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Variation in Glucose Homeostasis Traits Associated With P2RX7 Polymorphisms in Mice and Humans

Todd, Jennifer N.; Poon, Wenny LU ; Lyssenko, Valeriya LU ; Groop, Leif LU ; Nichols, Brendan; Wilmot, Michael; Robson, Simon; Enjyoji, Keiichi; Herman, Mark A. and Hu, Cheng, et al. (2015) In Journal of Clinical Endocrinology and Metabolism 100(5). p.688-696
Abstract
Context: Extracellular nucleotide receptors are expressed in pancreatic B-cells. Purinergic signaling via these receptors may regulate pancreatic B-cell function. Objective: We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction. Design: In humans, we mined genome-wide meta-analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes. We performed additional testing in two genomic regions (P2RX4/P2RX7 and P2RY1) in a cohort from the Prevalence, Prediction, and Prevention of Diabetes in Botnia (n = 3504), which includes more refined measures of glucose... (More)
Context: Extracellular nucleotide receptors are expressed in pancreatic B-cells. Purinergic signaling via these receptors may regulate pancreatic B-cell function. Objective: We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction. Design: In humans, we mined genome-wide meta-analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes. We performed additional testing in two genomic regions (P2RX4/P2RX7 and P2RY1) in a cohort from the Prevalence, Prediction, and Prevention of Diabetes in Botnia (n = 3504), which includes more refined measures of glucose homeostasis. In mice, we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background. Results: Variants in five genes were associated with glycemic traits and in three genes with diabetes risk. In the Prevalence, Prediction, and Prevention of Diabetes in Botnia study, the minor allele in the missense functional variant rs1718119 (A348T) in P2RX7 was associated with increased insulin sensitivity and secretion, consistent with its known effect on increased pore function. Both male and female P2x7-C57 mice demonstrated impaired glucose tolerance compared with matched P2x7-129 mice. Insulin tolerance testing showed that P2x7-C57 mice were also less responsive to insulin than P2x7-129 mice. Conclusions: We show association of the purinergic signaling pathway in general and hypofunctioning P2X7 variants in particular with impaired glucose homeostasis in both mice and humans. (Less)
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type
Contribution to journal
publication status
published
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Journal of Clinical Endocrinology and Metabolism
volume
100
issue
5
pages
688 - 696
publisher
The Endocrine Society
external identifiers
  • wos:000357669000003
  • scopus:84929302596
ISSN
1945-7197
DOI
10.1210/jc.2014-4160
language
English
LU publication?
yes
id
2ced8c0c-8240-4396-b567-ae376318b91a (old id 7790458)
date added to LUP
2015-09-01 16:05:52
date last changed
2017-04-20 09:11:17
@article{2ced8c0c-8240-4396-b567-ae376318b91a,
  abstract     = {Context: Extracellular nucleotide receptors are expressed in pancreatic B-cells. Purinergic signaling via these receptors may regulate pancreatic B-cell function. Objective: We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction. Design: In humans, we mined genome-wide meta-analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes. We performed additional testing in two genomic regions (P2RX4/P2RX7 and P2RY1) in a cohort from the Prevalence, Prediction, and Prevention of Diabetes in Botnia (n = 3504), which includes more refined measures of glucose homeostasis. In mice, we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background. Results: Variants in five genes were associated with glycemic traits and in three genes with diabetes risk. In the Prevalence, Prediction, and Prevention of Diabetes in Botnia study, the minor allele in the missense functional variant rs1718119 (A348T) in P2RX7 was associated with increased insulin sensitivity and secretion, consistent with its known effect on increased pore function. Both male and female P2x7-C57 mice demonstrated impaired glucose tolerance compared with matched P2x7-129 mice. Insulin tolerance testing showed that P2x7-C57 mice were also less responsive to insulin than P2x7-129 mice. Conclusions: We show association of the purinergic signaling pathway in general and hypofunctioning P2X7 variants in particular with impaired glucose homeostasis in both mice and humans.},
  author       = {Todd, Jennifer N. and Poon, Wenny and Lyssenko, Valeriya and Groop, Leif and Nichols, Brendan and Wilmot, Michael and Robson, Simon and Enjyoji, Keiichi and Herman, Mark A. and Hu, Cheng and Zhang, Rong and Jia, Weiping and Ma, Ronald and Florez, Jose C. and Friedman, David J.},
  issn         = {1945-7197},
  language     = {eng},
  number       = {5},
  pages        = {688--696},
  publisher    = {The Endocrine Society},
  series       = {Journal of Clinical Endocrinology and Metabolism},
  title        = {Variation in Glucose Homeostasis Traits Associated With P2RX7 Polymorphisms in Mice and Humans},
  url          = {http://dx.doi.org/10.1210/jc.2014-4160},
  volume       = {100},
  year         = {2015},
}