University of Oulu

Wang, M., Zhang, Z., Georgakis, M. K., Karhunen, V., & Liu, D. (2023). The impact of genetically proxied ampk activation, the target of metformin, on functional outcome following ischemic stroke. Journal of Stroke, 25(2), 266–271.

The impact of genetically proxied AMPK activation, the target of metformin, on functional outcome following ischemic stroke

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Author: Wang, Mengmeng1; Zhang, Zhizhong2; Georgakis, Marios K.3,4,5;
Organizations: 1Department of Neurology, The Third Affiliated Hospital of Soochow University, Changzhou, China
2Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
3Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany
4Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
5Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
7Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
8Department of Integrated Traditional Chinese and Western Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, China
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.1 MB)
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Language: English
Published: Korean Stroke Society, 2023
Publish Date: 2023-09-19


Background and Purpose: We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of genetically proxied AMP-activated protein kinase (AMPK) activation, which is the target of metformin, on functional outcome following ischemic stroke onset.

Methods: A total of 44 AMPK-related variants associated with HbA1c (%) were used as instruments for AMPK activation. The primary outcome was the modified Rankin Scale (mRS) score at 3 months following the onset of ischemic stroke, evaluated as a dichotomous variable (3–6 vs. 0–2) and subsequently as an ordinal variable. Summary-level data for the 3-month mRS were obtained from the Genetics of Ischemic Stroke Functional Outcome network, including 6,165 patients with ischemic stroke. The inverse-variance weighted method was used to obtain causal estimates. The alternative MR methods were used for sensitivity analysis.

Results: Genetically predicted AMPK activation was significantly associated with lower odds of poor functional outcome (mRS 3–6 vs. 0–2, odds ratio [OR]: 0.06, 95% confidence interval [CI]: 0.01–0.49, P=0.009). This association was maintained when 3-month mRS was analyzed as an ordinal variable. Similar results were observed in the sensitivity analyses, and there was no evidence of pleiotropy.

Conclusion: This MR study provided evidence that AMPK activation by metformin may exert beneficial effects on functional outcome following ischemic stroke.

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Series: Journal of stroke
ISSN: 2287-6391
ISSN-E: 2287-6405
ISSN-L: 2287-6391
Volume: 25
Issue: 2
Pages: 266 - 271
DOI: 10.5853/jos.2022.03230
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Funding: Mengmeng Wang received funding from the Changzhou Sci&Tech Program (Grant No. CJ20210084), and the Young Talent Development Plan of Changzhou Health Commission (No. CZQM2022001). Marios K. Georgakis was funded by a Walter-Benjamin fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG], GZ: GE 3461/1-1), the FöFoLe program of LMU Munich (FöFoLe-Forschungsprojekt Reg.-Nr. 1120), DFG Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy - ID 390857198), and a Research Grant from the Fritz-Thyssen Foundation (Ref. Ville Karhunen was funded by the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No 848158 (EarlyCause) and Academy of Finland Project 326291.
EU Grant Number: (848158) EarlyCause - Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity
Copyright information: © 2023 Korean Stroke Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.