Sirtuin 1-Mediated Cellular Metabolic Memory of High Glucose via the LKB1/AMPK/ROS Pathway and Therapeutic Effects of Metformin
Open accessAbstract
Cellular metabolic memory occurs in diabetic microvascular and macrovascular complications, but the underlying mechanisms remain unclear. Here, we investigate the role of sirtuin 1 (SIRT1) and metformin in this phenomenon. In bovine retinal capillary endothelial cells (BRECs) and retinas of diabetic rats, the inflammatory gene, nuclear factor-κB (NF-κB), and the proapoptotic gene, Bax, induced by hyperglycemia, remained elevated after returning to normoglycemia. BRECs with small interfering RNA-mediated SIRT1 knockdown had increased sensitivity to hyperglycemia stress, whereas SIRT1 overexpression or activation by metformin inhibited the increase of mitochondrial reactive oxygen species-mediated glyceraldehyde-3-phosphate dehydrogenase by poly (ADP-ribose) polymerase (PARP) activity through the upregulation of liver kinase B1/AMP-activated protein kinase (LKB1/AMPK), ultimately suppressing NF-κB and Bax expression. Furthermore, we showed that hyperglycemia led to PARP activation, which in turn may have downregulated SIRT1. Of importance, this study also demonstrated that metformin suppressed the "memory" of hyperglycemia stress in the diabetic retinas, which may be involved in the SIRT1/LKB1/AMPK pathway. Our data suggest that SIRT1 is a potential therapeutic target for the treatment of the cellular metabolic memory, and the use of metformin specifically for such therapy may be a new avenue of investigation in the diabetes field.
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BRECs with SIRT1 knocked down showed increased sensitivity to hyperglycemic stress, whereas SIRT1 overexpression or exposure to metformin inhibited increase of mitochondrial ROS by upregulation of LKB1 and suppressed expression of NF-κB and Bax.
“BRECs where SIRT1 was knocked down with siRNA knockdown demonstrated an increased sensitivity to hyperglycemic stress, whereas SIRT1 overexpression, or exposure to metformin, inhibited the increase of mitochondrial ROS by upregulation of LKB1, and suppressed the expression of NF-B and the apoptosis regulator protein, Bax (193).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [193]
In bovine retinal capillary endothelial cells and retinas from diabetic rats, hyperglycemia-induced elevated levels of NF-κB and Bax were sustained even after returning to normoglycemia.
“In bovine retinal capillary endothelial cells (BRECs) and retinas from diabetic rats, hyperglycemia-induced elevated levels of NF-κB, and Bax, a pro-apoptotic gene, were sustained even after returning to normoglycemia (193).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [193]
The authors suggested that metformin's action on NF-kB and metabolic memory proteins could be mediated by histone deacetylase sirtuin 1 (SIRT-1).
“The authors suggested that this action could be mediated by histone deacetylase sirtuin 1 (SIRT-1), a multifunctional protein involved in many intracellular pathways related to metabolism, stress response, cell cycle, and aging [103].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [103]
Treatment of bovine capillary endothelial cells incubated in hyperglycemic medium with metformin decreased activity of NF-kB and other intracellular proteins related to cellular metabolic memory.
“In this study, treatment of bovine capillary endothelial cells incubated in hyperglycemic medium with metformin was able to decrease the activity of NF-kB and others intracellular proteins related to cellular metabolic memory.”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [103]
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References 49 · Cited by 282
- Authors
- Zheng, Z., Chen, H., Li, J., Li, T., Zheng, B., Zheng, Y., Jin, H., He, Y., Gu, Q., & Xu, X.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Zheng, Zhi
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-12-12
- Volume
- 61
- Issue
- 1
- Pages
- 217-228
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3237662
- OpenAlex
- W2128188021
- Cited by
- 282
- References
- 49
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 24 · 2023: 16 · 2022: 22 · 2021: 25 · 2020: 25 · 2019: 11 · 2018: 15 · 2017: 28 · 2016: 22 · 2015: 25 · 2014: 19 · 2013: 18 · 2012: 10
- FWCI
- 7.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30871204, 30872828)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- SIRT1, metabolic memory, hyperglycemia, metformin, LKB1/AMPK pathway, reactive oxygen species, PARP activation, NF-κB, Bax, apoptosis, retinal endothelial cells, diabetic retinopathy, diabetes complications, glycolysis
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Adenylate Kinase, Animals, Blood Glucose, Cattle, Cells, Cultured, Diabetes Mellitus, Experimental, Hypoglycemic Agents, Metformin, Osmolar Concentration, Retina, Gene Expression Regulation, Enzymologic, NF-kappa B, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Endothelial Cells, bcl-2-Associated X Protein, Rats, Metabolic Networks and Pathways, Sirtuin 1
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