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Fat Cell Defect May Trigger Insulin Resistance In Muscle And Liver

Date:
February 8, 2001
Source:
Beth Israel Deaconess Medical Center
Summary:
Fat cells that can't take up blood sugar normally appear to trigger the same problem in muscle and a related problem in liver, say researchers from Beth Israel Deaconess Medical Center in Boston. Using a sophisticated genetic approach, the researchers wiped out the key protein in fat cells that insulin tells to move glucose from the blood into the cells. Soon, muscle also ignored insulin's orders to take up glucose, and liver disregarded insulin's instructions to shut down the organ's glucose production.

Boston -- Fat cells that can't take up blood sugar normally appear to trigger the same problem in muscle and a related problem in liver, say researchers from Beth Israel Deaconess Medical Center in Boston. Using a sophisticated genetic approach, the researchers wiped out the key protein in fat cells that insulin tells to move glucose from the blood into the cells. Soon, muscle also ignored insulin's orders to take up glucose, and liver disregarded insulin's instructions to shut down the organ's glucose production.

The findings in mice may begin to explain why obesity is a risk factor for type 2 diabetes in humans and may shed light on the earliest defect in type 2 diabetes -- insulin resistance. It also offers a potential new target for diabetes treatment and prevention. The study is published in the Feb. 8 issue of Nature.

"This paper clearly shows that fat also is important for whole-body insulin action. We think fat releases a molecule that circulates to muscle and liver and impairs insulin signaling in those cells, " says senior author Barbara Kahn, M.D., chief of the division of endocrinology and metabolism at Beth Israel Deaconess Medical Center. "For years, people have thought -- and data have shown -- that glucose uptake in muscle is very important for normal insulin action and to prevent diabetes. Researchers thought the decreased glucose uptake into fat of obese and diabetic people was not important in causing insulin resistance," says Kahn, also a professor of medicine at Harvard Medical School.

The new study reinforces a new appreciation of fat as an endocrine organ that influences other tissues. In January, for example, other researchers identified a hormone produced by fat cells, dubbed resistin, that prompts other tissues to resist insulin. Resistin is the latest in the list of active factors known to be secreted by fat that can affect insulin action. The list includes tumor-necrosis factor-alpha, fatty acids and leptin, which works through the brain to regulate feeding and metabolism. Kahn's research group excludes all of these as likely culprits in the new paper.

"One of the most important implications is that fat cells must use yet more messengers to communicate with liver and muscle cells," says Morris Birnbaum, M.D., Ph.D., in an accompanying commentary in the Feb. 8 issue of Nature. "It seems that adipose tissue is more than capable of telling other energy-storing organs what to do," says Birnbaum, a Howard Hughes Medical Institute investigator at the University of Pennsylvania Medical School.

Diabetes is one of the leading causes of death and disability in this country. An estimated 16 million Americans have diabetes, a serious condition that often leads to blindness, heart attacks, atherosclerosis, peripheral blood vessel disease, strokes, kidney failure, amputations and nerve damage. About one-third of diabetics are believed to be undiagnosed. Type 2, or adult onset, accounts for about 90 percent of diabetes cases. About 80 percent of people with type 2 diabetes are overweight.

Diabetes results from a lack of insulin or a lack of response to insulin by the body or both. After a meal, the hormone insulin prompts muscle and fat cells to take up glucose from the blood. Muscle takes up most of the body's glucose after a meal. Insulin also turns off glucose production by the liver. When type 2 diabetes is diagnosed, the pancreas is usually producing increased insulin, but the body cannot respond to the insulin effectively, a condition called insulin resistance. Pancreatic beta cells respond by making extra insulin, but eventually the insulin is inadequate to overcome the insulin resistance. When glucose cannot get into the cells that need it, the sugar builds up in the blood..

In the latest study, Beth Israel Deaconess postdoctoral fellows Dale Abel, M.D., D.Phil., and Odile Peroni, Ph.D., disabled insulin-stimulated glucose-uptake in fat cells in mice by knocking out the key glucose transporter, GLUT4. Normally, insulin triggers muscle and fat to send GLUT4 to cell membranes to transport glucose into the cells, where it is converted into complex carbohydrates and fat. Sugars are cells' main source of fuel. In nearly all species, including mice, rats, monkeys and humans, insulin acts as a dispatcher, calling the taxi cab GLUT4 out to the cell's membrane to transport glucose into the cell.

Kahn's team targeted GLUT4 selectively in fat in mice to mimic how GLUT4 levels are decreased only in fat and not in muscle in human obesity and type 2 diabetes. Although the researchers knocked out insulin-mediated glucose uptake only in fat cells, they soon noticed liver and muscle cells' responses to insulin were markedly reduced. All of the mice showed insulin resistance similar to that found in human obesity. Insulin resistance is the first step toward diabetes. As in humans, some of the mice were able to compensate, but other mice developed the high blood glucose levels that define diabetes.

"We're not saying that decreased GLUT4 in fat is the only cause of insulin resistance, but it is an important risk factor," Kahn says.

In hopes of finding an effective target for new therapies, Kahn's group is following up with more detailed studies to zero in on the crucial step in the cascade of molecules inside the cells that links insulin with GLUT4. Kahn also wants to identify the culprit molecule released by GLUT4-depleted fat that circulates and dampens insulin action in muscle and liver.

"This whole concept is extremely exciting in terms of the possibility of finding new drug targets for reducing insulin resistance, improving blood sugar control or even decreasing the possibility of developing diabetes," says Kahn,

The papers' lead co-authors are Abel, now an assistant professor at University of Utah, and Peroni. Other authors from Kahn's group are Young-Bum Kim, Ph.D., Olivier Boss, Ph.D., Ed Hadro and Timo Minnemann. Yale University collaborators on the paper include Jason Kim, Ph.D., and Howard Hughes Medical Investigator Gerald Shulman, M.D., Ph.D. The study was funded by grants from the National Institutes of Health and the American Diabetes Foundation. Other support was provided by the Robert Wood Johnson Foundation, the Eleanor and Miles Shore Scholars in Medicine Fellowship (Harvard Medical School), ALFEDIAM, Nestle (France) and the Human Frontier Sciences Program.

More information on diabetes can be found at:

* http://www.cdc.gov/diabetes/

* http://www.niddk.nih.gov/health/diabetes/diabetes.htm


Story Source:

The above story is based on materials provided by Beth Israel Deaconess Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Beth Israel Deaconess Medical Center. "Fat Cell Defect May Trigger Insulin Resistance In Muscle And Liver." ScienceDaily. ScienceDaily, 8 February 2001. <www.sciencedaily.com/releases/2001/02/010208074012.htm>.
Beth Israel Deaconess Medical Center. (2001, February 8). Fat Cell Defect May Trigger Insulin Resistance In Muscle And Liver. ScienceDaily. Retrieved October 21, 2014 from www.sciencedaily.com/releases/2001/02/010208074012.htm
Beth Israel Deaconess Medical Center. "Fat Cell Defect May Trigger Insulin Resistance In Muscle And Liver." ScienceDaily. www.sciencedaily.com/releases/2001/02/010208074012.htm (accessed October 21, 2014).

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