Animal models have long played an important role in understanding the etiology and clinical complications of human diabetic diseases. Historically, most diabetes models in mice and rats have been established by selective breeding of natural mutants based on their phenotypes 19,20. Therefore, only a few genetically modified animals with clear diabetic phenotypes are available. Genetically modified models are advantageous in the preciseness of the causative gene involved in pathophysiology, especially when the models have a defined genetic background, i.e., inbred mice. In mice, Irs2 KO strains are such typical models that they have been generated by mixed breeding of two inbred strains, such as C57BL/6 × CBA 21,22. Syrian hamsters are considered genetically homogeneous because all hamsters in laboratories are descendants of two females and one male captured from their native habitat 5. This study demonstrated that Irs2 KO hamsters consistently develop diabetes with typical hyperglycemia and glucose intolerance. Given their homogeneous genetic background, these phenotypes will be reproducible in any laboratory.
Mouse and hamster models with Irs2 deficiency share common diabetic phenotypes (hyperglycemia and glucose intolerance), but their pathophysiology seems to be largely different. Irs2 KO hamsters showed a lean phenotype throughout their lifespan, while Irs2 KO mice developed an obese phenotype due to heavy adiposity 23,24. Interestingly, unlike Irs2 KO mice 13, Irs2 KO hamsters normally responded to insulin treatment, indicating that they did not develop insulin resistance even under diabetic conditions. In relation to this, Irs2 KO hamsters lost the ability to increase serum insulin after glucose load, most likely because of the β-cell dysfunction indicated by immunohistochemistry. In Irs2 KO mice, it was reported that insulin secretion ability per β-cell increased to maintain the total insulin secretion level 13. Although we did not perform an in vitro assay on the insulin secretion ability of β-cells in Irs2 KO hamsters, it was very likely that they had little, if any, compensatory potential because KO hamsters did not increase serum insulin after glucose load (Fig. 2E).
Human T2D can be roughly classified into obese and non-obese cases. Irs2 KO mice have greatly contributed to understanding the pathophysiology of obese T2D, such as the underlying mechanisms of insulin resistance, the roles of Irs2 and related factors in different tissues, and the insulin signaling pathway under diabetic conditions 24–26. Therefore, much information has been accumulated on the pathophysiology of obese T2D by this mouse model. By contrast, the pathophysiology of non-obese T2D remains poorly understood, while its cases are rapidly increasing, especially in East Asian countries 15,16. T2D in East Asians is characterized by β-cell dysfunction and less obesity than in Caucasians 27–29. Thus, there may be some pathophysiological difference between the T2D of East Asians and Caucasians, which may reflect the long-term dietary difference between them; East Asians have been primarily agriculturalists since the domestication of rice in China about 10,000 years ago 30. The phenotypes of Irs2 KO hamsters we identified resemble those of human non-obese T2D regarding their non-obese feature and β-cell dysfunction tendency. Interestingly, it is known that hamsters prefer plant diets, such as grains, while mice have more omnivorous tendencies 5,31. Perhaps such differences in diet between mice and hamsters for over tens of thousands of years may have caused the differences in the β-cell robustness and the metabolic responsiveness to diabetic disorders.
A major clinical issue associated with human diabetes is that it is highly prone to various complications. Major complications include chronic kidney disease, visual impairment, nerve damage, and heart disease 32. However, Irs2 KO hamsters did not show such severe complications under our standard breeding condition. Although the serum UN level increased significantly in Irs2 KO hamsters, they showed no signs of renal pathological changes, at least at the microscopic level. In hamsters, the APA strain is known to be predisposed to glomerulopathy 33 and can develop persistent hyperglycemia and diabetic nephropathy after a single low dose of streptozotocin injection. Irs2 KO hamsters may also develop diabetic nephropathy if a strain prone to nephropathy can be used as the genetic background. Additionally, it would be interesting to see whether a high-fat diet may further aggravate hyperglycemia and compromise its systemic condition in Irs2 KO hamsters.
Another important characteristic of the golden hamster as a laboratory species is its susceptibility to many experimentally induced infectious diseases, especially coronavirus. Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, a high virus titer has been known to develop in the respiratory tract of hamsters following intranasal inoculation of SARS-CoV, the agent of SARS 34. In 2019, a new coronavirus outbreak (COVID-19) by SARS-CoV-2 occurred, and several waves of pandemics have followed to date. It is known that people with diabetes are more likely to experience severe outcomes 35. Hamsters are also infected with SARS-CoV-2 but with milder symptoms than humans 36,37. It is interesting to see if our diabetic hamsters would show severer symptoms than wild type hamsters upon infection with SARS-CoV-2.
In conclusion, we generated a T2D hamster model with a non-obese phenotype that may become a unique experimental model for human non-obese T2D with β-cell dysfunction. Further experiments, including high-fat diet treatment or detailed analysis at an early age, would elucidate their advantages as T2D models in the future. They would also provide important information on the mechanisms underlying the severe clinical symptoms of SARS-Co-2 infection in patients with diabetes. Our Irs2 KO hamsters are freely available from the RIKEN BioResource Research Center (AO) on request.