The Effect of SGLT2 Inhibition on Brain-related Phenotypes and Aging: A Drug Target Mendelian Randomization Study

被引：0

作者：

Chen, Zhihe ^{[1
,2
]}

Wu, Xueyan ^{[1
,2
]}

Yang, Qianqian ^{[1
,2
]}

Zhao, Huiling ^{[3
]}

Ying, Hui ^{[1
,2
]}

Liu, Haoyu ^{[1
,2
]}

Wang, Chaoyue ^{[4
]}

Zheng, Ruizhi ^{[1
,2
]}

Lin, Hong ^{[1
,2
]}

Wang, Shuangyuan ^{[1
,2
]}

Li, Mian ^{[1
,2
]}

Wang, Tiange ^{[1
,2
]}

Zhao, Zhiyun ^{[1
,2
]}

Xu, Min ^{[1
,2
]}

Chen, Yuhong ^{[1
,2
]}

Xu, Yu ^{[1
,2
]}

Lu, Jieli ^{[1
,2
]}

Ning, Guang ^{[1
,2
]}

Wang, Weiqing ^{[1
,2
]}

Luo, Shan ^{[5
]}

Au Yeung, Shiu Lun ^{[5
]}

Bi, Yufang ^{[1
,2
]}

Zheng, Jie ^{[1
,2
,3
]}

机构：

[1] Shanghai Jiao Tong Univ, Ruijin Hosp, Shanghai Inst Endocrine & Metab Dis, Sch Med,Dept Endocrine & Metab Dis, Shanghai 200025, Peoples R China

[2] Shanghai Jiao Tong Univ, Ruijin Hosp, Shanghai Natl Clin Res Ctr Metab Dis, Sch Med,Shanghai Digital Med Innovat Ctr,Key Lab E, Shanghai 200025, Peoples R China

[3] Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Oakfield House, Bristol BS8 2BN, England

[4] Shanghai Jiao Tong Univ, Ruijin Hosp, SJTU Ruijin UIH Inst Med Imaging Technol, Sch Med, Shanghai 200025, Peoples R China

[5] Univ Hong Kong, Li Ka Shing Fac Med, Sch Publ Hlth, Hong Kong 999077, Peoples R China

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2024年

基金：

中国国家自然科学基金;

关键词：

Mendelian randomization analysis; SGLT2; inhibition; chronological age; biological age; cognitive function; intelligence; brain imaging-derived phenotypes; LIFE-SPAN; METFORMIN; EMPAGLIFLOZIN; DYSFUNCTION; DISEASES; OUTCOMES; MEMORY; AGE;

D O I：

10.1210/clinem/dgae635

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Introduction An observational study suggested sodium-glucose cotransporter 2 (SGLT2) inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association is still a question. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological age, biological age, and cognition and explore the mediation effects of brain imaging-derived phenotypes (IDPs).Methods We selected genetic variants associated with both expression levels of SLC5A2 (Genotype-Tissue Expression and eQTLGen data; n = 129 to 31 684) and hemoglobin A1c (HbA1c) levels (UK Biobank; n = 344 182) and used them to proxy the effect of SGLT2 inhibition. Aging-related outcomes, including parental longevity (n = 389 166) and epigenetic clocks (n = 34 710), and cognitive phenotypes, including cognitive function (n = 300 486) and intelligence (n = 269 867) were derived from genome-wide association studies. Two-step MR was conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes and cognition.Results SGLT2 inhibition was associated with longer father's attained age [years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95% confidence interval (CI) 1.27-11.15], better cognitive function (beta = .17, 95% CI 0.03-0.31), and higher intelligence (beta = .47, 95% CI 0.19-0.75). Two-step MR identified 2 IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where 4 and 5 IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence, respectively (total proportion of mediation = 61.6% and 68.6%, respectively).Conclusion Our study supported that SGLT2 inhibition increases father's attained age, cognitive function, and intelligence, which was mediated through brain images of different brain regions. Future studies are needed to investigate whether a similar effect could be observed for users of SGLT2 inhibitors.

引用

页数：9