Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Los Angeles, California 90089-9176, USA.
J Endocrinol. 2011 Aug;210(2):209-17. doi: 10.1530/JOE-11-0012. Epub 2011 May 12.
The inositol 1,4,5-trisphosphate receptors (IP3Rs) as ligand-gated Ca(2)(+) 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/+ 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 diet-induced diabetes.
肌醇 1,4,5-三磷酸受体（IP3R）作为配体门控 Ca(2)(+)通道，是细胞过程的关键调节剂。尽管人们对其在调节神经元功能和细胞死亡方面的关键作用有了深入的了解，但该蛋白家族如何影响细胞代谢才刚刚开始显现。出人意料的是，一种转基因小鼠品系（D2D）由于转基因插入而表现出进行性葡萄糖不耐受。反向 PCR 用于鉴定 D2D 小鼠中的基因缺失。这导致发现 Itpr1 是染色体 6 中十个被破坏的基因之一。Itpr1 编码 IP3R1，这是小鼠大脑中最丰富的 IP3R 同工型，在胰腺 β 细胞中也高度表达。为了研究 IP3R1 在葡萄糖代谢中的功能，我们使用了 Itpr1 杂合突变小鼠 opt/+。通过代谢表型的多种方法检查雄性小鼠队列的葡萄糖稳态。在正常饮食下，opt/+ 小鼠表现出葡萄糖不耐受，但没有胰岛素抵抗。在 opt/+ 小鼠中观察到第二相葡萄糖刺激的血胰岛素水平下降，同时伴有β细胞数量和胰岛素含量减少。引人注目的是，当喂食高脂肪饮食时，opt/+ 小鼠更容易发展为高血糖、葡萄糖不耐受和胰岛素抵抗。总之，我们的研究确定了 D2D 小鼠中被打断的基因 Itpr1，并揭示了 IP3R1 在调节体内葡萄糖稳态和饮食诱导的糖尿病发展中的新作用。
