An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes

Abstract

Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of β-cell failure. In this study, microarray data were collected from mouse islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade inflammation in T2D. Genes with a cytokine-induced change of >2-fold were then examined for associations between single nucleotide polymorphisms and the acute insulin response to glucose (AIRg) using data from the Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in Arap3 (5q31.3), F13a1 (6p25.3), Klhl6 (3q27.1), Nid1 (1q42.3), Pamr1 (11p13), Ripk2 (8q21.3), and Steap4 (7q21.12). To assess the potential relevance to islet function, mouse islets were exposed to conditions modeling low-grade inflammation, mitochondrial stress, endoplasmic reticulum (ER) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except Arap3. Thapsigargin-induced ER stress up-regulated both Pamr1 and Klhl6. Three genes confirmed microarray predictions of significant cytokine sensitivity: F13a1 was down-regulated 3.3-fold by cytokines, Ripk2 was up-regulated 1.5- to 3-fold by all stressors, and Steap4 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade inflammation in murine islets and also with a marker for islet function (AIRg) in a diabetes-prone human population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to islet dysfunction during the development of T2D.

Association between -1082G/A, -819C/T, and -592C/A genetic polymorphisms in IL-10 and risk of type 2 diabetes mellitus in a Chinese population

“…Current genome-wide association studies have identified several genetic loci that play an important role in the development of type 2 diabetes mellitus (Sharma et al, 2015). In this study, we investigated the role of IL-10 -1082G/A, -819C/T, and -592C/A polymorphisms in the risk of type 2 diabetes mellitus, and identified a relationship between the AA genotype and A allele of IL-10 -592C/A and pathogenesis of type 2 diabetes mellitus in a Chinese population.…”

STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation

“…A number of genome-wide association studies suggest that STEAP4 is involved with numerous disorders related to obesity and metabolism including insulin resistance [8,9], metabolic syndrome [10,11], and insulin secretion [12,13]. Beyond its known role as a metalloreductase [14], studies have shown that STEAP4 plays an anti-inflammatory or protective role from cellular damage in adipocytes [15,9], mesangial cells [16], hepatocytes [17–19], and synoviocytes [20].…”

“…Our laboratory has recently demonstrated that STEAP4 is expressed in rodent islets and strongly upregulated in response to low-grade inflammation [13]. Further, single nucleotide polymorphisms in STEAP4 have been associated with differences in acute insulin response to glucose (AIRg) in humans [13], suggesting a role for STEAP4 in pancreatic islet function.…”

“…Further, single nucleotide polymorphisms in STEAP4 have been associated with differences in acute insulin response to glucose (AIRg) in humans [13], suggesting a role for STEAP4 in pancreatic islet function. In the present study, we compared STEAP4 expression in human islets collected from T2D donors and non-diabetic controls from two different sites to determine what factors are associated with differences in STEAP4 expression at the islet level.…”

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“…STAMP2 expression is dysregulated in patients with obesity and/or metabolic syndrome; however, STAMP2 expression was found to be both upregulated [33,34], and downregulated [26,27,32] in these conditions. Furthermore, a STAMP2 gene polymorphism has been associated with metabolic syndrome in Han-Chinese and Hispanic populations [35,36]. In addition, in vitro studies have linked STAMP2 to insulin sensitivity and glucose uptake in human hepatocytes and adipocytes [32,[37][38][39].…”