Mar. 5, 1999 Washington D.C. - A team of Canadian scientists has identified a potentially useful target for drugs to treat type II diabetes and obesity. In the scientists' experiments, genetically engineered mice lacking a specific enzyme were able to resist weight gain and to avoid the decreased sensitivity to insulin that characterizes type II diabetes, even when fed an extremely high calorie, high fat diet. The results are reported in the 5 March issue of Science.
The finding raises hopes that researchers might someday design a drug for humans that mimics these effects by targeting the same enzyme. "It will certainly take some time to find a compound useful for humans based on our mouse model, but it has the possibility of being a really significant drug if it works," said Brian Kennedy of the Merck Frosst Center for Therapeutic Research in Pointe Claire-Dorval, Quebec, Canada, who was a member of the research team.
In 1995, there were 35 million cases of type II diabetes, or "non-insulin-dependent diabetes," worldwide, according to the World Health Organization, which predicts that the number will radically increase over the next 25 years. Type II diabetes usually develops gradually in people over 40, and overweight people are at particularly high risk for the disease. Diabetes occurs when the body's cells are unable to absorb enough blood sugar, or glucose, into their cells. This lack of cellular "fuel" and the high levels of glucose in the blood stream cause weight loss, fatigue, and a variety of long-term complications.
To store and use glucose, cells need assistance from the hormone insulin, which controls a complex series of steps to remove glucose from the bloodstream and sequester it in the cells. This set of steps is called the insulin "signal." People with type I diabetes (the more severe and early-onset form of the disease) do not produce insulin at all and must give themselves regular insulin injections. People with type II diabetes do produce insulin but their bodies are resistant to its effects.
Previous research has suggested that an enzyme known as PTP-1B might somehow play a role in reducing insulin's ability to regulate blood sugar levels. To investigate this possibility, Mounib Elchebly of McGill University and his colleagues "knocked out" the mouse gene responsible for the production of this enzyme. Compared to normal mice, the mice lacking the enzyme had significantly lower amounts of glucose in their blood after eating and even lower amounts of insulin. Thus, deleting the PTP-1B enzyme appeared to increase the mice's sensitivity to insulin: they were able to use smaller amounts of the hormone to efficiently move glucose from the bloodstream into the cells.
To further probe the insulin signaling process, the scientists fed both normal and knockout mice a diet extremely high in calories, 50 percent of which were from fat. As expected, normal mice quickly gained extra weight and developed obesity-related insulin resistance. In contrast, the knockout mice did not gain much weight and had normal insulin and glucose levels.
The exact task that the PTP-1B enzyme performs in sending off the insulin signal has not been pinned down yet, but some of Elchebly and colleagues' results suggest a likely possibility. It appears that the enzyme deactivates the cell's insulin receptor. (Receptors are "docking points" on the cell's surface for molecules that interact with the cell.) "We knew how the receptor is turned on, but not how it might be turned off. PTP-1B could be one way to do that," Kennedy said.
With no interference from the enzyme, the insulin receptors of the knockout mice seemed to remain active longer than the receptors of normal mice. This larger window of opportunity for insulin signaling could render PTP-1B-deficient mice more sensitive to the effects of the hormone.
PTP-1B also appears to play a role in regulating metabolism, as evidenced by the fact that the knockout mice resisted gaining weight more successfully than the normal mice. However, more work must be done to understand how this occurs.
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