Letter to the Editor: Mechanisms of increased morbidity and mortality of SARS-CoV-2 infection in individuals with diabetes: what this means for an effective management strategy
Authors: Casey Means
Journal: Metabolism (2020)

A diagnosis of diabetes has been a key indicator of the severity of COVID-19, and in this regard, the virus has relentlessly highlighted our global Achilles heel of metabolic dysfunction, and points to a prime opportunity to fight back. That fight, however, is not going to be won with Clorox, Purell, masks, or anti-IL-6 drugs. The fight will only be won through a serious commitment to improving everyone's foundational metabolic health, starting with the lowest hanging evidence-based fruit: dietary and lifestyle interventions. Unfortunately, the overwhelming thrust of the literature published to date on COVID-19 and diabetes has emphasized medications as the lynchpin of glycemic control; this focus is important but too narrow in the face of the large body of research supporting nutritional and behavioral interventions to rapidly improve glucose levels and inflammation [[1]Butler M.J. Barrientos R.M. The impact of nutrition on COVID-19 susceptibility and long-term consequences [published online ahead of print, 2020 Apr 17].Brain Behav Immun. 2020; (S0889–1591(20)30537–7)https://doi.org/10.1016/j.bbi.2020.04.040Crossref PubMed Scopus (355) Google Scholar]. It's an epidemiologic and biologic fact that acquired disorders of glucose metabolism are mostly preventable [[2]Steinbrecher A. Morimoto Y. Heak S. et al.The preventable proportion of type 2 diabetes by ethnicity: the multiethnic cohort.Ann Epidemiol. 2011; 21: 526-535https://doi.org/10.1016/j.annepidem.2011.03.009Crossref PubMed Scopus (47) Google Scholar], and often reversible [[3]Hallberg S.J. McKenzie A.L. Williams P.T. et al.Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study [published correction appears in diabetes Ther. 2018 Mar 5].Diabetes Ther. 2018; 9: 583-612https://doi.org/10.1007/s13300-018-0373-9Crossref PubMed Scopus (220) Google Scholar], with healthy living strategies. With that, our war against SARS-CoV-2 must soon shift to focus on supporting Americans in getting to a healthy weight [[4]Muniyappa R, Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus [published online ahead of print, 2020 Mar 31]. Am J Physiol Endocrinol Metab 2020; (10.1152/ajpendo.00124.2020).Google Scholar], improving glycemic control, and restoring insulin sensitivity. Recent published models suggest that we may be moving in the wrong direction, predicting that glycemic control will severely worsen due to social isolation and lockdown, with an estimated 3.68% increase in HbA1c over 45 days for individuals with diabetes during this pandemic [[5]Ghosal S. Sinha B. Majumder M. Misra A. Estimation of effects of nationwide lockdown for containing coronavirus infection on worsening of glycosylated haemoglobin and increase in diabetes-related complications: a simulation model using multivariate regression analysis [published online ahead of print, 2020 Apr 10].Diabetes Metab Syndr. 2020; 14: 319-323https://doi.org/10.1016/j.dsx.2020.03.014Crossref PubMed Scopus (146) Google Scholar]. These models highlight the imperative need to support patients with clear, evidence based dietary and lifestyle strategies for glycemic control that they can implement at home. Examining the multifarious mechanisms through which SARS-CoV-2 increases morbidity in people with diabetes shows us that the relationship is complex, and is a testament to the fact that we are misplacing our resources attempting to fast-track targeted therapeutics, which may chip away at some detrimental inflammation in infected patients, but do little to foundationally improve metabolic and immune resilience against this pandemic or future ones. This commentary reviews the numerous biologic mechanisms that have been presented in recent literature that may explain why people with diabetes fare worse with COVID-19 than those without. Some of these mechanisms are related to general immune dysfunction, while others are specifically related to this virus. Together, they highlight the multi-system impact of hyperglycemia and metabolic dysfunction on the body's readiness to face infectious disease. In a 2011 study looking at 21 patients with type 2 diabetes and 21 healthy volunteers, it was found that there was a significant negative correlation between fasting glucose and ability of immune cells to perform phagocytosis [[6]Lecube A. Pachón G. Petriz J. Hernández C. Simó R. Phagocytic activity is impaired in type 2 diabetes mellitus and increases after metabolic improvement.PLoS One. 2011; 6e23366https://doi.org/10.1371/journal.pone.0023366Crossref PubMed Scopus (152) Google Scholar]. Promisingly, when patients with diabetes underwent intensive 5 day interventions to improve their blood glucose control under monitored conditions, phagocytosis ability improved [[6]Lecube A. Pachón G. Petriz J. Hernández C. Simó R. Phagocytic activity is impaired in type 2 diabetes mellitus and increases after metabolic improvement.PLoS One. 2011; 6e23366https://doi.org/10.1371/journal.pone.0023366Crossref PubMed Scopus (152) Google Scholar]. Both diabetes [[7]Ma R.C.W. Holt R.I.G. COVID-19 and diabetes.Diabet Med. 2020; 37: 723-725https://doi.org/10.1111/dme.14300Crossref PubMed Scopus (109) Google Scholar] and even short bouts of hyperglycemia [[8]Pal R. Bhansali A. COVID-19, diabetes mellitus and ACE2: the conundrum [published online ahead of print, 2020 Mar 29].Diabetes Res Clin Pract. 2020; 162: 108132https://doi.org/10.1016/j.diabres.2020.108132Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar] can acutely alter immune cells' ability to function properly through multiple mechanisms [[9]Jafar N. Edriss H. Nugent K. The effect of short-term hyperglycemia on the innate immune system.Am J Med Sci. 2016; 351: 201-211https://doi.org/10.1016/j.amjms.2015.11.011Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. First, high glucose alters chemotaxis and subsequent phagocytosis. What's more, high glucose levels may prevent a normal respiratory burst, the process by which immune cells kill pathogens by releasing toxic chemicals [[9]Jafar N. Edriss H. Nugent K. The effect of short-term hyperglycemia on the innate immune system.Am J Med Sci. 2016; 351: 201-211https://doi.org/10.1016/j.amjms.2015.11.011Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Additionally, in the setting of hyperglycemia, glucose can increasingly glycate antibodies, which may reduce their functionality and impair complement fixation [[10]Hennessey P.J. Black C.T. Andrassy R.J. Nonenzymatic glycosylation of immunoglobulin G impairs complement fixation.JPEN J Parenter Enteral Nutr. 1991; 15: 60-64https://doi.org/10.1177/014860719101500160Crossref PubMed Scopus (76) Google Scholar]. With this information in mind, it seems sensible to focus on minimizing hyperglycemia in order to enhance our immune cells' ability to function properly. Both diabetes and obesity can lead to a pro-inflammatory state in the body, with circulation of excess cytokines that keep the immune system in "threat" mode. These cytokines, including IL-6 and TNFα, have been found to be elevated in the patients that show severe disease in COVID-19 [[11]Maddaloni E. Buzzetti R. Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics [published online ahead of print, 2020 Mar 31].Diabetes Metab Res Rev. 2020; e33213321https://doi.org/10.1002/dmrr.3321Crossref PubMed Scopus (210) Google Scholar,[12]Singh A.K. Gupta R. Ghosh A. Misra A. Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations [published online ahead of print, 2020 Apr 9].Diabetes Metab Syndr. 2020; 14: 303-310https://doi.org/10.1016/j.dsx.2020.04.004Crossref PubMed Scopus (523) Google Scholar], and are associated with increased disease severity [[13]Gong J, Dong H, Xia SQ, Huang ZY, Wang D, Zhao Y, Liu W, Tu S, Zhang M, Wang Q, Lu F. Correlation analysis between disease severity and inflammation-related parameters in patients with COVID-19 pneumonia. Pre-print medRxiv doi: https://doi.org/10.1101/2020.02.25.20025643.Google Scholar]. Monoclonal antibody IL-6 inhibitors (normally used in autoimmune diseases like rheumatoid arthritis) are being tested as therapeutics to mitigate immune-mediated morbidity in COVID-19 patients [[14]Sarilumab enters clinical trial for COVID-19, spotlighting 'key role' for IL-6. 2020 Mar 19. Healio Rheumatology.https://www.healio.com/rheumatology/rheumatoid-arthritis/news/online/%7B1957db6e-f7a2-4e5d-939e-d4b5964b2dd3%7D/sarilumab-enters-clinical-trial-for-covid-19-spotlighting-key-role-for-il-6Google Scholar]. TNFα, IL-1 and IL-6 are, at baseline, more active in the setting of diabetes and obesity, and it has been posited that infection with SARS-CoV-2 may serve to amplify an already primed cytokine response in patients with these conditions, thus exacerbating the cytokine storm that appears to be driving the multiorgan failure seen in COVID-19 [[15]Ryan P.M. Caplice N.M. Is adipose tissue a reservoir for viral spread, immune activation and cytokine amplification in COVID-19 [published online ahead of print, 2020 Apr 21].Obesity (Silver Spring). 2020; https://doi.org/10.1002/oby.22843Crossref Scopus (225) Google Scholar]. It also appears that certain "helpful" immune cells (certain subsets of CD4+ and CD8+ T cells) that coordinate the immune response are decreased in concentration in the blood of people with diabetes who have COVID-19, and there is a higher proportion of pro-inflammatory immune cells (i.e. Th17 cells) [[4]Muniyappa R, Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus [published online ahead of print, 2020 Mar 31]. Am J Physiol Endocrinol Metab 2020; (10.1152/ajpendo.00124.2020).Google Scholar]. SARS-CoV-2 may infect circulating immune cells and cause increased cell death of these more helpful immune cells, leading to lymphocytopenia, which is associated with worse severity of COVID-19 [[4]Muniyappa R, Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus [published online ahead of print, 2020 Mar 31]. Am J Physiol Endocrinol Metab 2020; (10.1152/ajpendo.00124.2020).Google Scholar]. The death of CD4+ and CD8+ T cells relieves inhibition and effective modulation of the innate immune system, causing an exaggerated deluge of inflammatory cytokines, resulting in a cytokine storm. Specifically, recent reports have shown that there are reduced numbers of memory T lymphocytes, Treg subtypes, and helper T cells in patients with severe COVID-19 [[15]Ryan P.M. Caplice N.M. Is adipose tissue a reservoir for viral spread, immune activation and cytokine amplification in COVID-19 [published online ahead of print, 2020 Apr 21].Obesity (Silver Spring). 2020; https://doi.org/10.1002/oby.22843Crossref Scopus (225) Google Scholar]. In short COVID-19 generates an uncoordinated and aggressive immune response, specifically in those with diabetes, and this immune response causes intense damage to organs. The baseline pro-inflammatory state found in diabetes and obesity may serve to exacerbate this. A theorized potential link between diabetes and COVID-19 mortality lay in hemoglobin [[16]Liu Wenzhong Hualan L. COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism.2020https://doi.org/10.26434/chemrxiv.11938173.v7Crossref Google Scholar]. Because of higher circulating glucose levels, patients with diabetes will have a higher percentage of glycated hemoglobin. SARS-CoV-2 surface proteins seem to bind to and potentially impair the heme molecule within red blood cells, causing separation of iron from the molecule to form a porphyrin [[16]Liu Wenzhong Hualan L. COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism.2020https://doi.org/10.26434/chemrxiv.11938173.v7Crossref Google Scholar]. This results in red blood cells carrying less oxygen and carbon dioxide, and thereby can generate cell death and intense inflammation in the lungs. Because patients with diabetes and older people have more glycated hemoglobin, they may be preferentially affected by SARS-CoV-2 binding and dissociation of iron from heme to form porphyrins [[16]Liu Wenzhong Hualan L. COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism.2020https://doi.org/10.26434/chemrxiv.11938173.v7Crossref Google Scholar]. SARS-CoV-2 is able to enter human cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in lung tissue, cardiac tissue, endothelial cells of blood vessels, the kidney, intestinal cells, hepatocytes, and pancreas cells [[4]Muniyappa R, Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus [published online ahead of print, 2020 Mar 31]. Am J Physiol Endocrinol Metab 2020; (10.1152/ajpendo.00124.2020).Google Scholar], and which appears to have increased levels on the cells of people with diabetes, potentially thereby facilitating increased opportunity for the virus to infect cells [[17]Hanff T.C. Harhay M.O. Brown T.S. Cohen J.B. Mohareb A.M. Is there an association between covid-19 mortality and the renin-angiotensin system-a call for epidemiologic investigations.Clin Infect Dis. 2020; (ciaa329. [published online ahead of print, 2020 Mar 26])https://doi.org/10.1093/cid/ciaa329Crossref Scopus (208) Google Scholar]. The ACE2 receptor may be increased in patients taking specific medications, including GLP-1 agonists, thiazolidinediones, ACE inhibitors, statins, and angiotensin II type-1 receptor blockers (ARBs), all of which are frequently taken by individuals with diabetes [[4]Muniyappa R, Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus [published online ahead of print, 2020 Mar 31]. Am J Physiol Endocrinol Metab 2020; (10.1152/ajpendo.00124.2020).Google Scholar]. Aside from medications potentially increasing risk of COVID-19 via increasing levels of ACE2, there also may be an additional virus-specific mechanism. It is known that a diabetic state is associated with higher levels of plasmin(ogen), a protease enzyme that can cleave furin sites in COVID-19 S proteins and allow the virus to have easier infectivity [[18]Ji H.L. Zhao R. Matalon S. Matthay M.A. Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility.Physiol Rev. 2020; 100: 1065-1075https://doi.org/10.1152/physrev.00013.2020Crossref PubMed Scopus (276) Google Scholar]. According to a paper published recently in Physiologic Reviews, "the cleavage of the new furin sites in the S protein of the [COVID-19] virus by plasmin … may enhance its infectivity by expediting entry, fusion, duplication, and release in respiratory cells. Elevated plasmin(ogen) and furin levels are a common feature in COVID-19 patients with underlying medical conditions, and could be an independent factor for risk stratification of patients with COVID-19 [[4]Muniyappa R, Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus [published online ahead of print, 2020 Mar 31]. Am J Physiol Endocrinol Metab 2020; (10.1152/ajpendo.00124.2020).Google Scholar,[18]Ji H.L. Zhao R. Matalon S. Matthay M.A. Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility.Physiol Rev. 2020; 100: 1065-1075https://doi.org/10.1152/physrev.00013.2020Crossref PubMed Scopus (276) Google Scholar]." For the virus to infect, the S1 region of its spike fusion protein is cut and released by proteases, allowing the virus to be absorbed into the cell. In short, proteases normally elevated in diabetes may be facilitating viral entry into human cells [[4]Muniyappa R, Gubbi S. COVID-19 pandemic, corona viruses, and diabetes mellitus [published online ahead of print, 2020 Mar 31]. Am J Physiol Endocrinol Metab 2020; (10.1152/ajpendo.00124.2020).Google Scholar]. It is known that elevated blood glucose levels can directly increase glucose concentrations in airway secretions, and in the case of influenza, the process of exposing lung cells to elevated glucose significantly increased viral infection and replication [[19]Hill M.A. Mantzoros C. Sowers J.R. Commentary: COVID-19 in patients with diabetes [published online ahead of print, 2020 Mar 24].Metabolism. 2020; 107: 154217https://doi.org/10.1016/j.metabol.2020.154217Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar]. Together, this suggests that high blood glucose may increase the replication ability of the virus, although this has not been fully established in COVID-19. Furthermore, diabetes is associated with structural changes to lung tissue including collapse of portions of the lung and altered permeability of the blood vessels in the lung [[19]Hill M.A. Mantzoros C. Sowers J.R. Commentary: COVID-19 in patients with diabetes [published online ahead of print, 2020 Mar 24].Metabolism. 2020; 107: 154217https://doi.org/10.1016/j.metabol.2020.154217Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar]. This impact of diabetes on lung physiology and structure, in conjunction with the propensity of COVID-19 to infect lung tissue cells, may be contributing to increased mortality. Research published April 18th, 2020 found that patients exposed to highest amount of environmental nitrogen dioxide (NO2) had increased risk of death from COVID-19, and that long-term exposure to this pollutant may be one of the most important contributors to fatality by compounding lung inflammation [[20]Ogen Y. Assessing nitrogen dioxide (NO2) levels as a contributing factor to coronavirus (COVID-19) fatality [published online ahead of print, 2020 Apr 11].Sci Total Environ. 2020; 726: 138605https://doi.org/10.1016/j.scitotenv.2020.138605Crossref PubMed Scopus (615) Google Scholar]. Additionally, exposure to this trace-gas also has been linked to development of diabetes and many other chronic diseases, and is a potent driver of cytokine release and inflammatory cascades [[20]Ogen Y. Assessing nitrogen dioxide (NO2) levels as a contributing factor to coronavirus (COVID-19) fatality [published online ahead of print, 2020 Apr 11].Sci Total Environ. 2020; 726: 138605https://doi.org/10.1016/j.scitotenv.2020.138605Crossref PubMed Scopus (615) Google Scholar]. Minimizing exposure to environmental pollutants may serve a role in quelling the underlying pro-inflammatory state that characterizes metabolic disease and COVID-19 associated cytokine storms, however more research needs to be done to confirm this. Other environmental toxins, including persistent organic pollutants (POPs) found in air, water, and food generated from pesticides and industrial chemicals, are also strongly implicated in the pathogenesis of metabolic syndrome; promoting "clean living," toxin-avoidant strategies for patients as simple as emphasizing organic foods, home air purification, and non-toxic home supplies could be considered, although the clinical utility of these measures in the acute setting is unknown [[21]Yang C. Kong A.P.S. Cai Z. Chung A.C.K. Persistent organic pollutants as risk factors for obesity and diabetes.Curr Diab Rep. 2017; 17 (Published 2017 Nov 2. doi:10.1007/s11892-017-0966-0): 132Crossref PubMed Scopus (61) Google Scholar]. It is not just diabetes that is making COVID-19 more deadly; it's also possible that COVID-19 is making diabetes worse [[11]Maddaloni E. Buzzetti R. Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics [published online ahead of print, 2020 Mar 31].Diabetes Metab Res Rev. 2020; e33213321https://doi.org/10.1002/dmrr.3321Crossref PubMed Scopus (210) Google Scholar]. It is known that SARS-CoV-2 can infect endocrine pancreas cells via their expression of ACE2 receptors. As such, it's possible that pancreatic damage from the virus and resultant impairment in beta-cell insulin secretion could worsen preexisting diabetes or even predispose to new cases of diabetes in non-diabetic subjects. This could make hyperglycemia worse in the short term (and thus lead to a more severe COVID-19 disease course), and also trigger the emergence of increased rates of autoimmune diabetes, whereby the body coordinates an immune response to the damaged pancreas, with physiology akin to type 1 diabetes. Given this complexity, it is clear that a piecemeal pharmaceutical approach is misguided; foundationally improving metabolic health is key to resilience against this pandemic and those we will inevitably face in the future. It is important to remember that influenza and other bacterial and viral illnesses also discriminate against people with diabetes, with these individuals being six times more likely to need hospitalization during influenza epidemics than people without diabetes [[22]Casqueiro J. Casqueiro J. Alves C. Infections in patients with diabetes mellitus: a review of pathogenesis.Indian J Endocrinol Metab. 2012; 16 Suppl 1: S27-S36https://doi.org/10.4103/2230-8210.94253Crossref PubMed Google Scholar]. We must commit to evidence based dietary and lifestyle strategies that prevent and reverse disease, which have been shown to be highly effective (some studies showing reversal of diabetes in as little as 10 weeks of coaching and nutritional interventions) [[23]McKenzie A.L. Hallberg S.J. Creighton B.C. et al.A novel intervention including individualized nutritional recommendations reduces hemoglobin A1c level, medication use, and weight in type 2 diabetes.JMIR Diabetes. 2017; 2 (Published 2017 Mar 7. doi:10.2196/diabetes.6981)e5Crossref PubMed Scopus (94) Google Scholar]. Strategies that involve optimization of nutrition, exercise [[24]Colberg S.R. Sigal R.J. Yardley J.E. et al.Physical activity/exercise and diabetes: a position statement of the American Diabetes Association.Diabetes Care. 2016; 39: 2065-2079https://doi.org/10.2337/dc16-1728Crossref PubMed Scopus (1490) Google Scholar], sleep hygiene [[25]Arora T. Taheri S. Sleep optimization and diabetes control: a review of the literature.Diabetes Ther. 2015; 6: 425-468https://doi.org/10.1007/s13300-015-0141-zCrossref PubMed Scopus (18) Google Scholar], stress management [[26]Vasanth R. Ganesh A. Shanker R. Impact of stress on type 2 diabetes mellitus management.Psychiatr Danub. 2017; 29: 416-421PubMed Google Scholar], and toxin exposure [[27]Sargis R.M. Heindel J.J. Padmanabhan V. Interventions to address environmental metabolism-disrupting chemicals: changing the narrative to empower action to restore metabolic health.Front Endocrinol (Lausanne). 2019; 10 (Published 2019 Feb 4. doi:10.3389/fendo.2019.00033): 33Crossref PubMed Scopus (36) Google Scholar] all play a role in management of metabolic disease, and yet have been largely missing from existing literature on management of diabetes in the setting of COVID-19. Importantly, the standard Western diet is a known driver of a similar pro-inflammatory signature to that seen in severe COVID-19 physiology, and consuming healthy foods can have a rapid anti-inflammatory effect [[1]Butler M.J. Barrientos R.M. The impact of nutrition on COVID-19 susceptibility and long-term consequences [published online ahead of print, 2020 Apr 17].Brain Behav Immun. 2020; (S0889–1591(20)30537–7)https://doi.org/10.1016/j.bbi.2020.04.040Crossref PubMed Scopus (355) Google Scholar]. Consuming fresh, fiber-rich, whole foods could serve to mitigate some of the overwhelming immune response that appears to be compounded in patients with COVID-19 who have diabetes and obesity, and must be a central focus included in any clinical recommendations made to patients or healthcare systems during this pandemic [[28]Connaughton R.M. McMorrow A.M. McGillicuddy F.C. Lithander F.E. Roche H.M. Impact of anti-inflammatory nutrients on obesity-associated metabolic-inflammation from childhood through to adulthood.Proc Nutr Soc. 2016; 75: 115-124https://doi.org/10.1017/S0029665116000070Crossref PubMed Scopus (40) Google Scholar]. Wang, et al. recently put forth "Five No" rules for diabetes management during COVID-19 which included "no going out, no gatherings, no sedentariness, no stop on medications, no anxiety [[29]Wang W. Lu J. Gu W. Zhang Y. Liu J. Ning G. Care for diabetes with COVID-19: advice from China [published online ahead of print, 2020 Apr 13].J Diabetes. 2020; https://doi.org/10.1111/1753-0407.13036Crossref Scopus (35) Google Scholar]." What is starkly missing is the clear, simple, and strong recommendation for no added sugar or ultrarefined carbohydrates, both of which are known drivers of postprandial hyperglycemia and inflammation. As a medical community, we must not miss the opportunity to serve patients with straightforward, evidence-based nutritional and lifestyle strategies to assist in glycemic control. Incorporating more emphasis on these strategies could result in a silver lining of the COVID-19 tragedy being that we reverse the tide of the American chronic disease epidemic. If there's anything this COVID-19 pandemic has demonstrated, it's that if there is a collective will, action can happen. We must focus some of that collective will, in the form of practice habits, research efforts, and policy recommendations, on a central factor that will lead to a healthier and more prosperous future: foundational metabolic health. Casey Means, MD is the Chief Medical Officer of Levels. There was no funding source for this paper.