Chemokines in Gestational Diabetes Mellitus

Abstract

Background: Studies investigating chemokines in gestational diabetes mellitus (GDM) have yielded mixed results. The purpose of this meta-analysis was to explore whether concentrations of chemokines in patients with GDM differed from that of the controls.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched Web of Science, Embase, Cochrane Library, and PubMed databases for articles, published in any language, on chemokines and GDM through August 1st, 2021. The difference in concentrations of chemokines between patients with GDM and controls was determined by a standardized mean difference (SMD) with a 95% confidence interval (CI), calculated in the meta-analysis of the eligible studies using a random-effects model with restricted maximum-likelihood estimator.

Results: Seventeen studies met the inclusion criteria for the meta-analysis. Altogether, they included nine different chemokines comparisons involving 5,158 participants (1,934 GDM patients and 3,224 controls). Results showed a significant increase of these chemokines (CCL2, CXCL1, CXCL8, CXCL9, and CXCL12) in the GDM patients compared with the controls. However, there was a significant decrease of the chemokines, CCL4, CCL11 and CXCL10, in the GDM patients compared with the controls. Moreover, subgroup analysis revealed a potential role of chemokines as biomarkers in relation to laboratory detection (different sample type and assay methods) and clinical characteristics of GDM patients (ethnicity and body mass index).

Conclusion: GDM is associated with several chemokines (CCL2, CCL4, CCL11, CXCL1, CXCL8, CXCL9, CXCL10 and CXCL12). Therefore, consideration of these chemokines as potential targets or biomarkers in the pathophysiology of GDM development is necessary. Notably, the information of subgroup analysis underscores the importance of exploring putative mechanisms underlying this association, in order to develop new individualized clinical and therapeutic strategies.

Keywords: chemokines; gestational diabetes mellitus; immune microenvironment; inflammatory; meta-analysis.

Figure 1

Study selection flow chart. A flow chart demonstrating the selection process of articles included in the analysis as well as in the qualitative summary.

Figure 2

Forest plot of chemokines between GDM patients and controls. Study effect sizes of chemokines differences between GDM and controls. Each data marker represents a study, and the size of the data marker is proportional to the total number of individuals in that study. The summary effect size for each chemokines is denoted by a diamond; GDM, Gestational diabetes mellitus; SMD, standardized mean difference.

Figure 3

Egger funnel plots of GDM patients compared to controls. GDM patients chemokine and chemokines receptor compared to patients with controls, t = 2.03, p-value = 0.061. Egger funnel plots to assess publication bias. Plots show study size as a function of effect size for studies included in the meta-analysis. The dots represent each study. GDM, Gestational diabetes mellitus.

Figure 4

The complicated chemokines network in the pancreatic islets’ microenvironment of GDM. The chemokine system plays a variety of roles in the pancreatic islets microenvironment of GDM. First, pancreatic islets are exposed to an early damage by genetic or environmental factors. Then, chemokines can also cause a variety of immune cells to enter the pancreatic islets site to play the role of immune attack. All these processes impact endoplasmic reticulum stress, leading to a reduction in the ability to secrete insulin. Moreover, GDM progression is characterized by progressive secretion of pro-inflammatory chemokines/cytokines caused by β cell damage. Due to this process, various immune cell types (i.e., CD8+T cell, CD4+T cell (Th1 cell and Th17 cell), NK cell, eosinophil, macrophage, neutrophil, mast cells, and dendritic cell) are recruited in the pancreatic tissue. These immune cells further release more innate inflammatory cytokines, which contribute to a rapid increase β cell death. GDM, Gestational diabetes mellitus; NK, Natural killer. (Drawn by AK).