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研究发现胰岛素敏感性的调节因子

胰岛素是一种控制血糖水平的激素,来自美国圣路易斯华盛顿大学医学院的研究者发现了一种强有效地调节其敏感性的调节因子。这项新发现可能能够帮助科学家们发现新的治疗方法,尤其对于2型糖尿病、肥胖等由于体内无法正常准确调节血糖水平而引起的疾病。

这项研究结果发表于2月13日的PLoS ONE杂志上。

2型糖尿病患者体内的脂肪细胞和肌肉细胞对胰岛素有耐受性,这就导致了这2种细胞无法从血液中吸收葡萄糖。研究者们关注的只在人类和其他一些灵长类中存在的TBC1D3蛋白,能够保持胰岛素旁路持续开放,这样细胞能够持续吸收葡萄糖。

“细胞产生的TBC1D3蛋白越多,它对于胰岛素的反应就越大。”这项研究的通讯作者,细胞生物学和生理学教授PhilipStahl,PhD说道,“我们发现TBC1D3蛋白能够显著得减慢一种依赖于胰岛素受体信号的分子的失活,这就上调了细胞对于胰岛素的敏感性。”

G蛋白是一种转导激素信号,类似胰岛素使得细胞内发生特异性作用的分子,Stahl曾致力于G蛋白的研究。现在他着手研究TBC1D3是因为TBC1D3的某些区域与一些G蛋白相结合。

在这项新研究中,Stahl和他的同事们发现TBC1D3表达的升高阻止了细胞膜上受体对于胰岛素信号抑制的反馈调节过程。Stahl说:“在生物学中,类 似于这样的调节通路还有数个。为了确保信号通路不被永久性的打开,在通路中会加入数个因子来让信号水平回复到最初并关闭信号通路。”Stahl向我们解释 道:TBC1D3的表达升高阻止了反馈调节的过程,这就使得信号通路开启的时间更久。

Stahl和他的同事们深入研究了TBC1D3的作用,发现他与一些细胞重要功能的调控有关,比如营养物质的吸收,细胞生长,增殖和衰老。“我们发现TBC1D3能激活PP2A蛋白”Stahl说道,“而果蝇在除去PP2A基因后,寿命明显减少。这就提示了TBC1D3还可能影响衰老的进程。”

研究者们目前着手于调节TBC1D3活性的因子的研究。其中之一可能是个体DNA中TBC1D3基因的复制。TBC1D3是人类基因中复制最多的基因之一,几乎能在任何一条染色体上找到5至50个复制数。科学家们计划把TBC1D3基因复制数较大的细胞与复制数较小的细胞进行比较,来检测该基因的复制数是否与细胞对胰岛素反应的大小相一致。

原文:

Researchers identify potent regulator of sensitivity to insulin

Researchers at Washington University School of Medicine in St. Louis have identified a potent regulator of sensitivity to insulin, the hormone that controls blood sugar levels. The new findings may help scientists find better treatments for type 2 diabetes, obesity and other health problems caused by the body's inability to properly regulate blood sugar.

The research is published online Feb. 13 in PLoS ONE.

Fat and muscle cells in patients with type 2 diabetes become resistant to insulin, which normally causes them to take in glucose from the blood. The protein studied by the researchers, known as TBC1D3, keeps the insulin pathway open, so the cells can continue to take up glucose. TBC1D3 is found only in humans and certain other primates.

"When cells made more of the TBC1D3 protein, they had a much bigger response to insulin," says senior author Philip Stahl, PhD, professor of cell biology and physiology. "We found that TBC1D3 significantly slows the deactivation of a molecule that relays signals from the insulin receptor. This enhances the cells' response to insulin."

Stahl studies G proteins, which help convert signals from hormones like insulin into specific actions within cells. He became interested in TBC1D3 because part of it binds to some G proteins.

In the new study, Stahl and his colleagues showed that higher levels of TBC1D3 impede a feedback loop that normally deactivates the insulin signal into the cell from receptors on the cell membrane.

"There are quite a few regulatory pathways like this in biology," Stahl says. "To make sure the signal doesn't stay on indefinitely, there are factors built into the signaling pathway that reach back to the origin of the signal and attempt to shut it off."

More active TBC1D3 impedes that feedback process, keeping the insulin signaling pathway turned on longer, Stahl explains.

Stahl and his colleagues tracked the effects of TBC1D3 to a cluster of proteins that control some of the cell's most important functions, including nutrient uptake, cell growth and proliferation, and aging.

"We found that TBC1D3 activates a protein called PP2A," Stahl says. "Flies had shorter lifespans when the PP2A gene was knocked out. This suggests that TBC1D3 also may influence the aging process."

The researchers are now investigating the factors that regulate the activity of TBC1D3. One such influence may be the number of copies of the TBC1D3 gene in a person's DNA.

TBC1D3 is one of the most duplicated genes in humans, appearing anywhere from five to more than 50 times in an individual's DNA. The scientists plan to compare cells with many copies of the gene to others with fewer copies to see whether the number of copies is linked to changes in the cells' response to insulin.

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