LEADING THE WAY TO A CURE FOR DIABETES

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INSIDE: " Understanding beta-cell destruction " Helping youth avoid diabetes " Preventing kidney damage " Discovering genetic causes of diabetes and obesity " Hot Topics/Research Update LEADING THE WAY TO A CURE FOR DIABETES Winter/Spring 2005 Message from the American Diabetes Association Research Grant Review Panel Chair As the recently appointed Chair of the American Diabetes Association (ADA) Grant Review Panel, it is my pleasure to introduce the second issue of Forefront . As you know, only the most promising research ideas presented to the Grant Review Panel will ultimately receive funding, and this issue of Forefront showcases prime examples of the exciting and innovative research funded by ADA supporters. This year the Grant Review Panel has faced the daunting task of reviewing over 700 research grant applications 4 a record number.

In order to make this task more manageable, the Association has recruited an additional 40 panel members which brings our total membership to 100 scientists. To further expedite the review of such a large number of grant applications, the Association has implemented an online grant application and review process. This electronic process facilitates grant submissions and helps manage the review process much more efficiently.

While the increasing number of applications ... more. less.

creates additional challenges for the Association and the Grant Review Panel, we consider this a very positive sign. The growing number of applications means that the ADA research program, with its various types of grant awards, is becoming an increasingly sought-after means of research funding. This applies to more promising junior investigators, who are attracted to diabetes research by special awards targeted to their level, and to established investigators who can compete for substantial support for their research. The more grant applications we receive, the more competitive each award becomes. Despite these challenges, the Association is dedicated to making the review and funding process as fair as possible. During my four years of service as a member of the Grant Review Panel, I have been impressed by the fairness of my peers and the help they provide to their fellow scientists by helping them improve their science. During the review process, panel members assess the feasibility, novelty, scientific soundness and potential value of each project. By placing such importance on peer review, we can all be assured that only the highest quality science is funded by the ADA. Forefront is an important publication because it showcases the fruits of our collective efforts, whether you are a grant reviewer, researcher, or supporter of the research program. Each issue of Forefront focuses on four scientists in different areas of diabetes research 4 all fighting for a cure, better treatments, or methods for preventing this disease. I am happy to announce that this issue also includes a chot topics d section which highlights some of the latest and most innovative research into diabetes care. In these pages you will also find a report on the research results of ADA-supported studies 4 an important addition to this magazine that illustrates some of the many successes of ADA-funded research. I am proud to be a part of the American Diabetes Association and look forward to this coming year as Chair of the Grant Review Panel, ready to review more exciting research projects. Sincerely, Alberto Pugliese, MD 1 2 GFP-tagged myosin light chain in kidney mesangial cell. This live cell imaging technique is providing insight into the creal-time d effect of statins on kidney cells. Photo submitted by Farhad R. Danesh, MD Northwestern University Medical School Co-editors: Tory Asfahani Elizabeth Guzman Design: Nichols & Duncan, Inc. Table of Contents Message from the ADA Research Grant Review Panel Chair, Alberto Pugliese, MD 1 RESEARCH I Type 1 Gerald T. Nepom, MD, PhD Mentor-Based Postdoctoral Fellowship Award Autoreactive T cells in type 1 diabetes 3 RESEARCH I Type 2 Lisa Martin, PhD Career Development Award The metabolic syndrome: the role of plasma adiponectin and common genetic polymorphisms in adolescents 7 RESEARCH I Complications Balakuntalam S. Kasinath, MD Research Award Insulin receptor activation in pathogenesis of diabetic nephropathy 11 RESEARCH I Targeted Joel Hirschhorn, MD, PhD The Richard and Susan Smith Family Foundation Pinnacle Program Project Award Systematic identification of pathways contributing to diabetes and obesity in human patients 15 HotTopics 20 Research Update 23 Message from the ADA Research Foundation Chair, Mr. Don Wagner 30 LEADING THE WAY TO A CURE FOR DIABETES Gerald T. Nepom, MD, PhD Occupation: Director of the Benaroya Research Institute at Virginia Mason Medical Center Affiliate Professor of Immunology University of Washington School of Medicine Seattle, Washington Professional Focus: Understanding the interaction between MHC molecules, peptides and T cell recognition, focusing on the HLA molecules associated with autoimmune disease Outside Interests: Kayaking, hiking, bicycling Research Funding: Mentor-based Postdoctoral Fellowship Award Autoreactive T cells in type 1 diabetes Amount Awarded: $180,000 3 M Understanding Beta-Cell Destruction in Type 1 Diabetes y early scientific training was in fundamental immunogenetics at a time when the basic foundations of that field were being discovered. I had long thought about medicine as a career so when the opportunity presented itself after college to pursue both a research PhD and an MD, I took it. During my fellowship years, I basically was a cmouse doctor, d learning how genetics control immune responses, and I changed to studying humans when I set up my first independent labo- ratory in 1982. The switch paid off. My team developed methods to study the way key immune system genes are organized and how this organization is related to disease susceptibility as identified by cell surface markers called human leukocyte antigens (HLA 4 more on these later). Eventually, one of the first of these genetic associations which we were able to identify was with autoimmune diabetes. By 1985, I was devoting a lot of my efforts to the diabetes field because I became increasingly aware of both the great urgency and the unprece- dented opportunities in diabetes research. Today, we know that the seriousness of diabetes, and the widespread problems associated with it, demands accelerated and expanded research objectives 4not only to discover the means to prevent and cure diabetes, but also to develop better and more effective treatment strategies. The complexity of diabetes mellitus is made even more problematic because it is not a single disease but occurs in several forms, including type 1 (insulin-dependent; formerly known as 8juvenile © Scavone Photography 4 RESEARCH I Type 1 onset 9) diabetes which usually starts in childhood or adolescence, and type 2 (non-insulin dependent; formerly known as 8adult-onset 9) diabetes, which typically affects adults and increases dramatically with age and obesity. The immune system is basically an intersection where many scientific pathways meet, and a large number of serious medical challenges use these particular pathways, from infectious diseases to cancer to autoimmune diseases such as type 1 diabetes. Autoimmune diabetes is a prominent example where the basic science understanding has advanced to the point where clinical applications are possible. It is because I am convinced that new, exciting advances can be foreseen in the next few years that I am very appreciative of the support of the American Diabetes Association. In our ADA-funded grant, Autoreactive T cells in type 1 diabetes , we are attempting to understand the mechanisms which initiate and regulate the immune system attack on the insulin-producing beta cells of the pancreas in type 1 diabetes. Specifically, we are focusing on the interaction between immune T lymphocytes (T cells, a sub- group of leukocytes [i.e., white blood cells] involved in fighting infection and disease) and a cluster of genes called MHC molecules, and the immune system. The MHC genes can be divided into different classes of genes. For example, class I and II MHC genes code for proteins that are found on the surface of cells. These are the HLA proteins I previously mentioned. These HLA proteins code for proteins which vary from person to person, and by sitting on the surface of cells and cpresenting d themselves to the immune system, they help the body distinguish between its own tissue and foreign tissue that might potentially cause harm. In the case of some MHC genes, the body may not properly recognize its own tissue and T cells can begin attacking the body 9s own tissue and instructing other immune cells to do the same. Thisis how autoimmune diseases such as diabetes, multiple sclerosis and some forms of arthritis can develop. We would like to understand what the unique features are that cause these molecules to contribute to autoimmunity and to gain some practical insight into opportunities to detect, mod- ulate or block this process of disease development. Individuals who are genetically predisposed to develop type 1 diabetes can be identified, but only a small proportion of them will end up with diabetes. This is because progression of the disease may depend on two factors: activation of T cells (previously mentioned) and an inability c Using basic science research discoveries and technologies to influence patient management or clinical trial design is crucial to the advancement of diabetes treatments and the search for a cure. d 5 of the body to regulate its immune system. We have developed new substances (called tetramers) which can identify T cells that are affected by HLA proteins and can cause tissue destruction. We have recently begun to study a different type of T cell which can block the activation of other harmful T cells and thus regulate the immune system. These cells are known as regulatory T cells. We are now trying to turn normal T cells into regulatory T cells. Not only is it important to understand this regulation process, but it may be possible to isolate normal T cells from patients, turn them into regulatory T cells, and prevent some of the destruction of the pancreas and beta cells. Laboratory research is still needed to better understand in detail what mechanisms are involved in someone becoming diabetic. What makes this a relevant contribution to individuals with diabetes is that if we can better understand how and why someone progresses to diabetes, we will then be able to continuously improve on strategies to prevent or cure diabetes. I feel that using basic science research discoveries and technologies to influence patient manage- ment or clinical trial design is crucial to the advancement of diabetes treatments and the search for a cure. It is a source of great satisfaction to have some of our genetic and immunologic work lead to widespread clinical research use. Unfortunately, the uncertainty and instability of funding sources for research is a continuous challenge. Building an effective research team is a lengthy and important task. Moreover, holding the team together requires stable funding, which is extremely difficult to manage in the current environment. The flexibility and multi-year nature of the American Diabetes Association Mentor-Based Postdoctoral Fellowship Award is well suited to a rapidly changing field where new objectives are always evolving. In my case, the award is bring- ing together 20 years of intensive biomedical research with the fresh, new perspective of an accomplished, young diabetes investigator, Dr. Mindi Walker of Greenville, North Carolina (see cYoung Scientist in Training d on page 6). Dr. Walker, who did her initial research work in multiple sclerosis before joining my lab, is now exploring the regulation of autoimmune diseases with a specific focus on diabetes. I believe that public awareness and communica- tion are important foundational elements upon which we can build broader philanthropic and political support for diabetes research. Here, the American Diabetes Association plays an important role in creating this foundation. I have been a direct recipient of this gracious philanthropic support and am very appreciative of it. I am also very cognizant of the expectation that our work will lead to better outcomes for individuals with diabetes and their families. This is why our research program contains both basic and translational objectives which ultimately aim to influence the quality of care for individuals with diabetes. What better way to provide the public with a return on its research investment? Over much of the last two decades, I have been devoted to building a research institute which brings together an outstanding group of scientists to tackle biomedical problems in novel, collabo- rative ways. It is my goal to further the work of this institute by creating important research opportunities that, if seized now, can vastly improve the lives of people with or at risk for diabetes. 6 McCabe Glossary Postdoctoral Fellow in the Laboratory of Gerald Nepom, MD, PhD Mindi Walker earned her Bachelor 9s degree in Biology from Stetson University in DeLand, Florida, and her PhD in Microbiology and Immunology from East Carolina University School of Medicine in Greenville, North Carolina. Since completing her PhD in 2002, Dr. Walker has been a postdoctoral research associate at Benaroya Research Institute at Virginia Mason in Seattle, Washington, and is currently under the guidance of Dr. Gerald Nepom to research the mechanisms by which the immune system attacks pancreatic beta cells in the development of type 1 diabetes. Dr. Walker 9s first foray into research was in the area of multiple sclerosis, a disease caused by an immune system attack on the nerves of the brain and spinal cord. She is now broadening her understanding of autoimmune diseases by studying diabetes and, like Dr. Nepom, feels that the many recent laboratory dis- coveries leading the way to a cure for diabetes will soon be ready for study in human patients. Asked about the most satisfying part of her diabetes research experience, Dr. Walker stated, cScience is a constantly rewarding field. There are little rewards that happen everyday. With each new experiment, knowledge is gained, and excitement builds for where the research might lead. It is hard to pinpoint one place in time where research has been most rewarding. I find talking with other researchers and members of the community about my research very rewarding, especially when people are interested and are eager to learn more. d Postdoctoral fellow Mindi Walker, PhD Though early in her career, Dr. Walker has already begun building an impressive resumé. She has received several scholarships and awards and has made various presentations at scientific meetings. More importantly, she is making a name for herself in the world of immunology research by publishing in journals such as the Journal of Clinical Investigation , a highly respected and selective publication. Dr. Walker has several first author publications, meaning that she was responsible for writing the paper and leading the research effort. She has big plans for her future. cOver the course of my career, d Dr. Walker states, cI would like to learn more about the mechanisms that lead to autoimmunity, in particular diabetes, because if we can figure out the underlying problems, we are better capable of treatingthese diseases. I would eventually like to have my own lab with a focus on preventing or curing diabetes. d Young Scientist in Training 4 Mindi Walker, PhD 6 X aised in Manhattan, Kansas, a friendly and close-knit community known for its long history of accepting new ideas and supporting progressive movement, I developed an early appreciation for the power to transform lives and communities. Years later, I would go into medical research. What better arena to be in for really impacting the quality of life? As a young person, I always had an aptitude and interest in the biological sciences; however, I didn 9t consider the possibility of furthering my education and getting my doctorate until my junior year in college. It was around this time that my interest in diabetes research began, during my pre-doctoral fellowship, when I had the opportunity to train under a well known statistical geneticist, Dr. Tony Comuzzie of San Antonio, Texas. With a focus on the genetics of obesity, I began studying adiposity traits (weight, body mass index [BMI], and adipocyte [fat cell] proteins) as well as insulin,glucose, and diabetes. At that point, I realized that I wanted to strengthen my understanding of the role of genes in disease in order to improve prevention and treatment, and ultimately, contribute toward the cure of the disease that has plagued my family for years. For those touched by it, diabetes is woven into the emotional, intellectual, spiritual, and physical fabric of their lives. For some, diabetes becomes a part of their life story. Although not diabetic, I have a deep personal interest in diabetes research because I have a strong family history of type 2 diabetes. Both my mother and maternal grand- father have been diagnosed with this disease. Lisa Martin, PhD Occupation: Assistant Professor of Pediatrics Center for Epidemiology and Biostatistics and the Division of Human Genetics Cincinnati Children 9s Hospital Medical Center and the University of Cincinnati Department of Medicine Cincinnati, Ohio Professional Focus: The genetic epidemiology of obesity and diabetes-related phenotypes Outside Interests: Reading, cross-stitching, spending time with family Research Funding: Career Development Award The metabolic syndrome: the role of plasma adiponectin and common genetic polymorphisms in adolescents Amount Awarded: $674,292 R 7 Protecting the Future: Helping Youth Avoid Diabetes © Scavone Photography 8 Given my family history, it is likely that I may have a genetic predisposition to develop type 2 diabetes and that I might pass this on to my own children. Therefore, as a medical researcher and a mother, it is important to me to understand the reasons why some individuals develop diabetes while others do not. With the rising incidence of obese and overweight children, physicians are diagnosing type 2 diabetes more and more in young people. Yet, while we know there is a link between obesity and insulin resistance, the connection is not straightforward. Multiple genetic, environmental, and hormonal factors are implicated in the progression from insulin resistance to diabetes. Furthermore, insulin resistance is observed in both lean and obese individuals while many obese individuals with insulin resistance never progress to diabetes. So who gets diabetes and who doesn 9t? To attempt to find the answer, I approached the American Diabetes Association. I sought funding for my research project because I believe that by identifying the genes that predict diabetes, we will be able to identify individuals who will likely develop diabetes before any clinical symptoms are present and can initiate preventative therapy before they develop type 2 diabetes. Obesity, diabetes, and poor lipid profiles (blood fat levels) have been recognized to occur together. This clustering of disorders has been termed cthe metabolic syndrome d but the reasons for this clustering are not known. Interestingly, recent research has demonstrated that adiponectin, a fat-derived protein, is related to obesity, diabetes, and poor lipid profiles, which suggests that adiponectin might explain this clustering. However, the development of each of these diseases is a gradual process; therefore, to determine whether adiponectin is related to the clustering of the metabolic syndrome, we must look prior to the development of disease. My ADA-funded grant, The metabolic syndrome: the role of plasma adiponectin and common genetic polymorphisms in adolescents , focuses on why type 2 diabetes often occurs in combina- tion with obesity and poor lipid profiles. To understand this clustering, I am studying adiponectin and how it relates to measures of body fat, lipid levels (such as cholesterol), and glucose (sugar). I am focusing on adiponectin because it is produced by fat cells and influences the body's utilization of sugars and production of lipids. Given adiponectin's relationship to obesity, lipids, and insulin sensitivity, I believe adiponectin may explain this clustering. Because we are studying the same individuals over time as they grow from teenagers to young adults, we should be able to determine if adiponectin is the link between diabetes, obesity, and poor lipid RESEARCH I Type 2 c With the rising incidence of obese and overweight children, physicians are diagnosing type 2 diabetes more and more in young people. d 9 profiles. In addition, I am looking for differences in genes related to adiponectin to determine if specific changes in the genetic sequence (DNA) are predictive of disease. We have just completed the first year of our project and have made several exciting findings. First, in boys, adiponectin levels decline throughout puberty while girls 9 levels remain constant. This decrease in adiponectin through puberty in boys may explain why adult females exhibit higher levels of adiponectin than adult males, while in young children there appears to be no sex differ- ence in adiponectin levels. Second, adiponectin levels are higher in non-Hispanic whites than African-Americans. Third, adiponectin levels are strongly related to measures of obesity, diabetes, and poor lipid profiles. Lastly, variation in the adiponectin gene is related to higher adiponectin levels. These are exciting findings because the decline in adiponectin during puberty for boys but not girls may explain the increased risk of cardiovascular disease and diabetes in adult men, especially African-American men. This research project will have a role in both the treatment and prevention of type 2 diabetes. Specifically, by understanding why type 2 diabetes often occurs in combination with obesity and poor lipid profiles, we may be able to understand why other complications are also occurring (e.g. heart disease, stroke, eye disease, kidney disease, and nerve damage). If we find there is a form of the adiponectin gene that leads to low adiponectin levels and type 2 diabetes in affected individuals, these people might then receive a drug mimicking the action of adiponectin and never develop diabetes. Although no one can predict the future, I expect that this work will have broad implications. The largest potential impact of this research is the ability to identify individuals at risk for developing type 2 diabetes by identifying differences in genes. With the knowledge that these individuals are at increased risk for developing type 2 diabetes, physicians would then be able to assist those individuals to minimize their risk either through lifestyle modification or medications. Further, individuals who already have type 2 diabetes could be screened for these genetic differences and this information could help physicians choose the most appropriate therapy. As a researcher, one of the most rewarding experi- ences I have had to date was attending an annual meeting of the Take Off Pounds Sensibly (TOPS) weight-loss program. I was participating in a research project supported by TOPS and the goal of the project was to identify genes involved in adiposity regulation. After a brief presentation of our work, I had the opportunity to speak with some of the members. I was deeply touched by the gratitude these individuals had for my efforts in trying to understand the causes of obesity. At that point, I realized that by understanding the genetic etiology of obesity, we will not only gain insights into the underlying mechanisms but will also empower individuals who are struggling with their weight because we will be able to determine what treatments are most likely to succeed. Empowering people, I believe, is what the American Diabetes Association is all about. As a genetic epidemiologist and researcher, the Association 9s support is extremely important to me. First, as I had just completed my post-doc- toral training and moved to a new institution, it was important for me to establish a funding record. The ADA award is my first grant and thus is establishing me as an independent researcher. Second, this award is allowing me to establish a research program in the genetic epidemiology of adiponectin. My research project is already serving as the basis for additional research on adiponectin in my institution. Lastly, I am working with other researchers who have complementary interests so that multiple projects can be developed from one infrastructure. Being awarded an ADA Career Development Award is a privilege and an honor and one that I am most grateful for because it is made possible thanks to the kindness and generosity of benevolent donors who envision life without diabetes. By allowing me to explore critical research questions related to genetic and environmental variation of adiponectin, it is also helping me create a world without diabetes for all the children of the world, including my own, and I could not be more grateful for such a meaningful opportunity. 10 The American Diabetes Association is proud to support the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Studies to Treat or Prevent Pediatric Type 2 Diabetes (STOPP-T2D). The STOPP- T2D initiative consists of a group of research sites conducting clinical trials related to type 2 diabetes in children and adolescents. One of the trials supported by the STOPP-T2D initiative is a school-based preven- tion trial to decrease or eliminate the development of risk factors for type 2 diabetes in middle school children. This three-year intervention will include enhanced physical activity during gym class, modification of the foods available to children in school cafeterias and vending machines, and behavior change curriculum aimed at increasing physical activity and improving dietary habits outside of school. cNearly two-thirds of adults in the U.S. are overweight or obese, and approximately 15% of children are overweight with another 15% at risk for overweight. With obesity a major risk factor for type 2 diabetes, it is important that we take steps to prevent obesity and promote healthy diet and physical activity at a young age, d said Dr. Francine Kaufman, past President of the American Diabetes Association and Director of the Comprehensive Childhood Diabetes Center and Head of the Center for Endocrinology, Diabetes and Metabolism at Children 9s Hospital in Los Angeles. Pilot studies are currently underway and enrollment in the trial is expected to begin in September 2006. cBecause of the increasing prevalence of obesity among youth in the U.S., there are many children who already have type 2diabetes, and we also need to develop studies that will help us determine the best course of treatment for these children, d said Dr. Kaufman. To address the issue of treatment for children with diabetes, the ADA alsosupports the TODAY trial (Treatment Options for Type 2 Diabetes in Adolescents and Youth) , a second trial in the STOPP-T2D initiative. TODAY is a 12-site clinical trial to assess the best treatment for type 2 diabetes in youth 10-17 years of age. The goal of this study is to determine which combination of oral medication and/or lifestyle intervention is better at lowering blood glucose and improving other health factors such as high blood pressure and dyslipidemia. Preventing and Treating Type 2 Diabetes in Kids Balakuntalam S. Kasinath, MD D iabetes is the scourge of the human race. It is a pandemic in every sense of the term. It is the leading cause of kidney failure in the world and results in severely reduced lifespan and quality of life. Diabetes has even greater impact on certain populations such as the Hispanic Americans who form the majority of patients in my nephrology practice in San Antonio. On a personal note, several members of my own family have diabetes. These are the reasons that motivate me to investigate the processes of kidney injury in diabetes which I hope will lead to framing new and effective treatment strategies. Fortunately, this motivation to want to improve the quality of life came early to me. I was a student in high school in Ramanagaram, a small town in the State of Karnataka in India, when I decided that I wanted to be a physician. While earning my medical degree at Bangalore Medical College, I made the decision to make a career in academic medicine and waited until residency in internal medicine to select the area of medical sciences that I wanted to sub-specialize in. It turned out to be nephrology 4 the branch of medical science that deals with the kidney. After spending 18 months in the laboratory of my mentor, Dr Gary Toback, at the University of Chicago School of Medicine, my desire to pursue a research career really took off. In 1983, I began my research work by investigatingthe functions of podocytes 4 specialized cells in the kidney that are involved in regulating filtering of proteins 11 Preventing Kidney Damage in Type 2 Diabetes Occupation: Professor of Medicine, Division of Nephrology University of Texas Health Science Center Chief, Renal Section South Texas Veterans Healthcare System San Antonio, Texas Professional Focus: Understanding the cellular mechanisms by which the kidney gets injured in diabetes Outside Interests: Reading, classical music 3 Indian and Western, volunteering as a mentor to elementary school children, Sunday school teacher at Hindu Temple of San Antonio Research Funding: Research Award Insulin receptor activation in pathogenesis of diabetic nephropathy Amount Awarded: $300,000 © Scavone Photography from the blood into the urine. I characterized the metabolism of a protein called heparan sulfate proteoglycan that is secreted by the podocytes. This protein helps to control protein in the urine. An abnormal amount of protein in the urine is an early indication in the clinical setting of kidney damage in diabetes. Therefore, I initiated my studies on regulation of heparan sulfate proteoglycan in diabetes about 14 years ago, supported by funding from the National Institutes of Health. Today, our ADA-funded project, Insulin receptor activation in pathogenesis of diabeticnephropathy , addresses the mecha- nisms by which the kidney is injured in diabetes. Specifically, we want to know if high levels of insulin present in early stages of type 2 diabetes are injurious to the kidney. Expansion and growth of the tissue found between cells in the kidney is an important contributor to kidney failure in type 2 diabetes. This tissue located between cells is called the extracellular matrix or simply cmatrix d. We are studying increased produc- tion of matrix in mice in early stages of type 2 diabetes, at which time the mice have high blood insulin levels. We have found that insulin receptors found on the kidney tubule epithelial cell surface are activated in the kid- ney tissue of mice with diabetes. This suggests that the insulin receptor may have a role in stimulating production of matrix proteins and the aim of our ADA-funded proposal will rigorously test this possibility. To achieve our aim, we are studying kidney cells in culture dishes and in mice by selectively removing the insulin receptor from cells of the kidney tissue using a novel gene manipulation method. Since our study began, we have succeeded in (a) establishing a model of kidney cells in culture to test the effects of high glucose alone, high insulin alone, and both high glucose and high insulin together on the production of laminin, a matrix protein, and, (b) developing the tools required to generate mice that do not have insulin receptors in the kidney. These data should clarify the role of glucose and insulin in the accumulation of extracellular matrix in type 2 diabetes. The approach to prevention and treatment of diabetes complications should be based on an understanding of the basic mechanisms by which tissues such as the kidney are injured. Once this process is understood, it will open up the possibilities of interrupting such path- ways at several sites along pathways of injury, and prevent or cure tissue injury. Our project helps by proposing to unravel basic cellular mechanisms by which the kidney gets injured in early and established phases of diabetes. My investigative team and I are hopeful that the combination of improvements in our understanding of cellular processes of kidney injury and advances in pharmacology will help in the development of novel interventional strategies to combat kidney injury in diabetes. During the last 20 years of intense biomedical research, it has been both encouraging and a great source of satisfaction for me to be a small part of remarkable scientific discoveries that have improved our understanding of kid- ney injury in diabetes. These advances have saved lives, improved quality of life, and laid the foundation for today 9s management of diabetic kidney disease. Unfortunately, much remains unknown when it comes to diabetes and its impact on major organs such as the kidney. Although we can slow development of diabetic kidney disease, we cannot prevent it. Also, it is still unknown why some people are more predisposed to dia- betes and kidney disease than others. And although current therapies have done much to delay the need for dialysis or kidney trans- plant in people with diabetes who suffer from nephropathy, much more still needs to be done. In the meantime, as a physician investigator, I get to experience the best of two worlds in the context of diabetic kidney disease, that is, clinical medicine and basic cell biology. I take care of people with kidney disease who very often have diabetes as the underlying cause. As advances occur in clinical aspects of diabetic kidney disease, I have the pleasure of RESEARCH I Complications c Although we can slow development of diabetic kidney disease, we cannot prevent it. d 12 13 implementing them in the care of our patients. In the laboratory, I get to investigate a highly focused area of biology of kidney cells that may be relevant to kidney injury in diabetes. In both the clinic and the laboratory,I have a chance to interact with some very sharpminds. It is a distinct pleasure to go to work everyday and I couldn 9t ask for much more! However, in the clinical area, it is sobering to see the explosion of kidney disease due to diabetes. It is also saddening to see that this deadly complication of diabetes attacks the segments of populations that are less equipped to face it, that is, minorities and the economically challenged. It is hard to see that, as a society, we are not taking steps to prevent obesity and its horrible consequence, type 2 diabetes, particularly in children. Also troubling, specifically in the research area, is the paucity of funds available for research on kidney disease due to diabetes. I have been on the ADA Research Grant Review Panel for more than three years and we have had to limit the funding of grants, not because they are not meritorious, but because we do not have sufficient funds. How can we expect our bright, young people to pursue research careers if there is no financial support?Our only hope to find lasting solutions for diabetic kidney disease is to understand mechanisms by which kidneys are damaged by diabetes and apply that knowledge to develop logical therapeutic interventions. We are not doing enough in tackling diabetes in the clinical nor in the research arenas 4 although millions are suffering from the disease all over the world and the numbers are ever increasing. Lack of adequate financial support from other sources made me consider applying for grant support from the ADA. I can confidently say that one of the reasons I am able to continue in academic medicine is thanks to funding support from the ADA. I have received three awards from them over the years to continue our work on kidney disease in diabetes. Without support from the ADA, I would not have been able to get funding from other sources and I would not have been able to bring postdoctoral fellows to train in my laboratory from countries such as France, India and South Korea. I have been associated with the ADA in two capacities 4as a recipient of its grants and as a volunteer member of its Research Grant Review Panel. I am very impressed by several aspects of the ADA. First, the integrity of the research grant review process is unassailable. Grant proposals are funded based on merit and not on who the applicant is. Second, the array of services made available to all com- munities by the ADA is truly impressive. This includes, obviously, supporting research as well as advocacy for individuals with diabetes at all levels of society and orchestrating one of the most respected research and education meetings on diabetes in the world 4 the Association 9s annual Scientific Sessions. The ADA is truly at the forefront of the fight against the pandemic of diabetes and obesity. On behalf of my colleagues who have enjoyed this support, as well as myself, I would like to express our most sincere thanks and gratitude to donors who make ADA grants possible. Please keep up the good work and endeavor to increase the donations to the ADA. Earlier this year, I had the honor of addressing the American Diabetes Association Pinnacle Society (the prominent giving society of individuals who make major gifts to the Association) and was very impressed with the deep commitment these individuals possess in tackling diabetes. I assure you all that you are supporting many of the best minds in research today and we are constantly striving to deliver on the ADA mission 4 to prevent and cure diabetes and to improve the lives of all people affected by diabetes. 14 Dr. Kasinath is just one of an exceptional group of diabetes researchers at the University of Texas Health Science Center and the Texas Diabetes Institute (TDI). The Texas Diabetes Institute, founded in 1994, is a state-of-the-art facility located in San Antonio, Texas. The Institute 9s mission is to cprevent diabetes and its complications through health education, treatment and research. d To accomplish this mission, TDI takes a team management approach to diabetes care and has developed cultural- and language-appropriate patient care and research methods. It could be said that TDI is taking the best approach in the fight against diabetes by combining excellent patient care with high-tech research facilities in one location. Ralph DeFronzo, MD, with Postdoctoral Fellow Rachele Berria The American Diabetes Association funds several researchers at the University of Texas and TDI. Ralph DeFronzo, MD, is the Deputy Director of the Texas Diabetes Institute and a recipient of an ADA Mentor- Based Postdoctoral Fellowship Award, Effect of insulin sensitization on glucose metabolism, adipose tissue lipolysis and insulin sensitivity, muscle insulin signaling and muscle fat content and ovulation rate in patients affected by polycystic ovarian syndrome . Dr. DeFronzo is also a Professor of Medicine and Chief of the Diabetes Division at the University of Texas Health Science Center in San Antonio and the South Texas Veterans Health Care System, Audie L. Murphy Division in San Antonio. Eugenio Cersosimo,MD at the Texas Diabetes Institute is leading a major insulin pump study inHispanic patients with type 2 diabetes funded by the American DiabetesAssociation. Previous studies have shown that insulin pumps can provide better glucose control than insulin injections, and that better glucose control can reduce the number of complications experienced by patients with type 1 or type 2 diabetes. Now in the final year of his study, Dr. Cersosimo is finding that blood glucoselevels, insulin resistance, decreased levels of adiponectin(a hormone secreted by fat cells; decreased levels are associated with increased risk of heart attack), and markers of blood vessel inflammation can be warning signs of abnormal blood flow in the vessels of Hispanic patients with dia- betes. Based on this information, he anticipates that treatments which improve glucose control,such as insulin pumps, increase adiponectin levels and decrease inflammation of blood vessels are likely to restore normal blood flow and stop the development of coronary artery disease in patients with type 2 diabetes. Preventing and Treating Type 2 Diabetes in Kids Eugenio Cersosimo, MD X rying to understand the causes of diseases like diabetes and obesity presents many challenges. However, when I think about the suffering caused by these diseases, I realize how important it is to overcome those challenges and to help find better treatments, preventions, and cures. I feel privileged to be in a position to do research alongside bright, energetic and dedicated colleagues and to strive together to improve the human condition. Born and raised in New York City, I graduated from Stuyvesant High School at sixteen, and thought I would become a mathematician. But in my sophomore year at Harvard University, I was exposed to biology research and was fascinated. I studied yeast genetics in the lab of Dr. Fred Winston in Boston, Massachusetts, and realized that genetics was a powerful way to learn how living organisms work. It was also at this time that I decided to become a doctor, largely inspired by listening to the experiences of my parents and sister who are practicing physicians. I went on to get both an MD and a PhD, and realized that I could use my research training to try to understand not only how biology works but also what happens when things go wrong 4 why people become sick. I got further clinical training in pediatrics and pediatric endocrinology at Children 9s Hospital in Boston, where I treated many children with diabetes. Joel Hirschhorn, MD, PhD T © Scavone Photography 15 Discovering the Genetic Causes of Diabetes and Obesity Occupation: Assistant Professor of Genetics and Pediatrics Children 9s Hospital and Harvard Medical School Boston, Massachusetts Associate Member of the Broad Institute Cambridge, Massachusetts Professional Focus: Understanding how genetic variation in humans contributes to common endocrine disorders such as diabetes and obesity Outside Interests: Spending time with family, baseball fan (N.Y. Mets and the 2004 World Series Champion Boston Red Sox), and music Research Funding: The Richard and Susan Smith Family Foundation Pinnacle Program Project Award Systematic identification of pathways contributing to diabetes and obesity in human patients Amount Awarded: $1,500,000 When I started my pediatrics residency, almost all of our patients with diabetes were diagnosed with type 1 diabetes 4 seeing a child with type 2 diabetes was very unusual. I clearly remember when type 2 diabetes was referred to as cadult-onset diabetes. d Now, with the epidemic of obesity, this disease is increasing at an alarming rate in children. These children will be most vulnerable to the complications of diabetes because they will have diabetes for so many years. Adding to this growing concern is a recent statement from the Centers for Disease Control and Prevention that declared one in three Americans born in 2000 will develop type 2 diabetes in their lifetime. Obesity is also on the rise in children and adolescents. Fourteen percent of America 9s youth are now obese with ominous implications for our nation 9s future health. A risk factor for diabetes and a major problem of its own, obesity is causing concern nationwide because of its drastic health consequences in adults and children alike. Obesity contributes not only to diabetes, but also to heart disease, stroke, hypertension, some types of cancer, sleep apnea, osteoarthritis and gallbladder disease. Many obese children have high cholesterol and blood pressure levels, which are also risk factors for heart disease. Overweight adolescents have a 70 percent chance of becoming overweight or obese adults, and suffering the complications of obesity. During the past 30 years, the obesity rate in the United States has more than doubled for preschool children and adolescents and more than tripled for children ages six to 11. Approximately nine million American children older than age six are now considered obese. As a pediatric endocrinologist, I see an increasing number of obese children who go on to develop type 2 diabetes at remarkably early ages. Unless better treatments and preventive measures are developed, many of these children and children after them will go on to develop health problems and the dangerous complications of diabetes like heart disease, blindness, renal failure, and amputations, to name a few. Our goal is to understand why obesity devel- ops, and why some obese people go on to get diabetes. With that knowledge, we could identify people who were likely to become obese, and develop early and effective inter- ventions that could prevent obesity and its complications, including diabetes. There is reason to think that this line of research will pay off. At the office, I often treat children with chronic diseases like diabetes who, in the past, would have tragically suffered devastating or fatal consequences. Today, these kids are leading happy, normal lives. This is a frequent and potent reminder of the power modern medicine has to change people 9s c One in three Americans born in 2000 will develop type 2 diabetes in their lifetime. d RESEARCH I Targeted 16 lives for the better and the incredible progress we are making toward better understanding diabetes. It is also the reason why I and several of my esteemed colleagues believe we have the best jobs in the world. Thanks to the incredible generosity and forward thinking of the Richard and Susan Smith Family Foundation of Chestnut Hill, Massachusetts, funding was made possible through the American Diabetes Association for a collaborative, leading-edge approach to understanding type 2 diabetes and obesity (see cThe Importance of Teamwork d on page 19). I serve as the principal investigator for this team of experts who are researching the genetic causes of diabetes and obesity. In our research project, Systematic identifi- cation of pathways contributing to diabetes and obesity in human patients, we are studying genes and the human genome to identify the inherited genes and pathways (sets of genes) that are altered in individuals with type 2 diabetes or obesity. In particular, we are looking for variations in DNA that lead to increased risk of type 2 diabetes or its major risk factor, obesity. These genes and pathways, because they are altered in individuals in a way that leads to type 2 diabetes or obesity, represent good potential targets for drugs or other interventions to prevent diabetes and obesity. Different avenues of research in animals have been pursued to try to identify the genes that are the root causes of type 2 diabetes and obesity, resulting in long lists of poten- tially relevant genes. However, very few of these genes have been demonstrated to actu- ally contribute to diabetes or obesity in the general human population. New genomics tools and resources, that we helped create, now allow rigorous testing of genes for a role in human disease. Throughout our investigation, we will test high priority genes, identified through on- going complementary research in large patient samples. Specifically, we will charac- terize the DNA variation in these genes and test the DNA of large patient populations to c ...this research project will lead us to find some of the genes that underlie type 2 diabetes. d 17 18 find variations in genes that are more common in obese or diabetic individuals and thus, playa role in causing human obesity or diabetes. My colleagues and I are hopeful that this research project will lead us to find some of the genes that underlie type 2 diabetes. This knowledge should help guide the development of more effective treatments or preventive measures. In the short term, such develop- ments would translate into making life with diabetes more livable and reducing compli- cations. In the long run, they might help answer a child 9s question when she asks if her diabetes will be gone by her next birthday. Our investigation garnered financial support based on interdisciplinary grant activity. As individual knowledge becomes more specialized and understanding diabetes becomes more complex, teams become more and more important. The ctwo brains are better than one d approach has the potential to cut the long-term price of research by eliminating the inefficiency of working in isolation 4 a concept well supported by the Eli and Edythe Broad Institute where I have the distinct pleasure of serving as one its associate members. The Broad Institute represents a unique research collaboration among the Massachusetts Institute of Technology, Harvard University and its affiliated hospitals, and the Whitehead Institute for Biomedical Research. This partnership was catalyzed by a founding gift from philanthropists Eli and Edythe L. Broad to create a new type of biomedical research institute aimed at realizing the promise of the human genome to revolutionize clinical medicine and making this knowledge freely available to scientists worldwide. In this way, the Institute promotes international efforts to solve fundamental biomedical problems to treat disease. Another key goal of the Broad Institute is to empower the next generation of young scientists in the Boston area by providing access to the most powerful concepts and tools of genomics that will enable them to tackle biomedical problems. It is my profes- sional goal as well to train excellent students and fellows by teaching genetics to these gifted medical and graduate students as we continue to find some of the genes for diseases and important traits. I also plan to continue providing good patient care for children. The vision of a world without the health problems caused by diabetes and obesity is one so many people from all walks of life hold dear to their hearts. To these individuals, I would say that the best place for putting your hope and resources is in the hands of the world 9s most prominent research scientists supported by the American Diabetes Association. We find ourselves not only on the forefront of conquering diabetes but also at the healing edge of medical science. On behalf of my colleagues, we give our heartfelt thanks and gratitude to the Smith Family for their generosity and their vision and we pledge to work hard to fulfill their hopes and expectations. We are also very grateful to the American Diabetes Association and all passionate ADA supporters because you also make our research possible and lay the groundwork for future endeavors. c ...the best place for putting your hope and resources is in the hands of the world 9s most prominent research scientists supported by the ADA. d McNay McCabe Glossary The Richard and Susan Smith Family Foundation Pinnacle Program Project Award was established to stimulate new collaborations between investigators working on independent but complementary research projects in diabetes. Dr. Joel Hirschhorn and his colleagues (listed below) are the first recipients of this prestigious award. Each investigator in the project is working on an independent research study which complements the projects of the other investigators in the program and contributes toward the discovery of the genetic causes of obesity and diabetes. " Massachusetts General Hospital cPathway genetics in C. elegans d 4 Gary Ruvkun, PhD " Dana Farber Cancer Institute cPathway profiling in clinical samples and mammalian cells d 4 Todd Golub, MD " Massachusetts General Hospital cGenetic analysis of type 2 diabetes d 4 David Altshuler, MD, PhD " Children 9s Hospital Boston cHuman genetics of obesity d 4 Joel Hirschhorn, MD, PhD " Whitehead Institute for Biological Research cData integration and statistical genetics d (Data Integration Core) 4 Mark Daly, BS cThe Smith Foundation Pinnacle Program Project Award is unique in that it encourages several scientists, working in diversedisciplines, to collaborate and move forward toward a common goal, d said Richard Smith, Co-Chairman of theRichard and Susan Smith Family Foundation. cThis groupin Boston represents the cutting edge of diabetes science,and we 9re excited about the new inroads they could make toward prevention, treat- ment and even a cure. Left to right: Joel Hirschhorn, MD, PhD; David Altshuler, MD, PhD; and Vamsi Mootha, MD Two postdoctoral fellows working on the Smith Family Foundation grant have gone on to secure facultyposi- tions thanks to their contributions to the study. Kaveh Ashrafi, PhD, was a postdoctoral fellow working with Dr. Gary Ruvkun, and has recently accepted an Assistant Professor position at the University of California, San Francisco and also holds the title of Jack D. and DeLoris Lange Endowed Chair in Systems Physiology. Dr. Ashrafi continues to remain an active member of the Smith Family Foundation Pinnacle Program Project, and, in fact, has been able to expand the efforts of the group now that he has his own laboratory and can explore a variety of gene candidates. Vamsi Mootha, MD, who is a collaborating investigator with Dr. Todd Golub, has obtained an Assistant Professor position at Harvard University and Massachusetts General Hospital. In addition, this year the MacArthur Foundation granted Dr. Mootha one of its cgenius d awards. According to the MacArthur Foundation, Dr. Mootha received the award for using new technology to identify more than 100 previously unknown mito- chondrial proteins, and introduced 8a computational method for identifying patterns of gene activity in spe- cific diseases. In type 2 diabetes, for example, this method has identified aberrations in the regulation of genes related to aspecific metabolic pathway, an observation that may provide important clues to the cause of a prevalent and devastating condition. 9 The Importance of Teamwork 19 20 MOUTHWATERING RESEARCH What do a vampire bat and a Gila monster have in common? No, they 9re not the stars ofthe latest horror flick, but they are the starsof some of the latest drug development research in the area of diabetes and diabetes complications. Researchers have found that exenatide can stimulate insulin secretion in humans, too. When a person eats a meal and blood glucose levels rise, hormones in the gut called incretins act on the pancreas to increase insulin production. Because exenatide exerts its effects on incretin receptors, it is categorized in a new class of antidiabetic drugs called incretin mimetics. When administered, exenatide essentially stimulates the incretin effects and thereby stimulates the pancreas to make more insulin. The Gila Monster At the American Diabetes Association 64th Scientific Sessions in Orlando, researchers presented the results of not one but two clinical trials evaluating a new drug called exenatide in patients with type 2 diabetes. Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster. The Gila monster is native to the Southwestern United States and is one of only two species of venomous lizards. The lizard eats only four times a year and, when not eating, is able to turn its pancreas off, stopping the release of insulin. When it 9s time to eat again, it secretes the hormone exendin-4 to turn its pancreas on and stimulate insulin secretion. Hot Topics 21 Both of the randomized, blinded, placebo-controlled clinical trials performed with exenatide showed progressive weight loss and lower blood glucose levels in patients who received either 5 or 10µg subcutaneousinjections twice daily. Trial results were presented by Dr. Ralph DeFronzo of the Texas Diabetes Institute and Dr. David M. Kendall of the Park Nicollet International Diabetes Center. Patients in the studies had type 2 diabetes, and were not able to control their blood glucoselevels adequately with metformin (Glucophage), or metformin combined with a sulfonylurea drug (such as Glucotrol or Amaryl). Normally, patients with type 2 diabetes who cannot achieve glucose control with oralmedications are prescribed additional oral medications or insulin injections. Exenatide, which causes weight loss, could become a new alternative to making the move to insulin, which causes weight gain. Side effectsof exenatide injections were few and mainly included mild to moderate nausea. These trials described here were Phase III clinical trials, which is the last phase of clinical trial before a drug can be considered for Federal Drug Administration (FDA) approval. Exenatide may mean good news for people with type 1 diabetes as well. In addition to stimulating insulin secretion, the drug appears to promote pancreatic islet recovery and new growth. A Phase I trial led by Dr. Kristina Rother and collaborating investigator Dr. David Harlan, both at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), is currently underway to determine whether exenatide can be safely used to improve pancreatic beta-cell function in patients with type 1diabetes. The study enrolls adults with long-standing type 1 diabetes who still have some residual beta-cell function. Because stimulation of growth of new beta cells may activate the underlying autoimmune process, half of the study participants will receive immunosuppressive drugs. Investigators plan to study the effects of exenatide alone, immunosup- pressive drugs alone, and a combination of exenatide and immunosuppression on insulin secretion and glycemic control. Another human trial studying exenatide combined with an anti-CD3 monoclonal antibody (an immuno- suppressant) isscheduled to begin early next year and will be led by Dr. Kevan Herold at Columbia University in New York. This study is based on successful research in mice where a combination of an anti-lymphocyte serum and exendin-4 led to remission of diabetes in 88% of mice studied (Ogawa N, List JF, Habener JF, Maki T: Cure of Overt Diabetes in NOD Mice by Transient Treatment With Anti-Lymphocyte Serum and Exendin-4. Diabetes 53:1700-1705, 2004). Exenatide is being developed by Amylin Pharmaceuticals in the U.S. According to its website, Amylin currently plans to market exenatide in an injectable pen/cartridge delivery system, pending the necessary FDA approvals. 22 The Vampire Bat It may seem somewhat absurd that an animal whose name conjures images of Dracula would be able to help in the recovery of stroke vic- tims, but that is exactly what researchers have found in the saliva of the vampire bat. Vampire bats in tropical regions of South and Central America take in up to 50 grams of blood daily by biting animals such as cows. Similar to a mosquito which secretes enzymes to prevent blood from clotting when it bites, the vampire bat also secretes a protein in its saliva that prevents an animals 9 blood from clotting while it is feeding. In the mid-1980s the German biotechnology company PAION GmbH discovered that the vampire bat enzyme was genetically similar to an already known anti-clotting substance but was more potent. Currently there is only one FDA approved drug (IV rt-PA) for treating a stroke caused by blood clots blocking blood supply to the brain, and this drug can only be administered within three hours of the onset of stroke symptoms. Many stroke victims arrive at the hospital too late and are unable to receive this drug. Researchers in the U.S. at the University of Louisville in Kentucky are now testing the ability of the protein found in vampire bats, known as desmoteplase, to break up clots in the blood vessels of stroke victims up to nine hours after the onset of symptoms. Desmoteplase is the first drug to be developed in a new class of blood clot-dissolving agents. If you have diabetes, you are much more likely to have a stroke, heart disease, or heart attack. In fact, more than 65 percent of people with diabetes die from heart disease or stroke. This makes it the number one killer among people with diabetes. Development of a new drug to treat stroke may help save lives in the future. Desmoteplase is currently in Phase II clinical trials, and larger scale studies in humans in the U.S. must be successfully completed before researchers can seek FDA approval. According to the PAION GmbH website, desmoteplase was recently granted fast track status by the FDA. Fast track status is only grantedfor drugs that address an unmet medical need in a serious or life-threatening situation. Fast track designation means that the review of clinical trial results will be expedited, and the FDA will work closely with the developers of fast track drugs to ensure the final testing of the drug is designed in such a way as to support its quick approval. If the upcoming trials are successful,it is possible that a Biologics License Application (BLA) for desmoteplase would be sub- mitted to the FDA as early as 2007. Hot Topics Do you know the warning signs of a stroke? "weakness or numbness on one side of your body "sudden confusion or trouble understanding "trouble talking "dizziness,loss of balance,or trouble walking "trouble seeing out of one or both eyes "double vision "severe headache 23 IN THE NEWS Diabetes Linked to Inflammation An Associated Press article reports that James Meigs, MD of Harvard Medical School and Massachusetts General Hospital, has unearthed what may be a new predictor of diabetes. His ADA-funded study, Insulin resistance, endothelial dysfunction, and risk for type 2 diabetes led to the discovery of certain blood proteins that, when elevated, suggest the presence of inflammation or damage to the cells which line the blood vessels. Using data from the Nurses Health Study which began in 1976, Dr. Meigs studied blood samples for the presence of three proteins suggesting inflammation: E-selectin, ICAM-1 and VCAM-1. Women with higher levels of these proteins were more likely to develop diabetes than women with the lowest levels 3 in some cases up to five times more likely. According to Dr. Meigs, more studies are needed to determine if elevated levels of these proteins are as predictive of diabetes as other factors such as obesity or family history. Target identified for treatment of muscle wasting Muscle wasting is a debilitating consequence of many diseases, including diabetes, cancer, and AIDS. Thanks in part to an American Diabetes Association grant, researchers at Joslin Diabetes Center and other institutions in Boston, Massachusetts have discovered Research UP dates Dongsheng Cai, MD, PhD (left) with his mentor, Steven E. Shoelson, MD, PhD 24 Treatment for DKA The premier issue of Forefront featured a profile of Dr. Guillermo E. Umpierrez, an ADA-funded investi- gator at Emory University in Atlanta, Georgia, who is studying ways to prevent and treat a deadly condition known as diabetic ketoaci- dosis (DKA). Reuters news service reported in September 2004 that Dr. Umpierrez published results of a 40 patient study in the American Journal of Medicine demon- strating that a fast-acting insulin called lispro (Humalog) is an effective treatment for DKA. What are the implications of this study? Unlike regular insulin, lispro can be given via subcutaneous injection rather than being administered intravenously in a hospital 9s intensive care unit. This means that if lispro can be approved as a safe and effective means of treatingDKA, it can greatly reduce hospitalization time for patients with DKA and therefore lower treatment costs. (Umpierrez GE, Latif K, Stoever J, Cuervo R, Park L, Freire AX, E Kitabchi A. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. American Journal of Medicine. 117(5):291-296, 2004). called salicylates, which are known to inhibit NF- B, the mice regained muscle mass to near normal levels. Further studies may lead researchers to develop other drugs which target the NF- B pathway to prevent muscle wasting. This is an especially important discovery since there are currently no drugs approved to treat muscle wasting in humans. an important biochemical pathway involved in muscle wasting inmice. In October 2004, Medical News Today reported that Dr.

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