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Published in: Cardiovascular Diabetology 1/2017

Open Access 01-12-2017 | Original investigation

Serum levels of interleukin-22, cardiometabolic risk factors and incident type 2 diabetes: KORA F4/FF4 study

Authors: Christian Herder, Julia M. Kannenberg, Maren Carstensen-Kirberg, Cornelia Huth, Christa Meisinger, Wolfgang Koenig, Annette Peters, Wolfgang Rathmann, Michael Roden, Barbara Thorand

Published in: Cardiovascular Diabetology | Issue 1/2017

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Abstract

Aims

Interleukin-22 (IL-22) has beneficial effects on body weight, insulin resistance and inflammation in different mouse models, but its relevance for the development of type 2 diabetes in humans is unknown. We aimed to identify correlates of serum IL-22 levels and to test the hypothesis that higher IL-22 levels are associated with lower diabetes incidence.

Methods

Cross-sectional associations between serum IL-22, cardiometabolic risk factors and glucose tolerance status were investigated in 1107 persons of the population-based KORA F4 study. The prospective association between serum IL-22 and incident type 2 diabetes was assessed in 504 initially non-diabetic study participants in both the KORA F4 study and its 7-year follow-up examination KORA FF4, 76 of whom developed diabetes.

Results

Male sex, current smoking, lower HDL cholesterol, lower estimated glomerular filtration rate and higher serum interleukin-1 receptor antagonist were associated with higher IL-22 levels after adjustment for confounders (all P < 0.05). Serum IL-22 showed no associations with glucose tolerance status, prediabetes or type 2 diabetes. Baseline serum IL-22 levels (median, 25th/75th percentiles) for incident type 2 diabetes cases and non-cases were 6.28 (1.95; 12.35) and 6.45 (1.95; 11.80) pg/ml, respectively (age and sex-adjusted P = 0.744). The age and sex-adjusted OR (95% CI) per doubling of IL-22 for incident type 2 diabetes of 1.02 (0.85; 1.23) was almost unchanged after consideration of further confounders.

Conclusions

High serum levels of IL-22 were positively rather than inversely associated with several cardiometabolic risk factors. However, these associations did not translate into an increased risk for type 2 diabetes. Thus, our data argue against the utility of IL-22 as biomarker for prevalent or incident type 2 diabetes in humans, but identify potential determinants of IL-22 levels which merits further research in the context of cardiovascular diseases.
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Literature
1.
go back to reference Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines—from host defence to tissue homeostasis. Nat Rev Immunol. 2014;14:783–95.CrossRefPubMed Rutz S, Wang X, Ouyang W. The IL-20 subfamily of cytokines—from host defence to tissue homeostasis. Nat Rev Immunol. 2014;14:783–95.CrossRefPubMed
3.
go back to reference Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA, Kunisawa J, Shibata N, Grunberg S, Sinha R, Zahm AM, Tardif MR, Sathaliyawala T, Kubota M, Farber DL, Collman RG, Shaked A, Fouser LA, Weiner DB, Tessier PA, Friedman JR, Kiyono H, Bushman FD, Chang KM, Artis D. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science. 2012;336:1321–5.CrossRefPubMedPubMedCentral Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA, Kunisawa J, Shibata N, Grunberg S, Sinha R, Zahm AM, Tardif MR, Sathaliyawala T, Kubota M, Farber DL, Collman RG, Shaked A, Fouser LA, Weiner DB, Tessier PA, Friedman JR, Kiyono H, Bushman FD, Chang KM, Artis D. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science. 2012;336:1321–5.CrossRefPubMedPubMedCentral
4.
go back to reference Wang X, Ota N, Manzanillo P, Kates L, Zavala-Solorio J, Eidenschenk C, Zhang J, Lesch J, Lee WP, Ross J, Diehl L, van Bruggen N, Kolumam G, Ouyang W. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature. 2014;514:237–41.PubMed Wang X, Ota N, Manzanillo P, Kates L, Zavala-Solorio J, Eidenschenk C, Zhang J, Lesch J, Lee WP, Ross J, Diehl L, van Bruggen N, Kolumam G, Ouyang W. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature. 2014;514:237–41.PubMed
5.
go back to reference Hasnain SZ, Borg DJ, Harcourt BE, Tong H, Sheng YH, Ng CP, Das I, Wang R, Chen AC, Loudovaris T, Kay TW, Thomas HE, Whitehead JP, Forbes JM, Prins JB, McGuckin MA. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med. 2014;20:1417–26.CrossRefPubMed Hasnain SZ, Borg DJ, Harcourt BE, Tong H, Sheng YH, Ng CP, Das I, Wang R, Chen AC, Loudovaris T, Kay TW, Thomas HE, Whitehead JP, Forbes JM, Prins JB, McGuckin MA. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med. 2014;20:1417–26.CrossRefPubMed
6.
go back to reference Park O, Ki SH, Xu M, Wang H, Feng D, Tam J, Osei-Hyiaman D, Kunos G, Gao B. Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences. Cell Biosci. 2015;5:25.CrossRefPubMedPubMedCentral Park O, Ki SH, Xu M, Wang H, Feng D, Tam J, Osei-Hyiaman D, Kunos G, Gao B. Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences. Cell Biosci. 2015;5:25.CrossRefPubMedPubMedCentral
7.
go back to reference Fabbrini E, Cella M, McCartney SA, Fuchs A, Abumrad NA, Pietka TA, Chen Z, Finck BN, Han DH, Magkos F, Conte C, Bradley D, Fraterrigo G, Eagon JC, Patterson BW, Colonna M, Klein S. Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals. Gastroenterology. 2013;145:366–74.CrossRefPubMedPubMedCentral Fabbrini E, Cella M, McCartney SA, Fuchs A, Abumrad NA, Pietka TA, Chen Z, Finck BN, Han DH, Magkos F, Conte C, Bradley D, Fraterrigo G, Eagon JC, Patterson BW, Colonna M, Klein S. Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals. Gastroenterology. 2013;145:366–74.CrossRefPubMedPubMedCentral
8.
go back to reference Dalmas E, Venteclef N, Caer C, Poitou C, Cremer I, Aron-Wisnewsky J, Lacroix-Desmazes S, Bayry J, Kaveri SV, Clément K, André S, Guerre-Millo M. T cell-derived IL-22 amplifies IL-1β-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes. Diabetes. 2014;63:1966–77.CrossRefPubMed Dalmas E, Venteclef N, Caer C, Poitou C, Cremer I, Aron-Wisnewsky J, Lacroix-Desmazes S, Bayry J, Kaveri SV, Clément K, André S, Guerre-Millo M. T cell-derived IL-22 amplifies IL-1β-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes. Diabetes. 2014;63:1966–77.CrossRefPubMed
9.
go back to reference Zhao R, Tang D, Yi S, Li W, Wu C, Lu Y, Hou X, Song J, Lin P, Chen L, Sun L. Elevated peripheral frequencies of Th22 cells: a novel potent participant in obesity and type 2 diabetes. PLoS ONE. 2014;9:e85770.CrossRefPubMedPubMedCentral Zhao R, Tang D, Yi S, Li W, Wu C, Lu Y, Hou X, Song J, Lin P, Chen L, Sun L. Elevated peripheral frequencies of Th22 cells: a novel potent participant in obesity and type 2 diabetes. PLoS ONE. 2014;9:e85770.CrossRefPubMedPubMedCentral
10.
go back to reference Gong F, Wu J, Zhou P, Zhang M, Liu J, Liu Y, Lu X, Liu Z. Interleukin-22 might act as a double-edged sword in type 2 diabetes and coronary artery disease. Med Inflamm. 2016;2016:8254797. Gong F, Wu J, Zhou P, Zhang M, Liu J, Liu Y, Lu X, Liu Z. Interleukin-22 might act as a double-edged sword in type 2 diabetes and coronary artery disease. Med Inflamm. 2016;2016:8254797.
11.
go back to reference Rathmann W, Strassburger K, Heier M, Holle R, Thorand B, Giani G, Meisinger C. Incidence of type 2 diabetes in the elderly German population and the effect of clinical and lifestyle risk factors: KORA S4/F4 cohort study. Diabet Med. 2009;26:1212–9.CrossRefPubMed Rathmann W, Strassburger K, Heier M, Holle R, Thorand B, Giani G, Meisinger C. Incidence of type 2 diabetes in the elderly German population and the effect of clinical and lifestyle risk factors: KORA S4/F4 cohort study. Diabet Med. 2009;26:1212–9.CrossRefPubMed
12.
go back to reference The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(Suppl 1):5–20. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(Suppl 1):5–20.
13.
go back to reference Herder C, Ouwens DM, Carstensen M, Kowall B, Huth C, Meisinger C, Rathmann W, Roden M, Thorand B. Adiponectin may mediate the association between omentin, circulating lipids and insulin sensitivity: results from the KORA F4 study. Eur J Endocrinol. 2015;172:423–32.CrossRefPubMed Herder C, Ouwens DM, Carstensen M, Kowall B, Huth C, Meisinger C, Rathmann W, Roden M, Thorand B. Adiponectin may mediate the association between omentin, circulating lipids and insulin sensitivity: results from the KORA F4 study. Eur J Endocrinol. 2015;172:423–32.CrossRefPubMed
14.
go back to reference Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J. CKD-EPI (chronic kidney disease epidemiology collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.CrossRefPubMedPubMedCentral Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J. CKD-EPI (chronic kidney disease epidemiology collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.CrossRefPubMedPubMedCentral
15.
go back to reference Herder C, Haastert B, Müller-Scholze S, Koenig W, Thorand B, Holle R, Wichmann HE, Scherbaum WA, Martin S, Kolb H. Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). Diabetes. 2005;54(Suppl 2):S11–7.CrossRefPubMed Herder C, Haastert B, Müller-Scholze S, Koenig W, Thorand B, Holle R, Wichmann HE, Scherbaum WA, Martin S, Kolb H. Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). Diabetes. 2005;54(Suppl 2):S11–7.CrossRefPubMed
16.
go back to reference Herder C, Kolb H, Koenig W, Haastert B, Müller-Scholze S, Rathmann W, Holle R, Thorand B, Wichmann HE. Association of systemic concentrations of macrophage migration inhibitory factor with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg, Survey 4 (KORA S4). Diabetes Care. 2006;29:368–71.CrossRefPubMed Herder C, Kolb H, Koenig W, Haastert B, Müller-Scholze S, Rathmann W, Holle R, Thorand B, Wichmann HE. Association of systemic concentrations of macrophage migration inhibitory factor with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg, Survey 4 (KORA S4). Diabetes Care. 2006;29:368–71.CrossRefPubMed
17.
go back to reference Dalmas E, Donath MY. A role for interleukin-22 in the alleviation of metabolic syndrome. Nat Med. 2014;20:1379–81.PubMed Dalmas E, Donath MY. A role for interleukin-22 in the alleviation of metabolic syndrome. Nat Med. 2014;20:1379–81.PubMed
18.
go back to reference Fröhlich M, Sund M, Löwel H, Imhof A, Hoffmeister A, Koenig W. Independent association of various smoking characteristics with markers of systemic inflammation in men. Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95). Eur Heart J. 2003;24:1365–72.CrossRefPubMed Fröhlich M, Sund M, Löwel H, Imhof A, Hoffmeister A, Koenig W. Independent association of various smoking characteristics with markers of systemic inflammation in men. Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95). Eur Heart J. 2003;24:1365–72.CrossRefPubMed
19.
go back to reference Chellan B, Yan L, Sontag TJ, Reardon CA, Hofmann Bowman MA. IL-22 is induced by S100/calgranulin and impairs cholesterol efflux in macrophages by downregulating ABCG1. J Lipid Res. 2014;55:443–54.CrossRefPubMedPubMedCentral Chellan B, Yan L, Sontag TJ, Reardon CA, Hofmann Bowman MA. IL-22 is induced by S100/calgranulin and impairs cholesterol efflux in macrophages by downregulating ABCG1. J Lipid Res. 2014;55:443–54.CrossRefPubMedPubMedCentral
20.
go back to reference Weidenbusch M, Rodler S, Anders HJ. Interleukin-22 in kidney injury and regeneration. Am J Physiol Renal Physiol. 2015;308:F1041–6.CrossRefPubMed Weidenbusch M, Rodler S, Anders HJ. Interleukin-22 in kidney injury and regeneration. Am J Physiol Renal Physiol. 2015;308:F1041–6.CrossRefPubMed
21.
go back to reference Borghi M, De Luca A, Puccetti M, Jaeger M, Mencacci A, Oikonomou V, Pariano M, Garlanda C, Moretti S, Bartoli A, Sobel J, van de Veerdonk FL, Dinarello CA, Netea MG, Romani L. Pathogenic NLRP3 inflammasome activity during Candida infection is negatively regulated by IL-22 via activation of NLRC4 and IL-1Ra. Cell Host Microbe. 2015;18:198–209.CrossRefPubMed Borghi M, De Luca A, Puccetti M, Jaeger M, Mencacci A, Oikonomou V, Pariano M, Garlanda C, Moretti S, Bartoli A, Sobel J, van de Veerdonk FL, Dinarello CA, Netea MG, Romani L. Pathogenic NLRP3 inflammasome activity during Candida infection is negatively regulated by IL-22 via activation of NLRC4 and IL-1Ra. Cell Host Microbe. 2015;18:198–209.CrossRefPubMed
22.
go back to reference Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, Ki SH, Yoo SH, Dooley S, Wang FS, Young HA, Gao B. In vivo consequences of liver-specific interleukin-22 expression in mice: implications for human liver disease progression. Hepatology. 2011;54:252–61.CrossRefPubMedPubMedCentral Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, Ki SH, Yoo SH, Dooley S, Wang FS, Young HA, Gao B. In vivo consequences of liver-specific interleukin-22 expression in mice: implications for human liver disease progression. Hepatology. 2011;54:252–61.CrossRefPubMedPubMedCentral
24.
go back to reference Odegaard AO, Jacobs DR Jr, Sanchez OA, Goff DC Jr, Reiner AP, Gross MD. Oxidative stress, inflammation, endothelial dysfunction and incidence of type 2 diabetes. Cardiovasc Diabetol. 2016;15:51.CrossRefPubMedPubMedCentral Odegaard AO, Jacobs DR Jr, Sanchez OA, Goff DC Jr, Reiner AP, Gross MD. Oxidative stress, inflammation, endothelial dysfunction and incidence of type 2 diabetes. Cardiovasc Diabetol. 2016;15:51.CrossRefPubMedPubMedCentral
25.
go back to reference Herder C, Dalmas E, Böni-Schnetzler M, Donath MY. The IL-1 pathway in type 2 diabetes and cardiovascular complications. Trends Endocrinol Metab. 2015;26:551–63.CrossRefPubMed Herder C, Dalmas E, Böni-Schnetzler M, Donath MY. The IL-1 pathway in type 2 diabetes and cardiovascular complications. Trends Endocrinol Metab. 2015;26:551–63.CrossRefPubMed
26.
go back to reference Hasnain SZ, Prins JB, McGuckin MA. Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes. J Mol Endocrinol. 2016;56:R33–54.CrossRefPubMed Hasnain SZ, Prins JB, McGuckin MA. Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes. J Mol Endocrinol. 2016;56:R33–54.CrossRefPubMed
27.
go back to reference Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356:1517–26.CrossRefPubMed Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356:1517–26.CrossRefPubMed
28.
go back to reference Carstensen M, Herder C, Kivimäki M, Jokela M, Roden M, Shipley MJ, Witte DR, Brunner EJ, Tabák AG. Accelerated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: Whitehall II prospective cohort study. Diabetes. 2010;59:1222–7.CrossRefPubMedPubMedCentral Carstensen M, Herder C, Kivimäki M, Jokela M, Roden M, Shipley MJ, Witte DR, Brunner EJ, Tabák AG. Accelerated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: Whitehall II prospective cohort study. Diabetes. 2010;59:1222–7.CrossRefPubMedPubMedCentral
Metadata
Title
Serum levels of interleukin-22, cardiometabolic risk factors and incident type 2 diabetes: KORA F4/FF4 study
Authors
Christian Herder
Julia M. Kannenberg
Maren Carstensen-Kirberg
Cornelia Huth
Christa Meisinger
Wolfgang Koenig
Annette Peters
Wolfgang Rathmann
Michael Roden
Barbara Thorand
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2017
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-017-0498-6

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