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

Abstract

Coronavirus Disease 2019 (COVID-19), caused by a new strain of coronavirus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was declared a pandemic by WHO on March 11, 2020. Soon after its emergence in late December 2019, it was noticed that diabetic individuals were at an increased risk of COVID-19-associated complications, ICU admissions, and mortality. Maintaining proper blood glucose levels using insulin and/or other oral antidiabetic drugs (such as Metformin) reduced the detrimental effects of COVID-19. Interestingly, in diabetic COVID-19 patients, while insulin administration was associated with adverse outcomes, Metformin treatment was correlated with a significant reduction in disease severity and mortality rates among affected individuals. Metformin was extensively studied for its antioxidant, anti-inflammatory, immunomodulatory, and antiviral capabilities that would explain its ability to confer cardiopulmonary and vascular protection in COVID-19. Here, we describe the various possible molecular mechanisms that contribute to Metformin therapy's beneficial effects and lay out the scientific basis of repurposing Metformin for use in COVID-19 patients.

Fig 1. Bidirectional relationship of diabetes vs. COVID-19 and the potential benefits of the antidiabetic drug Metformin.

(A) The relation between COVID-19 and diabetes is two sided. COVID-19 in preexisting diabetes can aggravate the disease in the presence of comorbid conditions leading to a worse prognosis. Meanwhile, new-onset diabetes, reported in patients with COVID-19 with no prior history of diabetes, could be due to adverse SARS-CoV-2 infection–mediated immune reaction and the destruction of the pancreas’ β-cells. (B) Proper blood glucose management can mitigate the COVID-19–related complications. Metformin has multiple pleotropic actions, including immune modulation, antiviral, and anti-inflammatory effects that could mitigate disease prognosis in diabetic COVID-19 patients. Repurposing drugs through a systematic approach reduces the need for clinical testing and risk assessment and helps identify off-target effects or newly identified targets. Created with BioRender.com. ARDS, Acute Respiratory Distress Syndrome; COVID-19, Coronavirus Disease 2019; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Fig 2. RAAS/SARS-CoV-2 axis in exaggerated immune response and acute pancreatic injury.

RAAS is an essential player in immune response, glucose metabolism, and regulating blood pressure. In the RAAS system, Renin, a proteolytic enzyme, converts angiotensinogen to AngI, and, further, the enzyme ACE converts AngI to AngII. Subsequently, the membrane-bound ACE2 metabolizes AngII to Ang 1–7, which has beneficial metabolic effects. The RAAS cascade continues with the binding of AngII to AT1R or AT2R and exerts various pathophysiological effects. Under normal physiological conditions, the AngII/AT1R axis is kept under check by ACE2/Ang 1–7 axis. Down-regulation of ACE2 in SARS-CoV-2 infection weakens the ACE2/AngI/MAS axis’s inhibitory effect over ACE2/AngII/AT1R axis, which will result in the pro-inflammatory response and subsequent tissue/organ damage. Proper activation and control of RAAS system are essential for the cardiovascular and pulmonary systems’ proper functioning. It also has a significant role in the pathophysiology of insulin resistance. Increased activity of AngII can alter insulin signaling, insulin secretion, and insulin sensitivity. Created with BioRender.com. ACE2, angiotensin converting enzyme 2; IFN, interferon; IL, interleukin; RAAS, renin–angiotensin–aldosterone system; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; TNF, tumor necrosis factor.

Fig 3. Viral pathogenesis and Metformin’s host- and virus-directed interventions in the attenuation of the disease process.

Numerical indicators ①–⑩ illustrate the different stages of a typical viral infection, replication, transcription, protein translation, virion assembly, and release. Viral infection starts with binding of the spike [S] protein of the virus to the host receptor ACE2 to form the RBD–PD complex. This attachment is primed by another membrane protein called TMPRSS2 “①a.” “①b” indicates another form of viral entry through host membrane fusion. Viral entry by endocytosis is followed by uncoating “②a” and release of the viral RNA genome “②b,” which is translated into viral RNA polymerase proteins resulting in the formation of ③ sub-genomic (−) RNAs then used as a template from sub-genomic (+) mRNAs. After that, the following processes occur: the cytoplasmic viral RNA replication ④ and nucleocapsid [N] protein transcription ⑤ and subsequent translation ⑥ of structural viral proteins [S], membrane [M], and envelope [E] protein in the ER; followed by assembly of structural [S], [M], and [E] protein with the [N] protein viral genome RNA complex ⑦ and mature virion assembly ⑧ in the ERGIC. The assembled virions bud off from the Golgi vesicle ⑨ and are released ⑩ by exocytosis. Numerical indicators ❶–❾ illustrate the potential sites of virus–host-directed action of Metformin. ❶ Metformin can potentially inhibit the virus’s attachment to the host plasma membrane by blocking the virus from binding to the host receptor ACE2. Metformin directly ❷, indirectly via Akt inhibition ❸ or via AMPK activation ❹ inhibits mTOR activity ❺ resulting in the suppression of virus–host protein interaction ❻. Inhibition of respiratory complex I by Metformin “❼a” activates AMPK “❼b” and results in inhibiting the mTOR signaling. Metformin also inhibits mitochondrial generation of ROS “❼c,” which subsequently prevents ROS-induced ER calcium (Ca²⁺) depletion and suppresses the activation of CRAC channel “❼d,” preventing SOCE ultimately preventing a rise in intracellular Ca²⁺ and subsequent release of the inflammatory mediator IL-6 “❼e,” which is often associated with COVID-19 and mediates thrombosis. Metformin increases insulin sensitivity ❽ and inhibits viral infections, modifies endosomal pH, and reduces viral ❾ replication and maturation. Created with BioRender.com. ACE2, angiotensin converting enzyme 2; COVID-19, Coronavirus Disease 2019; CRAC, Ca²⁺ release-activated Ca²⁺ channel; ER, endoplasmic reticulum; ERGIC, ER–Golgi intermediate compartment; IL, interleukin; PD, peptidase domain; RBD, receptor-binding domain; ROS, reactive oxygen species; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; SOCE, store-operated calcium entry.