Inositol 1,4,5-trisphosphate receptor 1 mutation perturbs glucose homeostasis and enhances susceptibility to diet-induced diabetes

Risheng Ye, Min Ni, Miao Wang, Shengzhan Luo, Genyuan Zhu, Robert H. Chow, Amy S. Lee

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The inositol 1,4,5-trisphosphate receptors (IP3Rs) as ligandgated Ca2+ channels are key modulators of cellular processes. Despite advances in understanding their critical role in regulating neuronal function and cell death, how this family of proteins impact cell metabolism is just emerging. Unexpectedly, a transgenic mouse line (D2D) exhibited progressive glucose intolerance as a result of transgene insertion. Inverse PCR was used to identify the gene disruption in the D2D mice. This led to the discovery that Itpr1 is among the ten loci disrupted in chromosome 6. Itpr1 encodes for IP3R1, the most abundant IP3R isoform in mouse brain and also highly expressed in pancreatic β-cells. To study IP3R1 function in glucose metabolism, we used the Itpr1 heterozygous mutant mice, opt/+. Glucose homeostasis in male mice cohorts was examined by multiple approaches of metabolic phenotyping. Under regular diet, the opt/C mice developed glucose intolerance but no insulin resistance. Decrease in second-phase glucose-stimulated blood insulin level was observed in opt/+ mice, accompanied by reduced β-cell mass and insulin content. Strikingly, when fed with high-fat diet, the opt/+ mice were more susceptible to the development of hyperglycemia, glucose intolerance, and insulin resistance. Collectively, our studies identify the gene Itpr1 being interrupted in the D2D mice and uncover a novel role of IP3R1 in regulation of in vivo glucose homeostasis and development of dietinduced diabetes.

Original languageEnglish (US)
Pages (from-to)209-217
Number of pages9
JournalJournal of Endocrinology
Volume210
Issue number2
DOIs
StatePublished - Aug 2011

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Inositol 1,4,5-Trisphosphate Receptors
Homeostasis
Diet
Glucose
Mutation
Glucose Intolerance
Insulin Resistance
Insulin
Chromosomes, Human, Pair 6
High Fat Diet
Transgenes
Hyperglycemia
Transgenic Mice
Genes
Blood Glucose
Protein Isoforms
Cell Death
Polymerase Chain Reaction
Brain

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Inositol 1,4,5-trisphosphate receptor 1 mutation perturbs glucose homeostasis and enhances susceptibility to diet-induced diabetes. / Ye, Risheng; Ni, Min; Wang, Miao; Luo, Shengzhan; Zhu, Genyuan; Chow, Robert H.; Lee, Amy S.

In: Journal of Endocrinology, Vol. 210, No. 2, 08.2011, p. 209-217.

Research output: Contribution to journalArticle

Ye, Risheng ; Ni, Min ; Wang, Miao ; Luo, Shengzhan ; Zhu, Genyuan ; Chow, Robert H. ; Lee, Amy S. / Inositol 1,4,5-trisphosphate receptor 1 mutation perturbs glucose homeostasis and enhances susceptibility to diet-induced diabetes. In: Journal of Endocrinology. 2011 ; Vol. 210, No. 2. pp. 209-217.
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