糖尿病,基因突变 z-bo 2020-12-15 346

　　With age, almost everyone will become fatter, but some people may attribute more fat to their genes. Recently, researchers from Duke University in the United States and the Hong Kong University of Science and Technology in China have shown that two different mutations in the ankyrin-B gene can cause cells to absorb glucose at a faster rate, thereby making the body fat and ultimately causing obesity-related diabetes.

　　 Nearly one million Americans carry one of the more serious mutations, called R1788W. Another milder mutation, called L1622I, is shared by 7 percent of African Americans and is a common feature like sickle cell anemia.

　　 These research results are produced in mice, which can help identify people at risk of obesity, and they can reverse the situation by improving their diet and strengthening exercise. Related research results were published in the internationally renowned academic journal "JouRNAl of Clinical Investigation" on July 13. Vann Bennett, senior author of this article and professor of biochemistry, cell biology, and neurobiology at Duke University School of Medicine, pointed out: “This study exemplifies for the first time a susceptibility gene that is only manifested through modern lifestyles. Indeed, in the 1980s There has been an obesity epidemic. Sugary soda and French fries were very popular at the time. This does not seem to be that we suddenly changed our genes in the 1980s, but that the susceptibility genes we carry are exacerbated by this new diet. We think The results of this research are just the beginning, and there will be many genes like this."

　　 Bennett is also a researcher at the Howard Hughes Medical Institute. He discovered ankyrin-B (ankyrin-B) more than 30 years ago. He discovered that ankyrin-B acts as a protein anchor, tethering important proteins to the cell's plasma membrane. Since this discovery, Bennett and other researchers have found that ankyrin-B deficiency is related to a variety of human diseases, including irregular heartbeat, autism, muscular dystrophy, aging, and recently discovered that it is also related to diabetes.

　　 With the increase in waist circumference of people all over the world, diabetes is rapidly becoming one of the biggest threats to public health. As current trends continue, by 2050, one in three Americans will develop diabetes. People with type 1 diabetes do not produce enough insulin, a hormone that can help deal with the accumulation of glucose in the blood after meals. Patients with type 2 diabetes, the obesity-related form of diabetes, can produce insulin, but insulin is resistant to its effects.

　　 A few years ago, Bennett's laboratory found evidence that ankyrin-B mutation may play a role in insulin secretion and metabolism. Since then, some studies have found rare ankyrin-B variants associated with type 2 diabetes. One mutation, called R1788W, is more common in whites and Hispanics. Another mutation, called L1622I, is only found in African Americans, who are known to have a particularly high risk of diabetes. But it is not yet clear how these genetic code changes cause diabetes.

　　 To solve this problem, Bennett's graduate student Jane Healy created a mouse model carrying these same human genetic variants. She and her colleagues found that mice carrying two copies of the r1788w mutation produced less insulin than normal mice. Despite this defect, their blood sugar levels are normal. Therefore, the researchers conducted the commonly used glucose tolerance test, which is often used to screen patients with type 2 diabetes to determine how the blood sugar in the mutant mice is cleared. To their surprise, mutant mice had higher glucose metabolism than normal mice.

　　Healy said: "We originally thought that the main problem in these mice was the beta cells that produce and secrete insulin. Instead, our most important finding was that the target cells took up much more glucose than expected."

　　 If you rely entirely on yourself, glucose cannot enter cells and tissues, but instead depends on another molecule called the GLUT4 transporter. Normally, GLUT4 hangs outside the cell, waiting for the arrival of guests like a hostess. When insulin is lacking, it acts as a doorbell to alert GLUT4, make it act and open the door to let glucose enter the cell. When insulin disappears, the GLUT4 transporter closes the door, reverses direction, and returns to the middle of the cell.

　　 However, postdoc Damaris Lorenzo discovered that this is not the case in mutant mice. After conducting some biochemical experiments, Lorenzo found that there are a lot of GLUT4 on the surface of mouse muscle and fat cells, even if there is no insulin around. This means that glucose can enter the bloodstream without pressing the doorbell.

　　 When they are young, this open door strategy is an advantage because it protects the animals from low insulin levels. But when the mice get older-or switch to a particularly high-fat diet, it will make them fatter and fatter, eventually causing them to develop insulin resistance.

　　 Researchers believe that long ago, the R1788W mutation and the milder L1622I might provide an evolutionary advantage. The aging hunting type cannot find the next meal so efficiently and needs to get as much fat as possible to avoid hunger. Now, the world is rich in high-fat and high-calorie foods. These mutations increase people's risk of modern diseases (such as obesity and diabetes). Lorenzo, the first author of this article, said: “If carriers of these mutations are found early, they can choose personalized treatment intervention. This may involve specific strategies to manage their insufficient insulin secretion, and adhere to a normal diet and active Lifestyle, I hope they can avoid metabolic diseases that can seriously damage the quality of life."

　　 Next, the researchers wanted to explore whether the effects they observed in mice had an impact on humans. They plan to genotype the general population to find families with ankyrin mutations, and then conduct family history and glucose metabolism tests to assess the impact of these genetic variations at the cellular level.