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.