肌肉中 T 细胞蛋白酪氨酸磷酸酶（TCPTP）缺乏不会改变小鼠的胰岛素信号传导和葡萄糖稳态。
T cell protein tyrosine phosphatase (TCPTP) deficiency in muscle does not alter insulin signalling and glucose homeostasis in mice.
机构信息
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
出版信息
Diabetologia. 2012 Feb;55(2):468-78. doi: 10.1007/s00125-011-2386-z. Epub 2011 Nov 29.
AIMS/HYPOTHESIS: Insulin activates insulin receptor protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The insulin receptor can serve as a substrate for the protein tyrosine phosphatase (PTP) 1B and T cell protein tyrosine phosphatase (TCPTP), which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the insulin receptor in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates insulin receptor signalling and gluconeogenesis in the liver. In this study we assessed for the first time the role of TCPTP in the regulation of insulin receptor signalling in muscle.
METHODS
We generated muscle-specific TCPTP-deficient (Mck-Cre;Ptpn2(lox/lox)) mice (Mck, also known as Ckm) and assessed the impact on glucose homeostasis and muscle insulin receptor signalling in chow-fed versus high-fat-fed mice.
RESULTS
Blood glucose and insulin levels, insulin and glucose tolerance, and insulin-induced muscle insulin receptor activation and downstream PI3K/Akt signalling remained unaltered in chow-fed Mck-Cre;Ptpn2(lox/lox) versus Ptpn2(lox/lox) mice. In addition, body weight, adiposity, energy expenditure, insulin sensitivity and glucose homeostasis were not altered in high-fat-fed Mck-Cre;Ptpn2(lox/lox) versus Ptpn2(lox/lox) mice.
CONCLUSIONS/INTERPRETATION: These results indicate that TCPTP deficiency in muscle has no effect on insulin signalling and glucose homeostasis, and does not prevent high-fat diet-induced insulin resistance. Thus, despite their high degree of sequence identity, PTP1B and TCPTP contribute differentially to insulin receptor regulation in muscle. Our results are consistent with the notion that these two highly related PTPs make distinct contributions to insulin receptor regulation in different tissues.
目的/假设：胰岛素激活肌肉中的胰岛素受体蛋白酪氨酸激酶和下游磷脂酰肌醇-3-激酶（PI3K）/Akt 信号通路，促进葡萄糖摄取。胰岛素受体可作为蛋白酪氨酸磷酸酶（PTP）1B 和 T 细胞蛋白酪氨酸磷酸酶（TCPTP）的底物，它们在催化结构域中具有惊人的 74%序列同一性。PTP1B 是 2 型糖尿病中缓解胰岛素抵抗的一个经过验证的治疗靶点。PTP1B 使肝和肌肉中的胰岛素受体去磷酸化，以调节葡萄糖稳态，而 TCPTP 则调节肝中的胰岛素受体信号和糖异生。在这项研究中，我们首次评估了 TCPTP 在调节肌肉中胰岛素受体信号中的作用。
方法
我们生成了肌肉特异性 TCPTP 缺陷型（Mck-Cre；Ptpn2(lox/lox)）（Mck，也称为 Ckm）小鼠，并评估了其对进食标准饮食和高脂肪饮食的小鼠的葡萄糖稳态和肌肉胰岛素受体信号的影响。
结果
进食标准饮食的 Mck-Cre；Ptpn2(lox/lox) 与 Ptpn2(lox/lox) 小鼠的血糖和胰岛素水平、胰岛素和葡萄糖耐量、胰岛素诱导的肌肉胰岛素受体激活和下游 PI3K/Akt 信号没有改变。此外，高脂肪饮食喂养的 Mck-Cre；Ptpn2(lox/lox) 与 Ptpn2(lox/lox) 小鼠的体重、肥胖、能量消耗、胰岛素敏感性和葡萄糖稳态没有改变。
结论/解释：这些结果表明，肌肉中 TCPTP 的缺乏对胰岛素信号和葡萄糖稳态没有影响，也不能防止高脂肪饮食引起的胰岛素抵抗。因此，尽管它们具有高度的序列同一性，但 PTP1B 和 TCPTP 对肌肉中胰岛素受体的调节作用不同。我们的结果与这样一种观点一致，即这两种高度相关的 PTP 在不同组织中对胰岛素受体的调节有不同的贡献。
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