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NIDDK's Taylor Offers Parting Comments on Diabetes

By Anna Maria Gillis

"Diabetes is much more complicated than I ever dreamt," reflects Dr. Simeon Taylor, as he leaves his post as chief of the Diabetes Branch at NIDDK to become Lilly research fellow at Lilly Research Laboratories in Indianapolis. Still, he believes the scientific advances of the past 30 years and current research directions provide hope.

"Undoubtedly, the most striking progress has been in understanding how insulin works," said Taylor. In 1979, when he began at NIH as a research associate, scientists knew that insulin bound to receptors on the outside surfaces of cells and helped glucose into cells, but they were "clueless," he says, about how it happened. They had a general model for how hormones functioned: straightforward pathways with few steps. The pathway for insulin action, however, has proved to be nonlinear and multi-stepped.

NIDDK's Dr. Simeon Taylor has taken his expertise in diabetes research to a drug company.

Over the years, Taylor and his colleagues have made major contributions to understanding the insulin action pathway and insulin resistance. The inability to use the hormone effectively is characteristic of type 2 diabetes. In particular, Taylor's group has determined how and why insulin fails to act in patients with leprechaunism, Type A insulin resistance and other genetic forms of insulin resistance. They also have developed a mouse model for a form of insulin-resistant diabetes.

"Simeon was the lead person in the world studying genetic defects in the insulin receptor," said Dr. Phillip Gorden, director emeritus of NIDDK. "He attracted collaborators from all over the world, and they were able to relate specific receptor mutations to particular kinds of insulin resistance and to individual patients." These mutations reduced the number of receptors or inhibited the receptors' ability to mediate the effects of insulin on cells.

In 1992, Taylor received the American Diabetes Association's Outstanding Scientific Achievement Award for his discoveries. "He has done classic work," said Dr. Jesse Roth, professor of medicine at Johns Hopkins and former NIDDK scientific director. "Simeon's work has permanence. It will be work people look back on in 30 years."

"When I started in research, there was one camp that thought the whole problem in (type 2) diabetes was with insulin secretion and another that thought it was with insulin resistance," says Taylor. "Increasingly, the consensus is that the two are both important, and possibly not entirely independent of each other. In a given person, there may be one problem with the pancreatic beta cells that produce insulin, and a second defect in the insulin action pathway causing insulin resistance."

Seeing the relationship between obesity and insulin resistance is another advance, said Taylor, adding that progress has been rapid since the 1995 discovery of leptin, a protein secreted by fat cells. Leptin will soon be given to NIH study volunteers with lipoatrophic diabetes. They have lost a significant portion of their fat cells and are extremely insulin resistant. Published studies of lipoatrophic mice have encouraged the hope that leptin will lead to improvements in the metabolic abnormalities in the lipoatrophic patients, noted Taylor.

Taylor believes significant study is critical in two areas. First, people with type 2 diabetes need more effective behavioral and pharmacological therapies to help them lose weight and, especially, maintain it. The second great challenge is to understand diabetes complications such as blindness, kidney failure and cardiovascular disease.

"There is so much more that is unknown than known," he said, about how high blood sugar causes the development of problems. When scientists get a better understanding of these pathways, it may be possible to develop drugs to prevent or postpone chronic complications, he observed. "Maybe we can someday save people from going blind or having amputations.

"My patients have taught me just how hard it is to have diabetes and how much suffering it causes," he added. "It's one of the reasons I'm interested in drug development."

Increasingly, pharmaceuticals are being developed that target specific proteins on disease pathways. Yet, "it's humbling that none of the oral diabetes drugs presently on the market have grown out of a prior understanding of mechanisms," says Taylor. "They grew out of discoveries that a compound was lowering blood sugars, and only later was it determined how the drugs worked. In the case of metformin, we still don't know how it works."

With his many scientific accomplishments, Taylor is still most proud of having trained researchers at NIH who have gone on to start their own labs. He encourages those he mentors to be persistent and to take a long-range view. "When you do things that no one else has ever done, most of the time they're bound not to work," he cautioned. In science, as in baseball, "if you're hitting 30 percent of the time, you're doing well."

Still, he maintains, "We're in a golden age of biomedical science. With the genome available — with its amazing amount of relevant information — our challenge is to understand it to help people."

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