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BREAKTHROUGHS SUMMARY ARTICLE The Full-length version of this article is also available, published online as http://www.fasebj.org/cgi/content/full/16/14/1853e.< /FONT> |
Diabetes is rapidly reaching epidemic proportions in the United States and worldwide. According to the Centers for Disease Control and Prevention, 17 million people have diabetes in this country, and more than 200,000 people die each year from related complications. Some experts predict that 25 years from now as many as one in four people may develop diabetes unless we effectively battle the disease in its early stages.
Over the last century, dozens of researchers have whittled away at the mystery of what causes diabetes, and we have gained an extraordinary amount of insight into this disease. That insight has blossomed into an armory of drugs that not only effectively treat type 2 diabetes, but also are likely to prevent or forestall its development.
One of the first drugs used to treat diabetes, insulin, was not introduced until 1922. But insulin merely sustained life, and did not cure diabetes. As diabetic patients lived longer, it became apparent that even with insulin therapy, the disease wreaked havoc on many of their organs and tissues. To prevent diabetes and its complications, researchers needed to better understand what caused it.
Progress on that front could not be made until the 1930s, when clinician Harry Himsworth discovered that diabetes was not one disease, but at least two. His experiments revealed that people with type 1 diabetes were sensitive to insulin and had a history of suddenly developing the disease at a young age. Those with type 2 diabetes were relatively insensitive to insulin and tended to gradually develop a milder form of the disease at middle age or older.
Then, in the 1950s, research by nuclear physicist Rosalyn Yalow and internist physician Solomon Berson led to the finding that instead of producing less insulin after being given sugar, type 2 diabetics often generated more insulin than did those without diabetes. Other researchers discovered that although people in the early stages of type 2 diabetes produce greater than normal amounts of insulin, over time their insulin levels gradually fall. Eventually these levels dip below those in normal individuals.
The net result of these findings was the hypothesis that to compensate for their lack of sensitivity to insulin, people with type 2 diabetes initially produce excess insulin. That excess allows them to sufficiently convert the sugar in their diet to energy their tissues can use. But eventually the insulin-producing cells in the pancreas deteriorate and cannot keep up with the need for insulin. At this point, their diabetes becomes severe, requiring insulin treatment.
The notion that type 2 diabetes is a slowly progressing disease that starts years before people develop any obvious signs of it led researchers to search for drugs that could prevent it or slow its progression. One of the first oral drugs shown to do this was metformin (Glucophage), first marketed in this country in 1995. Metformin works mainly by lessening the liver’s production and release of sugar into the bloodstream. The drug also boosts the use of sugar by muscle tissue. In 2002, researchers showed that metformin reduced by one-third the number of those with prediabetes—people with impaired glucose tolerance—that progressed to diabetes during a three-year period.
But perhaps the biggest breakthrough in type 2 diabetes treatment since insulin are drugs that counter insulin resistance. These drugs did not come on the market until the 1990s. Scientists exploring the workings of a curious cell organelle, actions of blood fat-lowering drugs, and the development of fat cells all contributed pieces of knowledge that together gave a new picture of diabetes. These researchers collectively uncovered that insulin resistance often seems to result from insufficient activation of receptors, called PPAR’s, which are found in the nuclei of cells. In the past two decades, investigators have discovered several drugs, called glitazones, that activate these receptors and counter insulin resistance.
Two such drugs, rosiglitazone (Avandia) and pioglitazone (Actos), came on the market in 1999. Particularly exciting is the discovery that a glitazone drug given to type 2 diabetes-prone rodents prevented them from developing the disorder. It also prevented the loss of insulin-producing cells in the pancreas normally seen in the late stages of type 2 diabetes in these animals (and in humans). Researchers are testing Avandia and Actos to see whether they can prevent type 2 diabetes or its complications in people. In the meantime, millions of people in this country take these drugs because they slash type 2 diabetics’ blood sugar levels by about a quarter, cause a drop in triglyceride blood levels and boost HDL cholesterol levels.
The development of these anti-diabetes drugs offers a ray of hope to counter the gloomy forecast of a rapidly expanding diabetes epidemic. The more we learn about how this disease operates, the more we boost our odds of waging a winning battle. Thanks to the curiosity, ingenuity, and determination of scientists from various fields, we now have powerful new weapons to combat an old debilitating disease.
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FOOTNOTES |
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—Summary prepared by Margie Patlak. 
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