Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action

被引：58

作者：

Kimura, Kumi ^{[1
]}

Nakamura, Yusuke ^{[1
]}

Inaba, Yuka ^{[1
]}

Matsumoto, Michihiro ^{[2
]}

Kido, Yoshiaki ^{[3
,4
]}

Asahara, Shun-ichiro ^{[3
]}

Matsuda, Tomokazu ^{[3
]}

Watanabe, Hiroshi ^{[5
]}

Maeda, Akifumi ^{[5
]}

Inagaki, Fuyuhiko ^{[6
]}

Mukai, Chisato ^{[6
]}

Takeda, Kiyoshi ^{[7
]}

Akira, Shizuo ^{[8
]}

Ota, Tsuguhito ^{[9
]}

Nakabayashi, Hajime ^{[10
]}

Kaneko, Shuichi ^{[11
]}

Kasuga, Masato ^{[12
]}

Inoue, Hiroshi ^{[1
]}

机构：

[1] Kanazawa Univ, Brain Liver Interface Med Res Ctr, Dept Physiol & Metab, Kanazawa, Ishikawa, Japan

[2] Natl Ctr Global Hlth & Med, Dept Mol Metab Regulat, Diabet Res Ctr, Res Inst, Tokyo, Japan

[3] Kobe Univ, Div Diabet & Endocrinol, Grad Sch Med, Kobe, Hyogo 657, Japan

[4] Kobe Univ, Div Analyt Biomed Sci, Grad Sch Hlth Sci, Kobe, Hyogo 657, Japan

[5] Cerebos Pacific Ltd, BRANDS Brain Res Ctr, Singapore, Singapore

[6] Kanazawa Univ, Grad Sch Med Sci, Div Pharmaceut Sci, Kanazawa, Ishikawa, Japan

[7] Osaka Univ, Grad Sch Med, Dept Microbiol & Immunol, Lab Immune Regulat, Suita, Osaka, Japan

[8] Osaka Univ, Lab Host Def, Immunol Frontier Res Ctr, Dept Host Def,Res Inst Microbial Dis, Suita, Osaka, Japan

[9] Kanazawa Univ, Dept Cell Metab & Nutr, Brain Liver Interface Med Res Ctr, Kanazawa, Ishikawa, Japan

[10] Kanazawa Univ, Hlth Sci Serv Ctr, Kanazawa, Ishikawa, Japan

[11] Kanazawa Univ, Grad Sch Med Sci, Dept Dis Control & Homeostasis, Kanazawa, Ishikawa, Japan

[12] Natl Ctr Global Hlth & Med, Res Inst, Diabet Res Ctr, Tokyo, Japan

来源：

DIABETES | 2013年 / 62卷 / 07期

基金：

日本学术振兴会;

关键词：

AMINO-ACIDS; FOOD-INTAKE; BLOOD-GLUCOSE; GLUCONEOGENESIS; HISTAMINE; METABOLISM; RECEPTOR; LIVER; HOMEOSTASIS; INHIBITION;

D O I：

10.2337/db12-1701

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 H-1 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 HI 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.

引用

页码：2266 / 2277

页数：12

共 31 条

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