灰熊在冬眠前体重增加很多，或者说非常肥胖，但它们仍然能保持胰岛素敏感，不患糖尿病，但是人类肥胖者患糖尿病的几率非常高，这是什么原因？科学家最近研究揭示了这一秘密，原来是灰熊脂肪细胞内一种基因被选择性关闭，这种基因编码的蛋白就是PTEN，缺乏这种基因的人容易患癌症，但确实不容易发生糖尿病。当然我们不能为减少糖尿病而付出患癌症的代价，科学家认为只需要特异性关闭脂肪细胞内的这种基因就可以达到目的。这一研究给糖尿病治疗带来新的思路，研究论文最近发表在《细胞代谢》杂志上。

科学家早就知道，肥胖的灰熊代谢功能正常，但是一直不清楚具体原因。美国加州安进公司科学家KevinCorbit决定探讨这个秘密，他和华盛顿州立大学熊研究中心的科学家一起采集处于冬眠不同时期的灰熊血液等标本，分析血糖、胰岛素、体重等代谢数据，结果发现这些肥胖的灰熊在秋天虽然体重增加100多磅也不会发生代谢问题，它们的细胞的胰岛素敏感性很高，如果是人类显然会发生胰岛素抵抗。过去科学家从没有对灰熊的这种详细的代谢特征描述过。随后对这些灰熊的血液、肝脏和脂肪细胞分析发现，引起这种特殊功能的原因是PTEN基因被关闭。这也许是人类对付糖尿病的一种新思路。

Every fall, grizzly bears pack on the pounds inpreparation for their winter hibernation. In humans, such extreme weight gainwould likely lead to diabetes or other metabolic diseases, but the bears manageto stay healthy year after year. Their ability to remain diabetes-free,researchers have now discovered, can be chalked up to the shutting down of aprotein found in fat cells. The discovery could lead to new diabetes drugs thatturn off the same pathway in humans.

The findings are “provocative and interesting,” saysbiologist Sandy Martin of the University of Colorado, Denver, who was notinvolved in the new work. “They found a natural solution to a problem that wehaven’t been able to solve.”

As people gain weight, fat, liver, and muscle cellstypically become less sensitive to the hormone insulin—which normally helpscontrol blood sugar levels—and insulin levels rise. In turn, that increasedinsulin prevents the breakdown of fat cells, causing a vicious cycle that canlead to full-blown insulin resistance, or diabetes.

Developing new diabetes drugs has been hampered by thefact that findings from many mouse models of diabetes have not translated tohumans. So Kevin Corbit, a senior scientist at Thousand Oaks, California–baseddrug company Amgen, decided to start looking at obesity and metabolic diseasein other animals. “When I was thinking about things that are quite fat, one ofthe first things I thought of was bears, and what they do to prepare to go intohibernation,” he says. “But of course you don’t see bears running around withdiabetes and heart disease.”

Corbit and scientists at the Washington StateUniversity Bear Center in Pullman measured blood sugar levels, insulin levels,body weight, and other markers of the metabolism in six captive grizzly bearsbefore, during, and after hibernation—in October, January, and May.Surprisingly, even as each bear gained more than a hundred pounds in the fall,their cells remained sensitive to insulin, and their insulin and blood sugarlevels stayed constant. In people, such an immense weight gain would likelycause insulin resistance. It wasn’t until well after they’d begun hibernatingthat bears experienced a temporary, seasonal episode of insulin resistance, buteven that was completely reversed come springtime. “This type of physiology hadnever been described before and was completely opposite what’s seen in humans,”Corbit says.

When he and his collaborators analyzed levels of moremolecules in the bears’ blood, liver, and fat cells, they found out what wascontrolling the insulin sensitivity and resistance independently from weightgain or loss: a protein called PTEN. In the fall, thebears have switched-off versions of PTEN present in their fat cells,Corbit’s team reports today in CellMetabolism. As a result, the cells continue responding toinsulin—and the signals to store sugar—even as the bears gain weight. Forbears, the shutdown protein helps maximize sugar storage in their bodies forthe long winter ahead.

The finding could also help humans, Corbit says.Because shutting off PTEN helps obese bears maintain insulin sensitivity,turning off the pathway in overweight people could prevent or treat diabetes,he suggests. Interestingly, he points out, a previous study found that peoplemissing one gene for PTEN production are less likely to develop metabolic orcardiovascular disease even as they gain weight. Those people do develop otherdiseases, including cancer, but Corbit suspects that’s because the PTEN levelsare diminished body-wide. If scientists could turn it off only in fatcells—like bears do—these side effects might be diminished.

Metabolic disease specialist Abhimanyu Garg of theUniversity of Texas Southwestern Medical Center in Dallas says that moreevidence is needed to support any link between the bear finding and humandiabetes. And you’d have to be careful with a drug that turns off PTEN, even ifit’s only in fat cells, he says. Even if it could treat diabetes, it might alsocause increased weight gain. After all, it helps bears store up their winter fat,Garg notes. “You might create a situation where patients are metabolicallyhealthy but you’re trading that for joint problems and back problems andarthritis.”