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Title: Expression of cytokine-sensitive genes in islets from diabetes-prone mice      
keywords:
Transcriptome or Gene expression
ID:
PRJNA265865
description:
Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a major site of T2D risk. In this study, microarray data collected from mouse islets were used to identify genes that are regulated by cytokines at levels consistent with the chronic low-grade inflammation observed in T2D. The most cytokine-sensitive genes were then examined for association of single nucleotide polymorphisms (SNPs) with acute insulin response to glucose (AIRg) measured in the Genetics UndeRlying DIAbetes in HispaNics (GUARDIAN) study. In GUARDIAN, there was evidence of association of AIRg with SNPs in ARAP3 (5q31.3), F13A1 (6p25.3), KLHL6 (3q27.1), NID1 (1q42.3), PAMR1 (11p13), RIPK2 (8q21.3), and STEAP4 (7q21.12). These data support the mouse islet microarray data in detection of seven novel genes with potential importance to islet dysfunction in T2D. To further assess each gene, murine islets were exposed for 48-hrs to the following stressors representing models of beta-cell failure: 20nM rotenone (oxidative stress), 100nM thapsigargin (ER stress), 10pg/ml IL-1B + 20pg/ml IL-6 (cytokines/low-grade inflammation), 28mM glucose (hyperglycemia), or 50uM palmitate + 100uM oleate + 50uM linoleate (lipotoxicity). RT-PCR revealed that F13a1 was downregulated 3.3-fold by cytokines (P<0.05) and 2.6-fold by rotenone (P<0.05), Klhl6 was upregulated 4.3-fold by thapsigargin (P<0.01), Ripk2 was mildly (1.5-3-fold) but significantly upregulated by all stressors (P<0.05), and STEAP4 was profoundly cytokine-sensitive (167-fold upregulation, P<0.01). These findings reveal promising leads in elucidating islet dysfunction during the development of T2D. Overall design: Islets were isolated from prediabetic male BKS.Cg-m+/+Leprdb/J (db/db) mice and non-diabetic heterozygous controls. Islets were treated with proinflammatory cytokines overnight or left untreated and then collected for mRNA. Microarray analysis of Affymetrix chips was performed by the UVA Biomolecular Research Facility.
accesstypes:
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA265865
authentication:
none
authorization:
none
ID:
pmid:26018251
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • R01 DK089182/DK/NIDDK NIH HHS/United States

  • R01 DK085175/DK/NIDDK NIH HHS/United States

  • R01 DK061628/DK/NIDDK NIH HHS/United States

  • HL47902/HL/NHLBI NIH HHS/United States

  • HL047890/HL/NHLBI NIH HHS/United States

  • HL047887/HL/NHLBI NIH HHS/United States

  • HL060919/HL/NHLBI NIH HHS/United States

  • UL1 TR000124/TR/NCATS NIH HHS/United States

  • R01 HL060944/HL/NHLBI NIH HHS/United States

  • K01DK081621/DK/NIDDK NIH HHS/United States

  • P30 DK063491/DK/NIDDK NIH HHS/United States

  • R01 HL061019/HL/NHLBI NIH HHS/United States

  • HL047889/HL/NHLBI NIH HHS/United States

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