ONE IN EVERY 400 TO 600 CHILDREN IN THE UNITED STATES HAS BEEN DIAGNOSED WITH DIABETES. "IMAGINE, AS A PARENT, BEING TOLD THAT YOUR 2-YEAR-OLD OR YOUR 6-YEAR-OLD HAS DIABETES, "SAYS WENDY CHUNG, M.D., PH.D., DIRECTOR OF COLUMBIA'S CLINICAL GENETICS PROGRAM AND A MEMBER OF THE DIVISION OF MOLECULAR GENETICS IN THE DEPARTMENT OF PEDIATRICS. "IMAGINE THE ANXIETY ABOUT WHAT THE FUTURE HOLDS. OF COURSE, THESE PARENTS WANT TO BE AS AGGRESSIVE AS POSSIBLE ABOUT TREATMENT TO ENSURE THAT THEIR CHILD WILL BE PROTECTED."

But now, genetic research conducted by Dr. Chung is demonstrating that some children with diabetes may be spared the constant vigilance and daily insulin shots required of a chronic disease. “We’ve been able to use genetic testing to identify some types of diabetes that are going to be relatively mild.”
     It’s called “maturity onset diabetes of youth,” a type of diabetes that’s genetically distinct from autoimmune, or type 1, diabetes. By identifying genetic mutations in families, Dr. Chung can predict which children have this particular form of the disease and can safely go off insulin therapy and stay healthy with only modest attention paid to diet and other lifestyle factors. “The diagnosis I like to be able to give is due to a mutation in a gene called glucokinase. Anyone who has mutations in that gene tends to do very well. Their sugars are mildly elevated, and they don’t require daily injections of insulin,” she says. “We had to assume the worst before. Now, we can offer these families and children reassurance that they don’t have to go through daily finger-sticking and living life with a chronic disease if they maintain a healthy lifestyle.”
     While a welcome relief for some parents and children, this new genetic diagnosis doesn’t help the majority of people with diabetes. In an exciting new project that brings together Columbia’s Naomi Berrie Diabetes Center and a group of scientists at Harvard, researchers are using somatic cell nuclear transfer to study the molecular biology and genetics of diabetes.
     “We’re using cell nuclei from diabetics harvested here at Columbia by Drs. Robin Goland and Thomas Ludwig and putting them into eggs harvested in Boston,” explains Rudolph Leibel, M.D., professor of pediatrics and medicine, head of the Division of Molecular Genetics, and co-director of the Berrie Center. The goal: to successfully coax stem cells to differentiate into islets, the cells that actually control the production of insulin. “If we can do that, we’ll be able to study the islet cells of an individual with diabetes without doing something we really can’t do – biopsy the pancreas. If successful, this will revolutionize the ways in which we study the pathogenesis of diabetes. We’ll be able to look at the insulin-producing cells as they develop, figure out the mechanisms that control that development and how we might control it.”
     Of the 17 million Americans with diabetes, 90 percent to 95 percent have type 2 diabetes. Any solution to this enormous public health problem must tackle a growing American phenomenon: obesity, one of the single greatest risk factors for type 2 diabetes. As the population gains weight, type 2 diabetes gains momentum. Years ago, the disease was known as adult-onset diabetes because it rarely manifested in children, but as more and more children become obese, type 2 diabetes is increasingly common in young people. More than 39,000 youths age 12 to 19 now have the disease.
     “If we could understand the genetics of obesity and use that understanding to help manage and prevent it, we could prevent or effectively treat a great proportion of the cases of diabetes affecting our population today,” says Dr. Leibel. His laboratory is studying the pathogenesis of obesity and diabetes and how excess weight predisposes people to the disease by using a mouse model to identify some of the genes that contribute.

Aggressive research is needed for an aggressive disease: diabetes. Since up to 95 percent of Americans with diabetes have the type for which obesity is the single greatest risk factor, Wendy Chung, M.D., Ph.D., studies obese mice to try to reveal the molecular connections between obesity and diabetes and how the connection can be broken.

     In some instances, single genes such as FOXO1 influence multiple aspects of the biology of diabetes and body weight regulation. This gene affects the development of the islets of the pancreas, the function of insulin-producing cells in the islets, and the function of cells in the brain that regulate food intake. Domenico Accili, M.D., professor of medicine and head of the Columbia Diabetes and Endocrinology Research Center, is leading a group in the Naomi Berrie Diabetes Center studying this critically important gene and the pathways in which it acts.
     But no single gene accounts for the entire picture of diabetes. “It’s not a single gene. It’s a group of genes that may not be the same among all ethnic or racial groups and even may be different in the same individual depending on their age,” says Dr. Leibel. “Many of these genes are members of unique, discrete pathways for the control of body weight.” Studies in Dr. Leibel’s lab are now examining what happens when subtle differences in a series of related genes in the same pathway could add up to a significant impact on body weight. His team and others have identified many of the suspect genes based on their work in mice and have now begun initiating studies to show exactly how these genes interact in humans to make them susceptible to obesity.
     One study under way now uses data on some 18,000 New Yorkers. The study is coordinated by AMDeC Foundation, a nonprofit consortium of 35 New York medical schools, academic health centers, and research institutions. In a second study, Dr. Leibel is collaborating with a team in Alaska (Dr. Bert Boyer), examining some of the same genes within a large group of Yup’ik Eskimos. “We’re studying 25 or 30 genes at a time, with multiple markers inside and around the genes,” Dr. Leibel explains. “Each individual’s sample DNA may have 250 or 300 genetic tests performed, and those data are used to try and estimate the role of a specific gene in determining body weight. It’s quite complicated from a computational point of view, but we’re convinced that these are the tools we will need to really understand obesity and type 2 diabetes in humans.”
     Such research couldn’t be done outside an institution like Columbia, he says. “We have such a large patient population here, and ultimately we can use this resource to test across even larger numbers of individuals. We’re going to need tens of thousands of human subjects to work out the genetics of complex disorders like diabetes. A medical center like this isn’t just ideal, it’s sine qua non; the work wouldn’t be possible without access to this kind of center.”
     Using an exciting new genetic analysis technique called ROMA (Representational Oligonucleotide Microarray Analysis) developed at Cold Spring Harbor Laboratory, Dr. Chung is also trying to tackle the obesity question by studying individuals who have “syndromic” forms of obesity. “In about 5 percent of these people, there are contiguous gene deletions: They are missing several genes in tandem along a chromosome,” she says. Before ROMA, which allows scientists to detect duplications and deletions throughout the genome, these differences couldn’t have been detected. “Now we have been able to identify these small deletions and target new genes that we didn’t even know had to do with obesity.”
     Obesity and diabetes also go hand in hand with the leading cause of death in America: heart disease. Many of the primary genes involved in cardiovascular disease have already been identified, but they don’t tell the whole story. For example, what causes a condition like familial cardiomyopathy, in which seemingly healthy children or young adults – like basketball player Hank Gathers and figure skater Sergei Grinkov – die suddenly? “We know that there are genes that cause this predisposition, but not everyone has the same severity or age of onset, and not everyone responds to therapy in the same way,” says Dr. Chung. “We’ve recently identified modifier genes that help determine who will have the more severe form of these conditions and get them earlier, and in the case of cardiomyopathy, who will progress more rapidly to the need for a heart transplant.”
     Just as genes interact to produce a predisposition to heart disease, genes might also be used to help heal damaged hearts. One of these genes is called cyclin A2, and Hina Chaudhry, M.D., assistant professor of medicine, thinks it may be one of the most important genes for regenerating cells in the heart. Cyclin A2 plays a key role in heart growth in fetal development, but it goes silent as soon as any mammal is born. From that point on, the heart stops developing new cells. Now, in animal research, Dr. Chaudhry has discovered that when cyclin A2 is artificially switched back on, new heart cells continue to be generated. And when heart attacks are induced in mice that have switched-on cyclin A2, their heart tissue regenerates and retains its ability to pump. Dr. Chaudhry’s team has begun testing ways to deliver cyclin A2 as a drug, a potential treatment for people with heart failure or heart attacks. “Our current therapies for heart failure are limited,” she says. “We have an imperative need for cellular and molecular therapies to change that picture.”

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