Diabetes Treatments

Summarized below are TPI’s findings regarding major diabetes funding sources (public and The overwhelming majority of funding for diabetes research comes from the …

Overview of Efforts to Cure and Prevent Diabetes and Opportunities for Private Philanthropy
Excerpts of a Report Prepared by The Philanthropic Initiative, Inc TPI for The Russell Berrie Foundation June 2003

Executive Summary
A Overview of Key Findings Summarized below are TPIs findings regarding major diabetes funding sources public and private; strategies employed by various funders; diabetes research developments and targets of opportunity; and major diabetes research institutions Diabetes Research Funding Sources Currently, in the US alone, over 1 billion in public and private dollars is invested in diabetes research annually not including RD investments by pharmaceutical and biotechnology companies The overwhelming majority of funding for diabetes research comes from the National Institutes of Health NIH, primarily through the National Institute of Diabetes and Digestive and Kidney Disease NIDDK In 2002 the NIH invested 790 million into diabetes research 500 million through NIDDK This figure is estimated to increase in 2003 to 860 million which represents a doubling of investment over the past five years, due in large part to effective advocacy on the part of the Juvenile
Diabetes Research Foundation JDRF The two major private sources of funding for diabetes research are: JDRF, which invested 108 million in 2002 The American Diabetes Foundation ADA, which invested 32 million in 2002 We have uncovered only a few private foundations that have a strategic focus on diabetes, including the Smith Family Foundation and Iaccoca Foundation, both of which invest approximately 1 million annually In addition, the Howard Hughes Medical Institute supports a number of scientists involved in important diabetes research Support for diabetes research outside of the US appears to be relatively modest European governments including Finland, Sweden, the United Kingdom, Denmark, France, Germany, Italy, Belgium, and the Netherlands invest an estimated 60 million per year in diabetes

research Other governments for whom diabetes research funding is a priority include Australia and Canada While these countries invest much less than the US in diabetes research, diabetes researchers in other countries tend to receive more industry support than researchers in the US Funding Strategies Funding strategies employed by NIH, JDRF, ADA, and other funders vary widely The size of
grants awarded range from relatively small one-time grants eg, 30,000 Medical Scholars Awards from the ADA for medical students involved in basic and clinical research studies to very large multi-year grants eg, up to 6 million per year from NIDDK for complex research projects Grants are also directed for a variety of purposes, including grants to individual scientists; support for infrastructure and institutional capacity-building; and grants for specific research projects and program areas To help guide NIH funding strategies, a Diabetes Research Working Group DRWG has been formed, composed of scientific experts as well as representatives from the lay diabetes community According to the DRWGs report, many scientific opportunities are not being pursued due to insufficient funding, lack of appropriate mechanisms, and a shortage of trained researchers Research Developments Despite significant advances in treating and managing the symptoms and complications of diabetes, there is no method to prevent or cure diabetes, and available treatments have only limited success in controlling its devastating consequences1 Among the research community there is increasing consensus that while a
cure narrowly defined may not be found, preliminary studies indicates that modifying environmental and behavioral factors particularly obesity and inactivity can help prevent impaired glucose tolerance IGT and type 2 diabetes In the past few decades, scientists have made significant advances in understanding and treating diabetes Research has steadily contributed to a growing knowledge base, and breakthroughs have led to concrete improvements in survival and quality of life for people with diabetes Major advances include the development of human insulin; self-glucose monitoring; insulin pumps; better management of risk factors and complications; increased success in pancreas and islet cell transplantation; new drugs to treat type 2 diabetes; and new insulin delivery systems The Strategic Research Plan prepared by the Diabetes Research Working Group details: Extraordinary Opportunities rapidly expanding, crosscutting areas in which increased investment or development of new mechanisms will significantly speed research Special Needs for Special Populations more focused research areas targeted to specific populations, complications, and methodological approaches Resource and
Infrastructural Needs a bold plan for increasing research manpower, technology, and other infrastructure elements for diabetes-related research

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Based on the DRWGs recommendations, the NIH has identified several areas of promise for current diabetes research, including: The genetics of diabetes and its complications Autoimmunity and the beta cell Cell signaling and cellular regulation Obesity Clinical research and clinical trials Embedded within these broad research topics are a myriad of complex scientific questions As described in a December 2001 Howard Hughes Medical Institute HHMI bulletin, diabetes researchers are gaining increasing clarity on underlying causes of diabetes as the genetic work comes together with biochemical and physiological studies Alan Saltiel, a diabetes researcher at the University of Michigan in Ann Arbor, is encouraged by the many scientists who are tackling diabetes, and the varied routes they are traveling: This is a really exciting time We now have a lot of ideas for how to attack the disease No single approach will work, and no one researcher can move forward alone Major Research Institutions Within the US alone, there are scores of
institutions where important diabetes research is taking place These include 14 major research centers funded through the NIDDK Diabetes Centers Program, including eight Diabetes Endocrinology Research Centers DERCs and six Diabetes Research and Training Centers DRTCs The DERCs focus entirely on biomedical research while the DRTCs have an added component in training and translation The DERCs are located at: University of Washington University of Pennsylvania University of Iowa University of Massachusetts Medical School Joslin Diabetes Center University of Colorado Yale University School of Medicine Massachusetts General Hospital The DRTCs carry out basic and clinical research at the following major academic institutions: Albert Einstein College of Medicine DRTC University of Chicago DRTC Indiana University DRTC University of Michigan DRTC University of Michigan Medical School, Ann Arbor Vanderbilt University DRTC Vanderbilt University Medical Center, Nashville Washington University DRTC St Louis, MO As noted above, the DRWGs Strategic Research Plan includes recommendations for strengthening resource and infrastructure needed to further diabetes research, including
training, technology, and other institutional needs

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B Key Questions for Further Consideration Given its substantial interest and resources, the Berrie Foundation clearly has the opportunity to further efforts to prevent and cure diabetes Given the complexity of the disease and the numerous potential targets of opportunity, a key challenge is how to identify the most promising opportunities that complement existing diabetes research efforts NIH and others Based on our investigation and analysis TPI has identified the following key questions for the Foundation to explore further in order to shape its direction and strategies Question 1 Should the focus be type 1, type 2 or both? Question 2 How broadly to define cure? Question 3 — What funding strategies have the greatest promise? Question 4 What research issues/topics are of greatest interest to the Foundation? Question 5 How can the Foundation best leverage its resources and complement the NIH research agenda? Based on our interviews and review of relevant literature, a sampling of advice, comments, and other information regarding each of these questions is outlined below Question 1 Should the focus be type 1, type 2 or
both? This report addresses both type 1 and type 2 diabetes because: The Berrie Foundations gifts to date have focused on both types About 35 of the Berrie Centers work at Columbia is dedicated to type 1, according to Rudy Liebel Basic research on the developmental biology of the beta cell and treatment of complications is relevant to both types of diabetes Analysis of our research findings suggests a number of arguments for and against a focus on each type, some of which are summarized in the following table One researcher commented that private industry invests considerably in research for type 2 because that is the greater market, but that industrys research is focused on treating symptoms and managing the disease, not finding a cure or preventing diabetes Pro Type 1
may be closer to a cure genetics fairly well understood

Con
affects relatively small number of children significant private resources already dedicated JDRF environmental triggers not well understood understanding and responding to the role of obesity is a monumental and complex task role of genetics not well understood

Type 2

global public health epidemic Russ had type 2 major economic impact better
understanding of environmental triggers

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Both

basic beta cell biology issues are the same complications are the same RBF has focused on both types to date

limited resources

Question 2 How broadly to define cure? A key question for the Foundation is how it wants to define what it means by finding a cure for diabetes As stated by several diabetes researchers, the true cure for diabetes is prevention Should the Foundation focus on research on prevention of diabetes, finding a cure, more effective management in order to reduce or eliminate complications, or some combination? For example, some experts refer to islet transplantation as a cure, while others view it as a treatment Selected comments from experts: Define cure broadly to include prevention The term cure can be destructive and limiting in the long-term, prevention is the greatest need The Foundation should take a public health perspective diabetes is an epidemic that needs to be prevented A narrowly defined focus on finding a cure wont have the greatest impact on the most number of people for the longest period of time The focus should be broader than islet transplantation One expert commented: If I were a
parent of a type 1 child, I would never trade insulin dependence for immunosupressant therapy since that is still a lifelong commitment Question 3 — What funding strategies or combination of strategies have the greatest promise? Related to this broad question are questions relating to whether the Foundation should: 1 Support talented scientists; research projects and program areas; and/or institutional capacity and infrastructure needs eg, creation of more islet transplantation centers? 2 Give priority to funding for basic science research, translational research moving from bench research into clinical practice, or clinical research? Our interviews suggest a wide range of opinions in response to these questions Relevant comments included the following: Invest in the best people: Provide training and support for talented young scientists Support the best scientists involved in translational research Create a cadre of the most talented scientists and infuse them with financial support along the lines of the Howard Hughes model Increase the pipeline of talented researchers: According to Ron Kahn, head of the NIH Diabetes Research Working Group DRWG, the pipeline of new
investigators is not as robust as I would like it to be and the number of NIH scientists under 35 has dropped dramatically Invest in training and support for the best young investigators

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Availability of grant funding would help attract the brightest developmental biologists into diabetes research rather than heart disease or other research areas

Invest in infrastructure, including specialized training of scientists and lab workers; technology need functional, non-invasive ways to image beta cells; and other needs Create additional diabetes centers of excellence with a global or project focus, translational centers, or clinical research units Improve capacity for high-end translational work Develop and harness new technologies eg, invest in technology to facilitate understanding of beta cell functioning; use of MRI and PET to understand tissue functioning in diabetes how glucose and insulin are being used Target research projects and program areas: Fund program-projects vs individual researchers or institutions gets the best group of people to work together to work on different aspects of the same problem eg, Immune Tolerance Network, islet transplantation virtual
centers

Question 4 What research issues/topics are of greatest interest to the Foundation? While further scientific research is needed on a wide range of topics, specific areas of opportunity pinpointed by some experts include: Gaining a better understanding of the environmental triggers of type 1 Gaining a better understanding of the biological basis of obesity Identifying effective strategies to help people prevent obesity and modify their lifestyles relevant to behavioral and social aspects of type 2 Islet regeneration Enhancing mechanisms for obtaining human materials including stem cells for diabetes research Developing alternative sources of islets xenotransplants Insulin resistance Immune tolerance Further investigation could help point to other areas considered promising yet underfunded Question 5 How can the Foundation best leverage its resources and complement the NIH research agenda? Based on our preliminary inquiries, there are no easy answers to this overarching question Relevant advice from experts includes the following: Aim for high targets, not more targets Money can buy scientific progress if it is applied wisely and directed to attracting the best
people The Foundation would distinguish itself not by doing lots of small things, but larger more intense efforts that others cant take on Fund at sufficient levels bare minimum of 200,000 a year for 3 years Recognize that it is costly to set up the mechanisms to go into the traditional grant or fellowship business and do it well

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Some additional questions that could help the Foundation determine how best to target its resources include: To what extent does the Foundation want to support research considered to be high-risk and cutting edge and therefore perhaps less likely to receive NIH funding An example might be research on xenotransplants islets from pigs Is there a preference for short-term research vs efforts where results may not be seen for many years? Is there interest in research that could lead to more effective management of diabetes?

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Overview of Diabetes Current Knowledge Base2

Diabetes mellitus, one of the most common and serious chronic diseases in the United States and worldwide, is caused by inherited and/or acquired deficiency in production of insulin by the pancreas, or by the ineffectiveness of the insulin produced Such a deficiency results in
increased concentrations of glucose in the blood, which in turn damage many of the bodys systems, in particular the blood vessels and nerves Diabetes is the sixth leading cause of death in the US, contributing to over 180,000 deaths each year, and is associated with long-term complications that threaten life and the quality of life: Adults with diabetes have heart disease death rates about 2 to 4 times higher than adults without diabetes The risk for stroke is 2 to 4 times higher Diabetes is the leading cause of new cases of blindness Diabetes is the leading cause of treated end-stage renal disease 43 of new cases More than 60 of non-traumatic lower-limb amputations in the United States occur among people with diabetes Over 17 million Americans have diabetes 54 million of whom do not know they have the disease, and each year an additional 800,000 people are diagnosed with diabetes In addition to these 17 million, an estimated 16 million American have pre-diabetes with high glucose levels, but not yet as high as in diabetes The prevalence of diabetes is expected to continue to rise with the aging US population, the growth in minority populations most susceptible to type 2
diabetes, and the increasing prevalence of obesity among Americans Worldwide, according to recent World Health Organization estimates, about 177 million people have diabetes mellitus, and this number may well double by the year 2025 Much of this increase will occur in developing countries and will be due to population growth, aging, unhealthy diets, obesity and sedentary lifestyles By 2025, while most people with diabetes in developed countries will be aged 65 years or more, in developing countries most will be in the 45-64 year age bracket and affected in their most productive years Diabetes is a serious and costly disease, which is becoming increasingly common, especially in developing countries and disadvantaged minorities3 Types of Diabetes Diabetes is a metabolic disease in which the body does not produce or properly use insulin, a hormone that is needed to convert sugar, starches, and other food into energy needed for daily life, resulting in high levels of blood glucose sugar There are two main types of diabetes: Type 1 diabetes, or juvenile-onset diabetes, is an autoimmune disease that results when the bodys immune system attacks and destroys its own insulin-producing beta
cells in the pancreas People with type 1 diabetes need daily injections of insulin to live Type 1 diabetes develops most often in children or young adults About 5 to 10 of people with diabetes have Type 1 Although risk factors are still not well defined for type 1 diabetes,

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autoimmune, genetic and environmental factors are involved in its development Loss of beta cells can be determined prior to clinical onset of diabetes, which suggests the importance of understanding the environmental triggers for those at high genetic risk Type 2 diabetes, or adult-onset diabetes, is a disease that occurs when the body makes insulin, but cannot use it effectively insulin resistance While this form of diabetes usually develops in adults over the age of 40, there has been a sharp rise over the past decade in the number of children diagnosed with type 2 diabetes This increase is directly attributable to the epidemic of childhood obesity and inactivity, and disproportionately affects minority youth About 90 to 95 of people with diabetes have type 2 Type 2 diabetes is more common among people who are older; obese 80 of all type 2 diabetics; have a family history of diabetes; have had
gestational diabetes; and/or are of minority ethnicity
Comparison of Type 1 and Type 2 Diabetes Prevalence Type 1 5 10 of cases 800,000 17 million in US 885 177 million worldwide Autoimmune disease body destroys insulin producing beta cells Children Genetics — have been isolated Environmental triggers not known Insulin dependence Islet cell transplantation immunosuppressant therapy Type 2 90 95 of cases 153 162 million in US 159 168 million worldwide Body is unable to produce and use insulin insulin resistance Over 40 Increasing among obese children Genetics not well understood Environmental triggers obesity, inactivity, age, family history, minority status Diet Exercise Oral Medication Insulin

Causes

Age Risk factors

Management

Other types of diabetes: Gestational diabetes develops or is discovered during pregnancy Gestational diabetes usually disappears when the pregnancy is over, but women who have had gestational diabetes have a greater risk of developing type 2 diabetes later in life Pre-diabetic conditions Impaired glucose tolerance IGT is considered to be a prediabetic condition in which the blood glucose level is elevated but is not high enough to be
classified as diabetes Research suggests it may be reversible, and can be managed to dramatically reduce the onset of type 2 diabetes IGT affects 16 million adults 40 to 74 years of age in the US

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Prevalence and Incidence In the US, diabetes affects about 6 of the population, and about 800,000 new cases are diagnosed each year For reasons that are poorly understood, African Americans, Hispanic Americans, American Indians, and some Asian Americans and Pacific Islanders are at especially high risk for type 2 diabetes Worldwide, populations in many countries exhibit moderate 3-10 or high 11-20 prevalence of diabetes and impaired glucose tolerance Finland has an exceptionally high prevalence of type 1 diabetes 3 and 1/2 times higher than in the US, for unknown reasons Prevalence of diabetes rises with age in all populations4 The number of Americans with diagnosed diabetes is projected to increase 165, from 11 million in 2000 prevalence of 40 to 29 million in 2050 prevalence of 725 This projected increase will be the result of changes in demographic composition 37, population growth 27, and increasing prevalence rates 36 These increases will have the greatest impact on those over
75 years of age 271 for males and 437 for females from 2000 to 2050 and black males 363 from 2000 to 20506 Distribution of Diabetes among Americans in millions

12 160 158 type 1 type 2 pre-diabetes

BY AGE under 20 years of age 151,000 youth 019 of all youth 20 years or older 169 million 86 of all adults 65 years and older 7 million 201 of all elderly men 78 million 83 women 91 million 89 BY ETHNICITY Non-Hispanic whites 114 million 78 Non-Hispanic blacks 28 million 13 on average, non-Hispanic blacks are two times more likely to have diabetes than non-Hispanic whites

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Hispanic/Latino Americans 2 million 102 on average, Hispanic/Latino Americans are 19 times more likely to have diabetes than non-Hispanic whites American Indians and Alaska Natives who receive care from the Indian Health Service 105,000 151 most common among American Indians in the southeastern United States 257

Economic Cost The human and economic costs of diabetes are staggering Because of its chronic nature, the severity of its complications and the means required to control them, diabetes is a costly disease, not only for the affected individual and his/her family, but also for
governments and health care agencies In the US, the annual cost of diabetes in medical expenditures and lost productivity climbed from 98 billion in 1997 to 132 billion in 20027 Diabetes care hospitalizations, medical care and treatment supplies costs an estimated 441 billion a year Annual indirect costs disability payments, time lost from work and premature death total 541 billion Global diabetes drug sales exceed 8 billion a year Once diagnosed, the average life span with the disease is 30 years The total cost per person is an estimated 500,000 an average of 17,000 per year Globally, direct health care costs of diabetes range from 25 to 15 of annual health care budgets For most countries, the largest single diabetes-related expense is hospital admissions for the treatment of long-term complications, such as heart disease and stroke, kidney failure and foot problems Management of Diabetes Despite significant advances in treating and managing the symptoms and complications of diabetes, there are currently no known cures for type 1 or type 2 diabetes While the JDRF argues that islet transplantation is a cure for type 1, some researchers we spoke with did not share this view,
considering it more of a treatment Diabetes is a self-managed disease because people with diabetes must take responsibility for their day-to-day care Much of the daily care involves keeping blood glucose near normal levels at all times Management of type 1 diabetes: People with type 1 diabetes need daily injections of insulin because their bodies no longer produce insulin Treatment requires a strict regimen that typically includes a carefully calculated diet, planned physical activity, selftesting of blood glucose, and multiple daily insulin injections Because type 1 is an autoimmune disease, all insulin producing beta cells have been destroyed and in order to survive, people with type 1 diabetes must have insulin delivered by a pump or injections Recent successes with the Edmonton Protocol have enabled transplantation of human cadaver islet cells into people with type 1 diabetes Transplantation eliminates insulin dependence, but requires lifelong immunosuppressant therapy, which can have serious

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complications and health consequences In addition, there are only enough cadaver pancreases to treat 1500 individuals a year, out of the 15 million with type 1 diabetes Management of
type 2 diabetes: People with type 2 still have insulin producing cells, but they either dont have enough or their body doesnt effectively use the insulin it is producing As a result, treatment typically includes diet management, exercise, selftesting of blood glucose, and, in some cases, oral medication and/or insulin Approximately 40 of people with type 2 diabetes require insulin injections Many people with type 2 diabetes can control their blood glucose by following a careful diet and exercise program, losing excess weight, and taking oral medication The goal of diabetes management is to keep blood glucose levels as close to a normal range as safely possible, while avoiding blood glucose levels that are too high hyperglycemia or too low hypoglycemia Studies have shown that intensive glucose control can delay the onset and progression of eye disease, kidney disease and nerve disease by a range of 35 to more than 70 In fact, it demonstrated that any sustained lowering of blood glucose helps, even if the person has a history of poor control8 Advances in managing diabetes In recent years, advances in diabetes research have led to better ways to manage diabetes and treat its
complications Major advances include: New forms of purified insulin that are less likely to cause allergic reactions and are nearly identical to the insulin naturally produced by the body Development of external and implantable insulin pumps that deliver appropriate amounts of insulin, replacing daily injections New oral medications to improve control of type 2 diabetes Better ways for patients, doctors and other health professionals to monitor blood glucose notably, new devices for self-monitoring of blood glucose, performed by the patient, and the hemoglobin A1c also called H-b-A-one-c laboratory test, which measures blood glucose control during the previous 3-month period Effective treatment for diabetic eye disease Better ways to manage diabetic pregnancies, improving chances of successful outcomes Treatment strategies to reduce damage to the kidneys, eyes and nerves Prevention of diabetes complications As a result of recent advances, effective management can greatly help to prevent or reduce diabetes complications: Glucose control Research studies in the US and abroad have found that improved glycemic control benefits people with either type 1 or type 2 diabetes In
general, for every 1 reduction in results of hemoglobin A1C blood tests, the risk of developing microvascular diabetic complications eye, kidney, and nerve disease is reduced by 40 Blood pressure control Blood pressure control can reduce cardiovascular disease heart disease and stroke by 33-50 and can reduce microvascular disease eye, kidney, and nerve disease by about 33 In general, for every 10 millimeters of mercury reduction in

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systolic blood pressure, the risk for diabetes-related complications is reduced by 12 Control of blood lipids Improved control of cholesterol and lipids for example, HDL, LDL, and triglycerides can reduce cardiovascular complications by 20 to 50 Preventive care practices for eyes, kidneys, and feet: Detection and treatment of diabetic eye disease with laser therapy can reduce the development of severe vision loss by an estimated 50 to 60 Comprehensive foot care programs can reduce amputation rates by 45 to 85 Detection and treatment of early diabetic kidney disease can reduce the development of kidney failure by 30 to 70

Prevention of Diabetes There are no known methods to prevent type 1 diabetes, although several clinical trials are
currently in progress The JDRF views islet transplantation as a cure, but this perspective is not commonly held Research studies have found that lifestyle changes can prevent or delay the onset of type 2 diabetes among high-risk adults9 These studies included people with impaired glucose tolerance IGT and other high-risk characteristics for developing diabetes Patients with elevated glucose levels can prevent full-onset diabetes through management of weight and lifestyle, including diet and moderate-intensity physical activity such as walking for 2 hours each week For both sexes and all age and racial and ethnic groups, the development of diabetes was reduced 40 to 60 during these studies that lasted 3 to 6 years In studies of susceptible groups in China, lifestyle modifications appropriate diet and increased physical activity and a consequent reduction of weight, supported by a continuous education program, achieved a reduction of almost two-thirds in the progression to diabetes over a six-year period Similar results have also been achieved recently in Finland and the USA Studies have also shown that medications have been successful in preventing diabetes in some population groups
In the Diabetes Prevention Program, a large prevention study of people at high risk for diabetes, people treated with the drug metformin reduced their risk of developing diabetes by 31 Treatment with metformin was most effective among younger, heavier people those 25 to 40 years of age who were 50 to 80 pounds overweight and less effective among older people and people who were not as overweight

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Major Funding for Research to Cure, Prevent and Manage Diabetes

In the US, three major entities are the leading funders of research to cure, prevent and manage diabetes: National Institutes of Health NIH, mostly through National Institute of Diabetes, Digestive and Kidney Diseases NIDDK American Diabetes Foundation ADA Juvenile Diabetes Research Foundation JDRF

NIH mostly NIDDK 2002 funding 790 million

JDRF 108 million Type 1
Grants from 36,000 to 2 million per year: Center Grants up to 2 million/yr for 5 yrs Program Project Grants up to 660,000/yr for 3 yrs Clinical Investigation Research Grants up to 660,000/yr for 5 yrs Industry Research Grants up to 1M/yr for 3 yrs Regular Research Grants up to 165,000/yr for 3 yrs Innovative Grants up to 55,000 Training Awards: Career
Development Awards up to 625,000 over 5 yrs Early Career Patient-Oriented Diabetes Research Awards up to 75,000 over 5 yrs plus medical debt reimbursement Postdoctoral fellowships 3650,000/yr for 2 yrs

ADA 32 million type 1 and type 2
Grants from 30,000 to 350,000 per year: Career Development Awards up to 150,000/yr for 5 yrs Junior Faculty Awards 120,000/yr for 3 yrs Clinical Research Awards up to 100,000/yr for 3 yrs Innovation Awards up to 50,000/yr for 2 yrs ADA-EASD Trans-Atlantic Fellowship Award 50,000 Mentor-Based Postdoctoral Fellowships 35,000/yr for 4 yrs Medical Scholars Awards 30,000 Physician-Scientist Training Award 30,000/yr for 3 yrs Pinnacle Program Projects 350,000/yr for 3 yrs

Diabetes type type 1 and type 2 Grant size/types
Large multi-year grants for major research projects up to 6 million per year per project, larger for longitudinal clinical trials; total of 88 million for NIDDK research project grants Support for diabetes research centers total of 25 million in 2002 for 14 centers recommended by DRWG Support for other resource and infrastructure needs eg, research training and manpower development, technology, etc total of about 50 million in 2002
recommended by DRWG

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Described below are the major functions, goals and research agendas of these three entities National Institutes of Health Founded in 1887, the National Institutes of Health NIH is the Federal focal point for medical research in the United States The NIH, comprises 27 separate Institutes and Centers, which conduct research in their own laboratories; support research of non-Federal scientists in universities, medical schools, hospitals, and research institutions; and train research investigators Within the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases NIDDK is responsible for the majority of diabetes research increasingly the National Institute for Allergy and Infectious Disease is devoting support to immune tolerance research In 2002 the NIH dedicated 790 million of its 23 billion budget for diabetes research including 500 million from NIDDK Diabetes ranks 4th in NIH funding out of 29 major diseases only AIDS, breast cancer and mental health receive more NIH money than diabetes 10 NIH funding for diabetes research 2001-2004 in millions
1,000 800 600 400 200 2001 actual 2002 actual 2003 estimate 2004
estimate

680

790

860

946

Additional NIH funding for diabetes has been secured through the Bush Diabetes Plan, largely due to effective advocacy on the part of JDRF This Special Diabetes Program involves five years of funding totaling 15 billion fiscal year 2003 through fiscal year 2008, including: 150 million per year in additional funding for type 1 research 150 million per year for diabetes prevention and treatment programs for American Indians The Diabetes Research Working Group DRWG is an independent panel composed of 12 scientific experts in diabetes and four representatives of the lay diabetes community see Attachment C for a list of members, created to identify research needs and opportunities to advance the field of diabetes in order to guide NIH funding strategies The DRWGs 2002 Strategic Plan to conquer diabetes, Conquering Diabetes: Highlights of Program Efforts, Research Advances and Opportunities11, outlines areas of extraordinary opportunities12 as well as recommendations relating to special needs for special problems and resource and infrastructural needs These recommendations are summarized briefly below

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Extraordinary Research Opportunities 1 The
genetics of diabetes and its complications Both type 1 and type 2 diabetes result from complex interactions between multiple genes and environmental factors A cluster of genes HLA have been identified as predeterminants for type 1 Gene isolation for type 2 has proven more difficult but a series of genes have been identified as contributing to the disease Because 80 of type diabetes is attributable to obesity, the NIH supports research to understand the genetic basis of obesity The environment is clearly an important modifier for both type 1 and type 2, and basic research is being conducted and supported to understand the role of environmental triggers The DRWG recommends: a Establishing a national consortium for studying genetics of diabetes b Enhancing research efforts to understand how diabetes genes create susceptibility to diabetes and its complications 2 Autoimmunity and the beta cell Type 1 diabetes is an autoimmune disease in which the immune system attacks the insulin-producing beta cells of the pancreas The beta cell is also central to the development of type 2 diabetes because it must meet the increased requirements for insulin during the period of insulin resistance
that typically precedes disease onset Ultimately, the beta cell begins to fail under this strain, leading to type 2 diabetes NIH supports basic research to understand beta cell functioning NIH is also emphasizing prevention of type 1 diabetes so that islet transplantation will not be necessary The DRWG recommends: a Intensified efforts to understand the immunological basis of type 1 and develop methods for prevention b Further research on islet cell transplantation, including creation of additional islet cell transplantation centers c Expanding basic research to develop methods to stimulate beta cell growth and regeneration 3 Cell signaling and cellular regulation Cellular signaling involves many complex pathways and is central to insulin action, immunological function, and to understanding appetite regulation in the brain all important factors in the development of both type 1 and type 2 diabetes The NIH supports basic research on the role of cell signaling in diabetes and metabolism The DRWG recommends: a Increased research on cell signaling as it relates to diabetes and its complications b Establishing research centers to focus on cell signaling at the molecular and genetic
level c Expanding research to understand insulin resistance d Increased research on signaling pathways involved with beta cell functioning e Expanding support for interdisciplinary research on complications 4 Obesity Although diet and lifestyle are risk factors for obesity and diabetes, little is known about how to affect them Recent discoveries, however, have provided a revolutionary understanding of obesity at the molecular level, leading to extraordinary opportunities in

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biomedical and behavioral research Prevention and treatment of obesity is complex, and the DRWG has recommended: a Increasing the size, scope, number, and funding level of NIH-sponsored Obesity Research Centers b Increased research in the basic sciences underlying obesity to capitalize on recent advances in hormonal control of appetite, energy regulation, metabolism, and adipocyte development c Developing stronger industry relationships to support obesity research d Enhancing behavioral research on obesity 5 Clinical research and clinical trials of critical importance Much of the important research to date in diabetes has been at the basic science level The next step is to translate findings into clinical
therapies in patients Clinical studies are extremely expensive, yet essential to creating and testing effective treatments The DRWG recommends: a Creation of Diabetes TrialNet a national diabetes trial network of clinical research groups to create the infrastructure needed for effective and efficient clinical trials b Enhanced support for clinical trials of emerging therapies c Support for clinical trials on treatments for the complications of diabetes d Support for clinical research training in diabetes Special Needs for Special Problems Recommendations include research on: Micro- and macrovascular complications Methods to optimize glucose control Diabetes and the environment including retroviruses Diabetes in women, children, and the elderly Diabetes in minority populations Genetic engineering Behavioral and health services research Oral complications of diabetes

Resource and Infrastructural Needs Recommendations include the following: Strengthen human resources for research including recruitment, research training, and research career development of diabetes investigators, including efforts to attract investigators from other disciplines Enhance diabetes research
centers by creating new comprehensive diabetes research centers to provide enhanced infrastructure and support, and enhancing the effectiveness of existing diabetes centers Develop and harness new technologies including creation of new regional centers with advanced technologies required for imaging studies and related needs Establish regional centers for animal models of diabetes Expand efforts to procure human tissues and organs for cutting-edge diabetes research

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The table below summarizes the DRWG budget recommendations13 Summary of DRWG Budget Recommendations in millions of dollars Year 1 Year 2 Year 3 Year 4 2000 2001 2002 2003 Extraordinary Opportunities: Genetics of Diabetes 405 720 850 990 Autoimmunity and the Beta Cell 300 450 580 660 Cell Signaling and Cell Regulation 380 570 730 860 Obesity 150 250 370 460 Clinical Research and Clinical Trials 870 1390 1910 2520 Subtotal 2105 3380 4440 5490 Special Needs for Special Problems Microvascular Complications Macrovascular Complications Optimization of Glucose Control Diabetes and the Environment Special Needs in Women, Children, and the Elderly Special Needs in Minority Populations Genetic Engineering Behavioral and
Health Services Research Oral Complications of Diabetes Subtotal Resource and Infrastructural Needs Research Training and Manpower Development Diabetes Research Centers Program Technology Taskforce Regional Centers for Animal Models Human Materials for Diabetes Research NIH-Pharmaceutical and Biotechnology Interactions Review of Intramural Programs of NIH Taskforce for Strategic Planning Subtotal Increment over FY99 Base To Implement DRWG Recommendations FY99 Base for Diabetes Research Grand Total for Diabetes Research 510 340 95 30 200 90 80 80 10 1435 300 60 130 50 20 05 05 05 305 3845 4428 8273 800 580 160 40 400 150 150 135 15 2430 50 150 170 100 20 05 05 05 505 6315 4428 10743 1065 790 240 60 600 225 220 200 20 3420 80 250 210 160 20 05 05 05 735 8595 4428 13023 1240 950 290 80 800 300 280 270 25 4235 100 400 130 260 20 05 05 05 925 10650 4428 15078 Year 5 2004 1010 790 940 520 2800 6060 1295 1020 360 100 800 320 350 400 30 4675 100 400 130 260 20 05 05 05 925 11660 4428 16080

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NIDDK Funding Strategies Each year NIDDK establishes funding strategies based on the available resources Research proposals are ranked through a peer review process FY2003 funding strategies
include: Competing Continuation Grants and New Competing Grants Competing continuation program projects have a cap of 625 million in direct costs requested per year, for 5 years New program project grants may request up to 5 million in direct costs over five years Accelerated Funding to Advance Research AFAR NIDDK is implementing a new research project grant funding strategy called Accelerated Funding to Advance Research AFAR, in which a greater percentage of total research support can be awarded in the first year of the project period The goal is to enable the science to proceed at a more rapid pace

Diabetes research funding program areas, organized by type and by division, are listed in Attachment D American Diabetes Association ADA Founded in 1940 by a group of physicians, the ADA is the nations leading nonprofit health organization providing diabetes research, information and advocacy The ADAs mission is to prevent and cure diabetes and to improve the lives of all people affected by diabetes The ADA funds research, publishes scientific findings, and provides information and other services to people with diabetes, their families, health care professionals and the public In
2002 their budget included 32 million for research ADAs Allocation of Research Dollars 2002
Type 1 1 40 43

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Type 2

Complications, genetics, prediabetes Gestational

Through the ADA Research Foundation, the ADA supports basic and clinical research aimed at preventing, treating, and curing diabetes, ranging from islet cell biology and transplantation techniques to education and behavioral studies The ADA makes grants based on a peer review process It supports more than 350 researchers in more than 200 institutions The ADAs research funding program is designed to complement the NIH program by supporting new investigators and new research ideas With support from ADA, investigators are often able to prove that their ideas are solid enough to get more substantial funding from the
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United States federal government For example, its Innovations Awards 50,000/year for two years allow investigators to explore novel ideas that hold significant promise to prevent and cure diabetes The largest ADA grants, Pinnacle Program Projects 350,000/year for three years, provide support to two or three scientists working on independent but complementary research

Juvenile Diabetes Research
Foundation JDRF Founded in 1970 by parents of children with type 1 diabetes, JDRF is the leading charitable funder and advocate of type 1 diabetes research worldwide Its mission is to find a cure for diabetes and its complications through the support of research The JDRF funds a major portion of all type 1 diabetes research worldwide, more than any other charity, and provided 108 million for diabetes research in 2002 JDRF is responsible for more than 600 million in direct funding since its founding JDRFs Allocation of Research Dollars 2002
Type 1 stem cell and islet transplantation 16 Complications 21 63 Prevention

JDRF has developed a scientific review process that involves more than 100 scientists and 500 lay reviewers annually In FY2002, JDRF awarded more than 500 center and individual research grants, supporting scientists in 19 countries JDRF has articulated three major cure goals: 1 Restoring normal blood sugar half of its total funding, with emphasis on two major objectives 1 finding a way to induce tolerance to islet transplantation, and 2 developing alternative islet sources cadavers, xenotransplant, stem cell, etc JDRF also continues to fund research to preserve beta
cell function and prevent beta cell destruction 2 Preventing and reversing diabetes-related complications methods to predict risk of complications, early detection, and the development of new clinical interventions to treat diabetic kidney, nerve, and eye disease, prevention and treatment of hypoglycemia 3 Preventing diabetes focusing on genetics and genomics of type 1 diabetes and its complications JDRF describes itself as taking informed risks, continuously monitoring the global diabetes research landscape, and making research investments strategically, to ensure that resources are effectively directed to research with the greatest impact leading to a cure as soon as possible In addition to their investment in research, JDRFs advocacy efforts have led to significant government investment in type 1 diabetes research
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JDRF is credited with having a laser-like focus on finding a cure for type 1 diabetes They consider the success of islet transplantation Edmonton Protocol to be a cure There is not consensus on this perspective, however other major researchers consider islet transplantation a treatment, because it trades insulin dependence for immunosupressant therapy which has
serious complications and unknown long-term impact Despite the significant increases in type 2 diabetes among children, the JDRF does not focus any research on preventing or managing type 2 diabetes in children JDRF, in consultation with diabetes experts, updates milestones for the entire field of type 1related research The staff then determines, for each milestone, a global Diabetes Research Landscape an evaluation of contributions being made by JDRF, the NIH, other foundations and government funders worldwide, and industry This mapping process shows 1 the state of development of science on the continuum from basic to clinical; 2 where resources are being directed; 3 where JDRF can make an impact; and 4 how JDRFs activities should be directed eg, through direct funding or partnerships This review, conducted both for the entire field of type 1-related research as well as for work funded by JDRF, assesses how much progress has been made during the past year toward achieving the milestones JDRF issues a Request for Applications RFA to the scientific community for new diabetes research Proposals undergo peer review as well as lay review by JDRF volunteers JDRF then works with
scientists and other funding organizations throughout the world to influence research and share its view of how progress can best be accomplished for each milestone

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III

Other Funding for Diabetes

Federal sources In addition to the National Institutes of Health NIDDK and NIAID, the Centers for Disease Control CDC allocate funding for diabetes population-based prevention and education initiatives The CDC also supports the Division of Diabetes Translation which seeks to understand the impact of diabetes, influence health outcomes, and improve access to quality care The Division funds state-based diabetes control and prevention programs and implements education strategies The Department of Veterans Affairs and the Indian Heath Service also invest resources for education and awareness because diabetes disproportionately affects their constituents Examples of other private philanthropic efforts TPIs research has only uncovered a small number of private foundations that have diabetes research as a major focus Summarized below are examples of a few private foundations and institutions investing in diabetes research Smith Family Foundation Boston The Smith Family Foundation has
allocated up to 15 million over four years to support emerging investigators in the field of Type 2 diabetes It awards up to 200,000 a year for two years with possible renewal for up to two more years to three to five investigators or teams Funding is focused on basic early clinical or translational research to better the understanding or prevention of Type 2 diabetes The competitive awards are aimed at investigators who are 4 to 10 years out from their doctoral studies in the gap between training grants and substantial NIH funding The program is restricted to investigators at research institutions in New England An annual meeting of funded investigators and selected interested others is held with the intent of having the scientists inform each other about their work and encouraging collaboration where appropriate ADA matches the Smith Family Foundations 15 million contribution The ADA designs and manages the grants competition assembling the selection panel, managing the research progress review process, and coordinating the annual meeting of winning investigators Host research institutions are permitted to charge up to 15 of grants for administrative costs and the ADA receives 5
of the total grantmaking budget for its management and administrative costs Iacocca Foundation Boston Iacocca Foundation was founded in 1984, by Lee A Iacocca in memory of his late wife Mary K Iacocca who died of diabetic complications in 1983 The primary goal of the

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Iacocca Foundation is to fund innovative and promising diabetes research programs and projects that will lead to a cure for the disease and alleviate complications caused by the disease The Iacocca Foundation supports research in both type 1 and type 2 diabetes and their complications Grants are reviewed by a scientific review panel and by the board of trustees Since its inception, the Iacocca Foundation has committed over 20 million in research grants to fight diabetes about 1 million per year The Iacocca Foundation is currently in the process of developing the Iacocca Research Initiative, which would create an unbiased source of information to guide other donors interested in diabetes Oxford Foundation Strasburg, PA This family foundation was created in 1947 by the Ware Family, and awards over 3 million in annual grants to a variety of nonprofit organizations In 2003, the foundation gave 1 million to JDRF to
support research at the JDRF Oxford Foundation Islet Isolation Facility at the University of Pennsylvania Howard Hughes Medical Institute Chevy Chase, MD The Howard Hughes Medical Institute HHMI is a nonprofit medical research organization that employs hundreds of leading biomedical scientists working at the forefront of their fields In addition, through its grants program and other activities, HHMI helps to enhance science education at all levels and maintain the vigor of biomedical science worldwide With an endowment of about 11 billion, the Institute is one of the worlds largest philanthropies, with laboratories across the United States and grants programs throughout the world The Institutes scientists conduct research in cell biology, computational biology, genetics, immunology, neuroscience and structural biology While HHMI does not have a specific focus on diabetes research or any particular disease, it supports a number of scientists who are involved in important diabetes research

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IV

Overview of Private Industry Research Efforts

The pharmaceutical industry is extremely guarded regarding research and development The Iacocca Foundation conducted a recent review of
activity among the leading pharmaceutical and biotechnology companies based on annual reports and found a significant amount of money being invested in research for complications, insulin and equipment In the United States, there is relatively little type 1 research within private industry because the market is so small relative to type 2 Merck may be the only top pharmaceutical company conducting research in that area Company Pfizer GlaxoSmithKline Aventis Merck Novartis Lilly Nova-Nordisk Takeda Total Annual RD Diabetes Research Budgets mill 200214 Diabetic Complications 5,176 Type 2 diabetes 4,098 Insulin and different insulin formulations 3,606 Type 2 diabetes Type 1 diabetes 2,677 Complications of diabetes, ie cardiovascular disease 2,578 Type 2 diabetes Insulin and different insulin formulations 2,149 Insulin and different insulin formulations 630 Type 2 diabetes Private

Global sales of insulin topped 6 billion in 2002, and are projected to increase by 5-10 per year Sales of products to test and monitor blood-sugar levels in diabetics reached nearly 5 billion worldwide Industry analysts estimate 20 to 30 companies are working on ways to continuously monitor blood sugar
levels without actually drawing blood

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V

Major Research Institutions

There are scores of research institutions in the US alone conducting diabetes research Major NIH-funded research institutions include the Diabetes Endocrinology Research Centers DERCs and the Diabetes Research and Training Centers DRTCs While not directly funding major research projects, both types of center grants provide core resources to integrate, coordinate, and foster the interdisciplinary cooperation of a group of established investigators conducting research in diabetes and related areas of endocrinology and metabolism The two types of centers differ in that the DERCs focus entirely on biomedical research while the DRTCs have an added component in training and translation The Diabetes Endocrinology Research Centers DERCs are located at: University of Washington University of Pennsylvania University of Iowa University of Massachusetts Medical School Joslin Diabetes Center University of Colorado Yale University School of Medicine Massachusetts General Hospital The six Diabetes Research and Training Centers DRTCs supported by NIDDK were established through 1977 federal legislation recommended by
the National Commission on Diabetes The DRTCs carry out basic and clinical research at the following major academic institutions: Albert Einstein College of Medicine DRTC Bronx, NY University of Chicago DRTC Indiana University DRTC University of Michigan DRTC University of Michigan Medical School, Ann Arbor Vanderbilt University DRTC Vanderbilt University Medical Center, Nashville Washington University DRTC St Louis, MO As described further in Section II of this report, the Diabetes Research Working Groups Strategic Research Plan includes recommendations for strengthening resource and infrastructure needed to further diabetes research, including training, technology, and other institutional needs

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VI

Opportunities for Private Philanthropy

In TPIs discussions with various diabetes experts, some specific areas of need and opportunity were suggested, along with general advice and recommendations for how the Berrie Foundation might target its resources These comments are briefly summarized below Research needs/opportunities Suggestions include: Clinical trials translational research very expensive Type 1 research Replacing beta cells without the need for
immunosupressant therapy true cure Prevention of new onset type 1 for those who still have some islets left research on how to predict who will get the disease; how to replenish beta cells; and islet growth and regeneration to avoid transplantation Development of new sources of islets Research on prevention of Type 2 through lifestyle change diet, weight, exercise Development of an artificial pancreas closed loop system to sense insulin levels and then distribute appropriate amount Infrastructure needs/opportunities Suggestions include: Training of scientists and lab workers Technology need functional, non-invasive ways to image beta cells Institutional capacity-building General Advice and Recommendations We heard a wide range of comments on various issues These issues are outlined below, followed by a sampling of comments that seemed particularly useful or interesting These comments reflect differing opinions in some cases, and more consensus regarding other issues Type 1 vs Type 2: Need to decide on focus one researcher commented that private industry invests considerably in research for type 2 because that is the greater market, but that industrys research is focused
on treating symptoms and managing the disease, not finding a cure or preventing diabetes How broadly to define cure: Need to determine whether to focus on cure, prevention, or both Define cure broadly to include prevention

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Term cure can be destructive and limiting long-term need to focus on prevention If you focus on cure wont have the greatest impact on the most number of people for the longest period of time Foundation should take a public health perspective diabetes is an epidemic that needs to be prevented

Undertake important efforts: The Foundation would distinguish itself not by doing lots of small things, but larger more intense efforts that others cant take on Fund at sufficient levels bare minimum of 200,000 a year for 3 years It is costly, and requires a serious commitment, to set up the mechanisms to go into the traditional grant or fellowship business and do it well Aim for high targets, not more targets Money can buy scientific progress if it is applied wisely and directed to attracting the best people Invest in people: Increase the pipeline of talented researchers by investing in training and support for the best young investigators the
availability of grant funding helps bring the brightest developmental biologists into diabetes research vs heart disease, etc According to Ron Kahn, head of the DRWG, the pipeline of new investigators is not as robust as I would like it to be The number of NIH scientists under 35 has dropped dramatically Could follow Howard Hughes Model and create a cadre of the most talented people and infuse them with money with a diabetes focus Could focus on institutional support: Could create additional diabetes centers of excellence global or project focus, translational centers, or clinical research units Could fund research projects: Fund program-projects vs individual researchers or institutions gets the best group of people to work together to work on different aspects of the same problem eg, Immune Tolerance Network, islet transplantation virtual centers Complement the NIH agenda and research strategy: Too much investment in islet transplantation is not the way to go Prevention will have a greater-long term impact Islet regeneration is an important area of opportunity, and relevant to both types Need a broader focus than islet transplantation insulin resistance is critical for
type 2; prevention is critical for type 1; If I were a parent of a type 1 child, I would never trade insulin dependence for immunosupressant therapy still a lifelong commitment Enhance mechanisms for obtaining human materials including stem cells for diabetes research Improve capacity for high-end translational work Most diabetes centers dont have the capacity to do high-end imaging and therefore cant do high-end translational work Yale and Mayo are only ones

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Develop and harness new technologies eg, invest in technology to facilitate understanding of beta cell functioning currently no diagnostic ways to determine the number of beta cells a person has or their level of functioning; use of MRI and PET to understand tissue functioning in diabetes how glucose and insulin are being used No major centers in the US would need 10-20 million to start a center with technology and staffing Support research to understand the environmental triggers of type 1 and the behavioral and social aspects of type 2 Very little research is being done to develop and evaluate strategies to help people achieve healthy weight and exercise levels Need more and better models for how to counteract
media, increase activity/exercise, and improve diets Particularly in minority populations, studies show people can reverse IGT and prevent diabetes through oral medication and lifestyle change, suggesting the importance of population/community-based efforts to modify behavior early on Obesity research is new only 6-8 years since discovery of leptin, very important, and under-funded need to understand the biology of obesity

Scientific advisors: Recruit top-notch scientific advisors people with the greatest expertise Scientific advisors should be people the foundation can get to know and trust over time, and will be most helpful if engaged in ongoing conversations

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ENDNOTES
1

Diabetes Research Working Group, Conquering Diabetes: A Strategic Plan for the 21 st Century, Report Summary and Recommendations
2

National Institute of Diabetes and Digestive and Kidney Diseases National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, 2000 Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, 2002
3

http://wwwwhoint/mediacentre/factsheets/fs236/en
http://wwwwhoint/inf-fs/en/fact138html
4

http://carediabetesjournalsorg/cgi/content/abstract/16/1/157 Projection of Diabetes Burden Through 2050 Diabetes Care 24: November 2001 Economic Cost of Diabetes in the US in 2002 Diabetes Care, volume 26, number 3, March 2003

5

6

7

These data are based on an American Diabetes Association study and are 1997 estimates of both the direct costs cost of medical care and services and indirect costs cost of short-term and permanent disability, and premature death attributable to diabetes itself This study is a cost-of-disease study and estimates of the health care costs that are due specifically to diabetes
8

National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health Diabetes Prevention Program
9

Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin, Diabetes Prevention Program Research Group New England Journal of Medicine, February 7, 2002
10

The Relationship between Funding by the National Institutes of Heath and the Burden of Disease NEJM, 1999 Gross, KP, Anderson, GF, Rowe, NR
11

Recent Advances and Emerging Opportunities February 2003 NIH, NIDDK

12

NIH
defines extraordinary opportunities as research in which the current rapid expansion of knowledge and development of new technologies make it likely that intensified research efforts would lead to significant advances in the near future
13

Conquering Diabetes: A Strategic Plan for the 21st Century National Institute of Diabetes Digestive Kidney Diseases http://wwwniddknihgov/federal/dwg/dwgsummaryhtm
14

Researched and prepared by the Iaccoca Foundation May, 2003

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Source:lifestylecenter.org