 Science News |
The Quest to Cure Diabetes |
| October 17th, 2009 |
| In 1922, insulin was first administered to treat type 1 diabetes, transforming a deadly disease into a chronic one. But insulin is not a cure.
Periodic blood sugar monitoring and insulin injections cannot match the 24/7 efficiency of insulin-producing beta cells. According to the Juvenile Diabetes Research Foundation, type 1 diabetes reduces lifespan, on average, by seven to 10 years. Type 2 diabetes—a quite different disease—is associated with obesity and is fast becoming an epidemic in the United States. While type 1 results from a lack of insulin, type 2 appears when cells lose the ability to respond to insulin (See box, page 3). According to the American Diabetes Association, more than 23 million people have diabetes, mostly type 2. Though treatments for both forms of diabetes have advanced, cures remain elusive. At Burnham, significant work is being done on both coasts to understand these conditions and find new treatments. Making New Insulin-Producing Cells Both type I and type II diabetes are caused by a deficiency of the cells that produce insulin. Type 1 is an autoimmune disorder, in which the body’s immune system attacks and destroys beta cells, which monitor blood glucose and release insulin. In type 2 diabetes, high levels of fatty acids attack beta cells. As beta cells die, glucose accumulates in the blood, leading to deadly complications. However, if we could transplant or renew beta cells, the body could once again produce its own insulin. Currently, beta cells are transplanted from cadavers but quantities are very low. Fred Levine, M.D., Ph.D., directs the Sanford Children’s Health Research Center and is trying to solve the problem of making new beta cells—either outside the body for transplantation or by activating adult stem cells within the pancreas. “Our initial intent was to make a cell line that would mimic beta cells so well they could be transplanted,” says Dr. Levine. “While that goal proved overly ambitious, the cells that we made turned out to be ideal for high-throughput screening to search for drugs that affect beta cells. This project, done in collaboration with Burnham investigators Drs. Mark Mercola, Pamela Itkin-Ansari and Jeff Price, as well as the Conrad Prebys Center for Chemical Genomics, has been a long road but has recently borne fruit, with a number of compounds entering preclinical trials.” In addition to the studies with high-throughput screening, Dr. Levine’s laboratory is also pursuing other avenues. What if adult stem cells, or mature endocrine cells, could be transformed into beta cells? Dr. Levine is collaborating with Burnham stem cell scientists, such as Dr. Alexey Terskikh, to understand the genes that induce adult stem cells in the pancreas to become functioning beta cells. Possibilities in Regeneration Like Dr. Levine, Duc Dong, Ph.D., is trying to regenerate beta cells from cells that already exist in our bodies. “Usually in diabetes there are a few beta cells left,” says Dr. Dong. “How can we replenish them? If we understand the developmental biology, we may find therapeutic targets where you add a drug or apply gene therapy to encourage the body to regenerate the cells.” The Dong laboratory, which uses zebrafish as a research model, is also trying to encourage pancreatic exocrine cells, which produce digestive enzymes, to become beta cells. “They come from the same precursors,” says Dr. Dong. “We found that a particular gene helps decide the fate of these precursors. We hope that, by manipulating this gene, we can help make more beta cells.” Taking a different approach, Alex Strongin, Ph.D., is interested in what happens if the immune system can be selectively blocked. Dr. Strongin studies an enzyme that helps invasive cancer cells migrate to other parts of the body. The enzyme, called MT1-MMP, is a proteinase, a protein that cuts up other proteins. MT1-MMP interacts with a cell surface receptor called CD44, which plays a number of roles in cancer cells and autoimmune T cells—the culprits in beta cell destruction. Dr. Strongin has found that inhibiting MT1-MMP keeps T cells out of the pancreas. “We found that if you stop the killer cells from getting into the pancreas, it gives beta cells the opportunity to regenerate,” says Dr. Strongin. The tricky part is finding the right inhibitor. Dr. Strongin notes that an MT1-MMP inhibitor has failed in clinical trials for late-stage cancer. To be useful, the compound must be minimally toxic. “We would have to develop a less toxic inhibitor because patients would be taking it for the rest of their lives,” says Dr. Strongin. “It’s one thing to have a toxic treatment for cancer and another entirely for diabetes, where insulin is an effective treatment. So, there’s still a great deal of work to be done.” Protecting Cells from the Immune System For transplantation to be a viable treatment, the immune system must be controlled. Current transplant recipients must take immunosuppressive drugs to prevent their T cells from attacking replacement beta cells, presenting a stark choice between diabetes and a suppressed immune system. Recently, Burnham adjunct professor Pamela Itkin-Ansari, Ph.D., placed pancreatic precursor cells in an immunoprotective device and transplanted them into mice. She was testing whether precursor cells would mature into productive beta cells in the body and whether the protective device, made from a material akin to Gore-Tex, could prevent the immune system from attacking transplanted cells. “We wanted to see if we could protect the cells from the immune system rather than suppressing the immune system,” says Dr. Itkin-Ansari. Early studies have been very positive, as the transplanted cells responded to glucose and produced insulin and the immunoprotective device kept the immune system at bay. “We are excited to see how well they did,” says Dr. Itkin-Ansari. “We could see evidence of beta cells forming and replicating. That means the environment in the device was conducive to beta cells continuing to develop and survive. Also, we thought that T cells, although unable to penetrate the device, would cluster around it. But we found no evidence of an active immune response, suggesting that the cells in the device were invisible to the immune system.” The Problem with Fat At Burnham’s Orlando, Florida campus, researchers are focused on the underlying mechanisms behind type 2 diabetes, in which insulin levels are normal (or elevated) but cells do not respond to its signals. Scientists want to know why insulin resistance happens in the first place, how diabetes affects the heart and the role fat plays in diabetes, metabolic syndrome and other conditions. Philip A. Wood, D.V.M., Ph.D., is interested in fat: fat metabolism, fatty acids, fat signaling, fatty liver disease. Dr. Wood is trying to unravel the consequences of too much fat. “I’m interested in how the body reacts to excess fat and how fat metabolism and the genetics of fat metabolism play a role in insulin resistance and fatty liver disease,” says Dr. Wood. Given that recent statistics show a third of Americans are obese, the research being done by Dr. Wood and others could have a profound impact on the nation’s health. One key focus is the underlying genetics that make certain people susceptible to disease. “We’re not likely to find specific genes that cause type 2 diabetes,” says Dr. Wood. “Perhaps they exist in rare cases, but not enough for a genetic risk assessment. We’re not looking for the cause of the disease; we’re looking at the genetic and environmental determinants of the body’s response to this burden of excess fat. Why do some people have a predisposition towards insulin resistance in the face of obesity? So we’re looking at the genetics of response, not the genetics of cause.” On a practical level, Dr. Wood is particularly concerned with visceral fat, the extra baggage we may have hanging over our belts in front. “Excessive abdominal fat is linked to higher blood pressure and triglycerides and makes that person a candidate for heart attack, diabetes, or both,” says Dr. Wood. “Visceral fat tissue leaks fatty acids, which go to the liver and cause fatty liver disease, enter the blood as triglycerides and also cause inflammation. The most disturbing part is that today’s children may be the first in history to have a shorter lifespan than their parents because of obesityrelated diseases.” While Dr. Wood is focused on what goes wrong for people with type 2 diabetes, Tim Osborne, Ph.D., wants to understand the processes that make the metabolism run normally. “There’s a lot of synergy between Dr. Wood’s research and mine,” says Dr. Osborne. “He comes at it from the disease side, and we’re interested in identifying the pathways that occur normally. If we can understand the normal processes and how they go awry, it will help us find ways to reverse or alleviate the complications of the disease itself.” The collaboration between Drs. Wood and Osborne is typical of the Institute’s approach to research— different labs investigate pieces of the larger puzzle and pool their knowledge. As director of the Metabolic Signaling and Disease Program at Lake Nona, Dr. Osborne is eager to recruit new scientists who will carry on that tradition. “Right now, we are working to integrate people who study various cellular signaling pathways,” says Dr. Osborne. “All these pathways have common nodes. We want to bring this knowledge together to understand how these mechanisms function.” The Language of Fat Traditionally, people have thought of fat as being a relatively passive part of the body. But fat is no innocent bystander. Researchers are learning more about how fat signals other areas of the body, including the brain. Devanjan Sikder, Ph.D., is looking at how these signals can affect both biological processes and perceptions of food. Dr. Sikder studies the hormone orexin, which controls hunger and sleep/ wake cycles. High glucose after a meal reduces orexin levels and the activity of orexin-producing neurons, making us feel sluggish. Plunging glucose levels, following overnight fasting, elevate orexin, which wakes us to find food. The cyclic waxing and waning of orexin appears to be perturbed in type 2 diabetes, obesity and even cancer. “Several epidemiological studies have reported a correlation between lower orexin levels and a higher incidence of obesity and type 2 diabetes,” says Dr. Sikder. Dr. Sikder is also interested in how leptin affects the brain. Leptin is a hormone that controls appetite, telling us to stop eating. Mice without leptin become perilously obese. “Fat tissue produces leptin, which tells us to stop eating,” says Dr. Sikder. “But if you lose weight, the body produces less leptin and you have lost a physiological incentive to stop eating. This may be one reason why it can be so difficult for obese people to lose weight.” Moving Discoveries Forward Steve Gardell, Ph.D., director of Translational Research Resources, came to Burnham Lake Nona to help move basic science discoveries from the laboratory to the clinic. With more than 20 years experience in the pharmaceutical industry, Dr. Gardell understands the challenges of translating basic scientific knowledge into new medicines. However, he sees many opportunities in the work being done at Burnham. “My job is to help shepherd some of these incredible discoveries and check them for clinical effectiveness,” says Dr. Gardell. One area where Dr. Gardell hopes to have a big impact is metabolomics. Biochemical reactions produce small molecules, or metabolites, which can be measured. Dr. Gardell and others at Burnham are hoping to capitalize on this burgeoning young discipline to create new diagnostics. “Metabolomics is a powerful way to identify disease markers that could lead to new tests and early detection,” says Dr. Gardell. Dr. Gardell will also be working closely with Drs. Gregory Roth and Layton Smith to screen for compounds in the Conrad Prebys Center for Chemical Genomics. This painstaking process could lead to new chemical probes to illuminate the underlying mechanisms behind disease and possibly new medicines. One of the targets they aim for is specificity: finding the right chemicals that influence the exact protein to provide great clinical benefit with few side effects. “Medicine has done all the easy things,” says Layton Smith, Ph.D. “It’s not that difficult to knock out a protein. Vioxx (an antiinflammatory drug that was pulled from the market due to increased risk of heart attack) is a good example. It worked too well because it completely knocked out the Cox2 enzyme. Vioxx created Cox2-deficient people. So we need to create compounds that work more subtly. We’ve done the chainsaw; it’s time for a scalpel.” Contact:Burnham Institute for Medical Research 10901 North Torrey Pines Road La Jolla, CA 92037 Tel 858.646.3100 Fax 858.646.3199 info@burnham.org |
| This article is relevant to the following subject areas |
| •Medicine •Diabetes •Endocrinology |
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