Efficient and Safe Induction of Diabetes in Experimental Animals: A Review on Alternative Models and Techniques

Main Article Content

Kalpana Sen
Trilochan Satapathy

Abstract

Diabetes Mellitus (DM) is a multitudinous metabolic disorder that can occur due to insufficient or inefficient levels of insulin that leads to hyperglycemia. In many conditions, diabetes can also directly or indirectly lead to other functional disorders such as dyslipidemia and hypertension making them more severe and life-threatening. It is believed that Type 1 Diabetes can be caused by to process of auto-immune destruction of beta-cells of Islet of Langerhans of the pancreas responsible for the production of insulin whereas Type 2 diabetes is because of resistance against insulin along with the futilities of beta-cells to compensate the body with the required amount of insulin. The animal models are considered an essential component in the experimental studies and drug discovery process. Animal models provide safety, effectiveness, and dose of the test substance that needs to be extrapolated to human use. There are several methods for the induction of diabetes in experimental animal models. The present review aimed to discuss and explore currently used approaches including models from streptozotocin-induced diabetes to transgenic models for reproducible and safe diabetes induction in different experimental animals (rats, mice, guinea pigs, and dogs) and sex. Additionally, some genetically modified animal models are also included and discussed in this review which will pave the way for further studies.


 

Article Details

How to Cite
Sen, K., & Satapathy, T. (2024). Efficient and Safe Induction of Diabetes in Experimental Animals: A Review on Alternative Models and Techniques. Journal of Lab Animal Research, 3(5), 27–39. https://doi.org/10.58803/jlar.v3i5.47
Section
Review Article

References

Mishra G, Panda PK et al. Animal models for type 2 diabetes: A review. World Journal of Pharmaceutical Sciences. 2016: 141-7.

Kottaisamy CPD, Raj DS et al. Experimental animal models for diabetes and its related complications-a review. Lab Anim Res. 2021; 37(1):23. DOI: 10.1186/s42826-021-00101-4

Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australas Med J. 2014; 7(1):45–48. DOI: 10.4066/AMJ.2013.1979.

Yesudian CA, Grepstad M et al. The economic burden of diabetes in India: a review of the literature. Global Health. 2014; 10: 80. DOI: 10.1186/s12992-014-0080-x.

Ogurtsova K, da Rocha Fernandes JD et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017; 128: 40–50. DOI-10.1016/j.diabres.2017.03.024.

Dewangan H, Tiwari RK et al. Past and Future of in-vitro and in-vivo Animal Models for Diabetes: A Review. Indian Journal of Pharmaceutical Education and Research. 2017; 51(4S): s522-30. DOI: 10.5530/ijper.51.4s.79.

Athmuri DN, Shiekh PA. Experimental diabetic animal models to study diabetes and diabetic complications. MethodsX. 2023; 11: 102474. DOI-10.1538/expanim1978.29.1_1.

Sharma P, Garg A et al. Animal model used for experimental study of diabetes mellitus: an overview. Asian J. Biomater. Res. 2016; 2: 99–110.

Bryda EC. The mighty mouse: the impact of rodents on advances in biomedical research.Mol. Med. 2013; 110: 207.

Qamar F, Sultana S, Sharma M. Animal models for induction of diabetes and its complications. Journal of Diabetes & Metabolic Disorders. 2023; 22(2):1021-8. https://doi.org/10.1007/s40200-023-01277-3

Ragbetli C, Dede S, et al. The serum protein fractions in streptozotocin (STZ) administrated rat models. Pharmacognosy Journal. 2017; 9(1). DOI:10.5530/pj.2017.1.7

Bailey CC. Alloxan diabetes. InVitamins & Hormones 1949; 7: 365-382. Academic Press. https://doi.org/10.1016/S0083-6729(08)60833-X

Szkudelski T. Streptozotocin–nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Experimental biology and medicine. 2012; 237(5):481-90. https://doi.org/10.1258/ebm.2012.011372

Zhautikova SB, Abdikadirova KR, et al. Clinical and laboratory assessment of hormonal and metabolic disorders in experimental animals with alloxan, streptozotocin and dithizone diabetes. Bulletin of the Karaganda University Biology. Medicine. Geography series. 2023; 111(3):206-15. https://doi.org/10.31489/2023bmg3/206-215

Trivedi NA, Mazumdar B, et al. Effect of shilajit on blood glucose and lipid profile in alloxan-induced diabetic rats. Indian journal of pharmacology. 2004; 36(6):373-6.

Berger MR, Fink M, et al. Effects of diazoxide-induced reversible diabetes on chemically induced autochthonous mammary carcinomas in Sprague-Dawley rats. Int J Cancer. 1985; 35(3):395-401. doi: 10.1002/ijc.2910350316.

Rodrigues R. A Comprehensive Review: The Use of Animal Models in Diabetes Research. J Anal Pharm Res. 2016; 3(5): 00071. DOI: 10.15406/japlr.2016.03.00071

Yaku, K, Okabe, K, et al. Metabolism and biochemical properties of nicotinamide adenine dinucleotide (NAD) analogs, nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD). Sci Rep.2019; 9, 13102 (2019). https://doi.org/10.1038/s41598-019-49547-6

Hwang JL, Weiss RE. Steroid-induced diabetes: a clinical and molecular approach to understanding and treatment. Diabetes Metab Res Rev. 2014; 30(2):96-102. doi: 10.1002/dmrr.2486.

Nagata M, Nakajima M, et al. Mechanism underlying induction of hyperglycemia in rats by single administration of olanzapine. Biological and Pharmaceutical Bulletin. 2016; 39(5):754-61. https://doi.org/10.1248/bpb.b15-00842

Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001; 50(6):537-46.

Rakieten N, Rakieten ML et al. Studies on the diabetogenic action of streptozotocin (NSC-37917). Cancer Chemother Rep. 1963; 29:91-8.

Satapathy T, Chitra KS et al. Single dose drug interaction study between anti-hypertensive drug valsartan on anti-diabetic effect of sulphonylureas in normal and streptozotocin induced diabetic rats. International Journal of Medicobiological Research. 2013; 1(7): 356-360.

Dekel Y, Glucksam Y et al. Insights into modeling streptozotocin-induced diabetes in ICR mice. Lab Anim (NY). 2009; 38: 55–60. DOI-10.1038/laban0209-55.

Ghasemi A, Khalifi S et al. Streptozotocin-nicotinamide-induced rat model of type 2 diabetes. Acta Physiologica Hungarica. 2014; 101(4):408-20. DOI-10.1556/APhysiol.101.2014.4.2.

Lakshmi V, Agarwal SK et al. Antidiabetic potential of Musa paradisiaca in Streptozotocin-induced diabetic rats. J Phytopharmacol. 2014; 3(2):77-81.

Arulmozhi DK, Veeranjaneyulu A et al. Neonatal streptozotocin-induced rat model of Type 2 diabetes mellitus: A glance. Indian Journal of Pharmacology. 2004; 36(4):217. DOI-10.1155%2F2014%2F463264.

Srinivasan K, Viswanad B et al. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacological research. 2005; 52(4):313-20. DOI-10.1016/j.phrs.2005.05.004.

Frerichs H, Creutzfeldt W. In: Handbook of Experimental Pharmacology. Der experimentelle chemische Diabetes. 1971; 32/1: 159–202.

Maske H, Weinges K. The reaction of the guineapig to some substances producing diabetes. Alloxan and dithizone. Archiv fur experimentelle Pathologie und Pharmakologie. 1957; 230:406-20.

Malaisse WJ. Alloxan toxicity to the pancreatic B-cell: A new hypothesis. Biochemical pharmacology. 1982; 31(22):3527-34. DOI-10.1016/0006-2952(82)90571-8.

BAILEY CC, BAILEY OT. The production of diabetes mellitus in rabbits with alloxan: A preliminary report. Journal of the American Medical Association. 1943; 122(17):1165-6. DOI:10.1001/jama.1943.02840340013004.

Katsumata K, Katsumata Y et al. Potentiating effects of combined usage of three sulfonylurea drugs on the occurrence of alloxan diabetes in rats. Hormone and metabolic research. 1993; 25(02):125-6. DOI: 10.1055/s-2007-1002058.

Goldner MG, Gomori G. Alloxan diabetes in the dog. Endocrinology. 1943; 33(5):297-308. DOI-10.1210/endo-33-5-297.

Maqbool M, Dar MA et al. Animal models in diabetes mellitus: an overview. Journal of Drug Delivery and Therapeutics. 2019; 9(1-s):472-5. DOI-10.22270/jddt.v9i1-s.2351.

Pezzilli R. Diabetic control after total pancreatectomy. Digestive and liver disease. 2006; 38(6):420-2. DOI-10.1016/j.dld.2006.02.007.

Menge BA, Tannapfel A, et al. Partial pancreatectomy in adult humans does not provoke β-cell regeneration. Diabetes. 2008; 57(1):142-9. https://doi.org/10.2337/db07-1294

Sutton R, Peters M, et al. Isolation of Rat Pancreatic Islets by Ductal Injection of collagenase1. Transplantation. 1986; 42(6):689-90.

Hocking SL, Chisholm DJ, et al. Studies of regional adipose transplantation reveal a unique and beneficial interaction between subcutaneous adipose tissue and the intra-abdominal compartment. Diabetologia. 2008; 51:900-2. https://doi.org/10.1007/s00125-008-0969-0

Fahmy MK, Sayyed HG, et al. Superimposed effect of ovariectomy on type 2 diabetes mellitus in Wistar rats. Alexandria journal of medicine. 2018; 54(2):129-37. DOI: 10.1016/j.ajme.2017.05.011.

Maqbool M, Dar MA, et al. Animal models in diabetes mellitus: an overview. Journal of Drug Delivery and Therapeutics. 2019; 9(1-s):472-5. DOI: https://doi.org/10.22270/jddt.v9i1-s.2351

Rankin MM, Wilbur CJ, et al. β-Cells are not generated in pancreatic duct ligation–induced injury in adult mice. Diabetes. 2013; 62(5):1634-45. https://doi.org/10.2337/db12-0848

Rubino F, Marescaux J. Effect of duodenal–jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Annals of surgery. 2004; 239(1):1. DOI-10.1097%2F01.sla.0000102989.54824.fc.

Ward WK, Wallum BJ et al. Reduction of glycemic potentiation: sensitive indicator of β-cell loss in partially pancreatectomized dogs. Diabetes. 1988; 37(6):723-9. DOI-10.2337/diab.37.6.723.

Chen X, Huang Z et al. Type 2 diabetes mellitus control and atherosclerosis prevention in a non‑obese rat model using duodenal‑jejunal bypass. Experimental and therapeutic medicine. 2014; 8(3):856-62. DOI: 10.3892/etm.2014.1832.

McCarthy MI, Froguel P. Genetic approaches to the molecular understanding of type 2 diabetes. American Journal of Physiology-Endocrinology and Metabolism. 2002; 283(2):E217-25. https://doi.org/10.1152/ajpendo.00099.2002

Islam MS, Wilson RD. Experimentally induced rodent models of type 2 diabetes. Animal models in diabetes research. 2012:161-74. DOI: 10.1007/978-1-62703-068-7_10.

Lernmark A. The preparation of, and studies on, free cell suspensions from mouse pancreatic islets. Diabetologia. 1974; 10(5):431-8. https://doi.org/10.1007/BF01221634

Tsuchitani M, Saegusa T, et al. A new diabetic strain of rat (WBN/Kob). Laboratory animals. 1985; 19(3):200-7. https://doi.org/10.1258/002367785780893575

Weksler-Zangen S, Orlanski E, Zangen DH. 15 Cohen Diabetic Rat. Animal Models of Diabetes: Frontiers in Research. 2007:323.

Goto Y, Kakizaki M, Masaki N. Production of spontaneous diabetic rats by repetition of selective breeding. The Tohoku journal of experimental medicine. 1976; 119(1):85-90. https://doi.org/10.1620/tjem.119.85

Komeda K, Noda M, et al. Establishment of two substrains, diabetes-prone and non-diabetic, from Long-Evans Tokushima Lean (LETL) rats. Endocrine journal. 1998; 45(6):737-44. https://doi.org/10.1507/endocrj.45.737

Tofovic SP, Jackson EK. Rat models of the metabolic syndrome. Renal Disease: Techniques and Protocols. 2003:29-46. https://doi.org/10.1385/1-59259-392-5:29

Kumar S, Singh R, et al. Acute and chronic animal models for the evaluation of anti-diabetic agents. Cardiovascular diabetology. 2012; 11:1-3. https://doi.org/10.1186/1475-2840-11-9

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(11):1422-8. https://doi.org/10.2337/diab.41.11.1422

Kobayashi M, Iwanishi M et al. Pioglitazone increases insulin sensitivity by activating insulin receptor kinase. Diabetes. 1992; 41(4):476-83. DOI: 10.2337/diab.41.4.476.

Koletsky S. Obese spontaneously hypertensive rats—a model for study of atherosclerosis. Experimental and molecular pathology. 1973; 19(1):53-60. DOI: 10.1016/0014-4800(73)90040-3.

Shafrir EL, Sima AA. Diabetic animals for research into the complications: A general overview. Chronic complications in diabetes. Frontiers in animal diabetes research. 2000; 1:1-42.

Berdanier CD. The BHE rat: An animal model for the study of non‐insulin‐dependent diabetes mellitus. The FASEB journal. 1991; 5(8):2139-44. DOI: 10.1096/fasebj.5.8.2022312.

Wakasugi N, Tomita T, Kondo K. Differences of fertility in reciprocal crosses between inbred strains of mice: DDK, KK and NC. Reproduction. 1967; 13(1):41-50. https://doi.org/10.1530/jrf.0.0130041

Iwatsuka H, Shino A, Suzuoki Z. General survey of diabetic features of yellow KK mice. Endocrinologia japonica. 1970; 17(1):23-35. https://doi.org/10.1507/endocrj1954.17.23

Ogawa M, Murayama T, et al. The inhibitory effect of neonatal thymectomy on the incidence of insulitis in non-obese diabetes (NOD) mice. Biomedical research. 1985; 6(2):103-5. https://doi.org/10.2220/biomedres.6.103

Yoshioka M, Kayo T, et al. A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes. 1997; 46(5):887-94. https://doi.org/10.2337/diab.46.5.887

Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science. 1966; 153(3740):1127-8.

Sunnemark D, Harris RA, et al. Induction of early atherosclerosis in CBA/J mice by combination of Trypanosoma cruzi infection and a high cholesterol diet. Atherosclerosis. 2000; 153(2):273-82. https://doi.org/10.1016/S0021-9150(00)00406-8

Gould CL, McMannama KG et al. Virus-induced murine diabetes: enhancement by immunosuppression. Diabetes. 1985; 34(12):1217-21. DOI-10.2337/diab.34.12.1217.

Jun HS, Yoon JW. The role of viruses in type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals. Diabetologia. 2001; 44:271-85. DOI-10.1007/s001250051614.

Hirasawa K, Kim A et al. Effect of p38 mitogen-activated protein kinase on the replication of encephalomyocarditis virus. Journal of virology. 2003; 77(10):5649-56. DOI: 10.1128/JVI.77.10.5649-5656.2003.

Horwitz MS, Bradley LM et al. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nature medicine. 1998; 4(7):781-5. DOI-10.1038/nm0798-781.

Bhattacharya S, Kalra S, et al. The Interplay Between Pituitary Health and Diabetes Mellitus–The Need for ‘Hypophyseo-vigilance’. European Endocrinology. 2020; 16(1):25. doi: 10.17925/EE.2020.16.1.25

Cotes PM, Reid E et al. Diabetogenic action of pure anterior pituitary growth hormone. Nature. 1949; 164(4162):209-11. DOI: 10.1038/164209a0.

Ingle DJ, Li CH et al. The effect of adrenocorticotrophic hormone on the urinary excretion of sodium, chloride, potassium, nitrogen and glucose in normal rats. Endocrinology. 1946; 39(1):32-42. DOI-10.1210/endo-39-1-32.

Gao J, Gu X et al. Impaired glucose tolerance in a mouse model of sidt2 deficiency. PLoS One. 2013; 8(6):e66139. DOI-10.1371/journal.pone.0066139

Nagy C, Einwallner E. Study of in vivo glucose metabolism in high-fat diet-fed mice using oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Journal of visualized experiments: JoVE. 2018(131). doi: 10.3791/56672

Liang Y, Arakawa K, et al. Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. PloS one. 2012; 7(2):e30555. https://doi.org/10.1371/journal.pone.0030555

Chatenoud L. Immune therapy for type 1 diabetes mellitus—what is unique about anti-CD3 antibodies?. Nature Reviews Endocrinology. 2010; 6(3):149-57. https://doi.org/10.1038/nrendo.2009.275

Moloney PJ, Coval M. Antigenicity of insulin: diabetes induced by specific antibodies. Biochemical journal. 1955; 59(2):179. DOI: 10.1042/bj0590179

Wright PH. The production of experimental diabetes by means of insulin antibodies. The American Journal of Medicine. 1961; 31(6):892-900. DOI-10.1016/0002-9343(61)90031-6.

Kurtz, A. Insulin antibodies. Immunology of Endocrine Diseases. Dordrecht: Springer Netherlands. 1991: 89-102. https://doi.org/10.1007/978-94-009-4171-7_5

Pope CG. The immunology of insulin. Advances in immunology. 1966; 5:209-44. DOI- 10.1016/S0065-2776(08)60274-6.

Kottaisamy CPD, Raj DS, et al. Experimental animal models for diabetes and its related complications-a review. Lab Anim Res. 2021; 37(1):23. doi: 10.1186/s42826-021-00101-4. PMID: 34429169; PMCID: PMC8385906.

Athmuri DN, Sheikh PA. Experimental diabetic animal models to study diabetes and diabetic complications. MethodsX. 2023; 11:102474. https://doi.org/10.1016/j.mex.2023.102474

Chrissobolis S, Miller AA, et al. Oxidative stress and endothelial dysfunction in cerebrovascular disease. Front Biosci. 2011; 16(1):1733-45.

Al-Kharashi AS. Role of oxidative stress, inflammation, hypoxia and angiogenesis in the development of diabetic retinopathy. Saudi journal of ophthalmology. 2018; 32(4):318-23. https://doi.org/10.1016/j.sjopt.2018.05.002

Tarquini R, Lazzeri C, et al. The diabetic cardiomyopathy. Acta diabetologica. 2011;48:173-81. https://doi.org/10.1007/s00592-010-0180-x

Dobretsov M, Romanovsky D, et al. Early diabetic neuropathy: triggers and mechanisms. World journal of gastroenterology: WJG. 2007; 13(2):175. doi: 10.3748/wjg.v13.i2.175.

Chawla T, Sharma D, et al. Role of the renin angiotensin system in diabetic nephropathy. World journal of diabetes. 2010; 1(5):141. doi: 10.4239/wjd.v1.i5.141.

Lassen E, Daehn IS. Molecular mechanisms in early diabetic kidney disease: glomerular endothelial cell dysfunction. International journal of molecular sciences. 2020; 21(24):9456. https://doi.org/10.3390/ijms21249456

Baltzis D, Eleftheriadou I, et al. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights. Advances in therapy. 2014; 31:817-36. https://doi.org/10.1007/s12325-014-0140-x