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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Jennifer N. Todd
  • Wenny Poon
  • Valeriya Lyssenko
  • Leif Groop
  • Brendan Nichols
  • Michael Wilmot
  • Simon Robson
  • Keiichi Enjyoji
  • Mark A. Herman
  • Cheng Hu
  • Rong Zhang
  • Weiping Jia
  • Ronald Ma
  • Jose C. Florez
  • David J. Friedman
Organisations
External organisations
  • Steno Diabetes Center
  • Finnish Institute for Molecular Medicine
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)E688-E696
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number5
StatePublished - 2015
Peer-reviewedYes