Mouse Models with SGLT2 Mutations: Toward Understanding the Role of SGLT2 beyond Glucose Reabsorption

The sodium–glucose cotransporter 2 (SGLT2) mainly carries out glucose reabsorption in the kidney. Familial renal glycosuria, which is a mutation of SGLT2, is known to excrete glucose in the urine, but blood glucose levels are almost normal. Therefore, SGLT2 inhibitors are attracting attention as a new therapeutic drug for diabetes, which is increasing worldwide. In fact, SGLT2 inhibitors not only suppress hyperglycemia but also reduce renal, heart, and cardiovascular diseases. However, whether long-term SGLT2 inhibition is completely harmless requires further investigation. In this context, mice with mutations in SGLT2 have been generated and detailed studies are being conducted, e.g., the SGLT2(−/−) mouse, Sweet Pee mouse, Jimbee mouse, and SAMP10-ΔSglt2 mouse. Biological changes associated with SGLT2 mutations have been reported in these model mice, suggesting that SGLT2 is not only responsible for sugar reabsorption but is also related to other functions, such as bone metabolism, longevity, and cognitive functions. In this review, we present the characteristics of these mutant mice. Moreover, because the relationship between diabetes and Alzheimer’s disease has been discussed, we examined the relationship between changes in glucose homeostasis and the amyloid precursor protein in SGLT2 mutant mice.