Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets
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- 作者：Maggie M Ho (1)
Piriya Yoganathan (1)
Kwan Yi Chu (1)
Subashini Karunakaran (1)
James D Johnson (1) (2)
Susanne M Clee (1) - 关键词：Type 2 diabetes ; Gene expression ; Genome ; wide association ; High fat diet ; Feeding and fasting ; Mice ; Pancreatic islets ; Glucotoxicity
- 刊名：BMC Genetics
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：14
- 期：1
- 全文大小：264KB
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Piriya Yoganathan (1)
Kwan Yi Chu (1)
Subashini Karunakaran (1)
James D Johnson (1) (2)
Susanne M Clee (1)
1. Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada
2. Department of Surgery, University of British Columbia, Vancouver, Canada
文摘
Background Genome-wide association studies (GWAS) have recently identified many new genetic variants associated with the development of type 2 diabetes. Many of these variants are in introns of known genes or between known genes, suggesting they affect the expression of these genes. The regulation of gene expression is often tissue and context dependent, for example occurring in response to dietary changes, hormone levels, or many other factors. Thus, to understand how these new genetic variants associated with diabetes risk may act, it is necessary to understand the regulation of their cognate genes. Results We identified fourteen type 2 diabetes-associated genes discovered by the first waves of GWAS for which there was little prior evidence of their potential role in diabetes (Adam30, Adamts9, Camk1d, Cdc123, Cdkal1, Cdkn2a, Cdkn2b, Ext2, Hhex, Ide, Jazf1, Lgr5, Thada and Tspan8). We examined their expression in metabolically relevant tissues including liver, adipose tissue, brain, and hypothalamus obtained from mice under fasted, non-fasted and high fat diet-fed conditions. In addition, we examined their expression in pancreatic islets from these mice cultured in low and high glucose. We found that the expression of Jazf1 was reduced by high fat feeding in liver, with similar tendencies in adipose tissue and the hypothalamus. Adamts9 expression was decreased in the hypothalamus of high fat fed mice. In contrast, the expression of Camk1d, Ext2, Jazf1 and Lgr5 were increased in the brain of non-fasted animals compared to fasted mice. Most notably, the expression levels of most of the genes were decreased in islets cultured in high glucose. Conclusions These data provide insight into the metabolic regulation of these new type 2 diabetes genes that will be important for determining how the GWAS variants affect gene expression and ultimately the development of type 2 diabetes.