The Extraglycemic Effect of SGLT-2is on Mineral and Bone Metabolism and Bone Fracture

Dong, Bingzi; Lv, Ruolin; Wang, Jun; Che, Lin; Wang, Zhongchao; Huai, Zhouyang; Wang, Yangang; Xu, Lili

doi:10.3389/fendo.2022.918350

Cited by 17 publications

(19 citation statements)

References 82 publications

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“…Ageing can predispose kidney state into acute and chronic kidney disease. [18][19][20] lowering blood glucose, [22][23][24] the off-target roles of SGLT2i were independent of lowering glucose. 18,19,25 The renal anti-senescence role of SGLT2i has been reported, most likely related to increasing the expression of klotho.…”

Section: Discussionmentioning

confidence: 97%

“…SGLT2i mainly focus on the sodium‐glucose cotransporter distributed on proximal tubular cells, through promoting the excretion of glucose to lower blood glucose and to exert beneficial effects 21 . Although SGLT2i mainly focus on regulating physiologically glucose level, several researches have demonstrated that SGLT2i played beneficial roles transcending lowering blood glucose, 22–24 the off‐target roles of SGLT2i were independent of lowering glucose 18,19,25 . The renal anti‐senescence role of SGLT2i has been reported, most likely related to increasing the expression of klotho 26,27 .…”

Section: Discussionmentioning

confidence: 99%

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SGLT2i improves kidney senescence by down‐regulating the expression of LTBP2 in SAMP8 mice

Zeng,

Li,

Gao

et al. 2024

J Cellular Molecular Medi

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Senescent kidney can lead to the maladaptive repairment and predispose age‐related kidney diseases. Here, we explore the renal anti‐senescence effect of a known kind of drug, sodium‐dependent glucose transporters 2 inhibitor (SGLT2i). After 4 months intragastrically administration with dapagliflozin on senescence‐accelerated mouse prone 8 (SAMP8) strain mice, the physiologically effects (lowering urine protein, enhancing glomerular blood perfusion, inhibiting expression of senescence‐related biomarkers) and structural changes (improving kidney atrophy, alleviating fibrosis, decreasing glomerular mesangial proliferation) indicate the potential value of delaying kidney senescence of SGLT2i. Senescent human proximal tubular epithelial (HK‐2) cells induced by H2O2 also exhibit lower senescent markers after dapagliflozin treatment. Further mechanism exploration suggests LTBP2 have the great possibility to be the target for SGLT2i to exert its renal anti‐senescence role. Dapagliflozin down‐regulate the LTBP2 expression in kidney tissues and HK‐2 cells with senescent phenotypes. Immunofluorescence staining show SGLT2 and LTBP2 exist colocalization, and protein‐docking analysis implies there is salt‐bridge formation between them; these all indicate the possibility of weak‐interaction between the two proteins. Apart from reducing LTBP2 expression in intracellular area induced by H2O2, dapagliflozin also decrease the concentration of LTBP2 in cell culture medium. Together, these results reveal dapagliflozin can delay natural kidney senescence in non‐diabetes environment; the mechanism may be through regulating the role of LTBP2.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

SGLT2i improves kidney senescence by down‐regulating the expression of LTBP2 in SAMP8 mice

Zeng,

Li,

Gao

et al. 2024

J Cellular Molecular Medi

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“…The effects of diabetes medications on bone and mineral metabolism have been observed. SGLT2 inhibitors may not increase the risk of bone fracture, but their effects are controversial and require further study [ 64 ]. SGLT2 inhibitors are also thought to promote renal phosphate reabsorption, increase fibroblast growth factor 23 and PTH, and act by decreasing active vitamin D, causing calciuria [ 65 ]; however, the effects of diabetes medications on bone health need further study.…”

Section: Discussionmentioning

confidence: 99%

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

Unno

Taguchi

Takagi³

et al. 2023

IJMS

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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.

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“…In observational studies, the relative fracture risk for SGLT2 inhibitors was compared with other hypoglycemic drugs currently in use, such as DPP-4 inhibitors, (11)(12)(13)(14)(15) sulphonylurea, (16) and GLP-1 receptor agonists, (17)(18)(19) and most studies yielded negative results. (46) Compared with observational studies, which may be subject to potential confounders and draw relative risks, the MR study is less likely to be affected by confounders and directly evaluate the causal effect of SGLT2 inhibition on fracture risk.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Effect of Sodium-Glucose Cotransporter 2 Inhibition on Fracture Risk: Evidence From Mendelian Randomization and Genetic Association Study

Dai

Zheng

Zhu

et al. 2023

Journal of Bone and Mineral Research

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This study aims to evaluate the causal effect of sodium‐glucose cotransporter 2 (SGLT2) inhibition on bone mineral density (BMD), osteoporosis, and fracture risk using genetics. Two‐sample Mendelian randomization (MR) analyses were performed utilizing two sets of genetic variants as instruments (six and two single‐nucleotide polymorphisms [SNPs]) associated with SLC5A2 gene expression and glycated hemoglobin A1c levels. Summary statistics of BMD from the Genetic Factors for Osteoporosis consortium (BMD for total body, n = 66,628; femoral neck, n = 32,735; lumbar spine, n = 28,498; forearm, n = 8143) and osteoporosis (6303 cases, 325,717 controls) and 13 types of fracture (≤17,690 cases, ≤328,382 controls) data from the FinnGen study were obtained. One‐sample MR and genetic association analyses were conducted in UK Biobank using the individual‐level data of heel BMD (n = 256,286) and incident osteoporosis (13,677 cases, 430,262 controls) and fracture (25,806 cases, 407,081 controls). Using six SNPs as the instrument, genetically proxied SGLT2 inhibition showed little evidence of association with BMD of total body, femoral neck, lumbar spine, and forearm (all p ≥ 0.077). Similar results were observed using two SNPs as instruments. Little evidence was found for the SGLT2 inhibition effect on osteoporosis (all p ≥ 0.112) or any 11 major types of fracture (all p ≥ 0.094), except for a nominal significance for fracture of lower leg (p = 0.049) and shoulder and upper arm (p = 0.029). One‐sample MR and genetic association analysis showed that both the weighted genetic risk scores constructed from the six and two SNPs were not causally associated with heel BMD, osteoporosis, and fracture (all p ≥ 0.387). Therefore, this study does not support an effect of genetically proxied SGLT2 inhibition on fracture risk. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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The Extraglycemic Effect of SGLT-2is on Mineral and Bone Metabolism and Bone Fracture

Cited by 17 publications

References 82 publications

SGLT2i improves kidney senescence by down‐regulating the expression of LTBP2 in SAMP8 mice

SGLT2i improves kidney senescence by down‐regulating the expression of LTBP2 in SAMP8 mice

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

Evaluation of the Effect of Sodium-Glucose Cotransporter 2 Inhibition on Fracture Risk: Evidence From Mendelian Randomization and Genetic Association Study

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