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Connect the dots that connect diabetes and severity of infection

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PThe protection and treatment of people at high risk of serious infections is a paramount public health concern underscored by the COVID-19 pandemic. Although vulnerability to infection may seem like a one-way dilemma for some pre-existing conditions, when it comes to metabolic disorders such as diabetes, the relationship with severe COVID-19 infection is a two-way street. In one way, people with diabetes are predisposed to serious viral infections, and in the other, SARS-CoV-2 infection can exacerbate underlying metabolic syndromes by raising blood sugar.1

“There is this complex relationship between blood sugar and COVID,” explained Jie Sun, a professor at the University of Virginia School of Medicine. “The underlying mechanism is still very unknown.” Sun’s research focuses on respiratory infections and immunometabolism, the interface between immunology and metabolism. To learn more about the mechanisms linking metabolism and the severity of viral infection, Sun and his research team studied a metabolic protein called mitochondrial pyruvate transporter (MPC) and recently published their findings in Sciences Immunology.2

Sun’s interest in MPC stems from its involvement in metabolism, immune activation and inflammatory responses. Under normal metabolic conditions, the MPC imports pyruvate into the mitochondria, which fuels energy production in the cell through glycolysis.2,3 Although metabolic processes such as glycolysis encompass a range of useful chemical reactions that provide energy for cell survival, dysregulated metabolic function can cause damage by promoting inflammation. For example, researchers have linked insulin resistance and β-cell dysfunction in type 2 diabetes to immune activation and chronic low-grade inflammation. Glycolysis is involved in immune cell activation and MPC activity plays a role in the irregular glucose homeostasis of type 2 diabetes.2–4

Sun’s team first deleted the gene encoding MPC in the immune cells of otherwise healthy mice, which improved how the mice responded to influenza virus or infection with SARS-CoV-2. The researchers then studied a drug designed to treat metabolic disorders, called MSDC-0602K or MSDC for short. This drug inhibits MPC, and researchers found that treating mice with MSDC reduced the severity of respiratory infections.

The researchers also examined a mouse model of diabetes-related metabolic syndrome to investigate the potential benefits of targeting MPC in high-risk patients with metabolic disorders. Blocking MPC, either genetically or with MSDC, reduces lung inflammation and promotes lung recovery in the mouse model. MSDC also simultaneously lowered blood sugar and cholesterol, which increased after infection with influenza virus or SARS-CoV-2.

“Besides a flu model, using the mouse version of SARS-CoV-2, doing both models genetically and both models chemically with MSDC-0602K…that’s pretty extensive,” said Eric Taylor, professor of molecular physiology and biophysics at the University of Iowa, who was not involved in the study. By studying several types of infection and modes of blockade of MPC, Sun gained a better understanding of the molecular pathways downstream of this protein. The researchers found that inhibiting MPC attenuates specific inflammatory pathways in lung immune cells called alveolar macrophages. These pathways underlie the unique bidirectional relationship between diabetes and COVID-19 severity.

Scientists originally developed insulin-sensitizing drugs like MSDC to control pathological metabolic hell in disorders such as diabetes and non-alcoholic fatty liver disease (NAFLD).5 Sun’s work highlights how these drugs have the potential to treat more than metabolic disorders. “Metabolism is something we need, but it’s still a handicap, kind of like a fire burning,” Taylor explained. “It has to burn just right, because if it gets out of control and gets fueled at the wrong time, there’s collateral damage.”

Sun’s findings in these preclinical models raise hope that inhibiting MPC could offer a safer alternative to steroid treatments for such collateral damage, including during severe COVID-19 infections. Standard of care treatments for severe cases of COVID-19, such as dexamethasone, target inflammation. However, dexamethasone can raise blood sugar, making it unsuitable for many people with pre-existing metabolic disorders, who are among those most likely to need treatment for serious complications from COVID-19.6,7 “We thought [MSDC] would, presumably, have a better effect than dexamethasone for treating people with underlying metabolic disorders,” Sun explained. “We really want to test the therapeutic potential.”

The references

  1. Lim S, Bae JH, Kwon HS, Nauck MA. COVID-19 and diabetes mellitus: from pathophysiology to clinical management. Nat Rev Endocrinol. 2021;17(1):11-30. do I:10.1038/s41574-020-00435-4
  2. Zhu B, Wei X, Narasimhan H, et al. Inhibition of mitochondrial pyruvate transporter simultaneously attenuates hyperinflammation and hyperglycemia in COVID-19. Sci Immunol. 2023;8(82):eadf0348. do I:10.1126/sciimmunol.adf0348
  3. Zhu H, Wan H, Wu L, et al. Mitochondrial pyruvate carrier: a potential target for diabetic nephropathy. BMC Nephrol. 2020;21(1):274. do I:10.1186/s12882-020-01931-5
  4. Hameed I, Masoodi SR, Mir SA, Nabi M, Ghazanfar K, Ganai BA. Type 2 diabetes mellitus: from a metabolic disorder to an inflammatory state. World J Diabetes. 2015;6(4):598-612. do I:10.4239/wjd.v6.i4.598
  5. Ozturk ZA, Kadayifci A. Insulin sensitizers for the treatment of non-alcoholic fatty liver disease. World J Hepatol. 2014;6(4):199-206. do I:10.4254/wjh.v6.i4.199
  6. Tamez-Pérez HE, Quintanilla-Flores DL, Rodríguez-Gutiérrez R, González-González JG, Tamez-Peña AL. Steroidal hyperglycemia: prevalence, early detection and treatment recommendations: a narrative review. World J Diabetes. 2015;6(8):1073-81. do I:10.4239/wjd.v6.i8.1073
  7. Underlying medical conditions associated with a higher risk of severe COVID-19: information for healthcare professionals. Centers for Control and Prevention of Disasters. Updated February 9, 2023. Accessed May 3, 2023. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html
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