Animal Models in Type 2 Diabetes Mellitus Research: Pros and Cons

Zainab Zaki  Zakaria; Mousa Numan  Ahmad; Nidal Adel Qinna

doi:10.35516/jjas.v17i4.95

Authors

Zainab Zaki Zakaria University of Jordan, Amman 11942, Jordan
Mousa Numan Ahmad University of Jordan, Amman 11942, Jordan
Nidal Adel Qinna University of Petra, Amman, Jordan

DOI:

https://doi.org/10.35516/jjas.v17i4.95

Keywords:

Type 2 diabetes mellitus, Animal models, Rats, Mice, Pigs, Non-human primates

Abstract

Worldwide, the prevalence of type 2 diabetes mellitus (T2DM) continues to rise at an alarmingly high rate, constituting one of the leading causes of mortality and morbidity. Research is central to the investigation, creation, and design of new therapeutic approaches for T2DM. For this purpose, and because not many tests can be conducted on humans; so, animal models are the only currently available alternative. This article discusses the pros and cons of different animal models used in T2DM research. PubMed, Medline, Science Direct, ADI, and WHO databases were searched through June 2021. Mice and rats are the most widely used models for diabetes studies. Many other animals are also used, such as pigs and non-human primates. Animal models develop diabetes either spontaneously or by using chemical toxins, such as streptozotocin and alloxan, or by surgical or genetic techniques and depict clinical features or related phenotypes of the disease. Although their importance is generally accepted, animal models are criticized for their poor accuracy in predicting human outcomes due to the low rate of translation between preclinical and clinical studies. However, this problem is partly explained by inadequate methodologies and designs in animal trials. It remains to emphasize that animal models add an indispensable value to the basic, clinical, and applied science of T2DM by opening new avenues of research and innovation.

Downloads

Download data is not yet available.

Author Biographies

Zainab Zaki Zakaria, University of Jordan, Amman 11942, Jordan

¹Department of Nutrition and Food Technology, Human Nutrition and Dietetics, University of Jordan, Amman 11942, Jordan

Mousa Numan Ahmad, University of Jordan, Amman 11942, Jordan

Department of Nutrition and Food Technology, Human Nutrition and Dietetics, University of Jordan, Amman 11942, Jordan

Nidal Adel Qinna, University of Petra, Amman, Jordan

Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan

References

Ahmad M.N., Farah A.I., Al-qirim T.M. (2020a). The cardiovascular complications of diabetes: a striking link through protein glycation. Romanian Journal of Internal Medicine, 58(4):188-198. DOI: 10.2478/rjim-2020-0021.

Ahmad M.N., Farah A.I., Al-qirim T.M. (2020b). Examining the role of alpha-lipoic acid and epigallocatechin-c-gallate in inhibiting sugar-induced myoglobin glycation: Scientific gaps in current knowledge? Nature and Science,18(6):17-25. DOI:10.7537/marsnsj 180620.04.

Ajlouni K., Khader C., Batieha A., Jaddou H., El-Khateeb M. (2020). An Alarmingly high and increasing prevalence of obesity in Jordan. Epidemiology and Health, 42: e2020040. DOI.org/10.4178/epih.

Akbarzadeh A., Norouzian D., Mehrabi M., Jamshidi S., Farhangi A., Verdi A., et al. (2007). Induction of diabetes by streptozotocin in rats. Indian Journal of Clinical Biochemistry, 22(2): 60–64. DOI: 10.1007/BF02913315.

Anghel S., Wahli W. (2007). Fat poetry: A kingdom for PPAR gamma. Cell Research.17: 486–511. DOI: 10.1038/cr.2007.48.

Arulmozhi DK., Veeranjaneyulu A., Bodhankar S. (2004). Neonatal streptozotocin-induced rat model of Type 2 diabetes mellitus: A glance. Indian Journal of Pharmacology, 36(4):217-221.

Bajaj S., Khan A. (2012). Antioxidants and diabetes. Indian Journal of Endocrinology and Metabolism, 16(2): S267–S271. DOI 10.4103/2230-8210.104057.

Benuck I., Wilson D., McNeal C. (2020). Secondary Hypertriglyceridemia. Institute for Laboratory Animal Research (ILAR). 74(2): 196-214. DOI: 10.1297lar.473186.

Bradley L., Forman E., Kerrigan S., Goldstein S., Butryn M., Thomas J., et al. (2017). A remotely delivered behavioral intervention for weight regains after bariatric surgery. Obesity Surgery, 27(3):586–98. DOI: 10.1007/s11695-016-2337-3.

Cefalu W. (2006). Animal models of type 2 diabetes: clinical presentation and pathophysiological relevance to the human condition. Institute for Laboratory Animal Research Journal, 47(3): 186-198. DOI: 10.1093/ilar.47.3.186.

Denroche H., Huynh F., Kieffer T. (2012). The role of leptin in glucose homeostasis. Journal of Diabetes Investigation, 3: 115-129. DOI: 10.1111/j.2040-1124.2012.00203.x.

Di Luccia B., Crescenzo R., Mazzoli A., Cigliano L., Venditti P., Walser J. (2015) Rescue of fructose-induced metabolic syndrome by antibiotics or fecal transplantation in a rat model of obesity. Public Library of Science, 10(8):e013489. DOI: 10.1371/journal.pone.0134893.

Drel V., Mashtalir N., Ilnytska O., Shin J., zogubov V., Obrosova I. (2006). The leptin-deficient (ob/ob) mouse: A new animal model of peripheral neuropathy of type 2 diabetes and obesity. Diabetes, 55(12): 3335-3343. DOI: 10.2337/db06-0885.

Durham H., Truett G. (2006). Development of insulin resistance and hyperphagia in Zucker fatty rats. American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 290(3): R652-8. DOI.org/10.1152/ajpregu.00428.2004.

Duszka K., Gregor A., Guillou H., König J., Wahli W. (2020). Peroxisome proliferator-activated receptors and caloric restriction are common pathways affecting metabolism, health, and longevity. Cells 9: 1708. DOI: 10.3390/cells9071708.

Farah AI, Ahmad MN, Al-qirim TM. (2020). The antioxidant and prooxidant impacts of varying levels of α-lipoic acid on biomarkers of myoglobin oxidation in vitro. Jordan Journal of Agricultural Sciences, 16(4): 83-93.

Fang J., Lin C., Huang T., Chuang S. (2018). In vivo rodent models of type 2 diabetes and their usefulness for evaluating flavonoid bioactivity. Nutrients, 11(3), 530.

Geer E., Islam J., Buettner C. (2014). Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. Endocrinology and Metabolism Clinics of North America, 43(1): 75–102. DOI.org/10.1016/j.ecl.2013.10.005.

Ghibaudi L., Cook J., Farley C., Vanheek M. (2002). Fat intake affects adiposity, comorbidity factors, and energy metabolism of Sprague-Dawley rats. Obesity Research.10.9: 956-963. DOI.org/10.1186/1758-5996-6-3.

Goldenberg R., Punthakee Z. (2018). Definition, classification, and diagnosis of diabetes, prediabetes, and metabolic syndrome. Canadian Journal of Diabetes. 37. S8– S11. 10.1016/j.jcjd.2018.01.011. DOI: 10.1016/j.jcjd.2017.10.003.

Ighodaro O., Adeosun A., Akinloye O. (2017). Alloxan-induced diabetes, a common model for evaluating the glycemic-control potential of therapeutic compounds and plants extracts in experimental studies. Medicina(kaunas), 53(6): 365-374. DOI: 10.1016/j.medici.2018. 02.001.

Jurgens H., Neschen S., Ortmann S., Schernec. (2007). Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction. Diabetologia, 50 :1481–1489. DOI: 10.1007/s00125-007-0662-8.

Kahle M., Horsch M., Fridrich B., Seelig A., Schultheiss J. (2013). Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis. Molecular Metabolism, 2: 435–446. DOI: 10.1016/j.molmet.2013.07.009.

Kahn S., Cooper M., Delprato S. (2014). Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet, 383(9922), 1068–1083. DOI: 10.1016/ S0140-6736(13)62154-6.

Kolb H., Martin S. (2017). Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes. BioMed Central Medicine, 15(1), 131. DOI: 10.1186/s12916-017-0901-x.

Koopmans S., Schuurman T. (2015). Considerations on pig models for appetite, metabolic syndrome and obese type 2 diabetes: From food intake to metabolic disease. European Journal of Pharmacology,759: 231–239. DOI: 10.1016/j.ejphar.2015.03.044.

Leggio M., Lombardi M., Caldarone E., Mazza A., Fusco A. (2018). High body mass index, healthy metabolic profile and low visceral adipose tissue: the paradox is to call it obesity again. European Journal of Internal Medicine, 52: e15–6.

Lenzen S. (2008). The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia ,51: 216-226. DOI.org/10.1007/s00125-007-0886-7.

Ling C., Rönn, T. (2019). Epigenetics in human obesity and type 2 diabetes. Cell Metabolism, 29(5): 1028–1044. DOI: 10.1016/j.cmet.2019.03.009.

Mahmoud A., Elshazly S. (2014). Ursodeoxycholic acid ameliorates fructose-induced metabolic syndrome in rats. The Public Library of Science. 9. e106993.DOI.org/10.1371/journal. pone.0106993.

Mamikutty N., Thent Z. C., Sapri S. R., Sahruddin,N. N., Mohd Yusof, M. R., Haji Suhaimi F. (2014). The establishment of metabolic syndrome model by induction of fructose drinking water in male Wistar rats. Biomedical Research International 26389739. DOI: 10.1155/ 2014/263897.

Mambiya M., Shang M., Wang Y., Yang L., Zhang Q., Zhang K., et al. (2019). The play of genes and non-genetic factors on type 2 diabetes. Frontiers in Public Health, 7: 349. DOI: 10.3389/fpubh.2019.00349.

Mansour S., Zaki H., El-Denshary E. (2013). Beneficial effects of co-enzyme Q10 and rosiglitazone in fructose-induced metabolic syndrome in rats. Cell Metabolism, 51: 13-21. DOI.org/10.1016/j.bfopcu.2012.10.001.

Masuyama T., Komeda K., Hara A., Noda M., Shinohara M., et al. (2004). Chronological characterization of diabetes development in male spontaneously diabetic torii rats. Biochemical and Biophysical Research Communications, 314:870-877. DOI: 10.1016/ j.bbrc.2003.12.180.

Masuyama T., Katsuda Y., Shinohara M. (2005). A novel model of obesity-related diabetes: introgression of the leprfa allele of the Zucker fatty rat into nonobese spontaneously diabetic torii rats. Experimental Animals, 54(1): 13-20. DOI: 10.1538/expanim.54.13.

McCarthy M. (2010). Genomics, type 2 diabetes, and obesity. New England Journal of Medicine, 363:2339– 2350. DOI: 10.1056/NEJMra0906948.

Momose K., Nunomiya S., Nakata M., Yada T., Kikuchi M., Yashiro T. (2006). Immunohistochemical and electron-microscopic observation of beta-cells in pancreatic islets of spontaneously diabetic goto-kakizaki rats. Medical Molecular Morphology, 39(3):146-53. DOI: 10.1007/s00795-006-0324-9.

Morris A. P., Voight B. F., Teslovich T. M., Ferreira T., Segre A. V., Steinthorsdottir V., et al. (2012). Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nature Genetics, 44:981–990. DOI.org/10.1038/ ng.2383.

Nolan C., Damm P., Prentki M. (2011). Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet, 378.9786: 169-181.

DOI: 10.1016/S0140-6736(11)60614-4.

Neubauer N., Kulkarni R. (2006). Molecular approaches to study control of glucose homeostasis. Institute for Laboratory Animal Research, 47:199-211. DOI: 10.1093/ilar. 47.3.199.

Oron-Herman M., Kamari Y., Grossman E., Yeger G., Peleg E., Shabtay Z., et al. (2008). Metabolic syndrome: comparison of the two commonly used animal models. American Journal of Hypertension, 21(9): 1018-1022. DOI: 10.1038/ajh.2008.218.

Pais R., Gribble F., Reimann F. (2016). Stimulation of incretin secreting cells. Endocrinol Metabolism, 7(1):24-42. DOI:10.1177/2042018815618177.

Pang Y., Hu J., Liu G., Lu S. (2018). Comparative medical characteristics of zdf- T2DM rats during the course of development to late stage disease. Animal Model Experimental Medicine, 1(3):203-211.DOI:10.1002/ame2.12030.

Pang X., Zhao J., Zhang W., Zhuang X., Wang J., Xu R., et al. (2008). Antihypertensive effect of total flavones extracted from seed residues of hippophae rhamnoides L. in sucrose-fed rats. Journal of Ethnopharmacology, 117(2): 325-331. DOI: 10.1016/j.jep.2008.02.002.

Portha B., Giroix M. H., Serradas P., Gangnerau,M. N., Movassat J., Rajas F., et al. (2001). Beta-cell function and viability in the spontaneously diabetic gk. rat. Diabetes, 50(1): S89-93. DOI: 10.2337/diabetes.50. 2007.s89.

Thirunavukkarasu V., Nandhini A. A., Anuradha C. V. (2004). Lipoic acid attenuates hypertension and improves insulin sensitivity, kallikrein activity and nitrite levels in high fructose-fed rats. Journal of Comparative Physiology, 174(8):587-92. DOI:10.1007/ s00360-004-0447-z.

Rees D., Alcolado J. (2005). Animal models of diabetes mellitus. Diabetic Médecine, 22(4):359-70. DOI.org/10.1111/j.1464-5491.2005. 01499.x.

Reed M. J., Meszaros K., Entes L. J., Claypool M. D., Pinkett J. G., Gadbois T. M., et al. (2000). A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism, 49(11):1390-4. DOI: 10.1053/meta.2000.17721.

Rehman K., Akash M. (2016). Mechanisms of inflammatory responses and development of insulin resistance how are they interlinked. Journal of Biomedical Science, 23(1): 87. DOI.org/10.1186/s12929-016-0303-y.

Srinivasan K., Ramarao P. (2007). Animal model in type 2 diabetes research: an overview. Indian Journal of Medical Research, 125(3): 451. PMID: 17496368.

Straub L.G., Efthymiou V., Grandl G., Balaz M., Challa T.D., Truscello L. et al. (2019). Antioxidants protect against diabetes by improving glucose homeostasis in mouse models of inducible insulin resistance and obesity. Diabetology, 62(11):2094-2105. DOI: 10.1007/s00125-019-4937-7.

Solis-Herrera C., Triplitt C., Reasner C., DeFronzo R. A., Cersosimo E. (2018). Classification of diabetes mellitus. Journal of Diabetes Research, DOI: 21,1155/2013/976209.

Tremmel M., Gerdtham U., Nilsson P., Saha S. (2017). Economic burden of obesity: a systematic literature review. International Journal of Environmental Research and Public Health, 14(4):435. DOI: 10.3390/ijerph14040435.

Wagner J., Kavanagh K., Ward G., Auerbach B., Harwood H., Kaplan J., et al. (2006). Old world non-human primate models of type 2 diabetes mellitus. Institute for Laboratory Animal Research, 47(3):259-71. DOI.org/10.1093/ilar.47.3.259.

Wang Y., Garyantes T. (2018). Improving the reliability and utility of streptozotocin-induced rat diabetic model. Journal of Diabetes Research, 8054073. https://doi.org/10.1155/2018/ 8054073.

Yang R., Wang L., Xie J., Li X., Liu S., Qiu S., et al. (2018). Treatment of type 2 diabetes mellitus via reversing insulin resistance and regulating lipid homeostasis in vitro and in vivo using Cajanonic acid A. International Journal Molecular Medicine, 42(5): 2329-2342. DOI: 10.3892/ijmm.2018.3836.

Yehya A., Sadhu A. (2018). New therapeutic strategies for type 2 diabetes. Indian Journal of Medical Research, 125(3): 451.

Zhuo J., Zeng Q., Cai D., Zeng X., Chen Y., Gan H., et al. (2018). Evaluation of type 2 diabetic mellitus animal models via interactions between insulin and mitogen-activated protein kinase signaling pathways induced by a high fat and sugar diet and streptozotocin. Molecular Medicine Reports, 17(4): 5132–5142. DOI: 10.3892/mmr.2018.8504.