Soluble CD14 and CD14 Variants, Other Inflammatory Markers, and Glucose Dysregulation in Older Adults: The Cardiovascular Health Study

Sanyog G. Shitole, Mary L. Biggs, Alexander P. Reiner, Kenneth J. Mukamal, Luc Djoussé, Joachim H. Ix, Joshua I. Barzilay, Russell P. Tracy, David Siscovick, Jorge R. Kizer

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: Experimental studies have implicated soluble (s)CD14, an effector of lipopolysaccharide-induced inflammation, in insulin resistance, but its role in human metabolic endotoxemia has not been studied. We evaluated sCD14 in relation to dysglycemia in older adults and how this compares to other markers of inflammation. RESEARCH DESIGN AND METHODS: We investigated associations of sCD14, interleukin-6 (IL-6), CRP, and white blood cell (WBC) count with insulin resistance (quantitative insulin-sensitivity check index and HOMA 2 of insulin resistance) and incident type 2 diabetes in a population-based cohort of older adults. We also assessed the causal role of sCD14 in insulin resistance using an instrumental variable approach by Mendelian randomization. RESULTS: After adjustment for conventional risk factors, each of the four biomarkers showed positive cross-sectional associations with both insulin resistance measures. These associations persisted after mutual adjustment for all markers except sCD14. Over a median follow-up of 11.6 years, 466 cases of diabetes occurred. All biomarkers except sCD14 were positively associated with diabetes, although only WBC count remained associated (hazard ratio 1.43 per doubling [95% CI 1.07, 1.90]) after mutual adjustment. Instrumental variable analysis did not support a causal role for sCD14 in insulin resistance. CONCLUSIONS: Among older adults, sCD14 was associated with insulin resistance, but this disappeared after adjustment for other biomarkers, showed no evidence of a causal basis, and was not accompanied by a similar association with diabetes. IL-6, CRP, and WBC count were each associated with insulin resistance and diabetes, WBC count most robustly. These findings do not support a central role for sCD14, but they highlight the preeminence of WBC count as an inflammatory measure of diabetes risk in this population.

Original languageEnglish (US)
Pages (from-to)2075-2082
Number of pages8
JournalDiabetes care
Volume42
Issue number11
DOIs
StatePublished - Nov 1 2019

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Insulin Resistance
Glucose
Leukocyte Count
Health
Biomarkers
Interleukin-6
Inflammation
Endotoxemia
Random Allocation
Type 2 Diabetes Mellitus
Population
Lipopolysaccharides
Research Design

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

Cite this

Shitole, S. G., Biggs, M. L., Reiner, A. P., Mukamal, K. J., Djoussé, L., Ix, J. H., ... Kizer, J. R. (2019). Soluble CD14 and CD14 Variants, Other Inflammatory Markers, and Glucose Dysregulation in Older Adults: The Cardiovascular Health Study. Diabetes care, 42(11), 2075-2082. https://doi.org/10.2337/dc19-0723

Soluble CD14 and CD14 Variants, Other Inflammatory Markers, and Glucose Dysregulation in Older Adults : The Cardiovascular Health Study. / Shitole, Sanyog G.; Biggs, Mary L.; Reiner, Alexander P.; Mukamal, Kenneth J.; Djoussé, Luc; Ix, Joachim H.; Barzilay, Joshua I.; Tracy, Russell P.; Siscovick, David; Kizer, Jorge R.

In: Diabetes care, Vol. 42, No. 11, 01.11.2019, p. 2075-2082.

Research output: Contribution to journalArticle

Shitole, SG, Biggs, ML, Reiner, AP, Mukamal, KJ, Djoussé, L, Ix, JH, Barzilay, JI, Tracy, RP, Siscovick, D & Kizer, JR 2019, 'Soluble CD14 and CD14 Variants, Other Inflammatory Markers, and Glucose Dysregulation in Older Adults: The Cardiovascular Health Study', Diabetes care, vol. 42, no. 11, pp. 2075-2082. https://doi.org/10.2337/dc19-0723
Shitole, Sanyog G. ; Biggs, Mary L. ; Reiner, Alexander P. ; Mukamal, Kenneth J. ; Djoussé, Luc ; Ix, Joachim H. ; Barzilay, Joshua I. ; Tracy, Russell P. ; Siscovick, David ; Kizer, Jorge R. / Soluble CD14 and CD14 Variants, Other Inflammatory Markers, and Glucose Dysregulation in Older Adults : The Cardiovascular Health Study. In: Diabetes care. 2019 ; Vol. 42, No. 11. pp. 2075-2082.
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abstract = "OBJECTIVE: Experimental studies have implicated soluble (s)CD14, an effector of lipopolysaccharide-induced inflammation, in insulin resistance, but its role in human metabolic endotoxemia has not been studied. We evaluated sCD14 in relation to dysglycemia in older adults and how this compares to other markers of inflammation. RESEARCH DESIGN AND METHODS: We investigated associations of sCD14, interleukin-6 (IL-6), CRP, and white blood cell (WBC) count with insulin resistance (quantitative insulin-sensitivity check index and HOMA 2 of insulin resistance) and incident type 2 diabetes in a population-based cohort of older adults. We also assessed the causal role of sCD14 in insulin resistance using an instrumental variable approach by Mendelian randomization. RESULTS: After adjustment for conventional risk factors, each of the four biomarkers showed positive cross-sectional associations with both insulin resistance measures. These associations persisted after mutual adjustment for all markers except sCD14. Over a median follow-up of 11.6 years, 466 cases of diabetes occurred. All biomarkers except sCD14 were positively associated with diabetes, although only WBC count remained associated (hazard ratio 1.43 per doubling [95{\%} CI 1.07, 1.90]) after mutual adjustment. Instrumental variable analysis did not support a causal role for sCD14 in insulin resistance. CONCLUSIONS: Among older adults, sCD14 was associated with insulin resistance, but this disappeared after adjustment for other biomarkers, showed no evidence of a causal basis, and was not accompanied by a similar association with diabetes. IL-6, CRP, and WBC count were each associated with insulin resistance and diabetes, WBC count most robustly. These findings do not support a central role for sCD14, but they highlight the preeminence of WBC count as an inflammatory measure of diabetes risk in this population.",
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T1 - Soluble CD14 and CD14 Variants, Other Inflammatory Markers, and Glucose Dysregulation in Older Adults

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AU - Reiner, Alexander P.

AU - Mukamal, Kenneth J.

AU - Djoussé, Luc

AU - Ix, Joachim H.

AU - Barzilay, Joshua I.

AU - Tracy, Russell P.

AU - Siscovick, David

AU - Kizer, Jorge R.

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Y1 - 2019/11/1

N2 - OBJECTIVE: Experimental studies have implicated soluble (s)CD14, an effector of lipopolysaccharide-induced inflammation, in insulin resistance, but its role in human metabolic endotoxemia has not been studied. We evaluated sCD14 in relation to dysglycemia in older adults and how this compares to other markers of inflammation. RESEARCH DESIGN AND METHODS: We investigated associations of sCD14, interleukin-6 (IL-6), CRP, and white blood cell (WBC) count with insulin resistance (quantitative insulin-sensitivity check index and HOMA 2 of insulin resistance) and incident type 2 diabetes in a population-based cohort of older adults. We also assessed the causal role of sCD14 in insulin resistance using an instrumental variable approach by Mendelian randomization. RESULTS: After adjustment for conventional risk factors, each of the four biomarkers showed positive cross-sectional associations with both insulin resistance measures. These associations persisted after mutual adjustment for all markers except sCD14. Over a median follow-up of 11.6 years, 466 cases of diabetes occurred. All biomarkers except sCD14 were positively associated with diabetes, although only WBC count remained associated (hazard ratio 1.43 per doubling [95% CI 1.07, 1.90]) after mutual adjustment. Instrumental variable analysis did not support a causal role for sCD14 in insulin resistance. CONCLUSIONS: Among older adults, sCD14 was associated with insulin resistance, but this disappeared after adjustment for other biomarkers, showed no evidence of a causal basis, and was not accompanied by a similar association with diabetes. IL-6, CRP, and WBC count were each associated with insulin resistance and diabetes, WBC count most robustly. These findings do not support a central role for sCD14, but they highlight the preeminence of WBC count as an inflammatory measure of diabetes risk in this population.

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