Diabetes and coronavirus (SARS-CoV-2): Molecular mechanism of Metformin intervention and the scientific basis of drug repurposing

Varghese, Elizabeth; Samuel, Samson Mathews; Líšková, Alena; Kubatka, Peter; Büsselberg, Dietrich

doi:10.1371/journal.ppat.1009634

Cited by 54 publications

(59 citation statements)

References 124 publications

(199 reference statements)

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“…Studies also show that SARS-CoV-2 can gain entry into endothelial cells via the endothelial cell surface ACE2 receptors [12][13][14]. Another study reported a different mechanism for impaired endothelial function.…”

Section: Evidence Of Ace2 and Tmprss2 On Pancreatic Beta Cellsmentioning

confidence: 97%

Replication of SARS CoV2 in Pancreatic Cells via ACE2 Cell Surface Receptors

Jamil¹

2021

Madridge J Case Rep Stud

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Earlier studies have reported that Diabetes mellitus (DM) increases the complications of Severe acute respiratory syndrome coronavirus 2 (SARS CoV2) or Coronavirus disease 2019 (COVID19), and patients are more likely to experience severe symptoms that could lead to mortality. One hypothesis states that hyperglycemic conditions facilitate the virus entry into the cell since the virus and the Angiotensin-Converting Enzyme 2 (ACE2) both require glucose for their function. However the exact interaction between the two has not been clearly defined from the cell biology point of view. The underlying mechanism for this differential effect in individuals with and without diabetes is not clearly understood. The reason for this could be due to the preexisting pathological pathways in patients with poorly controlled diabetes, which increases the risk of infectivity and are responsible for the higher levels of tissue injury and death in patients with diabetes [1]. However in this article we have focused mainly on COVID-19 induced diabetes as this area has lacuna. The diabetes specialists point out that many key metabolic tissues in the body, including pancreatic beta cells (b-cell) in the pancreas, adipose (fat storage) tissue, the small intestine, and kidneys, contain ACE2 receptors. They believe that when these viruses bind to ACE2 receptors, they may trigger changes in glucose metabolism that worsen preexisting diabetes or cause the condition to develop diabetes for the first time.

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Section: Evidence Of Ace2 and Tmprss2 On Pancreatic Beta Cellsmentioning

confidence: 97%

Replication of SARS CoV2 in Pancreatic Cells via ACE2 Cell Surface Receptors

Jamil¹

2021

Madridge J Case Rep Stud

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“…Currently, metformin is gaining huge attention as a repurposed drug, as analyses of clinical data revealed reduced mortality rates of COVID-19 patients who had been treated with the anti-diabetic drug (Crouse et al, 2021;Ibrahim et al, 2021;Varghese et al, 2021). These findings suggest an urgent need of large clinical trials with metformin as prophylactic intervention for immune aging and ageassociated diseases.…”

Section: Autophagy Induction By Rapamycinmentioning

confidence: 99%

Autophagy takes it all – autophagy inducers target immune aging

Zinecker

Simon

2022

Disease Models &Amp; Mechanisms

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Autophagy, as the key nutrient recycling pathway, enables eukaryotic cells to adapt to surging cellular stress during aging and, thereby, delays age-associated deterioration. Autophagic flux declines with age and, in turn, decreases in autophagy contribute to the aging process itself and promote senescence. Here, we outline how autophagy regulates immune aging and discuss autophagy-inducing interventions that target senescent immune cells, which are major drivers of systemic aging. We examine how cutting-edge technologies, such as single-cell omics methods hold the promise to capture the complexity of molecular and cellular phenotypes associated with aging, driving the development of suitable putative biomarkers and clinical bioassays. Finally, we debate the urgency to initiate large-scale human clinical trials. We give special preference to small molecule probes and to dietary interventions that can extend healthy lifespan and are affordable for most of the world's population.

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“…Patients who used metformin before hospitalization also showed lower severity parameters at admission 293 . During SARS-CoV-2 infection, in addition to controlling the glucose level, metformin may attenuate ED, inhibit viral entry and infection, resist oxidative stress, and change inflammatory and immune responses that would explain its ability to achieve cardiovascular protection in COVID-19 294 , 295 . Therefore, metformin may represent a drug candidate for treating COVID-19 and gain the advantage of fighting SARS-CoV-2 induced immune storm in COVID-19 patients with diabetes 296 .…”

Section: Future Directionsmentioning

confidence: 99%

Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function

et al. 2021

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As a first-line treatment for diabetes, the insulin-sensitizing biguanide, metformin, regulates glucose levels and positively affects cardiovascular function in patients with diabetes and cardiovascular complications. Endothelial dysfunction (ED) represents the primary pathological change of multiple vascular diseases, because it causes decreased arterial plasticity, increased vascular resistance, reduced tissue perfusion and atherosclerosis. Caused by “biochemical injury”, ED is also an independent predictor of cardiovascular events. Accumulating evidence shows that metformin improves ED through liver kinase B1 (LKB1)/5'-adenosine monophosphat-activated protein kinase (AMPK) and AMPK-independent targets, including nuclear factor-kappa B (NF-κB), phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), forkhead box O1 (FOXO1), krüppel-like factor 4 (KLF4) and krüppel-like factor 2 (KLF2). Evaluating the effects of metformin on endothelial cell functions would facilitate our understanding of the therapeutic potential of metformin in cardiovascular diabetology (including diabetes and its cardiovascular complications). This article reviews the physiological and pathological functions of endothelial cells and the intact endothelium, reviews the latest research of metformin in the treatment of diabetes and related cardiovascular complications, and focuses on the mechanism of action of metformin in regulating endothelial cell functions.

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Diabetes and coronavirus (SARS-CoV-2): Molecular mechanism of Metformin intervention and the scientific basis of drug repurposing

Cited by 54 publications

References 124 publications

Replication of SARS CoV2 in Pancreatic Cells via ACE2 Cell Surface Receptors

Replication of SARS CoV2 in Pancreatic Cells via ACE2 Cell Surface Receptors

Autophagy takes it all – autophagy inducers target immune aging

Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function

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