Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.
Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.
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DOI：
10.1172/jci.insight.88766
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发表时间：
2016-10-20
期刊：
影响因子：
8
通讯作者：
Semple RK
中科院分区：
文献类型：
--
作者：
Huang-Doran I;Tomlinson P;Payne F;Gast A;Sleigh A;Bottomley W;Harris J;Daly A;Rocha N;Rudge S;Clark J;Kwok A;Romeo S;McCann E;Müksch B;Dattani M;Zucchini S;Wakelam M;Foukas LC;Savage DB;Murphy R;O'Rahilly S;Barroso I;Semple RK
肥胖相关的胰岛素抵抗与脂肪肝、血脂异常和低血浆脂联素有关。胰岛素受体 (INSR) 功能障碍导致的胰岛素抵抗与这些都无关，但当下游激酶 AKT2 功能障碍导致肥胖相关的胰岛素抵抗时，就会表现出肥胖相关的胰岛素抵抗。我们报告了 5 例患有 SHORT 综合征和 PIK3R1 C 端突变的患者，PIK3R1 编码 PI3K 的 p85α/p55α/p50α 亚基，在胰岛素信号传导中作用于 INSR 和 AKT 之间。 5 名患者中有 4 名患有极端胰岛素抵抗，但没有血脂异常或肝脂肪变性。在这 4 例中，有 3 例血浆脂联素得以保留，胰岛素受体功能障碍也是如此。第四位患者和她健康的母亲血浆脂联素水平较低，这与脂联素本身的潜在新突变 p.Asp231Ala 相关。对一名 p.Tyr657X PIK3R1 突变患者的细胞进行研究，表达丰富的截短的 PIK3R1 产物，并显示突变体（而非 WT p85α）与 IRS1 的胰岛素刺激关联严重减少，而是正常的下游信号传导。在 3T3-L1 前脂肪细胞中，突变型 p85α 过表达减弱了胰岛素诱导的 AKT 磷酸化和脂肪细胞分化。因此，PIK3R1 C 端突变仅在某些细胞环境中损害胰岛素信号传导，并产生类似于 INSR 功能障碍但与 AKT2 功能障碍不同的胰岛素抵抗亚表型，这表明 PI3K 参与了代谢综合征关键组成部分的发病机制。在没有血脂异常或肝脂肪变性的情况下，人 PIK3R1 的 C 端突变与严重的胰岛素抵抗相关。
Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome. C-terminal mutations in human PIK3R1 are associated with severe insulin resistance in the absence of dyslipidemia or hepatic steatosis.
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影响因子：
15.9
作者：
Cusi, K;Maezono, K;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
13.5
作者：
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作者：
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作者：
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影响因子：
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作者：
Clark, Jonathan;Anderson, Karen E.;Juvin, Veronique;Smith, Trevor S.;Karpe, Fredrik;Wakelam, Michael J. O.;Stephens, Len R.;Hawkins, Phillip T.
通讯作者：
Hawkins, Phillip T.