ENPP1 affects insulin action and secretion: evidences from in vitro studies.
ENPP1 affects insulin action and secretion: evidences from in vitro studies.
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DOI：
10.1371/journal.pone.0019462
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发表时间：
2011-05-05
期刊：
影响因子：
3.7
通讯作者：
Frittitta L
中科院分区：
文献类型：
--
作者：
Di Paola R;Caporarello N;Marucci A;Dimatteo C;Iadicicco C;Del Guerra S;Prudente S;Sudano D;Miele C;Parrino C;Piro S;Beguinot F;Marchetti P;Trischitta V;Frittitta L
本研究旨在深入探讨胰岛素受体（IR）激活的负调节因子ENPP1在胰岛素信号传导、胰岛素分泌和最终葡萄糖代谢中的作用机制。ENPP1 cDNA（携带K121或Q121变体）转染HepG2肝、L6骨骼肌和INS1E β细胞。研究了胰岛素诱导的ir -自磷酸化（HepG2, L6, INS1E）， Akt-Ser473， ERK1/2-Thr202/Tyr204和gsk3 - β Ser9磷酸化（HepG2, L6）， PEPCK mRNA水平（HepG2）和2-脱氧-d -葡萄糖摄取（L6）。glut4 mRNA （L6）、胰岛素分泌和caspase-3激活（INS1E）也进行了研究。胰岛素诱导的ir -自磷酸化在HepG2-K、L6-K、INS1E-K中降低（与未转染细胞相比分别降低20%、52%和11%），在HepG2-Q、L6-Q、INS1E-Q中降低两倍（44%、92%和30%）。在HepG2和L6中，Akt-Ser473、ERK1/2-Thr202/Tyr204和gsk3 - β Ser9也获得了类似的数据。在未转染的HepG2-K和HepG2-Q细胞中，胰岛素诱导的PEPCK mRNA减少量逐渐降低（65%,54%,23%）。在未转染的L6细胞中，胰岛素诱导的葡萄糖摄取（比基础细胞增加60%）在L6- k和L6- q细胞中完全消失。GLUT 4 mRNA在L6-K中略有减少，在L6-Q中减少两倍（与未转染的细胞相比减少13%和25%）。葡萄糖诱导的胰岛素分泌在INS1E-K组减少60%，在INS1E-Q组几乎消失。在未转染的INS1E、INS1E- k和INS1E- q中，血清缺乏激活了caspase-3的2倍、3倍和4倍。与来自KK和KQ个体的人相比，来自纯合子QQ供体的人胰岛中格列本脲诱导的胰岛素分泌减少了50%。我们的数据清楚地表明，ENPP1，特别是当Q121变异起作用时，影响骨骼肌细胞和肝细胞的胰岛素信号传导和葡萄糖代谢，以及胰岛素分泌β细胞的功能和存活，因此代表了胰岛素抵抗、胰岛素分泌缺陷和糖代谢异常的强致病因素。
The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities.
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