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.

Figure 1

Protective effect of metformin on cardiovascular diseases at the molecular level. Metformin activates the LKB-1/AMPK pathway to modulate other signaling pathways. AMPK activation can enhance the eNOS/NO pathway, which leads to vasodilation and protects against fibrosis and vascular calcification. AMPK-mediated activation of SIRT1/PGC-1α and inhibition of Drp1 improves mitochondrial biogenesis and protects against mitochondrial fission. Inhibition of mTOR signaling by AMPK/TSC2 can enhance autophagy. Moreover, metformin inhibits major molecules involved in the inflammatory response such as TLR4, NLRP3, and NF-κB. Activation and nuclear translocation of NF-κB leads to the expression of several inflammatory mediators. Furthermore, metformin can attenuate ER stress through PPARδ and prevent ER-stress-mediated apoptosis.

Figure 2

Effect of metformin on hormonal changes and obesity. Metformin can lead to a modest weight loss or prevent weight gain. It increases insulin sensitivity, leptin sensitivity and adiponectin/leptin ratio, and reduces insulin requirement. Furthermore, it can suppress appetite by increasing GLP-1 and GDF-15 secretion and decreasing ghrelin.

Figure 3

Underlying mechanisms involved in the protective effects of metformin against cancers. Metformin hinders the development of cancers and inhibits cancer cells proliferation, invasion, and metastasis through different mechanisms. The drug attenuates cancer cell proliferation through inhibition of major proliferative pathways such as PI3K/AKT/mTOR, DVL3/Wnt/β-catenin, and Raf/MEK/ERK. Simultaneously, metformin increases the expression of tumor suppressors such as PTEN, P21, P27, and P57. These tumor suppressors inhibit CKD that results in cell cycle arrest. Furthermore, metformin downregulates Snail, Slug, and ZEB1 to maintain E-cadherin expression and prevent cancer cell metastasis. Interestingly, metformin decreases PD-1 and PD-L1 and impairs tumor cell immune-evasion. Metformin also attenuates the growth signals mediated by EGFR and IGF1 receptors. The drug downregulates Nrf2, thereby impairing tumor cells’ antioxidant defense and improving chemoresistance. Furthermore, metformin can reduce the expression of HIF-1α and c-Myc. HIF-1α and c-Myc can promote the expression of glycolytic enzymes, enhance intratumor angiogenesis, and increase tumor cell invasion and metastasis.

Figure 4

Effect of metformin on different dimensions of PCOS. The effects of metformin on PCOS is not restricted to its beneficial effects on metabolic syndrome. Metformin can mitigate infertility and pregnancy complications. The drug improves anovulation, pregnancy loss, PIH, preeclampsia, LGA, neonatal hypoglycemia, and preterm labor. In addition, it was observed that metformin can decrease androgens and hyperandrogenism symptoms such as hirsutism and acne.

Figure 5

Underlying molecular mechanisms involved in the protective effects of metformin on osteoporosis. Metformin protects against MSC damage. The drug accelerates osteoblastogenesis through promoting the AMPK/SIRT6/BMP-2/RUNX-2 pathway. Moreover, metformin promotes the expression of OPG and downregulates RANKL/RANK/NF-κB pathway to decrease osteoclastogenesis.

Figure 6

Protective effects of metformin on cellular senescence, other than its protective effects on inflammation, cancer, cardiovascular, renal and neuronal diseases. Metformin reprograms intracellular signaling pathways to exert its antiaging effects. Metformin activates several mechanisms to prevent ER stress, oxidative stress, apoptosis, and stem cell exhaustion and improves mitochondrial biogenesis and autophagy. Additionally, metformin activates the SIRT3/PINK1/Parkin signaling pathway to enhance mitophagy. Meanwhile, it activates DDR through ATM/CHK2. DRR can prevent tumorigenesis, genomic instability, and telomere shortening.