New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway

Abstract

Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.

Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK/NLRP3 Inflammasome Pathway

“…MET activates AMPK through STK11 (also experienced as LKB1), which has to do with multiple signaling pathways and affects cell growth, development, apoptosis, and other biological functions [ 13 , 23 , 24 ]. AMPK is the main regulator of cellular energy producing and the interaction between metabolism and tumors [ 25 , 26 ].…”

Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals

“…AMPK also inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling which may contribute to its anti-aging effects ( Yu et al, 2021 ), but lowering mTORC1 activity in muscle by metformin may also limit protein synthesis in response to PRT ( Goodman, 2019 ). Numerous potentially beneficial effects of metformin have been observed in anti-cancer, immunosuppression, cardiovascular, and neurodegenerative trials, suggesting a broad effect across multiple AMPK- independent mechanisms ( Jin et al, 2016 ; Minamii et al, 2018 ; Saini and Yang, 2018 ; Hsu et al, 2021 ). Enhanced mitochondrial respiration and oxidative metabolism, reduced inflammatory response, reversal of endothelium dysfunction, autophagy induction, and reduced endoplasmic reticulum stress have all been noted and recent evidence suggests that metformin may also work in the intestine with effects on gut microbiota ( Vaiserman et al, 2021 ).…”

The Role of Nonapoptotic Programmed Cell Death — Ferroptosis, Necroptosis, and Pyroptosis — in Pancreatic Ductal Adenocarcinoma Treatment

“…Noncanonical pyroptosis is mediated by caspase-4/-5/-11 (caspase-4/-5 in humans and caspase-11 in mice) or caspase-3. The former induces GSDMD cleavage, while the latter facilitates GSDME cleavage ( Table 1 ) ( Figure 3 ) ( 26 , 82 , 83 ).…”