Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next?

Abstract

Diabetes is accompanied by several complications. Higher prevalence of cancers, cardiovascular diseases, chronic kidney disease (CKD), obesity, osteoporosis, and neurodegenerative diseases has been reported among patients with diabetes. Metformin is the oldest oral antidiabetic drug and can improve coexisting complications of diabetes. Clinical trials and observational studies uncovered that metformin can remarkably prevent or alleviate cardiovascular diseases, obesity, polycystic ovarian syndrome (PCOS), osteoporosis, cancer, periodontitis, neuronal damage and neurodegenerative diseases, inflammation, inflammatory bowel disease (IBD), tuberculosis, and COVID-19. In addition, metformin has been proposed as an antiaging agent. Numerous mechanisms were shown to be involved in the protective effects of metformin. Metformin activates the LKB1/AMPK pathway to interact with several intracellular signaling pathways and molecular mechanisms. The drug modifies the biologic function of NF-κB, PI3K/AKT/mTOR, SIRT1/PGC-1α, NLRP3, ERK, P38 MAPK, Wnt/β-catenin, Nrf2, JNK, and other major molecules in the intracellular signaling network. It also regulates the expression of noncoding RNAs. Thereby, metformin can regulate metabolism, growth, proliferation, inflammation, tumorigenesis, and senescence. Additionally, metformin modulates immune response, autophagy, mitophagy, endoplasmic reticulum (ER) stress, and apoptosis and exerts epigenetic effects. Furthermore, metformin protects against oxidative stress and genomic instability, preserves telomere length, and prevents stem cell exhaustion. In this review, the protective effects of metformin on each disease will be discussed using the results of recent meta-analyses, clinical trials, and observational studies. Thereafter, it will be meticulously explained how metformin reprograms intracellular signaling pathways and alters molecular and cellular interactions to modify the clinical presentations of several diseases.

Metformin Reverses the Effects of Angiotensin 2 in Human Mammary Arteries by Modulating the Expression of Nitric Oxide Synthases

“…In the past decades the drug has also been systematically investigated for its protective effects in several other pathologies, such as: cancer, neurodegenerative diseases, inflammatory bowel disease, tuberculosis, polycystic ovarian syndrome, osteoporosis, periodontitis, and more recent, COVID-19 via modulating several signaling pathways such as: NF-κB, PI3K/AKT/mTOR, SIRT1/PGC-1α, NLRP3, ERK, P38 MAPK, Wnt/β-catenin, Nrf2, JNK as recently reviewed in ref. (20).…”

Protection by metformin against severe Covid-19: An in-depth mechanistic analysis

“…The antidiabetic agent metformin (MET) deserves particular attention in this respect because type 2 diabetes mellitus (T2DM) is one of the main comorbidities associated with the severity of Covid-19 [2] , and most current guidelines recommend MET as the first-line drug treatment for T2DM [3] . Indeed, MET is a pleiotropic drug with beneficial effects that go far beyond its impact on blood glucose homeostasis [4] . This pleiotropic profile makes MET a good drug candidate for attenuating the severity of Covid-19 [5] .…”

Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

“…Apart from cardiovascular benefits, there is growing evidence that metformin may be beneficial for other age-related diseases, such as cancer, cognitive impairment and dementia. Additionally, metformin has been studied in various other diseases, such as polycystic ovary syndrome (PCOS), osteoporosis, periodontitis, inflammatory bowel disease, non-alcoholic fatty liver disease, COVID-19 and as anti-aging drug in general [ 5 ].…”