糖尿病等代谢疾病主要是因为机体无法正常准确地调节血糖水平，而胰岛素是一种调控血糖水平的重要激素。患有2型糖尿病的人体内脂肪细胞以及肌肉细胞往往对胰岛素有耐受性，这一耐受性引发上述两种细胞丧失了从机体血液中吸取葡萄糖的能力。

近日，据PLoS ONE杂志刊登的一项由美国圣路易斯华盛顿大学医学院研究者完成的研究论文，科学家们发现了一种能有效调节胰岛素敏感性的调节因子，这一新发现有助于科研人员开发出2型糖尿病、肥胖等代谢疾病新的治疗手段。

研究人员发现TBC1D3这一调节因子能保持机体胰岛素旁路持续性开放，这样一来脂肪细胞以及肌肉细胞就能通过这一旁路持续性的吸取消耗葡萄糖。

TBC1D3蛋白只存在于人类及其他一些灵长类动物体内，上述细胞产生TBC1D3蛋白的量越多，细胞吸取胰岛素的能力就越大。论文通讯作者--细胞生物学和生理学专业的Philip-Stahl教授称：TBC1D3蛋白能明显减慢一种依赖于胰岛素受体信号的分子的失活过程，一旦这一分子失活得到改善就能上调细胞对胰岛素的敏感性。

G蛋白是一种转导激素的信号蛋白是一不争的事实，在这项研究中，工作人员认为TBC1D3发挥调节胰岛素敏感性的功效或许主要是因为TBC1D3蛋白的某些活性区域结合了一些G蛋白。

深入研究发现TBC1D3蛋白能调控一些细胞的重要功能如吸收营养成分、细胞生长、增殖以及衰老等。果蝇敲除PP2A基因后，寿命明显减少，而TBC1D3能激活PP2A蛋白，这暗示了TBC1D3或许还可影响我们衰老进程。

TBC1D3, a Hominoid-Specific Gene, Delays IRS-1 Degradation and Promotes Insulin Signaling by Modulating p70 S6 Kinase Activity

Marisa J. Wainszelbaum1#, Jialu Liu1#, Chen Kong1, Priya Srikanth1, Dmitri Samovski1, Xiong Su1,2*, Philip D. Stahl1*

Insulin/IGF-1 signaling plays a pivotal role in the regulation of cellular homeostasis through its control of glucose metabolism as well as due to its effects on cell proliferation. Aberrant regulation of insulin signaling has been repeatedly implicated in uncontrolled cell growth and malignant transformations. TBC1D3 is a hominoid specific gene previously identified as an oncogene in breast and prostate cancers. Our efforts to identify the molecular mechanisms of TBC1D3-induced oncogenesis revealed the role of TBC1D3 in insulin/IGF-1 signaling pathway. We document here that TBC1D3 intensifies insulin/IGF-1-induced signal transduction through intricate, yet elegant fine-tuning of signaling mechanisms. We show that TBC1D3 expression substantially delayed ubiquitination and degradation of insulin receptor substrate-1 (IRS-1). This effect is achieved through suppression of serine phosphorylation at S636/639, S307 and S312 of IRS-1, which are key phosphorylation sites required for IRS-1 degradation. Furthermore, we report that the effect of TBC1D3 on IRS-1:S636/639 phosphorylation is mediated through TBC1D3-induced activation of protein phosphatase 2A (PP2A), followed by suppression of T389 phosphorylation on p70 S6 kinase (S6K). TBC1D3 specifically interacts with PP2A regulatory subunit B56γ, indicating that TBC1D3 and PP2A B56γ operate jointly to promote S6K:T389 dephosphorylation. These findings suggest that TBC1D3 plays an unanticipated and potentially unique role in the fine-tuning of insulin/IGF-1 signaling, while providing novel insights into the regulation of tumorigenesis by a hominoid-specific protein.