Histidine augments the suppression of hepatic glucose production by central insulin action.
Histidine augments the suppression of hepatic glucose production by central insulin action.
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作者：
Kimura K;Nakamura Y;Inaba Y;Matsumoto M;Kido Y;Asahara S;Matsuda T;Watanabe H;Maeda A;Inagaki F;Mukai C;Takeda K;Akira S;Ota T;Nakabayashi H;Kaneko S;Kasuga M;Inoue H
2型糖尿病葡萄糖耐受不良与肝脏糖异生酶表达增加导致的肝糖生成（HGP）增加有关。先前，我们发现肝脏STAT3降低肝脏糖异生酶的表达并抑制HGP。在这里，我们发现血浆组氨酸增加导致肝脏STAT3激活。静脉和脑室内（ICV）给予组氨酸激活的肝STAT3可降低G6Pase蛋白和mRNA水平，增强胰岛素对HGP的抑制作用。组氨酸对肝脏糖异生的抑制作用被肝STAT3缺乏或肝库普弗细胞耗竭所消除。组氨酸对HGP的抑制作用也被组胺H1受体拮抗剂ICV阻断。因此，组氨酸激活肝STAT3并通过中枢组胺作用抑制HGP。组胺H1受体敲除（Hrh1KO）小鼠的肝STAT3磷酸化减弱，而神经元特异性胰岛素受体敲除（NIRKO）小鼠的肝STAT3磷酸化减弱。相反，胰岛素ICV给药后，肝脏STAT3磷酸化在NIRKO小鼠中减弱，而在Hrh1KO小鼠中没有减弱。这些发现表明，中枢组氨酸的作用独立于中枢胰岛素的作用，而两者都对HGP抑制有附加作用。我们的研究结果表明，中枢组氨酸/组胺介导的HGP抑制是治疗2型糖尿病的潜在靶点。
Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.
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DOI：
10.1073/pnas.93.23.13316
发表时间：
1996-11-12
影响因子：
11.1
作者：
Inoue, I;Yanai, K;Watanabe, T
通讯作者：
Watanabe, T
DOI：
10.1073/pnas.1115183109
发表时间：
2012-02-21
影响因子：
11.1
作者：
Kyriazis, George A.;Soundarapandian, Mangala M.;Tyrberg, Bjoern
通讯作者：
Tyrberg, Bjoern
影响因子：
15.9
作者：
FLOYD, JC;FAJANS, SS;RULL, J
通讯作者：
RULL, J
影响因子：
16.2
作者：
NUTTALL, FQ;MOORADIAN, AD;KREZOWSKI, P
通讯作者：
KREZOWSKI, P
影响因子：
82.9
作者：
Inoue, H;Ogawa, W;Kasuga, M
通讯作者：
Kasuga, M