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CD14 Monocyte Receptor, Involved in the Inflammatory Cascade, and Insulin Sensitivity

Section of Diabetes, Endocrinology and Nutrition (J.M.F.-R., A.L.-B., W.R.), University Hospital of Girona "Dr. Josep Trueta", 17007 Girona; and Unit of Endocrinology and Nutrition (M.B., C.R., J.V.), University Hospital of Tarragona "Joan XXIII", Unit of Advanced Studies, 43007 Tarragona, Spain

Address all correspondence and requests for reprints to: J. M. Fernández-Real, M.D., Ph.D., Unitat de Diabetes, Endocrinologia i Nutrició, Hospital de Girona "Dr Josep Trueta", Carretera de França s/n, 17007 Girona, Spain. E-mail: uden.jmfernandezreal{at}htrueta.scs.es.

Soluble CD14 (sCD14), detectable at high concentrations constitutively present in the circulation, plays a key role in the neutralization of lipopolysaccharide, one of the most potent biologic response modifiers currently recognized and involved in the regulation of the inflammatory cascade. We tested whether circulating sCD14 was linked to inflammatory parameters and to insulin resistance in apparently healthy subjects.

Serum sCD14 concentration did not significantly correlate with body mass index (BMI), waist to hip ratio, systolic or diastolic blood pressure, serum glucose, fasting insulin, fasting insulin resistance index [homeostasis model assessment (HOMA)], or serum uric acid among 123 subjects. The association between sCD14 and fasting insulin (r = -0.19, P = 0.08) and between sCD14 and HOMA (r = -0.21, P = 0.06) tended toward statistical significance among men. Unexpectedly, sCD14 correlated positively with fasting triglycerides (TG) in all the subjects (r = 0.22, P = 0.014), and this association was most significant in men (r = 0.34, P = 0.002). After controlling for TG, the relationships between sCD14 levels and fasting insulin (r = -0.25, P = 0.029), HOMA (r = -0.28, P = 0.014), and uric acid (r = -0.30, P = 0.006) were significant in men. Among nonsmoking men (n = 44), sCD14 significantly correlated with waist diameter (r = -0.30, P = 0.03), diastolic blood pressure (r = -0.34, P = 0.022), and HOMA (r = -0.30, P = 0.03). In a multiple linear regression analysis, BMI (P < 0.00001), TG (P = 0.003), and sCD14 (P = 0.04) (but not age, sex, waist, or smoking status) independently contributed to 26% of HOMA variance.

A polymorphism of the CD14 gene, a C-to-T transition at bp -159 from the major transcription start site, seems to play a significant role in regulating serum sCD14 levels. In a subsample of 33 healthy subjects, carriers of the T allele were similar (in age, sex, BMI, fat mass, waist to hip ratio, blood pressure, and fasting glucose and insulin levels) to C/C homozygotes. In the former, integrated area under the curve for serum glucose concentrations after an oral glucose tolerance test was significantly lower (P = 0.02), and insulin sensitivity (SI) index (minimal model analysis) significantly higher (P = 0.036), than in C/C homozygotes. Among 32 type 2 diabetic subjects, carriers of the T allele also showed a significantly higher SI index (P = 0.03) and had significantly lower C-reactive protein (P = 0.03) and lower circulating soluble intercellular adhesion molecule-1 concentrations (P = 0.01) than did C/C homozygotes.

To our knowledge, this is the first study to suggest an effect of a genetic polymorphism on both SI (healthy subjects and type 2 diabetic patients) and endothelial dysfunction (sICAM-1 levels) in type 2 diabetes mellitus.

At the authors’ request, publication was postponed.

This work was partially supported by Grant 00/0024-01 from the Fondo de Investigaciones Sanitarias, National Health Institute of Spain.

Abbreviations: AUC, Area under the curve; BMI, body mass index; DBP, diastolic blood pressure; FM, fat mass; HOMA, homeostasis model assessment; LPS, lipopolysaccharide(s); OGTT, oral glucose tolerance test; SBP, systolic blood pressure; sCD, soluble CD; SI, insulin sensitivity; sICAM, soluble intercellular adhesion molecule; sTNFR, soluble TNF receptor; TG, triglycerides; WHR, waist to hip ratio.

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