Abstract
BackgroundChanges in gene expression in pancreatic beta-cells from type 2 diabetes (T2D) should provide insights into their abnormal insulin secretion and turnover.Methodology/Principal FindingsFrozen sections were obtained from cadaver pancreases of 10 control and 10 T2D human subjects. Beta-cell enriched samples were obtained by laser capture microdissection (LCM). RNA was extracted, amplified and subjected to microarray analysis. Further analysis was performed with DNA-Chip Analyzer (dChip) and Gene Set Enrichment Analysis (GSEA) software. There were changes in expression of genes linked to glucotoxicity. Evidence of oxidative stress was provided by upregulation of several metallothionein genes. There were few changes in the major genes associated with cell cycle, apoptosis or endoplasmic reticulum stress. There was differential expression of genes associated with pancreatic regeneration, most notably upregulation of members of the regenerating islet gene (REG) family and metalloproteinase 7 (MMP7). Some of the genes found in GWAS studies to be related to T2D were also found to be differentially expressed. IGF2BP2, TSPAN8, and HNF1B (TCF2) were upregulated while JAZF1 and SLC30A8 were downregulated.Conclusions/SignificanceThis study made possible by LCM has identified many novel changes in gene expression that enhance understanding of the pathogenesis of T2D.
Highlights
Pancreatic beta-cells play a central role in the development and progression of type 2 diabetes (T2D) [1]
It was important to do this because human islets are known have clumps of a and d cells in the islet core [6], which means that great care must be taken with laser capture microdissection (LCM) to avoid the non beta-cells
It cannot be excluded that betacells in islets of different size and locations may be subjected to different paracrine and environmental influences that could alter gene expression
Summary
Pancreatic beta-cells play a central role in the development and progression of type 2 diabetes (T2D) [1]. Beta-cell dysfunction is accepted to be associated with reduced beta-cell mass [4,5], which has even been shown to be present in the state of impaired glucose tolerance [4]. Beta–cell abnormalities likely result from a combination of genetic and environmental factors. This reduction in beta-cell mass could be caused by either inadequate birth of beta-cells, increased death by apoptosis or necrosis, or some combination of the two [6]. Changes in gene expression in pancreatic beta-cells from type 2 diabetes (T2D) should provide insights into their abnormal insulin secretion and turnover
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