From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin
Abstract
1. Introduction
2. Metformin in T2DM: A Longstanding Therapeutic Application
3. Multifaceted Metformin: Exploring Its Role in Age-Related Diseases
3.1. Alzheimer’s Disease
3.2. Parkinson’s Disease
Preclinical Studies | |||
---|---|---|---|
Model | Metformin Dose/Concentration and Duration | Treatment Effects | Reference |
In vitro. MPP+-treated SH-SY5Y cells In vivo. MPTP/p PD mouse model | 2 mM for 1 h 5 mg/mL in drinking water for 5 weeks | Protection against apoptosis ↓ the proportion of dysfunctional mitochondria and ROS generation Improvement in motor deficits ↑ dopamine levels ↓ DA neuron degeneration and SNCA accumulation ↓ NLRP3 inflammasome activity, ↓ IL-1 production, ↓ TNF-α, IL-6 mRNAs, ↑ IL-10 mRNA levels, no effect on IL-4 and TGF-β mRNA levels | [140] |
In vitro. Tetracycline-treated SH-SY5Y cells In vitro. Transfected human SNCA HeLa cells In vivo. WT C57BL/6 mice | 0.5, 1.0, or 2.5 mM for 16 h or 24 h 0.5, 1.0, or 2.5 mM for 16 h 5 g/kg in food pellets for 1 month or 5 g/L in drinking water for 6 months | ↓ phospho-Ser129 SNCA levels ↓ phospho-Ser129 SNCA levels ↓ phosphorylated SNCA protein | [145] |
In vitro. MPP+-treated SH-SY5Y cells In vivo. MPTP PD mouse model | 0.1, 0.25, or 0.5 mM for 48 h 200 or 400 mg/kg in drinking water for 14 days | ↑ mitochondrial marker proteins (SDHA, PDHA, VDAC, and HSP60) ↑ PGC-1α expression ↑ SOD1, SOD2, GPX1, CAT1, NRF1, TFAM, and UCP2 mRNAs ↑ mitochondrial marker proteins (SDHA, PDHA, VDAC, and COXIV) ↑ PGC-1α expression Protection of dopaminergic neurons Improvement in motor behaviour | [142] |
In vitro. BV2 cells treated with LPS In vitro. BV2 cells treated with IL-4 In vivo. LPS-induced PD rat model | 1 mM for 12 h Two daily oral doses (150 mg/kg) dissolved in tap water for 7 days | ↓ microglial activation (↓ IL-1β mRNA levels, no effect on iNOS and TNF-α mRNAs) ↓ ROS production ↓ NLRP3 inflammasome activation ↓ microglial activation (↓ arginase mRNA levels, no effect on IL-10 mRNA levels) ↓ number of activated microglial cells ↓ TNF-α, IL-1β, and IL-6 mRNA levels; ↑ MCP-1, CD200, and CX3CR1 mRNA levels No effect on dopaminergic neuronal loss protection | [136] |
In vitro. SH-SY5Y cells treated with rotenone | 10 μM, 100 μM, 1 mM, or 10 mM for 2 h, 3 h, 6 h | ↓ cellular death and 3/7 caspase activation ↓ ROS production ↑ GSH and SOD levels Upregulation of Nrf2/HO-1 pathway ↑ PGC-1α levels | [150] |
In vitro. MPP+-treated SH-SY5Y cells In vivo. MPTP PD mouse model | 0.5 mM for 4 h Once daily intraperitoneal injection (200 mg/kg) for 7 days | Neuroprotection is partially mediated by the BDNF/TrkB signaling pathway ↓ Caspase-3 ↑ Dopamine and DOPAC levels Improvement in motor deficits ↓ Astroglial activation ↓ SNCA levels ↑ BDNF, AKT and ERK1/2 | [143] |
In vitro. MPP+ -N27 dopaminergic cell line derived from rat ventral mesencephalon In vivo. MPTP PD mouse model | 0.1 mM or 1 mM for 24 h Two daily doses (150 mg/kg) for 7 days | ↓ ATP production ↑ ROS production ↓ TNF-α, IL-1β, and iNOS mRNAs levels No effect on dopaminergic neuronal loss ↓ DOPAC | [138] |
In vivo. 6-OHDA PD mouse model | Once daily oral doses (100 mg/kg or 200 mg/kg) for 4 weeks | Improved motor impairments No protective effect against dopaminergic cell death ↑ AMPK, AKT, GSK3b, CREB phosphorylation, and BDNF levels ↓ Astrocyte activation | [146] |
In vivo. MPTP PD mouse model | 500 mg/kg orally for 21 days | Improved locomotor and muscular activities ↑ SOD, CAT, and GSH levels ↓ Lipid peroxidation ↑ BDNF levels | [137] |
In vivo. Haloperidol-induced catalepsy PD mouse model | Once daily oral doses (20, 50, or 100 mg/kg) for 21 days | No effect on motor coordination, but improvement in memory deficit ↓ Duration of catalepsy score ↓ MDA and nitric oxide levels, and ↑ GSH and CAT activity No effect on SOD activity | [139] |
In vivo. MPTP AMPK WT and KO PD mouse model | 100 mg/kg dissolved in water for 27 days | Attenuation in the loss of neuron number and volume, as well as an increase in gliosis ↓ DOPAC:DA ratio | [141] |
In vivo. MDMA PD mouse model | 200–400 mg/kg orally 11 h intervals for 48 h and 7 days | Attenuation of TH-positive neuronal loss | [144] |
In vivo. Rotenone PD mouse model | Once daily oral doses (100 or 200 mg/kg) for 18 days administered through a gastric gavage tube | Improvement in animals’ motor function ↓ MDA, ↑ GSH, HO-1, and dopamine levels ↑ Nrf2, thioredoxin, AMPK, and FOXO3 mRNA levels ↑ Nrf2, HO-1, AMPK, FOXO3, and thioredoxin protein expression ↓ Cleaved-caspase 3 and VEGF levels ↑ the number of TH-positive neurons | [147] |
In vivo. Rotenone PD mouse model | Once daily intraperitoneal injection (300 mg/kg) for 10 days | No difference in motor behaviour Partial attenuation of dopaminergic neuronal loss ↓ Caspase-3 ↓ SNCA accumulation ↓ 4-HNE and MDA levels | [149] |
In vivo. 6-OHDA PD C. elegans strain BZ555 model | Oral doses (5 mM or 10 mM) for 72 h | Increase in lifespan ↓ Dopaminergic neurons degeneration ↓ SNCA aggregation ↑ TH gene cat3 and antioxidant gene sod3 | [148] |
In vivo. RNAi-mediated knockdown of C. elegans bcat-1 PD model | 50 μM for 5 days | ↑ the number of dopaminergic cell bodies Improvement in neurite morphologies of dopaminergic neurons Restoration of normal mitochondrial activity levels | [177] |
Clinical Studies | |||
Study Method | Subjects | Treatment Effects | Reference |
Retrospective cohort study | n = 1879 T2DM patients treated with metformin only for 11 years n = 3431 T2DM patients treated with sulfonylureas only for 11 years n = 6420 T2DM patients treated with metformin + sulfonylureas for 11 years | Increased PD risk in T2DM patients treated with sulfonylureas (HR = 1.57, 95% CI = 1.15–2.13) No effect on PD risk in T2DM patients treated with metformin (HR = 0.95, 95% CI = 0.53–1.71) and with sulfonylureas plus metformin (HR = 0.78, 95% CI = 0.61–1.01) | [151] |
Retrospective cohort study | n = 4651 T2DM patients treated with metformin for at least 90 days n = 4651 T2DM patients with no metformin therapy | Higher PD risk (HR = 2.27, 95% CI = 1.68–3.07) in the metformin group Higher PD risk in patients with T2DM receiving metformin therapy for 300–399 days (aHR = 2.20, 95% CI = 1.47–3.28) and ≥400 days (aHR = 4.49, 95% CI = 3.06–6.58) PD risk increased from 1.58 (95% CI = 1.02–2.44) in patients receiving average doses of metformin ≤ 130 g per year to 3.54 in patients receiving average doses of >385 g per year (95% CI = 2.41–5.20) | [152] |
Retrospective cohort study | n = 8396 T2DM patients treated with glitazones for 10 years n = 94,349 T2DM patients treated with metformin for 10 years | Lower PD risk in patients with T2DM receiving glitazone drug compared to the metformin group (HR = 0.72, 95% CI = 0.54–0.94) | [153] |
Cross-sectional study | n = 384,716 T2DM patients treated with metformin | Higher ORs for PD in patients with T2DM with increased cDDD of metformin after 3 years: <300 (OR = 0.88, 95% CI = 0.83–0.94), 300–500 (OR = 1.09, 95% CI = 0.72–1.65), and >500 (OR = 2.59, 95% CI = 0.83–8.03) g per year Higher ORs for PD in patients with T2DM with increased intensity of metformin use (DDD/month) after 3 years: <10 (OR = 0.87, 95% CI = 0.81–0.93), 10–25 (OR = 0.92, 95% CI = 0.83–1.02), and ≥25 (OR = 1.17, 95% CI = 0.80–1.72) g per month Higher ORs for PD in patients with T2DM with increased cDDD of metformin after 5 years: <300 (OR = 0.94, 95% CI = 0.90–0.98), 300–500 (OR = 1.01, 95% CI = 0.75–1.35), and >500 (OR = 1.24, 95% CI = 0.40–3.83) g per year Higher ORs for PD in patients with T2DM with increased intensity of metformin use (DDD/month) after 5 years: <10 (OR = 0.93, 95% CI = 0.89–0.98), 10–25 (OR = 0.97, 95% CI = 0.90–1.04), and ≥25 (OR = 1.02, 95% CI = 0.77–1.35) g per month | [154] |
Retrospective longitudinal cohort study | n = 2756 T2DM patients without metformin treatment n = 849 T2DM patients treated with metformin for less than 1 year n = 513 T2DM patients treated with metformin for 1–2 years n = 710 T2DM patients treated with metformin for 2–4 years n = 700 T2DM patients treated with metformin for more than 4 years | Lower risk of PD in elderly patients with T2DM after more than 4 years of metformin exposure (aHR = 0.04, 95% CI 0.00–0.37) | [71] |
3.3. Cardiovascular Disease
3.4. Age-Related Macular Degeneration
3.5. Osteoporosis
3.5.1. Effects on Osteoblasts
3.5.2. Effects on Osteoclasts
3.5.3. Clinical Insights into the Impact of Metformin on Bone Health in Older Adults
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Database/Centre/Study | Cohort | Main Outcome | Reference |
---|---|---|---|
VALCODIS Cohort | N = 213 T2DM (50–80 y.o.) | ↓ p-tau (CSF) | [62] |
National Alzheimer’s Coordinating Center (NACC) | N = 48,605 MCI (>39 y.o.) | ↓ MCI-to-dementia progression | [63] |
NCT01965756 | N = 48,605 MCI | Stabilized protein biomarker score (AZU1, CASP-3, CCL11, CCL20, IL32, PRTN3, and REG1A) (plasma + CSF) | [64] |
N.A. | N = 527,138 (middle-aged) | ↓ mitochondrial complex I (brain cortex) | [65] |
ADNI study | N = 6937 MCI-AD (55–90 y.o.) | ↑ Cognition, cortical thickness, hippocampal volume = glycemia, triglycerides, cholesterol | [66] |
Korean National Health Insurance Service DM cohort | N= 10,050 T2DM (n = 1675 AD) (50–85 y.o.) | ↑ Cognition | [67] |
National Alzheimer’s Coordinating Center database | N = 1999 T2DM (n = 807 AD) | ↑ Memory (in T2DM non-AD) | [68] |
FAERS database | N = 66,085 (>64 y.o.) T2DM (n = 1250 AD) | No improvement | [69] |
Korean cohort registry | N = 732 (>59 y.o.) | ↓ MMSE, verbal scores = daily activity index | [70] |
US Veterans Affairs electronic medical record | N = 5528 T2DM (>49 y.o.) | ↓ Neurodegenerative risk | [71] |
University of Pennsylvania Health System (UPHS) | N = 20 MCI (55–80 y.o.) | ↑ Execution performance, memory, attention, learning ↑/= orbitofrontal cerebral blood flow | [72] |
Columbia University Medical Center | N = 80 MCI (55–90 y.o.) overweight/obese | ↑ Selective Reminding Test (SRT) | [73] |
United Kingdom-based General Practice Research Database (GPRD) | N = 7086 AD (>65 y.o.) | ↑ AD risk | [74] |
Swedish Registry for Cognitive/Dementia Disorders (SveDem) | N = 15,428 AD (77.29 mean y.o.) | ↑ Cognition | [75] |
National Alzheimer’s Coordinating Center database | N = 1393 T2DM (>49 y.o.) | ↓ AD risk | [76] |
ICES Database, Ontario, Canada | N = 34,700 T2DM (>65 y.o.) | = AD risk | [77] |
Preclinical Studies | |||
---|---|---|---|
Mechanism | Model | Main Outcome | Reference |
Activation of AMPK/autophagy axis (atheroprotection) | ApoE(−/−) mice | Attenuation of Ang-II-induced atheromatous plaque formation and aortic aneurysm partly | [187] |
Normoglycemic Ldlr−/− hyperlipidaemic mice | Suppression of atherogenesis | [188] | |
GFP-LC3 transgenic mice by PCSK9 | Improvement in autophagy-mediated cholesterol efflux | [189] | |
Suppression of mitochondrial ROS-mediated pro-inflammatory pathway (atheroprotection) | Male Sprague–Dawley rats treated with glucose/metformin | Alteration in cellular redox state and reduction in glucose production by inhibiting complex IV | [190] |
Mice exposed to PM and treated with metformin | Prevention in PM-induced generation of METC-ROS | [191] | |
Activation of sirtuin signaling (myocardial protection) | Male C57BL/6J Sirt2 knockout mice | Activation of AMPK signaling Protection against cardiac hypertrophy | [192] |
2-Hit PH-HFpEF model in rats with multiple features of metabolic syndrome due to a double-leptin receptor defect (obese ZSF1) | Normalization of pulmonary hypertension associated with HF | [193] | |
Salt-induced hepatic inflammation in mouse model | Amelioration of high-salt diet-induced hepatic inflammation and myocardial damage | [194] | |
Activation of autophagy-dependent pathway (myocardial protection) | Diabetic mice | Prevention of cardiomyopathy | [195] |
Carfilzomib-induced cardiotoxicity in mice | Protection against carfilzomib-induced cardiotoxicity | [196] | |
Fly stocks | Activation of autophagy | [197] | |
Clinical Studies | |||
Database/Centre Cohort | Metformin Treatment | Main Outcome | Reference |
n = 33 non-diabetic women with angina | n = 16 patients: 0.5 g twice daily for 8 weeks | Improvement in vascular function Decrease in myocardial ischemia | [198] |
CAMERA study: n = 173 non-diabetic patients with coronary heart disease and on statin therapy | n = 86 patients: 850 mg twice daily for 18 months | No significant effect on cIMT Reduction in body weight, body fat, BMI, and waist circumference | [199] |
DPPOS study: n = 3234 individuals with pre-diabetes | n = 926 patients: 850 mg twice daily (14 years of follow-up) | Reduction in CAC only in male subjects | [200] |
CODYCE study: n = 258 propensity-matched patients with stable angina | n = 86 patients: 850 mg twice a day (6–12–24 months of follow-up) | Suppression of inflammation and oxidative stress | [201] |
n = 849 non-diabetic patients with an inflammatory disease treated with continuous prednisolone | n = 26 patients: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently for 12 weeks | Reduction of metabolic complications, inflammation, LDL-cholesterol, and cIMT | [202] |
REMOVAL study: n = 428 patients with T1DM (40 years and older) | n = 219 patients: 1 g twice daily for 3 years | Reduction in the maximal cIMT, body weight and blood LDL-cholesterol No adequate improvement in glycemic control | [203] |
EMERALD study: n = 48 T1DM adolescents (12–21 years) | n = 25 patients: 2000 mg daily for 3 months | Reduction in cIMT, BMI, and fat mass Improvement in aortic dysfunction | [204] |
n = 380 patients with diabetes and HF | n = 87 patients: 1000 mg (29 patients), lower than 1000 mg (18 patients), between 1000 and 2000 mg (14 patients), and 2000 mg (25 patients) daily or higher | Signs of more stable HF (lower BNP levels, reduced mitral and tricuspid regurgitation severity, improved left and right ventricular function, and decreased diuretic dosage) Increase in survival | [205] |
SAVOR-TIMI 53 trial: n = 12,156 patients with T2DM and high cardiovascular risk with or without HF or kidney dysfunction | n = 8971 patients exposed to metformin | Lower risk of all-cause mortality and cardiovascular death No difference in risk of the composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke | [206] |
n = 36 patients with HF | n = 19 patients: 1450 ± 550 mg/day for 3 months | Increase in relative efficiency Reduction in myocardial oxygen consumption Preservation of cardiac stroke work No effects on resting and exercise ejection fraction, global longitudinal strain, and exercise capacity | [207] |
MET-REMODEL study: N = 68 patients without diabetes, but with CAD, LVH, IR, and/or pre-diabetes | n = 34 patients: 2000 mg daily for 12 months | Reduction in LVMI, LVM, body weight, subcutaneous adipose tissue, office systolic blood pressure, and in concentration of thiobarbituric acid reactive substances | [208] |
MET-DIME trial: N = 54 non-diabetic patients with diastolic dysfunction | n = 27 patients: 1000 mg twice daily (2 years of follow-up) | Improvement in e-wave’ velocity Reduction in the HOMA-IR index No effect on LVMI, and hs-CRP and N-terminal -pro-BNP plasma levels | [209] |
Type of Study, Follow-Up Periods (yrs), Patient Characteristics (Age Mean in Yrs (SD) N. Participants (Exposed/Nonexposed)) | Daily Metformin Dosage (mg) | AMD Type | Main Outcome | Reference |
---|---|---|---|---|
Case-control in the United States, 2 yrs, 74.9 yrs (10.3), 81,262/79,497 | Various doses, mean: 163 | N.A. | Metformin use was associated with reduced odds of developing AMD. This association was dose dependent, with low to moderate doses of metformin showing the greatest potential benefit. | [232] |
Case-control in the United States, N.A, N.A, Control: 77 Case: 75.09 | N.A. | Dry and wet | Patients who had taken metformin had decreased odds of developing AMD, suggesting that metformin may have a therapeutic role in AMD development or progression in those who are at risk. | [233] |
Retrospective cohort in Taiwan, 6.7 yrs, 56.1 yrs (12.6), 45,524/22,681 | Various doses (400–2100) | N.A. | Metformin use was associated with reduced odds of developing AMD. Also, the trend of a significantly lower AMD risk was found with a higher dose of metformin. | [234] |
Retrospective cohort in United States, N.A, 67.5 yrs (8.9), 166,115/841,111 | Various doses, mean 1000 | Dry | There is not sufficient evidence to suggest that metformin has a meaningful impact on the development of AMD | [235] |
Retrospective cohort in United Kingdom, 5.7 yrs (4.1), 62.8 yrs (11.6), 154,016/19,673 | N.A. | Dry and Wet | There is not sufficient evidence to suggest that metformin has a meaningful impact on the development of AMD | [236] |
Retrospective cohort in Taiwan, 5 yrs, 62.06 yrs old (8.83), 377,873/350,825 | Various doses | N.A. | Metformin use is associated with a dose-dependent risk of AMD in patients with DM. Indeed, the greater benefit is observed at lowest dose, while the highest dose exhibited an increased risk of AMD. | [237] |
Retrospective cohort in China, 6 months to 10 yrs, Median 67 yrs, 209/115 | More than 250 | Any type | Among patients with DM for ≥10 years, metformin users were less likely to develop any AMD and early AMD than non-users | [238] |
Retrospective Cohort in Taiwan, 5.6 yrs, 65.04 yrs (8.3), 13,303/13,303 | Various doses | N.A. | The results of this study supported a lower risk of AMD in ever users of metformin when compared to never users | [239] |
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Campagnoli, L.I.M.; Varesi, A.; Fahmideh, F.; Hakimizad, R.; Petkovic, P.; Barbieri, A.; Marchesi, N.; Pascale, A. From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin. Int. J. Mol. Sci. 2025, 26, 9748. https://doi.org/10.3390/ijms26199748
Campagnoli LIM, Varesi A, Fahmideh F, Hakimizad R, Petkovic P, Barbieri A, Marchesi N, Pascale A. From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin. International Journal of Molecular Sciences. 2025; 26(19):9748. https://doi.org/10.3390/ijms26199748
Chicago/Turabian StyleCampagnoli, Lucrezia Irene Maria, Angelica Varesi, Foroogh Fahmideh, Reza Hakimizad, Petra Petkovic, Annalisa Barbieri, Nicoletta Marchesi, and Alessia Pascale. 2025. "From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin" International Journal of Molecular Sciences 26, no. 19: 9748. https://doi.org/10.3390/ijms26199748
APA StyleCampagnoli, L. I. M., Varesi, A., Fahmideh, F., Hakimizad, R., Petkovic, P., Barbieri, A., Marchesi, N., & Pascale, A. (2025). From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin. International Journal of Molecular Sciences, 26(19), 9748. https://doi.org/10.3390/ijms26199748