Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19

Alexi Vasbinder; Elizabeth Anderson; Husam Shadid; Hanna Berlin; Michael Pan; Tariq U. Azam; Ibrahim Khaleel; Kishan Padalia; Chelsea Meloche; Patrick O’hayer; Erinleigh Michaud; Tonimarie Catalan; Rafey Feroze; Pennelope Blakely; Christopher Launius; Yiyuan Huang; Lili Zhao; Lynn Ang; Monica Mikhael; Kara Mizokami-Stout; Subramaniam Pennathur; Matthias Kretzler; Sven H. Loosen; Athanasios Chalkias; Frank Tacke; Evangelos J. Giamarellos-Bourboulis; Jochen Reiser; Jesper Eugen-Olsen; Eva L. Feldman; Rodica Pop-Busui; Salim S. Hayek

doi:10.2337/dc21-2102

Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19

Alexi Vasbinder, Elizabeth Anderson, Husam Shadid, Hanna Berlin, Michael Pan, Tariq U. Azam, Ibrahim Khaleel, Kishan Padalia, Chelsea Meloche, Patrick O’hayer, Erinleigh Michaud, Tonimarie Catalan, Rafey Feroze, Pennelope Blakely, Christopher Launius, Yiyuan Huang, Lili Zhao, Lynn Ang, Monica Mikhael, Kara Mizokami-StoutSubramaniam Pennathur, Matthias Kretzler, Sven H. Loosen, Athanasios Chalkias, Frank Tacke, Evangelos J. Giamarellos-Bourboulis, Jochen Reiser, Jesper Eugen-Olsen, Eva L. Feldman, Rodica Pop-Busui^*, Salim S. Hayek^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

Abstract

OBJECTIVE Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicen-ter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospi-tal death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plas-minogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

Original language	English (US)
Pages (from-to)	692-700
Number of pages	9
Journal	Diabetes care
Volume	45
Issue number	3
DOIs	https://doi.org/10.2337/dc21-2102
State	Published - Mar 2022

Funding

Funding. A.V. is supported by a National Heart, Lung, and Blood Institute–funded postdoctoral fellowship (T32HL007853). S.S.H. is funded by National Heart, Lung, and Blood Institute grant 1R01HL153384-01, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants 1R01DK12801201A1 and U01DK119083-03S1, and the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor award (U-M G024231). R.P.-B. is supported by NIDDK grants 1R01DK107956-01 and U01DK119083, JDRF Australia grant 5-COE-2019-861-S-B, and Michigan Diabetes Research Center pilot and feasibility NIDDK grant P30-DK020572. E.G.B. is supported by the Hellenic Institute for the Study of Sepsis. F.T. is supported through intramural funds from Charité Universit€atsmedizin Berlin and the Berlin Institute of Health. S.P. is supported by the University of Michigan O’Brien Kidney Translational Core Center (NIDDK grant P30DK081943). The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; and preparation, review, or decision to publish the manuscript. Duality of Interest. J.R. and S.S.H. are members of the scientific advisory board of Walden Biosciences. J.E.O. is a cofounder, shareholder, and chief scientific officer of ViroGates and a named inventor on patents related to suPAR. No other potential conflicts of interest relevant to this article were reported. Author Contributions. A.V. wrote the first draft. A.V., Y.H., L.Z., R.P.-B., and S.S.H. performed the statistical analyses. H.S., I.K., T.C., E.A., H.B., M.P., T.U.A., C.M., P.O., E.M., R.F., P.B., C.L., and S.S.H. collected the data and performed quality control. L.A., M.M., K.M.-S., S.P., M.K., S.H.L., A.C., F.T., E.J.G.-B., J.R., J.E.O., E.L.F., R.P.-B., and S.S.H. provided expert interpretation of the findings. All authors reviewed the initial draft and provided critical revisions and approved the final version of the manuscript. R.P.-B. and S.S.H. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Data Sharing. Study protocol, statistical code, and data set summary data are available upon request after publication through a collaborative process. Data sets can be accessed upon approval of a submitted research proposal. Please contact [email protected]. edu for additional information.

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Advanced and Specialized Nursing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2337/dc21-2102

Cite this

Vasbinder, A., Anderson, E., Shadid, H., Berlin, H., Pan, M., Azam, T. U., Khaleel, I., Padalia, K., Meloche, C., O’hayer, P., Michaud, E., Catalan, T., Feroze, R., Blakely, P., Launius, C., Huang, Y., Zhao, L., Ang, L., Mikhael, M., ... Hayek, S. S. (2022). Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19. Diabetes care, 45(3), 692-700. https://doi.org/10.2337/dc21-2102

@article{4a3a6fe0dc864f8bae004e7aa253f684,

title = "Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19",

abstract = "OBJECTIVE Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicen-ter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospi-tal death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plas-minogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.",

author = "Alexi Vasbinder and Elizabeth Anderson and Husam Shadid and Hanna Berlin and Michael Pan and Azam, {Tariq U.} and Ibrahim Khaleel and Kishan Padalia and Chelsea Meloche and Patrick O{\textquoteright}hayer and Erinleigh Michaud and Tonimarie Catalan and Rafey Feroze and Pennelope Blakely and Christopher Launius and Yiyuan Huang and Lili Zhao and Lynn Ang and Monica Mikhael and Kara Mizokami-Stout and Subramaniam Pennathur and Matthias Kretzler and Loosen, {Sven H.} and Athanasios Chalkias and Frank Tacke and Giamarellos-Bourboulis, {Evangelos J.} and Jochen Reiser and Jesper Eugen-Olsen and Feldman, {Eva L.} and Rodica Pop-Busui and Hayek, {Salim S.}",

note = "Publisher Copyright: {\textcopyright} 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www. diabetesjournals.org/journals/pages/license.",

year = "2022",

month = mar,

doi = "10.2337/dc21-2102",

language = "English (US)",

volume = "45",

pages = "692--700",

journal = "Diabetes care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

number = "3",

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Vasbinder, A, Anderson, E, Shadid, H, Berlin, H, Pan, M, Azam, TU, Khaleel, I, Padalia, K, Meloche, C, O’hayer, P, Michaud, E, Catalan, T, Feroze, R, Blakely, P, Launius, C, Huang, Y, Zhao, L, Ang, L, Mikhael, M, Mizokami-Stout, K, Pennathur, S, Kretzler, M, Loosen, SH, Chalkias, A, Tacke, F, Giamarellos-Bourboulis, EJ, Reiser, J, Eugen-Olsen, J, Feldman, EL, Pop-Busui, R & Hayek, SS 2022, 'Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19', Diabetes care, vol. 45, no. 3, pp. 692-700. https://doi.org/10.2337/dc21-2102

TY - JOUR

T1 - Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19

AU - Vasbinder, Alexi

AU - Anderson, Elizabeth

AU - Shadid, Husam

AU - Berlin, Hanna

AU - Pan, Michael

AU - Azam, Tariq U.

AU - Khaleel, Ibrahim

AU - Padalia, Kishan

AU - Meloche, Chelsea

AU - O’hayer, Patrick

AU - Michaud, Erinleigh

AU - Catalan, Tonimarie

AU - Feroze, Rafey

AU - Blakely, Pennelope

AU - Launius, Christopher

AU - Huang, Yiyuan

AU - Zhao, Lili

AU - Ang, Lynn

AU - Mikhael, Monica

AU - Mizokami-Stout, Kara

AU - Pennathur, Subramaniam

AU - Kretzler, Matthias

AU - Loosen, Sven H.

AU - Chalkias, Athanasios

AU - Tacke, Frank

AU - Giamarellos-Bourboulis, Evangelos J.

AU - Reiser, Jochen

AU - Eugen-Olsen, Jesper

AU - Feldman, Eva L.

AU - Pop-Busui, Rodica

AU - Hayek, Salim S.

N1 - Publisher Copyright: © 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www. diabetesjournals.org/journals/pages/license.

PY - 2022/3

Y1 - 2022/3

N2 - OBJECTIVE Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicen-ter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospi-tal death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plas-minogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

AB - OBJECTIVE Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicen-ter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospi-tal death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plas-minogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

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U2 - 10.2337/dc21-2102

DO - 10.2337/dc21-2102

M3 - Article

C2 - 35045184

AN - SCOPUS:85129353776

SN - 0149-5992

VL - 45

SP - 692

EP - 700

JO - Diabetes care

JF - Diabetes care

IS - 3

ER -

Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19

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