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The role of pathway-selective insulin resistance and responsiveness in diabetic dyslipoproteinemia

机译：途径选择性胰岛素抵抗和反应性在糖尿病性脂脂蛋白血症中的作用

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Purpose of Review: Type 2 diabetes mellitus (T2DM) and related syndromes exhibit a deadly triad of dyslipoproteinemia, which leads to atherosclerosis, hyperglycemia, which causes microvascular disease, and hypertension. These features share a common, but unexplained, origin-namely, pathway-selective insulin resistance and responsiveness (SEIRR). Here, we review recent work on hepatic SEIRR indicating that deranged insulin signaling may have a remarkably simple molecular basis. Recent Findings: Comprehensive examination of a set of 18 insulin targets revealed that T2DM liver in vivo exhibits a specific defect in the ability of the NAD(P)H oxidase 4 (NOX4) to inactivate protein tyrosine phosphatase gene family members after stimulation with insulin, and that impairment of this single molecule, NOX4, in cultured hepatocytes recapitulates all features of hepatic SEIRR in vivo. These features include insulin-stimulated generation of an unusual monophosphorylated form of AKT at Thr308 (pT308-AKT) with only weak phosphorylation at Ser473, impaired insulin-stimulated pathways for lowering plasma levels of lipids and glucose, but continued lipogenic pathways and robust extracellular signal-regulated kinase activation. This new study, in combination with important prior work, provides clues to several long-standing mysteries, such as how AKT might regulate lipid-lowering and glucose-lowering pathways that become insulin-resistant but also lipogenic pathways that remain insulin-responsive, as well as a potential role for NOX4 in insulin-stimulated generation of oxysterol ligands for LXR, a key lipogenic factor. Summary: These findings suggest a unified molecular explanation for fatty liver, atherogenic dyslipoproteinemia, hyperglycemia, and hence accelerated atherosclerosis and microvascular disease in T2DM, obesity, and related syndromes of positive caloric imbalance.
机译：审查目的：2型糖尿病（T2DM）和相关综合症表现出致命的三脂代谢异常，导致动脉粥样硬化，高血糖症（导致微血管疾病）和高血压。这些特征具有共同但未解释的起源，即途径选择性胰岛素抵抗和反应性（SEIRR）。在这里，我们回顾了有关肝SEIRR的最新研究，表明胰岛素信号异常可能具有非常简单的分子基础。最近的发现：对一组18个胰岛素靶标的综合检查显示，体内T2DM肝在胰岛素刺激后NAD（P）H氧化酶4（NOX4）失活蛋白酪氨酸磷酸酶基因家族成员的能力方面表现出特定缺陷，并且这种单分子NOX4在培养的肝细胞中的损伤在体内概括了肝SEIRR的所有特征。这些特征包括胰岛素刺激在Thr308（pT308-AKT）处产生异常的单磷酸化AKT（pT308-AKT），在Ser473处仅有弱的磷酸化作用，胰岛素刺激的降低血脂和葡萄糖血浆水平的途径受损，但持续的脂肪生成途径和强大的细胞外信号-调节的激酶激活。这项新的研究与重要的先前工作相结合，为一些长期存在的谜团提供了线索，例如AKT如何调节变成胰岛素抵抗的降脂和降糖途径，以及仍然保持胰岛素反应的脂肪生成途径。以及NOX4在胰岛素刺激的LXR（主要的致脂因子）的氧固醇配体生成中的潜在作用。摘要：这些发现为T2DM，肥胖症和热量代谢失衡的相关综合征中的脂肪肝，动脉粥样硬化性脂蛋白血症，高血糖症以及由此加速的动脉粥样硬化和微血管疾病提供了统一的分子解释。

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