Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study

Abstract

The immune response involved in each phase of type 2 diabetes (T2D) development might be different. We aimed to identify novel inflammatory markers that predict progression from normoglycemia to pre-diabetes, incident T2D and insulin therapy. We used plasma levels of 26 inflammatory markers in 971 subjects from the Rotterdam Study. Among them 17 are novel and 9 previously studied. Cox regression models were built to perform survival analysis.

Main outcome measures: During a follow-up of up to 14.7 years (between April 1, 1997, and Jan 1, 2012) 139 cases of pre-diabetes, 110 cases of T2D and 26 cases of insulin initiation were identified. In age and sex adjusted Cox models, IL13 (HR = 0.78), EN-RAGE (1.30), CFH (1.24), IL18 (1.22) and CRP (1.32) were associated with incident pre-diabetes. IL13 (0.62), IL17 (0.75), EN-RAGE (1.25), complement 3 (1.44), IL18 (1.35), TNFRII (1.27), IL1ra (1.24) and CRP (1.64) were associated with incident T2D. In multivariate models, IL13 (0.77), EN-RAGE (1.23) and CRP (1.26) remained associated with pre-diabetes. IL13 (0.67), IL17 (0.76) and CRP (1.32) remained associated with T2D. IL13 (0.55) was the only marker associated with initiation of insulin therapy in diabetics. Various inflammatory markers are associated with progression from normoglycemia to pre-diabetes (IL13, EN-RAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE is a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start.

Keywords: EN-RAGE; IL13; IL17; Inflammatory markers; Insulin therapy; Novel; Phase-specific; Pre-diabetes; Type 2 diabetes.

Fig. 1

Associations of inflammatory markers with fasting glucose. CD40, cluster of differentiation 40; CD40 ligand, cluster of differentiation 40 ligand; EN-RAGE, Extracellular Newly identified Receptor for Advanced Glycation End-products binding protein; FAS, Fas Cell Surface Death Receptor; HCC4, Human CC chemokine-4; IL13, interleukin 13; IL16, interleukin 16; IL17, interleukin 17; IL8, interleukin 8; MDC, Monocyte Derived Chemokine; MIP1alpha, Macrophage Inflammatory Protein 1 alpha; MIP1beta, Macrophage Inflammatory Protein 1 beta; PARC, Pulmonary and Activation-Regulated Chemokine; sRage, Soluble Receptor of Advanced Glycation End-products; TRAILR3, Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor 3; CFH, Complement Factor H; IL18, interleukin 18; MCP1, Monocyte Chemotactic Protein 1; RANTES, Regulated Upon Activation, Normally T-Expressed, And Presumably Secreted; TNFR-II, Tumor Necrosis Factor Receptor 2; IL1ra, Interleukin 1 Receptor Antagonist; CRP, C-Reactive Protein. *Significant associations between the marker and fasting glucose. Adjusted for age, sex, BMI, waist circumference (WC), Total Cholesterol, HDL, medication for hypertension, smoking, prevalent CVD, lipid lowering medication

Fig. 2

Associations of inflammatory markers with fasting insulin. CD40, cluster of differentiation 40; CD40 ligand, cluster of differentiation 40 ligand; EN-RAGE, Extracellular Newly identified Receptor for Advanced Glycation End-products binding protein; FAS, Fas Cell Surface Death Receptor; HCC4, Human CC chemokine-4; IL13, interleukin 13; IL16, interleukin 16; IL17, interleukin 17; IL8, interleukin 8; MDC, Monocyte Derived Chemokine; MIP1alpha, Macrophage Inflammatory Protein 1 alpha; MIP1beta, Macrophage Inflammatory Protein 1 beta; PARC, Pulmonary and Activation-Regulated Chemokine; sRage, Soluble Receptor of Advanced Glycation End-products; TRAILR3, Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor 3; CFH, Complement Factor H; IL18, interleukin 18; MCP1, Monocyte Chemotactic Protein 1; RANTES, Regulated Upon Activation, Normally T-Expressed, And Presumably Secreted; TNFR-II, Tumor Necrosis Factor Receptor 2; IL1ra, Interleukin 1 Receptor Antagonist; CRP, C-Reactive Protein. ^*Significant associations between the marker and fasting insulin. Adjusted for age, sex, BMI, waist circumference (WC), Total Cholesterol, HDL, medication for hypertension, smoking, prevalent CVD, lipid lowering medication