A novel approach to childhood obesity: circulating chemokines and growth factors as biomarkers of insulin resistance

Abstract

Summary Background Insulin resistance (IR) in children with obesity constitutes a risk factor that should be precisely diagnosed to prevent further comorbidities. Objective Chemokines were evaluated to identify novel predictors of IR with clinical application. Methods We analysed the levels of cytokines (tumour necrosis factor [TNF] α and interleukins [ILs] 1β, 4, 6 and 10), chemokines (stromal cell derived factor 1α, monocyte chemoattract protein [MCP] 1, eotaxin and fractalkine) and growth factors (brain‐derived neurotrophic factor, pro‐fibrotic platelet‐derived growth factor [PDGF‐BB] and insulin‐like growth factor 1) in serum of prepubertal children with obesity (61 girls/59 boys, 50% IR and 50% non‐IR) and 32 controls. Factor analysis, correlation, binary logistic regression and receiver operating characteristic analysis of combined biomarkers were used to validate their capability for preventive interventions of IR. Results Changes in MCP1, eotaxin, IL1β and PDGF‐BB were observed in IR children with obesity. Bivariate correlation between stromal cell derived factor 1α, MCP1, eotaxin, TNFα, brain‐derived neurotrophic factor and/or PDGF‐BB explained the high variance (65.9%) defined by three components related to inflammation and growth that contribute towards IR. The combination of leptin, triglyceride/high‐density lipoprotein, insulin‐like growth factor 1, TNFα, MCP1 and PDGF‐BB showed a sensitivity and specificity of 93.2% for the identification of IR. The percentage of correct predictions was 89.6. Conclusions Combined set of cytokines, adipokines and chemokines constitutes a model that predicts IR, suggesting a potential application in clinical practice as biomarkers to identify children with obesity and hyperinsulinaemia.

Insulin resistance and type 2 diabetes in children

“…In particular, changes in circulating concentrations of TNF-α, MCP1, and PDGF-BB were consistently correlated with IR in obese children. 67) Da Silva et al 70) examined the accuracy of HOMA-Adiponectin in detecting IR based on the hyperglycemic clamp technique in adolescents. Adiponectin increases fatty-acid oxidation in muscle and liver via activation of AMP-activated protein kinase and peroxisome proliferator-activated receptor alpha mediated by a specific receptor.…”

Iron Metabolism in Obesity and Metabolic Syndrome

“…Such local inflammation eventually induces IR [ 40 ]. Based on the analytical changes in the chemokine, adipokine and cytokine profiles of obese children, Rivera et al developed a diagnostic tool for IR, rendering a sensitivity and specificity of 93.2%, including levels of leptin, triglyceride:HDL-col ratio, insulin-like growth factor-I (IGF-I), TNFα, monocyte chemoattract protein 1 (MCP1) and pro-fibrotic platelet-derived growth factor (PDGF-BB) [ 41 ]. In obese children, higher obesity severity is associated with higher free fatty acid (FFA) levels.…”

A combination of circulating chemokines as biomarkers of obesity‐induced insulin resistance at puberty

“…Thus, the alterations of these chemoattractors in adolescents with obesity might be associated with differential infiltration of adipose tissue or to differential release of these signals from adipose tissue cells, something should be studied in future approaches by analysing the adipose tissue at this crucial developmental stage. This obesity-induced inflammatory response begins at younger ages 6 ; however, pubertal patients with obesity present an increase in SDF-1, eotaxin, IL1β and IL10 that is not observed in prepubertal children with obesity, 18 indicating an obesity-associated change in adipose tissue throughout development. This is in line with the concept that during puberty, the cellular and secretory features of adipose tissue become more similar to that observed in adults: the recruitment of pre-adipocytes decreases, adipocyte hypertrophy increases, secretory patterns, such as increased MCP-1 secretion, are modified and there is an increase in macrophages with a proinflammatory profile (M1) with the consequent increase in production of ILs.…”

“…After assessing binary logistic regression (n = 143; Table S2) The models presented here differ slightly from those proposed in our previous study of inflammatory biomarkers of IR in prepubertal children with obesity. 18 We can appreciate that chemokines are rele- During obesity, adipose tissue undergoes massive macrophage infiltration due to increased secretion of MCP-1 and this plays a crucial role in the obesity-related inflammatory response. These infiltrated macrophages are responsible for secretion of pro-inflammatory molecules with more than 50% of the TNFα secreted from adipose tissue being produced by macrophages.…”

“…17 However, even at this early age increased circulating levels of cytokines and chemokines (chemoattracting proteins) have been shown to be involved in the development of insulin resistance, the first step of obesity-associated metabolic derangement, with changes in TNFα, MCP-1 and the growth factors PDGF-BB and IGF-1 associating with IR. 18 However, as puberty is a time of accelerated somatic growth compared to childhood and this involves adipose tissue expansion, the infiltration of macrophages and other cells of the immune system could also increase with adipose tissue becoming the main source of proinflammatory cytokines/chemokines. [9][10][11] Puberty is known to result in a degree of physiological IR, and there is also an increase in insulin required in adolescents with T1DM.…”