Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling.
Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling.
复制标题
作者：
Matveyenko AV;Liuwantara D;Gurlo T;Kirakossian D;Dalla Man C;Cobelli C;White MF;Copps KD;Volpi E;Fujita S;Butler PC
胰岛素以离散的胰岛素分泌脉冲形式以5分钟的间隔分泌到肝门静脉，这些脉冲在1型和2型糖尿病(T2 DM)发展的早期被减弱。门脉内胰岛素输注(脉冲式、恒定式或再生式)表明，通过门静脉输送的脉动性胰岛素分泌模式对肝脏胰岛素的作用是重要的，因此，可能对肝脏胰岛素信号也是重要的。为了验证这一点，我们利用麻醉大鼠的连续肝活组织检查了暴露于相同的三种门静脉胰岛素给药模式的大鼠肝脏中的胰岛素信号。门脉内恒定和脉动给药导致肝脏胰岛素受体底物(IRS)-1和IRS-2信号的激活延迟和受损，下游胰岛素信号效应分子AKT和Foxo1的激活受损，葡萄糖激酶(GCK)表达减少。我们进一步证实，在T2 DM的HIP大鼠模型中，肝脏GCK的表达减少，这一缺陷与进行性的脉动性胰岛素分泌缺陷有关。我们得出结论，胰岛素的生理脉动模式在肝脏胰岛素信号转导和血糖控制中是重要的。糖尿病患者的肝脏胰岛素抵抗可能部分是由于搏动性胰岛素分泌受损所致。
Insulin is secreted as discrete insulin secretory bursts at ∼5-min intervals into the hepatic portal vein, these pulses being attenuated early in the development of type 1 and type 2 diabetes mellitus (T2DM). Intraportal insulin infusions (pulsatile, constant, or reproducing that in T2DM) indicated that the pattern of pulsatile insulin secretion delivered via the portal vein is important for hepatic insulin action and, therefore, presumably for hepatic insulin signaling. To test this, we examined hepatic insulin signaling in rat livers exposed to the same three patterns of portal vein insulin delivery by use of sequential liver biopsies in anesthetized rats. Intraportal delivery of insulin in a constant versus pulsatile pattern led to delayed and impaired activation of hepatic insulin receptor substrate (IRS)-1 and IRS-2 signaling, impaired activation of downstream insulin signaling effector molecules AKT and Foxo1, and decreased expression of glucokinase (Gck). We further established that hepatic Gck expression is decreased in the HIP rat model of T2DM, a defect that correlated with a progressive defect of pulsatile insulin secretion. We conclude that the physiological pulsatile pattern of insulin delivery is important in hepatic insulin signaling and glycemic control. Hepatic insulin resistance in diabetes is likely in part due to impaired pulsatile insulin secretion.
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影响因子：
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