Winnay Jonathon N, Solheim Marie H, Dirice Ercument, Sakaguchi Masaji, Noh Hye-Lim, Kang Hee Joon, Takahashi Hirokazu, Chudasama Kishan K, Kim Jason K, Molven Anders, Kahn C Ronald, Njølstad Pål R
J Clin Invest. 2016 Apr 1;126(4):1401-12. doi: 10.1172/JCI84005. Epub 2016 Mar 14.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85α regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome - a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism.
磷脂酰肌醇3激酶（PI3K）信号通路是胰岛素和许多生长因子作用的核心。在患有SHORT综合征的患者中已鉴定出编码PI3K的p85α调节亚基（PIK3R1）的基因中的杂合突变，SHORT综合征是一种以身材矮小、部分脂肪营养不良和胰岛素抵抗为特征的疾病。在这里，我们通过生成对Pik3r1Arg649Trp突变杂合的敲入小鼠来评估与SHORT综合征相关的PIK3R1突变是否解释了异常背后的病理生理学，该突变与大多数受影响个体中发现的突变同源。与患者相似，突变小鼠体重和体长降低、出现部分脂肪营养不良以及全身性胰岛素抵抗。这些紊乱与胰岛素和其他生长因子在肝脏、肌肉和脂肪中激活PI3K的能力降低有关；携带突变的动物肝脏和脂肪中存在明显的胰岛素抵抗；以及这些小鼠来源的细胞在体外表现出胰岛素抵抗。此外，突变小鼠在体内和体外均表现出胰岛素分泌缺陷以及胰岛对胰高血糖素样肽-1（GLP-1）的反应受损。这些数据证明了这种杂合突变在体内改变PI3K活性的能力以及PI3K在胰岛素/生长因子作用、脂肪细胞功能和葡萄糖代谢中的核心作用。
