Regulation of inflammation in diabetes: From genetics to epigenomics evidence

Abstract

Background Diabetes is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of preventive and therapeutic approaches. Genetic and environmental factors are the culprits involved in diabetes risk. Evidence from the last decade has highlighted that deregulation in the immune and inflammatory responses increase susceptibility to type 1 and type 2 diabetes. Spatiotemporal patterns of gene expression involved in immune cell polarisation depend on genomic enhancer elements in response to inflammatory and metabolic cues. Several studies have reported that most regulatory genetic variants are located in the non-protein coding regions of the genome and particularly in enhancer regions. The progress of high-throughput technologies has permitted the characterisation of enhancer chromatin properties. These advances support the concept that genetic alteration of enhancers may influence the immune and inflammatory responses in relation to diabetes. Scope of review Results from genome-wide association studies (GWAS) combined with functional and integrative analyses have elucidated the impacts of some diabetes risk-associated variants that are involved in the regulation of the immune system. Additionally, genetic variant mapping to enhancer regions may alter enhancer status, which in turn leads to aberrant expression of inflammatory genes associated with diabetes susceptibility. The focus of this review was to provide an overview of the current indications that inflammatory processes are regulated at the genetic and epigenomic levels in diabetes, along with perspectives on future research avenues that may improve understanding of the disease. Major conclusions In this review, we provide genetic evidence in support of a deregulated immune response as a risk factor in diabetes. We also argue about the importance of enhancer regions in the regulation of immune cell polarisation and how the recent advances using genome-wide methods for enhancer identification have enabled the determination of the impact of enhancer genetic variation on diabetes onset and phenotype. This could eventually lead to better management plans and improved treatment responses in human diabetes.

Chronic tissue inflammation and metabolic disease

“…While early GWASs showed that T2DM is associated with genetic variations in genes associated with insulin secretion and β-cell function (McCarthy et al 2010;Dimas et al 2014), later studies found that genes involved in peripheral insulin sensitivity and adipose tissue function such as PPARG and KLF14 are also associated with the incidence of T2DM (Voight et al 2010). Moreover, variations in genes regulating T-cell (e.g., PTPRJ and CMIP) or macrophage (e.g., MAEA) function or inflammatory signaling pathways (e.g., WWOX, MAP8IP1, IFNGR1, ST6GAL1, JAZF1, MAP3K1, MACROD1, NFE2L3, and TLR4) are also associated with the incidence of T2DM (Waeber et al 2000;Kooner et al 2011;Cho et al 2012;Manning et al 2012;Locke et al 2015;Shungin et al 2015;Flannick et al 2019;Liao et al 2019;Diedisheim et al 2020). While more inclusive GWAS and wholeexome sequencing studies are being updated (Mahajan et al 2018;Flannick et al 2019), many genetic variations associated with the incidence of T2DM are found in noncoding DNA regions.…”

TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway

“…However, glucose and lipid metabolism disorders caused by defects in insulin secretion and reduced responses to insulin-stimulated glycometabolism are the main pathological features of diabetes. Recent studies have found that metabolic disorder-induced glucotoxicity, oxidative stress, lipotoxicity, and endoplasmic reticulum stress can lead to systemic chronic inflammation that exacerbates the course of diabetes and diabetes-associated complications [ 2 , 3 ]. Increased activation of proinflammatory factors, such as IL-1β, has been reported to cause defective insulin secretion and insulin resistance [ 4 ].…”

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells

“… 17 , 18 Similarly, many genome-wide studies have confirmed that the genes associated with the development of type 2 diabetes are also oncogenes. 19 , 20 Although miR-140-5p was closely associated with tumors, it remained unclear whether miR-140-5p played an important role in insulin resistance and the development and progression of T2DM.…”