Metformin Monotherapy Downregulates Diabetes-Associated Inflammatory Status and Impacts on Mortality

Abstract

Aging is the main risk factor for developing diabetes and other age-related diseases. One of the most common features of age-related comorbidities is the presence of low-grade chronic inflammation. This is also the case of metabolic syndrome and diabetes. At the subclinical level, a pro-inflammatory phenotype was shown to be associated with Type-2 diabetes mellitus (T2DM). This low to mid-grade inflammation is also present in elderly individuals and has been termed inflammaging. Whether inflammation is a component of aging or exclusively associated with age-related diseases in not entirely known. We used clinical data and biological readouts in a group of individuals stratified by age, diabetes status and comorbidities to investigate this aspect. While aging is the main predisposing factor for several diseases there is a concomitant increased level of pro-inflammatory cytokines. DM patients show an increased level of sTNFRll, sICAM-1, and TIMP-1 when compared to Healthy, Non-DM and Pre-DM individuals. These inflammatory molecules are also associated with insulin resistance and metabolic syndrome in Non-DM and pre-DM individuals. We also show that metformin monotherapy was associated with significantly lower levels of inflammatory molecules, like TNFα, sTNFRI, and sTNFRII, when compared to other monotherapies. Longitudinal follow up indicates a higher proportion of death occurs in individuals taking other monotherapies compared to metformin monotherapy. Together our finding shows that chronic inflammation is present in healthy elderly individuals and exacerbated with diabetes patients. Likewise, metformin could help target age-related chronic inflammation in general, and reduce the predisposition to comorbidities and mortality.

Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits

“…Patients with T2D included in the study are part of the Singapore Longitudinal Aging study 2 (SLAS-2), which is a population-based cohort to study the biology of aging among Singaporean elderly individuals >55 years old 68 . PBMCs from the blood samples collected from overnight fasting individuals were washed with PBS and cryopreserved in liquid nitrogen.…”

A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin

“…In the face of chronic infection or disease, metformin also reduces genes encoding for cytokines associated with inflammation response by suppression of tumor necrosis factor-α (TNF- α ) dependent NF- κ B signaling and expression of interleukin (IL)-6 (IL-6), IL- β (IL-1 β ), MCP-1 (CCL2 chemokine ligand 2), CXCL5, and IP-10 (CXCL10) [ 51 , 58 , 59 ]. Collectively, this results in lower levels of circulating proinflammatory cytokines, and in a recent report in older persons with T2DM, the reduction in proinflammatory signaling was associated 5-year all-cause mortality risk [ 60 ]. Furthermore, metformin treatment diminished LPS-induced acute lung injury [ 61 ], suggesting that metformin may be able to reduce the cytokine storm-like response and prevent exaggerated lung damage due to SARS-CoV-2 as well.…”

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“…We would also suggest that even non-diabetic staff with the Metabolic Syndrome be offered treatment with Metformin. 22,23 This drug improves insulin resistance which is a known association with eosinopenia, a major predictor of risk in COVID-19, 9 and has been show to protect against post-infective pulmonary fibrosis. 24…”