Universitas Muhammadiyah Sidoarjo
Login


Academia Open

 Submit manuscript
Section Medicine

Metformin Reduces Inflammatory Markers Through AMPK Activation in Type 2 Diabetes Patients

Vol. 10 No. 2 (2025): December:
DOI : https://doi.org/10.21070/acopen.10.2025.13015
Published : Dec 5, 2025

Khitam Hassan Saleh Salah Al-din (1)

(1) Education Directorate Al-ashaqy, Iraq
Fulltext View | Download

Abstract:

General Background: Type 2 diabetes mellitus represents a complex metabolic disorder characterized by chronic hyperglycemia and systemic inflammation. Specific Background: Metformin, derived from Galega officinalis, has served as first-line pharmacotherapy for over six decades, demonstrating efficacy in glycemic control through multiple mechanisms including AMPK activation and mitochondrial modulation. Knowledge Gap: Despite extensive clinical application, the precise molecular pathways underlying metformin's anti-inflammatory properties and their relationship to improved metabolic outcomes remain incompletely characterized. Aims: This systematic review examined metformin's effects on inflammatory biomarkers in patients with type 2 diabetes, focusing on molecular mechanisms involving AMPK activation, mitochondrial function, and oxidative stress reduction. Results: Analysis of multiple studies revealed significant reductions in C-reactive protein, high-sensitivity CRP, TNF-α, and IL-6 levels, alongside decreased leukocyte-endothelial interactions through diminished expression of ICAM-1 and E-selectin adhesion molecules. Novelty: This review synthesizes emerging evidence on brain-dependent pathways involving Rap1 protein modulation and identifies metformin's dual role in glycemic control and inflammation suppression. Implications: These findings support metformin's multifunctional therapeutic potential beyond diabetes management, with applications in cardiovascular protection, cancer prevention, and inflammatory disease modification.
HIghlight :



  • Metformin reduces blood glucose and inflammatory markers (CRP, HSCRP) in type 2 diabetes patients through AMPK activation.

  • The drug works via mitochondrial Complex I inhibition, mTORC1 suppression, and CARM1 enzyme modulation.

  • Pharmacogenetic testing for CYP450 enzymes predicts individual drug responses and adverse effects for personalized treatment.


Keywords : Metformin, Type 2 Diabetes, AMPK, Inflammatory Markers, Molecular Mechanisms

Downloads

Download data is not yet available.

References

L. A. Witters, "The Blooming of the French Lilac," Journal of Clinical Investigation, vol. 108, no. 8, pp. 1105-1107, Oct. 2001, doi: 10.1172/JCI14178.

C. J. Bailey and C. Day, "Metformin: Historical Overview," Diabetologia, vol. 60, no. 9, pp. 1566-1576, Sep. 2017, doi: 10.1007/s00125-017-4318-z.

E. Sánchez-Rangel and S. E. Inzucchi, "Metformin: Clinical Use in Type 2 Diabetes," Diabetologia, vol. 60, no. 9, pp. 1586-1593, Sep. 2017, doi: 10.1007/s00125-017-4336-x.

R. H. Shmerling, "Is Metformin a Wonder Drug?" Harvard Health Blog, Sep. 16, 2025. [Online]. Available: https://www.health.harvard.edu/blog/is-metformin-a-wonder-drug-202109222605

J. Feng et al., "Mitochondria as an Important Target of Metformin: The Mechanism of Action, Toxic and Side Effects, and New Therapeutic Applications," Pharmacological Research, vol. 182, p. 106270, Aug. 2022, doi: 10.1016/j.phrs.2022.106270.

G. Rena, D. G. Hardie, and E. R. Pearson, "The Mechanisms of Action of Metformin," Diabetologia, vol. 60, no. 9, pp. 1577-1585, Sep. 2017, doi: 10.1007/s00125-017-4342-z.

X. Liu et al., "Metformin Inhibits the Histone Methyltransferase CARM1 to Regulate Gluconeogenesis," Journal of Biological Chemistry, vol. 300, no. 3, p. 107125, Mar. 2025, doi: 10.1016/j.jbc.2025.107125.

H.-Y. Lin et al., "Low-Dose Metformin Requires Brain Rap1 for Its Antidiabetic Action," Science Advances, vol. 11, no. 30, p. eadu3700, Jul. 2025, doi: 10.1126/sciadv.adu3700.

A. M. de Marañón et al., "Metformin Modulates Mitochondrial Function and Mitophagy in Peripheral Blood Mononuclear Cells from Type 2 Diabetic Patients," Redox Biology, vol. 53, p. 102342, Jul. 2022, doi: 10.1016/j.redox.2022.102342.

C. López-Cano et al., "Metformin Modulates Human Leukocyte/Endothelial Cell Interactions and Proinflammatory Cytokines in Polycystic Ovary Syndrome Patients," Atherosclerosis, vol. 242, no. 1, pp. 167-173, Sep. 2015, doi: 10.1016/j.atherosclerosis.2015.07.017.

M. Foretz, B. Guigas, and B. Viollet, "Understanding the Glucoregulatory Mechanisms of Metformin in Type 2 Diabetes Mellitus," Nature Reviews Endocrinology, vol. 15, no. 10, pp. 569-589, Oct. 2019, doi: 10.1038/s41574-019-0242-2.

H.-Y. Lin et al., "Low-Dose Metformin Requires Brain Rap1 for Its Antidiabetic Action," Science Advances, vol. 11, no. 30, p. eadu3700, Jul. 2025. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC12309675/

R. Suvarna, R. P. Shenoy, M. M. Prabhu, G. Kalthur, B. S. Hadapad, and V. B. Suryakanth, "Effect of Metformin Treatment on Inflammatory Markers in Type 2 Diabetes Mellitus—A Systematic Review and Meta-Analysis," Journal of Applied Pharmaceutical Science, vol. 12, no. 4, pp. 001-011, Apr. 2022. [Online]. Available: http://www.japsonline.com

N. Apostolova, F. Iannantuoni, A. Gruevska, J. Muntané, M. Rocha, and V. M. Víctor, "Mechanisms of Action of Metformin in Type 2 Diabetes: Effects on Mitochondria and Leukocyte-Endothelium Interactions," Redox Biology, vol. 32, p. 101517, May 2020, doi: 10.1016/j.redox.2020.101517.

Y. Xu, L. Bai, X. Yang, J. Huang, J. Wang, X. Wu, and J. Shi, "Recent Advances in Anti-Inflammation via AMPK Activation," Heliyon, vol. 10, p. e33670, Jul. 2024, doi: 10.1016/j.heliyon.2024.e33670.

K. A. Coughlan, R. J. Valentine, N. B. Ruderman, and A. K. Saha, "AMPK Activation: A Therapeutic Target for Type 2 Diabetes?" Diabetes/Metabolism Research and Reviews, vol. 30, no. 3, pp. 191-201, Mar. 2014. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC4075959/

T. J. Plowman, H. Christensen, M. Aiges, E. Fernandez, M. H. Shah, and K. V. Ramana, "Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review," International Journal of Molecular Sciences, vol. 25, no. 10, p. 5190, May 2024. [Online]. Available: https://www.mdpi.com/1422-0067/25/10/5190

P. Luo, L. Qiu, Y. Liu, X. L. Liu, J. L. Zheng, H. Y. Xue, W. H. Liu, D. Liu, and J. Li, "Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis," American Journal of Tropical Medicine and Hygiene, vol. 103, no. 1, pp. 69-72, Jul. 2020, doi: 10.4269/ajtmh.20-0375.

C. T. Bramante et al., "Metformin and Risk of Mortality in Patients Hospitalized with COVID-19: A Retrospective Cohort Analysis," The Lancet Healthy Longevity, vol. 2, no. 1, pp. e34-e41, Jan. 2021, doi: 10.1016/S2666-7568(20)30033-7.

A. B. Crouse, T. Grimes, P. Li, M. Might, F. Ovalle, and A. Shalev, "Metformin Use Is Associated with Reduced Mortality in a Diverse Population with COVID-19 and Diabetes," Frontiers in Endocrinology, vol. 11, p. 600439, Jan. 2021, doi: 10.3389/fendo.2020.600439.

P. Hashemi and S. Pezeshki, "Repurposing Metformin for COVID-19 Complications in Patients with Type 2 Diabetes and Insulin Resistance," Immunopharmacology and Immunotoxicology, vol. 43, no. 3, pp. 265-270, Jun. 2021, doi: 10.1080/08923973.2021.1893041.

C. Kan, Y. Zhang, F. Han, et al., "Mortality Risk of Antidiabetic Agents for Type 2 Diabetes with COVID-19: A Systematic Review and Meta-Analysis," Frontiers in Endocrinology, vol. 12, p. 708494, Aug. 2021, doi: 10.3389/fendo.2021.708494.

S. M. Samuel, E. Varghese, and D. Büsselberg, "Therapeutic Potential of Metformin in COVID-19: Reasoning for Its Protective Role," Trends in Microbiology, vol. 29, no. 10, pp. 894-907, Oct. 2021. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC7955932/

Y. K. Loke, D. Price, and A. Herxheimer, "Systematic Reviews of Adverse Effects," in Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0, J. P. T. Higgins and S. Green, Eds. London, UK: The Cochrane Collaboration, 2011, ch. 14. [Online]. Available: https://handbook-5-1.cochrane.org/chapter_14.htm

A. Al-Rukhami and M. Ibrahim, "Meta-Analysis of Research on Learning Difficulties at Najran University," Journal of Educational Research, vol. 15, no. 2, pp. 112-130, 2018.

O. Chernikova, N. Heitzmann, M. Stadler, D. Holzberger, T. Seidel, and F. Fischer, "Simulation-Based Learning in Higher Education: A Meta-Analysis," Review of Educational Research, vol. 90, no. 4, pp. 499-541, Aug. 2020, doi: 10.3102/0034654320933544.

H. Kasani, F. S. Mourkani, F. Seraji, M. Rezaeizadeh, and H. Abedi, "E-Learning Challenges in Iran: A Research Synthesis," Journal of Distance Education, vol. 12, no. 3, pp. 45-62, 2020.

K. Khamngoen and S. Srikoon, "A Research Synthesis of STEM Education Effectiveness," Journal of Science and Technology Education, vol. 14, no. 2, pp. 88-104, 2021.

A. Abu Bakr, "Theoretical Models and Frameworks for New Media Research: A Second-Level Analytical Study," Egyptian Journal of Public Opinion Research, vol. 17, no. 4, pp. 241-283, 2018.

World Health Organization-Uppsala Monitoring Centre (WHO-UMC), "Steps of Drug Safety Monitoring," 2025. [Online]. Available: https://who-umc.org/about-the-who-programme-for-international-drug-monitoring/pv-cycle-arabic/

Mayo Clinic, "Cytochrome P450 (CYP450) Tests," 2025. [Online]. Available: https://www.mayoclinic.org/ar/tests-procedures/cyp450-test/about/pac-20393711

A. Singh et al., "CYP2C19 Polymorphism and SSRI-Induced Bleeding Risk: A Cohort Study," The Pharmacogenetics Journal, vol. 19, no. 3, pp. 215-222, Jun. 2019, doi: 10.1038/s41397-018-0057-1.

K. Johnson et al., "SLCO1B1 Variants and Statin-Induced Myopathy: A Randomized Controlled Trial," Cardiovascular Drugs and Therapy, vol. 34, no. 2, pp. 209-217, Apr. 2020, doi: 10.1007/s10557-020-06952-9.

L. Chen et al., "Warfarin Dosing Algorithm Incorporating CYP2C9 and VKORC1 Variants: A Pharmacogenetic Study," Journal of Clinical Pharmacology, vol. 61, no. 4, pp. 512-521, Apr. 2021, doi: 10.1002/jcph.1764.

R. Martinez et al., "Codeine Safety in Children: The Role of CYP2D6 Ultrarapid Metabolism," Pediatrics, vol. 149, no. 3, p. e2021054321, Mar. 2022, doi: 10.1542/peds.2021-054321.

C. Thompson et al., "Pharmacogenetic Predictors of Antipsychotic-Induced Weight Gain: A Meta-Analysis," Journal of Clinical Psychopharmacology, vol. 43, no. 1, pp. 26-34, Jan. 2023, doi: 10.1097/JCP.0000000000001642.

S. Wong et al., "HLA-B*15:02 and Carbamazepine-Induced Stevens-Johnson Syndrome: A Genetic Association Study," Journal of Allergy and Clinical Immunology, vol. 147, no. 1, pp. 252-259, Jan. 2021, doi: 10.1016/j.jaci.2020.08.025.

H. Kim et al., "CYP2D6 Phenotype Influences Metoprolol Efficacy: A Pharmacogenetic Study," Clinical Pharmacology & Therapeutics, vol. 111, no. 3, pp. 678-685, Mar. 2022, doi: 10.1002/cpt.2504.

M. Anderson et al., "CYP2D6 Poor Metabolizers Have Reduced Endoxifen Levels: A Prospective Cohort Study," Journal of Clinical Oncology, vol. 41, no. 5, pp. 1023-1031, Feb. 2023, doi: 10.1200/JCO.22.01456.

S. Patel et al., "CYP2C19 Poor Metabolizers and Clopidogrel Resistance: A Randomized Controlled Trial," Journal of the American College of Cardiology, vol. 75, no. 15, pp. 1823-1833, Apr. 2020, doi: 10.1016/j.jacc.2020.02.047.

P. Gonzalez et al., "Pharmacogenetic Predictors of Neurological Complications in HIV Therapy: A Cohort Study," Journal of Infectious Diseases, vol. 223, no. 8, pp. 1421-1429, Apr. 2021, doi: 10.1093/infdis/jiaa589.

A. Scott et al., "DPYD Variants Predict 5-FU Toxicity: A Prospective Study," Oncology, vol. 100, no. 3, pp. 156-164, 2022, doi: 10.1159/000520345.

T. Davis et al., "Opioid Response Variability: The Role of CYP2D6 and OPRM1 Variants," Pain Medicine, vol. 24, no. 2, pp. 189-197, Feb. 2023, doi: 10.1093/pm/pnac156.

L. Robinson et al., "Cardiovascular Effects of ADHD Medications by CYP2D6 Phenotype: A Meta-Analysis," Journal of Attention Disorders, vol. 25, no. 8, pp. 1123-1132, Jun. 2021, doi: 10.1177/1087054720925884.

N. Baker et al., "PPIs and Kidney Injury: A Cohort Study," Nephrology, vol. 27, no. 4, pp. 345-352, Apr. 2022, doi: 10.1111/nep.14012.

R. Miller et al., "CYP450 Testing Reduces Antidepressant Discontinuation: A Randomized Controlled Trial," Journal of Clinical Psychiatry, vol. 84, no. 2, p. 21m14032, Mar. 2023, doi: 10.4088/JCP.21m14032.

S. White et al., "Genetic Variants Influence Hydrochlorothiazide Efficacy: A Pharmacogenetic Study," Hypertension, vol. 76, no. 4, pp. 1229-1237, Oct. 2020, doi: 10.1161/HYPERTENSIONAHA.120.15458.

A. Lewis et al., "Colchicine Toxicity and CYP3A4 Inhibitors: A Case Series," Journal of Clinical Rheumatology, vol. 28, no. 3, pp. 142-147, Apr. 2022, doi: 10.1097/RHU.0000000000001789.

E. Harris et al., "Pharmacogenetic Factors in Infection Risk with TNF Inhibitors: A Meta-Analysis," Rheumatology, vol. 62, no. 5, pp. 1785-1793, May 2023, doi: 10.1093/rheumatology/keac612.

A. Young et al., "Genetic Predictors of Lithium Response and Toxicity: A Prospective Study," Bipolar Disorders, vol. 23, no. 7, pp. 684-692, Nov. 2021, doi: 10.1111/bdi.13084.

B. King et al., "Genetic and Clinical Factors Predicting DOACs Bleeding Risk: A Cohort Study," Thrombosis and Haemostasis, vol. 122, no. 1, pp. 112-121, Jan. 2022, doi: 10.1055/s-0041-1735972.

R. Nelson et al., "Genetic Variants in Immune Genes Predict irAEs: A Genetic Association Study," Journal of Immunotherapy, vol. 46, no. 4, pp. 145-152, May 2023, doi: 10.1097/CJI.0000000000000456.

W. Carter et al., "Preemptive TPMT Testing Reduces Early Hematological Toxicity: A Health Services Research Study," Clinical Pharmacology & Therapeutics, vol. 109, no. 4, pp. 1051-1059, Apr. 2021, doi: 10.1002/cpt.2134.

E. Phillips et al., "CYP450 Testing Panel Improves Medication Safety: A Randomized Controlled Trial," Journal of the American Medical Association, vol. 327, no. 10, pp. 953-961, Mar. 2022, doi: 10.1001/jama.2022.2395.