.1039/D1FO03958J
  64. 64. Ji J, Tao P, Wang Q, et al. SIRT1: mechanism and protective effect in diabetic nephropathy. Endocr Metab Immune Disord Drug Targets. 2021;21(5):835-842. doi: 10.2174/1871530320666201029143606
  65. 65. Cao X, Wei R, Zhou J, et al. Wenshen Jianpi recipe, a blended traditional Chinese medicine, ameliorates proteinuria and renal injury in a rat model of diabetic nephropathy. BMC Complement Altern Med. 2019;19(1):1-9. doi: 10.1186/s12906-019-2598-1
  66. 66. Jin D, Liu F, Yu M, et al. Jiedu Tongluo Baoshen formula enhances podocyte autophagy and reduces proteinuria in diabetic kidney disease by inhibiting PI3K/Akt/mTOR signaling pathway. J Ethnopharmacol. 2022;293:115246. doi: 10.1016/j.jep.2022.115246
  67. 67. Olivares AM, Althoff K, Chen GF, et al. Animal models of diabetic retinopathy. Curr Diab Rep. 2017;17:1-17. doi: I 10.1007/s11892-017-0913-0
  68. 68. Quiroz J, Yazdanyar A. Animal models of diabetic retinopathy. Ann Transl Med. 2021;9(15):1272. doi: 10.21037/atm-20-6737
  69. 69. Naderi A, Zahed R, Aghajanpour L, et al. Longterm features of diabetic retinopathy in streptozotocin-induced diabetic Wistar rats. Exp Eye Res. 2019;184:213-220. doi: 10.1016/j.exer.2019.04.025
  70. 70. de Melo IMF, Ferreira CGM, da Silva Souza EHL, et al. Melatonin regulates the expression of inflammatory cytokines, VEGF, and apoptosis in diabetic retinopathy in rats. Chem Biol Interact. 2020;327:109183. doi: 10.1016/j.cbi.2020.109183
  71. 71. Calcutt NA. Diabetic neuropathy and neuropathic pain: a (con) fusion of pathogenic mechanisms? Pain. 2020;161(Suppl 1):S65. doi: 10.1097/j.pain.0000000000001922
  72. 72. Jin HY, Moon S-S, Calcutt NA. Lost in translation? Measuring diabetic neuropathy in humans and animals. Diabetes Metab J. 2021;45(1):27-42. doi: 10.4093/dmj.2021.0034
  73. 73. Kale M, Nimje N, Aglawe MM, Umekar M, Taksande B, Kotagale N. Agmatine modulates anxiety and depression-like behaviour in diabetic insulin-resistant rats. Brain Res. 2020;1747:147045. doi: 10.1016/j.brainres.2020.147045
  74. 74. Ergenc M, Ozacmak HS, Turan I, et al. Melatonin reverses depressive and anxiety-like behaviours induced by diabetes: involvement of oxidative stress, AGE, RAGE, and S100B levels in the hippocampus and prefrontal cortex of rats. Arch Physiol Biochem. 2022;128(2):402-410. doi: 10.1080/13813455.2019.1684954
  75. 75. Yuan P, Zhang J, Li L, Song Z. Fluoxetine attenuated anxiety-like behaviors in streptozotocin-induced diabetic mice by mitigating inflammation. Mediators Inflamm. 2019;2019(1):4315038. doi: 10.1155/2019/4315038
  76. 76. Kimura N. Diabetes mellitus induces Alzheimer’s disease pathology: histopathological evidence from animal models. Int J Mol Sci. 2016;17(4):503. doi: 10.3390/ijms17040503
  77. 77. Takeda S, Sato N, Uchio-Yamada K, et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci. 2010;107(15):7036-7041. doi: 10.1073/pnas.1000645107
  78. 78. Ou Z, Deng L, Lu Z, et al. Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer’s disease. Nutr Diabetes. 2020;10(1):12. doi: 10.1038/s41387-020-0115-8
  79. 79. Matinfar P, Peeri M, Azarbayjani MA. Swimming exercise attenuates anxiety-like behavior by reducing brain oxidative stress in type 2 diabetic mice. Physiol Behav. 2021;237:113449. doi: 10.1016/j.physbeh.2021.113449
  80. 80. Margaritis I, Angelopoulou K, Lavrentiadou S, et al. Effect of crocin on antioxidant gene expression, fibrinolytic parameters, redox status, and blood biochemistry in nicotinamide-streptozotocin-induced diabetic rats. J Biol Res Thessalon. 2020;27:1-15. doi: 10.1186/s40709-020-00114-5
  81. 81. Wang K, Song F, Xu K, et al. Irisin attenuates neuroinflammation and prevents the memory and cognitive deterioration in streptozotocin-induced diabetic mice. Mediators Inflamm. 2019;2019(1):1567179. doi: 10.1155/2019/1567179
  82. 82. Keskin E, Uluisik D. The effect of melatonin on some coagulation parameters in streptozotocin-induced diabetic rats. Kocatepe Vet J. 2019;12(2):130-134. doi: 10.30607/kvj.511340
  83. 83. Iheagwam FN, Garuba PA, Ogunlana OO, Chinedu SN. Counteractive role of Terminalia catappa leaf extract on hematological and coagulation disturbance in Type 2 diabetic rats. Veterinary World. 2023;16(8):1593. doi: 10.14202/vetworld.2023.1593-1599
  84. 84. Phang SJ, Arumugam B, Kuppusamy UR, et al. A review of diabetic wound models—Novel insights into diabetic foot ulcer. J Tissue Eng Regen Med. 2021;15(12):1051-1068. doi: 10.1002/term.3246
  85. 85. Rai V, Moellmer R, Agrawal DK. Clinically relevant experimental rodent models of diabetic foot ulcer. Mol Cell Biochem. 2022;477(4):1239-1247. doi: 10.1007/s11010-022-04372-w