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

Abstract

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.

A Comparative Kidney Transcriptome Analysis of Bicarbonate-Loaded insrr-Null Mice

“…Na + /glucose cotransporter 2 (SGLT2) encoded by slc5a2 is a main glucose transporter in kidneys. Ninety percent of glucose is reabsorbed in proximal tubule cells via SGLT2 [33]. And according to our dataset the expression of Na + /glucose cotransporter 1 (SGLT1) does not change at all (see Supplement Data File S1).…”

DNA Mutagenicity of Hydroxyhydroquinone in Roasted Coffee Products and Its Suppression by Chlorogenic Acid, a Coffee Polyphenol, in Oxidative-Damage-Sensitive SAMP8 Mice

“…In this case, the mutation was caused by spontaneous mutation, suggesting that the SAMP8 mouse, which has a similar genetic background, is also a mutation-prone strain. The use of the mutagen N-ethyl-N-nitrosourea in creating SGLT2 mutant mice [20] indicates that HHQ is also a potential mutagen for SAMP8 mice.…”

Preclinical Studies of Canagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, and Donepezil Combined Therapy in Alzheimer’s Disease

“…However, AD is not a consequence of a single factor like AChE, but rather is a multifactorial condition, and this needs to be considered when designing a drug [14]. Other factors, such as chronic disturbances of glucose metabolism, disrupted integrity of the blood-brain barrier, increased inflammation, mitochondrial dysfunction and intracellular oxidative stress, play a significant role in memory and cognitive decline [3,7,15]. The lack of safe and effective agents capable of impacting this devastating disease and its progression is concerning, and invites the repurposing of commonly used drugs and the expanded testing of new mechanistic hypotheses to attack the disease from different angles.…”