NDLI: Variation in glucose homeostasis traits associated with P2RX7 polymorphisms in mice and humans.

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Variation in glucose homeostasis traits associated with P2RX7 polymorphisms in mice and humans.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Todd, Jennifer N. Jia, Weiping Enjyoji, Keiichi Wilmot, Michael Herman, Mark A. Groop, Leif Ma, Ronald Hu, Cheng Nichols, Brendan Robson, Simon Lyssenko, Valeriya Florez, Jose C. Zhang, Rong Friedman, David J. Poon, Wenny
Description	Country affiliation: Hong Kong Author Affiliation: Todd JN ( Division of Endocrinology (J.N.T.), Boston Children's Hospital, and Departments of Pediatrics (J.N.T.) and Medicine (S.R., K.E., M.A.H., J.C.F., D.J.F.), Harvard Medical School, and Department of Medicine (B.N., M.W., S.R., K.E., M.A.H., D.J.F.) and Center for Vascular Biology Research (B.N., M.W., D.J.F.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115)
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.
ISSN	0021972X
e-ISSN	19457197
DOI	10.1210/jc.2014-4160
Journal	The Journal of Clinical Endocrinology & Metabolism
Issue Number	5
Volume Number	100
Language	English
Publisher	Oxford University Press
Publisher Date	2015-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Blood Glucose Genetics Diabetes Mellitus, Type 2 Homeostasis Polymorphism, Single Nucleotide Receptors, Purinergic P2x7 Alleles Animals B-lymphocytes Genetic Association Studies Genetic Predisposition To Disease Mice Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Endocrinology Discipline Metabolism
Content Type	Text
Resource Type	Article
Subject	Biochemistry (medical) Endocrinology, Diabetes and Metabolism Clinical Biochemistry Biochemistry Endocrinology

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