Department of Medicine, Faculty of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Québec, Québec, Canada.
Diabetes. 2012 Aug;61(8):1949-58. doi: 10.2337/db11-1502. Epub 2012 Jun 14.
The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific Shp1 knockout mice (Ptpn6(H-KO)), which were subjected to extensive metabolic monitoring throughout an 8-week standard chow diet (SD) or high-fat diet (HFD) feeding. We report for the first time that Shp1 expression is upregulated in metabolic tissues of HFD-fed obese mice. When compared with their Shp1-expressing Ptpn6(f/f) littermates, Ptpn6(H-KO) mice exhibited significantly lowered fasting glycemia and heightened hepatic insulin sensitivity. After HFD feeding, Ptpn6(H-KO) mice developed comparable levels of obesity as Ptpn6(f/f) mice, but they were remarkably protected from liver insulin resistance, as revealed by euglycemic clamps and hepatic insulin signaling determinations. Although Ptpn6(H-KO) mice still acquired diet-induced peripheral insulin resistance, they were less hyperinsulinemic during a glucose tolerance test because of reduced insulin secretion. Ptpn6(H-KO) mice also exhibited increased insulin clearance in line with enhanced CC1 tyrosine phosphorylation in liver. These results show that hepatocyte Shp1 plays a critical role in the development of hepatic insulin resistance and represents a novel therapeutic target for obesity-linked diabetes.
蛋白酪氨酸磷酸酶 Shp1 负向调节肝脏和肌肉中胰岛素对葡萄糖稳态的作用，但它在肥胖相关胰岛素抵抗中的潜在作用尚未被研究。为了研究 Shp1 在肝胰岛素抵抗中的作用，我们生成了肝细胞特异性 Shp1 敲除小鼠（Ptpn6(H-KO)），这些小鼠在 8 周标准饮食（SD）或高脂肪饮食（HFD）喂养期间接受了广泛的代谢监测。我们首次报道 Shp1 在 HFD 喂养肥胖小鼠的代谢组织中表达上调。与表达 Shp1 的 Ptpn6(f/f)同窝仔相比，Ptpn6(H-KO)小鼠表现出明显降低的空腹血糖和增强的肝脏胰岛素敏感性。在 HFD 喂养后，Ptpn6(H-KO)小鼠与 Ptpn6(f/f)小鼠相比发展出相当水平的肥胖，但它们显著免受肝脏胰岛素抵抗的影响，这通过正葡萄糖钳夹和肝胰岛素信号测定揭示。尽管 Ptpn6(H-KO)小鼠仍获得了饮食诱导的外周胰岛素抵抗，但由于胰岛素分泌减少，它们在葡萄糖耐量试验中胰岛素血症程度较低。Ptpn6(H-KO)小鼠还表现出增强的胰岛素清除率，与肝中 CC1 酪氨酸磷酸化增强一致。这些结果表明肝细胞 Shp1 在肝胰岛素抵抗的发展中起着关键作用，代表肥胖相关糖尿病的一个新的治疗靶点。
