Chemokines in Prediabetes and Type 2 Diabetes: A Meta-Analysis

Abstract

Background: A growing number of studies found inconsistent results on the role of chemokines in the progression of type 2 diabetes (T2DM) and prediabetes (PDM). The purpose of this meta-analysis was to summarize the results of previous studies on the association between the chemokines system and T2DM/PDM.

Methods: We searched in the databases, PubMed, Web of Science, Embase and Cochrane Library, for eligible studies published not later than March 1, 2020. Data extraction was performed independently by 2 reviewers, on a standardized, prepiloted form. Group differences in chemokines concentrations were summarized using the standardized mean difference (SMD) with a 95% confidence interval (CI), calculated by performing a meta-analysis using the random-effects model.

Results: We identified 98 relevant studies that investigated the association between 32 different chemokines and T2DM/PDM. Altogether, these studies involved 14,708 patients and 14,574 controls. Results showed that the concentrations of CCL1, CCL2, CCL4, CCL5, CCL11, CXCL8, CXCL10 and CX3CL1 in the T2DM patients were significantly higher than that in the controls, while no difference in these concentrations was found between the PDM patients and controls.

Conclusion: Progression of T2DM may be associated with elevated concentrations of chemokines.

Meta-analysis registration: PROSPERO, identifier CRD42019148305.

Keywords: chemokines; inflammation; meta-analysis; prediabetes; type 2 diabetes.

Figure 1

Forest plot of CC chemokine (A) and CXC chemokine (B) between T2DM patients and controls. Study effect sizes of chemokines differences between T2DM 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. T2DM, type 2 diabetes mellitus; SMD, standardized mean difference.

Figure 2

Forest plot of chemokine between PDM patients and controls. Study effect sizes of chemokines differences between PDM 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. PDM, prediabetes diabetes mellitus; SMD, standardized mean difference.

Figure 3

The complicated chemokines and their receptors network in the microenvironment of T2DM. The chemokine system plays a variety of roles in the T2DM microenvironment. Pancreatic islets and PAT are exposed to an early damage by genetic or environmental factors and start to secrete numerous pro-inflammatory chemokines. The chemokines and their receptors can also cause a variety of immune cells to enter the pancreatic islets and PAT site to play the role of immune attack. Pro-inflammatory chemokines are bind to their receptors activating the NF-κB/IκBα and AMPK activation pathway, which stimulates a proinflammatory condition. Free fatty acid may also activate inflammatory pathways and DNA damage. As a result of the Free fatty acid dysfunction, superoxide and subsequently hydrogen peroxide generation (which can combine with nitric oxide, an example of ONOO-, to create peroxynitrite, such as ROS/RNS) may occur due to compromised mitochondrial ETC and reducing ATP synthesis. All these processes impact ER stress, leading to a reduction in the ability to secrete insulin. Moreover, T2DM 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., neutrophils, macrophages, NK cell, dendritic cell and specifically T cells) are recruited in the pancreatic tissue. These immune cells further release more innate inflammatory cytokines, which contribute to a rapid increase β cell death. T2DM, Type 2 diabetes mellitus; ROS, reactive oxygen species; RNS, reactive nitrogen species; NF-κB/IκBα, nuclear factor-kappaB; ATP, adenosine triphosphate; PAT, peri-pancreatic adipose tissue; CCR, CC chemokines receptor; CXCR, CXC chemokines receptor; ETC, electron transport chain; AMPK, Adenosine 5-monophosphate activated protein-kinase; ER, endoplasmic reticulum; Protein kinase B (AKT); ONOO-, peroxynitrite; GLUT, glucose transporters; NK, Natural killer; Tregs, Regulatory T cells. (Drawn by AK.).