Extraordinary Opportunity: Clinical Trials and Clinical Research of Critical Importance The DRWG emphasized the importance of a substantial investment in clinical trials and clinical research to validate in humans fundamental observations made in test tubes, cells, and animals, and permit true testing of therapeutic strategies. While clinical research is essential for a comprehensive program for tackling major public health problems such as diabetes, the DRWG noted that a shortage of clinical investigators and the high costs, long-term nature, and complexity of clinical trials have limited clinical research in diabetes. Since the issuance of the DRWG's Strategic Plan, the NIH has significantly expanded clinical research directed at advancing the prevention and care of diabetes. In particular, considerable work has been done to establish the clinical infrastructure needed to efficiently conduct large, long-term trials by creating national, multi-center research networks or consortia, as suggested by the DRWG. Many of these consortia provide opportunities for partnerships among the NIH, academia, and industry for collaboration and co-funding of clinical trials and for support of clinical research training in diabetes. They also provide for collection of biologic specimens for use in ancillary clinical research studies to address key questions of disease pathogenesis and mechanisms of response to therapies as well as opportunities for development and validation of surrogate markers that can be used to gauge the health of the patient before development of diabetes or its complications. The DRWG noted that such markers are particularly useful for prevention studies as they permit early detection of disease. The NIH has also been responsive to the DRWG's recommendation to achieve appropriate representation of high risk, but understudied, populations such as women and minority groups. This section of the report describes major new results achieved and new clinical research undertaken since issuance of the DRWG Strategic Plan, to address the prevention and treatment of diabetes and its many complications. 85 Major New Findings from Diabetes Clinical Research
PREVENTION OF TYPE 2 DIABETES IN PEOPLE AT HIGH RISK
The Diabetes Prevention Program (DPP) demonstrated that individuals at substantial risk of developing type 2 diabetes could prevent or delay disease onset and improve their blood sugar levels through modest improvements in diet and exercise. The DPP compared three approaches -- lifestyle modification, treatment with metformin, and standard medical advice -- in more than 3,200 individuals with pre-diabetes. On the advice of the DPP's external data monitoring board, the trial ended a year early because the data had so clearly answered the main research questions. Importantly, the DPP, conducted at 27 centers nationwide, is the first major clinical trial to show that diet and exercise can effectively reduce diabetes in a diverse American population of overweight people with pre-diabetes. The lifestyle intervention, which targeted a 7 percent (or an approximate 15 pound) weight loss, and 150 minutes of walking or other moderate-intensity exercise per week, reduced the risk of getting type 2 diabetes by 58 percent compared to the control group, which received standard medical advice. The same study found that treatment with metformin also reduced diabetes risk, though by a less dramatic 31 percent, in people at high risk for type 2 diabetes. DPP participants ranged from age 25 to 85, with an average age of 51 years. Upon entry to the study, all had pre-diabetes and were overweight. Minority groups who suffer disproportionately from type 2 diabetes -- African Americans, Hispanic Americans, Asian Americans and Pacific Islanders, and Native Americans -- made up 45 percent of those enrolled. The trial also recruited other groups known to be at higher risk for type 2 diabetes, including individuals age 60 and older, women with a history of gestational diabetes, and people with a first-degree relative with type 2 diabetes. Significantly, lifestyle modification worked equally well in men and women and in all the ethnic groups. It also worked particularly well in people age 60 and older, who have a nearly 20 percent prevalence of diabetes and who constituted 20 percent of the study population, reducing the development of diabetes by 71 percent in this subgroup. In total, about 29 percent of the DPP standard group developed diabetes during the average follow-up period of three years. In contrast, 14 percent of the diet and exercise arm and 22 percent of the metformin arm developed diabetes. Long-term follow-up studies are under way to assess the durability of the DPP interventions in preventing or delaying diabetes and to determine whether the interventions reduce cardiovascular disease and atherosclerosis, major causes of death in people with type 2 diabetes. This approach will also provide important information on the clinical course of new-onset type 2 diabetes in this diverse study population.
86 Conquering Diabetes: Extraordinary Research Opportunities An estimated 16 million Americans have prediabetes, putting them at increased risk for developing type 2 diabetes. The DPP findings, which establish that changes in diet and exercise can substantially reduce risk, represent a major step toward the goal of containing and ultimately reversing the epidemic of type 2 diabetes in this country. Moreover, every year that a person can live free of diabetes means an added year of life free of the burden of this disease and its associated micro- and macrovascular complications. PREVENTION OF DIABETES COMPLICATIONS
The Epidemiology of Diabetes Interventions and Complications study (EDIC) is a ten-year, observational study that tracks participants of the landmark Diabetes Control and Complications Trial (DCCT) to determine the long-term outcome of intensive blood glucose control on micro- and macrovascular complications. The DCCT documented dramatic health benefits of intensive versus conventional treatment of blood glucose levels in 1,441 individuals with type 1 diabetes studied for an average of 6.5 years. In 1993, the DCCT was stopped early because of compelling evidence that intensive glycemic control significantly reduced the development and progression of diabetic eye, kidney, and nerve disease, and volunteers in the conventional treatment group were offered instruction in intensive treatment. Since then, glucose control has been very similar in the former intensive and conventional treatment groups. With participant retention at more than 90 percent, these volunteers are being followed to examine the continued effects of a 6.5 year period of separation in glucose control on the development of diabetes complications. Strikingly, EDIC found that seven years after the end of the DCCT individuals who received intensive therapy during the trial continued to have a dramatically lower risk of complications than those who had been on conventional treatment. Taking as the new baseline state for EDIC the eye exams done at the end of the DCCT, researchers found that those in the former intensively treated group had a 62 percent reduction in progression of eye disease (retinopathy), seven years after intensive glycemic control was extended to the conventional group. These observations demonstrate that, not only is intensive management of blood glucose levels extremely effective in reducing the painful, debilitating, and costly complications of diabetes, but also that the benefits of intensive therapy persist for years. SUCCESS WITH ISLET TRANSPLANTATION
The dramatic findings of the DCCT/EDIC underscore the importance of near normalization of blood glucose in preventing the devastating complications of diabetes, such as blindness, kidney failure, amputation, and nerve damage. Yet, with the medicines and tools available, most patients with diabetes are not able to achieve this level of blood glucose control. Islet transplantation is one approach to achieving normal glucose control in diabetes, but for many years, fewer than 10 percent of patients receiving insulin-producing islets isolated from a donor pancreas became insulin independent. continued Clinical Trials and Clinical Research of Critical Importance 87 Recently, there has been tremendous progress with a modified approach to islet cell transplantation, developed by researchers in Edmonton, Canada. This approach has now been used in more than seventy people with poorly controlled type 1 diabetes and has improved control of diabetes in nearly all those studied and actually freed many from the need for insulin for as long as two years. This success has now been repeated at several centers, including the NIH, and is being tested in an international multi-center study to see if it can be more generally reproduced. While tremendously exciting, these results do not yet represent the cure that everyone seeks for this disease. We do not know if complications will occur with long-term use of the immunosuppressive drugs needed to prevent rejection of the islets, and, over time, some of the transplants have begun to fail. Also, should further studies be successful, we would not have enough islets for all the people who might benefit from this therapy, a problem being addressed through research discussed in the section of this progress report on "Autoimmunity and the Beta Cell." Nonetheless, the encouraging initial clinical results have led to several initiatives to further develop this exciting therapeutic approach. These include new clinical trials involving alternate approaches to modulation of the immune system that may prevent rejection and recurrent autoimmunity with fewer side effects, development of a registry to track and compare results of trials undertaken at various sites, and support for pancreas collection and islet isolation centers to provide islets for future clinical trials. Creation of Networks for Prevention and Treatment of Diabetes with a Focus on Children and Adolescents Type 1 diabetes, formerly known as juvenile onset diabetes, is a devastating disease that can strike in early childhood, adolescence, or young adulthood. More recently, type 2 diabetes, traditionally viewed as a disease largely affecting older adults, has been reported with increasing frequency in children. Data from many pediatric diabetes clinics suggest that type 2 diabetes has increased from less than 5 percent to 20 to 30 percent of childhood diabetes over the past decade, with particularly high rates among certain minority populations. The increase of type 2 diabetes in children and adolescents is presumed to be a consequence of increased obesity and decreased physical activity. The NIH, together with the CDC, is conducting a major surveillance study in six representative areas of the country to determine the true incidence and prevalence of both types of diabetes in children. 88 Conquering Diabetes: Extraordinary Research Opportunities Photo: NIDDK. While serious at any age, the occurrence of diabetes in childhood is particularly troublesome because the complications of diabetes become more severe with the duration of the disease. Thus, adults who developed diabetes as children are at particularly high risk for the premature disability and mortality associated with diabetes. A study of Americans diagnosed with type 1 diabetes between 1950 and 1981 found death rates up to seven times higher than in the general population. New therapies have improved the prognosis for children with diabetes. One recent study found that death rates between 10 and 20 years after diagnosis for type 1 diabetes declined from 8.4 percent in those diagnosed between 1965 and 1969 to 3.5 percent in those diagnosed between 1975 and 1979. However, despite these improvements, new methods to treat and prevent childhood forms of diabetes are urgently needed. type 1 diabetes in high risk individuals. TrialNet centers are completing the Diabetes Prevention Trial for Type 1 Diabetes, an ongoing clinical trial to determine if the use of oral insulin in non-diabetic relatives of persons with type 1 diabetes can delay the onset of diabetes. Furthermore, TrialNet will design and execute pilot and expanded studies of new agents to prevent or ameliorate type 1 diabetes as well as natural history and genetics studies in populations screened for or enrolled in these studies. Fourteen clinical centers and approximately 350 satellites and sites affiliated with these centers throughout the U.S. and Canada are participating in this consortium. The TrialNet will conduct studies in collaboration with the Immune Tolerance Network, a consortium of leading immunologists, that is focused on assessing methods to reprogram the immune system to reverse autoimmunity in a number of autoimmune disorders, including type 1 diabetes. TrialNet will facilitate the rapid, preliminary testing of emerging therapeutic strategies for immunoprevention of type 1 diabetes; candidate agents will be evaluated to obtain safety and optimal dosage data. Those agents that prove most promising can then be quickly moved into larger-scale trials. To further leverage the resources supported by TrialNet, biological samples and other data collected from trial participants may be placed in repositories for use by many investigators. Importantly, TrialNet is formulating surrogate endpoints for diabetes and its complications. A surrogate marker is a reliable, easily measured biological event that can precede and predict the development of a disease or condition. The identification of informative markers could save time and costs in clinical trials of new treatments for diabetes. TYPE 1 DIABETES TRIALNET
A consortium of investigators, clinical recruitment centers, and core support facilities has been established to perform intervention studies to preserve pancreatic beta cell function in patients with new-onset type 1 diabetes and to prevent Clinical Trials and Clinical Research of Critical Importance 89  ENVIRONMENTAL TRIGGERS OF TYPE 1 DIABETES
The NIH is creating a consortium of collaborating investigators to participate in the development and implementation of studies to identify infectious agents, dietary factors, or other environmental factors, which trigger type 1 diabetes in genetically susceptible individuals. Several independent population-based studies are under way to achieve this objective. Creation of the consortium will lead to a coordinated, multi-disciplinary approach to this complex problem, collection of information and samples in a standardized manner, and greater statistical power than can be achieved in smaller, independent studies. Clinical centers will recruit and enroll subjects, obtain genetic and other samples from newborns and parents, and prospectively follow selected newborns throughout childhood or until development of diabetes. The clinical research projects designed and implemented by this consortium will elucidate the environmental triggers and genetic interactions that initiate the autoimmune process and lead to diabetes. With NIH support, American investigators are participating in an international "Trial to Reduce the Incidence of Type 1 Diabetes in the Genetically-at-Risk" (TRIGR). This trial examines an intervention targeted at cows' milk, one putative environmental trigger of type 1 diabetes. Newborns identified as being at high genetic risk for type 1 diabetes are being randomly assigned to receive either standard or modified cows' milk formula. In the modified formula, the milk is treated to break its proteins into subcomponents in the hope that this will reduce the milk's antigenicity. In addition to testing whether modifying cows' milk will reduce the development of diabetes, this trial will provide an opportunity for careful study of newborns at high risk for type 1 diabetes. It may generate important information about other factors that influence the development of diabetes with important implications for novel strategies to prevent type 1 diabetes. NETWORK FOR TYPE 2 DIABETES IN CHILDREN AND ADOLESCENTS
The NIH has created a network of investigators to develop trials for treatment of type 2 diabetes in children and to develop and test interventions to reduce children's risk of developing type 2 diabetes. The majority of children with type 2 diabetes are in the pre-adolescent or adolescent age range, a period that presents special challenges to health care providers and families when attempting to promote behavior and lifestyle changes. Prevention and treatment programs must also consider cultural differences among racial and ethnic groups that may influence acceptance of medical regimens. This is especially important for type 2 diabetes in children, which disproportionately affects minority populations. In addition to those with frank diabetes, significant numbers of children may be at high risk of developing diabetes based on the presence of insulin resistance and blood glucose levels above normal but not as high as in diabetes. The Diabetes Prevention Program showed that lifestyle modification could reduce the development of diabetes in adults at high risk by 58 percent, but these results may not be directly applicable to 90 Conquering Diabetes: Extraordinary Research Opportunities children. The Network for Type 2 Diabetes in Children and Adolescents is developing a prevention trial protocol that will focus on costeffective, school-based interventions to decrease risk factors for type 2 diabetes and thus lower the incidence of this disease in children and adolescents. It is anticipated that the prevention strategies developed and tested will have the potential for broad, population-wide application. To address its other major research goal, the Network will design trials to identify appropriate and effective treatment regimens for type 2 diabetes in children. The drugs currently available for the treatment of this disease in adults have not been used widely in children. Treatment options, including lifestyle changes and pharmacologic therapy, need to be studied in this population to determine the most efficacious, safe, and costeffective strategies to achieve and maintain near normal blood glucose levels in the pediatric age group. Such treatment strategies are essential for reducing the long-term progression to diabetic complications for those who were diagnosed with diabetes during childhood and are at particularly high risk due to early development, and therefore longer duration, of their disease. New Trials Focus on Preventing Complications of Diabetes While prevention of diabetes is a critical public health issue, prevention of the development of complications of diabetes in the 17 million Americans who already have diabetes is another compelling goal. In addition to the seminal findings described previously about the reduction in eye, nerve and kidney complications that can be achieved with improved control of blood glucose, recent clinical trials have demonstrated other interventions, such as blood pressure and lipid lowering, to be highly effective in preventing onset or progression of complications. Notably, drugs that reduce the production or action of angiotensin, a hormone that acts on the blood vessels of the kidney, have been shown to dramatically reduce the rate of progression to kidney failure in people with the earliest signs of diabetic damage to the kidneys. Two thirds of deaths in diabetes are due to premature cardiovascular disease, and rates of cardiovascular disease are elevated two- to four-fold in people with diabetes compared to the general population. While rates of cardiovascular disease are falling in the American population overall, this improvement is not seen in those with diabetes. Information on treatments that will reduce the increased risk of cardiovascular disease associated with diabetes is urgently needed and is the focus of several major new clinical trials supported by the NIH. Clinical Trials and Clinical Research of Critical Importance 91  LOOK AHEAD: ACTION FOR HEALTH IN DIABETES
We now know that weight loss can dramatically reduce the development of type 2 diabetes in those at high risk, but a benefit of weight loss in preventing complications in people with diabetes has not yet been established through clinical trials. Because support from health care providers for achievement of weight loss is costly, it is important to establish the benefits and the cost-effectiveness of weight loss in people with type 2 diabetes. To address this issue, the NIH is conducting the largest clinical trial to date to examine the long-term health effects of voluntary weight loss. This multi-center, randomized clinical trial will examine the consequences of a lifestyle intervention designed to achieve and maintain weight loss over the long term through decreased caloric intake and increased exercise. Look AHEAD will focus on the disease most associated with overweight and obesity, type 2 diabetes, and on the outcome that causes the greatest morbidity and mortality, cardiovascular disease. In June 2001, 16 Look AHEAD Clinical Centers and a Data Coordinating Center began the two and one-half year process of enrolling 5,000 obese patients with type 2 diabetes. Trial participants, who will be followed for up to 11.5 years, are randomly assigned to one of two protocols, the Lifestyle Intervention, which is designed to help participants achieve and maintain weight loss over the long term, or Diabetes Support and Education. Look AHEAD will primarily study the impact of these two interventions on major cardiovascular events: heart attack, stroke, and cardiovascular death. The trial also will investigate the effect of the interventions on other cardiovascular disease-related outcomes, cardiovascular risk factors, and all-cause mortality. Additional outcomes include diabetes control and complications, fitness, general health, health-related quality of life and psychological outcomes. The cost and cost-effectiveness will be assessed for each of the two interventions. ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES (ACCORD)
This randomized, multi-center trial is being undertaken by the NIH to study three key approaches to preventing major cardiovascular events in individuals with type 2 diabetes. The risk factors to be targeted in the ACCORD interventions are control of blood glucose, blood pressure, and lipid levels. Despite the two- to four-fold elevation of cardiovascular disease in the American population with type 2 diabetes, there is a lack of definitive data on the effects of intensive control of blood glucose on cardiovascular disease event rates in diabetic patients. ACCORD is designed to compare current practice guidelines with more intensive glycemic control in 10,000 individuals with type 2 diabetes, including those at especially high risk for cardiovascular disease events because of age, evidence of subclinical atherosclerosis, or existing clinical cardiovascular disease. More intensive control of blood pressure than is called for in current guidelines and a medication to reduce triglyceride levels and raise HDL (good) cholesterol levels will also be studied in subgroups of these 10,000 volunteers. Each treatment strategy will be accompanied by standard advice regarding lifestyle, including diet, physical activity, and smoking cessation, appropriate for diabetic individuals. 92 Conquering Diabetes: Extraordinary Research Opportunities The primary outcome that ACCORD will measure is the first occurrence of a major cardiovascular disease event, specifically heart attack, stroke, or cardiovascular death. In addition, the study will investigate the impact of the treatment strategies on other cardiovascular outcomes, total mortality, limb amputation, eye, kidney, or nerve disease, health-related quality of life, and cost-effectiveness. Volunteers will be treated and followed for four to eight years at approximately 60 clinical sites associated with seven clinical center networks in the U.S. and Canada. randomized to receive medical therapy or either angioplasty or bypass surgery and, simultaneously, are randomly assigned to an insulinproviding or insulin-sensitizing strategy of blood glucose control. Patients in both groups will be followed for five years with aggressive management of risk factors. The primary trial outcome is total mortality; also, secondary outcomes such as cardiac mortality, heart attack, angina, and quality of life will be examined.
Although several clinical trials have examined optimal management of blood pressure in type 2 diabetes, this issue has not been examined through clinical trials in type 1 diabetes. Since different mechanisms may underlie the increased risk of cardiovascular disease in the two forms of diabetes, it is important to establish optimal practices for prevention of cardiovascular disease for each. TREATMENT OF NON-ALCOHOLIC STEATOHEPATITIS (NASH)
NASH is a chronic liver disease involving fat accumulation (steatosis) and inflammation in the liver. The cause of NASH is unknown but it is associated with diabetes, obesity, and insulin resistance. Liver cirrhosis, which may progress to liver failure, ultimately requiring liver transplantation, occurs in 10 to 15 percent of patients with NASH and significant liver scarring in another 30 percent. Currently no effective treatment exists for patients with this disease. To accelerate research on this poorly understood disease, the NIH has created a NASH Clinical Research Network. This group will study the causes, contributing factors, natural history, complications, and therapies of NASH; develop common definitions, nomenclature and terms for the diagnosis and staging of NASH; and generate preliminary data for further investigator-initiated research. In a pilot clinical research study of patients with NASH, researchers will investigate the effectiveness of pioglitazone, a new diabetes medicine that increases sensitivity to insulin, on improving liver function. If pioglitazone therapy is safe and appears beneficial in improving liver disease in these patients, then a larger, controlled clinical trial will be planned. BYPASS ANGIOPLASTY REVASCULARIZATION INVESTIGATION IN TYPE 2 DIABETICS TRIAL (BARI 2D)
This multi-center clinical trial will compare medical versus early surgical management of patients with type 2 diabetes who also have coronary artery disease and stable angina or ischemia. At the same time, BARI 2D will study the effect of two different strategies to control blood sugar -- providing more insulin versus increasing the sensitivity of the body to insulin -- on risk of cardiovascular mortality and morbidity. A total of 2,800 patients, both men and women, are being entered into BARI 2D at 30 clinical centers. Upon enrollment, study volunteers are Clinical Trials and Clinical Research of Critical Importance 93  TREATMENT OF DIABETIC EYE DISEASE
A clinical research consortium will examine new therapies for diabetic eye disease and conduct a pilot clinical trial in patients with diabetic macular edema, a common complication in patients with diabetes. The pilot study will compare two methods of laser therapy as well as the value of vitamin E and aggressive lipid lowering in preventing eye damage in the setting of laser therapy. In diabetic eye disease, blood vessels in the retina become leaky and the retina swells. The macula -- the center part of the retina that is responsible for fine vision -- may also swell and cause vision loss. Laser therapy reduces leaking from blood vessels in the retina and its value is well established in reducing vision loss in patients with diabetic retinopathy. However, traditional laser treatment causes scarring that can adversely impact vision, particularly in the critical macular area, despite its overall benefit in preserving vision. A different type of laser has been shown to have no such adverse effects in short-term studies but long-term effects of this treatment are unknown. In a pilot study, forty adult patients with either type 1 or type 2 diabetes and macular edema will be randomly assigned to receive one of the two laser treatments and either vitamin E or a placebo. Subjects with high cholesterol may also be randomized to either conventional or more aggressive treatment to lower these levels. This pilot study is an important first step in planning a large multi-center clinical trial to evaluate medical and laser approaches to improving the visual outcome for patients with diabetic retinopathy. To detect diabetic eye disease, the doctor uses an ophthalmoscope to examine the light-sensitive tissue at the back of the eye called the retina. He looks for early signs of disease, such as: (1) leaking blood vessels, (2) swelling, (3) pale, fatty deposits on the retina -- a sign of leaking blood vessels, (4) damaged nerve tissue, and (5) abnormal blood vessels. Photo: National Eye Institute. SLOWING OR PREVENTING DIABETIC NEPHROPATHY
Many patients with diabetes develop progressive renal disease even when they adequately manage their blood sugar and receive the most effective known therapy for diabetic nephropathy. Thus, new strategies to prevent and slow progression of diabetic nephropathy are desperately needed. Pilot clinical trials will test the ability of new agents or drug combinations to slow or prevent progressive kidney disease. These trials will use blockade of the renin-angiotensin system (RAS) as the current standard of care and examine either addition of alternate agents or incremental effects of RAS blockade. Recruitment will focus on patient populations in young- to mid-adulthood, with a strong representation of patients with type 1 diabetes. If successful in small-scale clinical trials, these therapies will then be tested in large phase III interventional trials. 94 Conquering Diabetes: Extraordinary Research Opportunities Translating the Results of Clinical Research into Clinical Practice The past few years have seen encouraging progress in development of effective new treatments for diabetes. Now, a key challenge is to ensure the American people benefit from what researchers have discovered. One approach to this challenge is education -- dissemination, to those at risk and their care providers, of information about measures proven effective for treating type 1 and type 2 diabetes and for preventing type 2 diabetes in individuals at high risk for this disease. However, providing information alone is not sufficient to translate what we know into practice. We need to develop methods to take interventions that have been demonstrated to be beneficial in careful clinical investigations, and extend or adapt them to larger populations or other settings. There is also increasing recognition that behavioral factors play a major role in the increased prevalence of obesity and type 2 diabetes and in the management of diabetes and its complications. BEHAVIORAL RESEARCH -- KEY TO PREVENTION AND TREATMENT OF DIABETES
Recent clinical trials have provided definitive evidence that type 2 diabetes can be prevented with lifestyle change and that rigorous control of blood glucose, blood pressure and lipid levels can delay or prevent diabetes complications. Yet, this control can be arduous -- requiring adherence to a complex regimen of medications, diet and physical activity -- and it is optimal in very few Americans with this disorder. The DRWG recognized the importance of understanding the health-related behaviors that contribute to the risk of diabetes and diabetes complications and the critical need to apply this information to develop behavioral interventions that can produce sustained changes. In response to the DRWG's scientific recommendations, the NIH has acted to stimulate application of behavioral science to diabetes through multiple initiatives. One solicitation called for research related to sociocultural, environmental, and behavioral mechanisms that contribute to successful self-management of diabetes. A subsequent solicitation specifically addressed diabetes self-management in the minority populations who are disproportionately affected by diabetes continued Clinical Trials and Clinical Research of Critical Importance 95 and its complications. A broader NIH-wide solicitation addressed the clarification of disease-relevant social and cultural factors and the linking of behavioral research to practices for improved prevention and treatment. More targeted research has focused on the role of psychological disorders -- such as depression and eating disorders -- on the risk of developing diabetes and its complications. People with diabetes have twice the rates of depression seen in the general population; moreover, people with depression have increased prevalence of diabetes. An NIH conference focused on research issues in depression in diabetes and other selected chronic diseases; this was followed by a solicitation to increase research on the relationships among depression, eating disorders, diabetes and obesity, and to explore how treatment of psychological disorders may improve outcomes in diabetes. Latinos, Native Americans/Alaska Natives, and Asian and Pacific Islanders who are disproportionately affected by diabetes. Among its many educational efforts, the NDEP is the primary mechanism for translating the striking results of the DPP into real health improvements for the public. The NDEP and its partners will promote clinical recommendations for health care providers and consumer information for people at risk of developing diabetes so that they will know what these findings mean to them and what steps they can take to reduce their risk. By mobilizing its partners at the national, state, and local levels, the NDEP will use the important, science-based diabetes prevention findings of the DPP to help reverse the rising tide of diabetes in this country. NATIONAL DIABETES EDUCATION PROGRAM (NDEP)
The National Diabetes Education Program (NDEP) is a collaborative initiative of the NIH and the CDC that uses over 200 public and private partnerships to promote, through education, routine clinical application of the therapies and other activities that have demonstrated value in the prevention of diabetes and its complications. A key feature of this program is the participation of individuals who represent communities such as African Americans, Hispanics/
Photo: NIDDK. 96 Conquering Diabetes: Extraordinary Research Opportunities  DIABETES COMPLICATIONS
The NDEP also plays a central role in dissemination of information about prevention of complications. Its new campaign, "Get Smart About Your Heart: Know the ABC's of Diabetes," is focused on increasing awareness of evidencebased guidelines regarding targets for hemoglobin A1c (a measure of glycemic control), blood pressure, and cholesterol in patients with diabetes. Complementary campaigns of the National Cholesterol Education Program and the National High Blood Pressure Education Program also promulgate guidelines for patients with diabetes, based on data that people with diabetes and no known heart disease are at the same degree of risk for heart attack and other cardiovascular events as people without diabetes who have had a heart attack. We now know this risk can be reduced with aggressive management of risk factors but very few people with diabetes are taking all of the steps that have been proven effective in reducing their risk of cardiovascular disease. Because diabetes is the leading cause of kidney failure and blindness in the U.S., moving into practice therapies proven to reduce the risk of these diabetes complications is a major focus of the NIH's new National Kidney Disease Education Program and the National Eye Health Education Program. NIH EDUCATION PROGRAMS TARGET TRANSLATIONAL RESEARCH FOR THE PREVENTION AND CONTROL OF DIABETES
Sadly, advances from "gold standard" clinical trials on therapy of diabetes and prevention of its complications have not been successfully incorporated into general health care practice. Underutilization of current knowledge was highlighted in a recent study of individuals with diabetes that demonstrated a low frequency of self-monitoring of blood glucose, good glycemic control, regular foot care, and ophthalmic examinations, all of which markedly reduce the development and progression of diabetic complications. With the demonstration that modest lifestyle changes can dramatically reduce the risk of developing type 2 diabetes in high risk individuals comes the imperative to develop both population-based and clinic-based strategies to establish cost-effective programs to identify individuals at high risk who could benefit from prevention programs and/or successfully promote lifestyle change. Additional research is also needed on improved methods of health care delivery to patients with diabetes and to compare the effectiveness and use of different clinical practices, interventions, and technologies in particular population subgroups. These opportunities are being explored through new Diabetes Prevention and Control projects. Clinical Trials and Clinical Research of Critical Importance 97 Opportunities to Answer Important, Remaining Questions
The DRWG noted that, compared to other common diseases that impact dramatically on public health such as hypertension and cardiovascular disease, relatively few trials have been carried out in diabetes, where age-adjusted disease mortality has risen by epidemic proportions. Since the DRWG report was issued, there has been progress in expanding both the number of clinical trials and the infrastructure to conduct clinical research in diabetes. Already, we have garnered important new information from recently completed clinical trials. From newly begun studies, we anticipate a further expansion of knowledge that will greatly improve therapy for people with diabetes or at risk for this disease. However, many important questions remain to be answered about prevention of diabetes and its optimal therapy. For example, trials comparing the various classes of drugs available for treating type 2 diabetes could define optimal initial glycemic therapy that might preserve the function of the insulin-producing beta cell and optimal glycemic therapy to prevent cardiovascular disease. Studies in multiple populations could determine how optimal therapy may differ for people with onset of type 2 diabetes in youth or older age, or in different racial and ethnic groups. Much could also be learned through the implementation of common outcome measures in medical studies across different cultures and environments. Many questions remain about optimal management of lipids and blood pressure and use of antioxidants and anti-inflammatory agents in people with diabetes, and how these may differ for those with type 1 or type 2 diabetes. The optimal glycemic target for type 1 diabetes in pre-pubertal children remains to be defined as does how to maximize implementation of intensive therapy for type 1 diabetes. Evidence-based medicine from clinical trials needs to be translated into clinical practice in a rigorous, science-based manner across various models of health care delivery systems. Approaches to the study of improved outcomes in clinical settings might include trials in which physician groups or other care providers are randomized. A critical need is for development of low-cost ways to influence patient and provider behavior. A key area of clinical research relates to the pathophysiology and natural history of obesity. We would like to understand how some people stay thin in an environment in which most Americans are overweight and to know more about how and why body weight changes occur during particular times, such as puberty and menopause in women. Information is also needed on the relationship between risk of diabetes and particular patterns of weight gain or particular stage of life in which weight gain occurs. Weight loss maintenance strategies are critically important and should be developed in coordinated studies in which approaches can be evaluated with common endpoints. New technologies will create major new opportunities for clinical trials and clinical research. These include development of continuous and/or non- or minimally-invasive methods for measuring blood sugar; development of new approaches for gene therapy; development of new methods to grow, harvest, or encapsulate islets; development of new approaches to modulation of the immune system; development of new technologies for metabolic assessment; progress in the application of genomic, proteomic and other approaches to phenotype and identify subgroups of patients who might benefit from particular therapeutic approaches; and development of reliable biomarkers of disease, imaging technologies, and surrogate markers reflecting clinical outcomes. 98 Conquering Diabetes: Extraordinary Research Opportunities Story of Discovery
On the Road to a Cure: From Identification of Insulin to Islet Transplantation
A major milestone in the quest for a cure for type 1 diabetes is recent progress in the transplantation of pancreatic islets, the body's precious insulin-producing factories. While scientists have attempted islet transplantation for years with little success, a new, significantly-advanced procedure is showing promise in preliminary trials with a small number of patients. Following islet transplantation, many patients have remained free from the need for daily insulin injections to control their blood sugar for as long as two years -- providing "proof-of-principle" that replacing lost or damaged islets may be sufficient to restore normal insulin-regulation of blood sugar levels in patients with diabetes. These encouraging results reflect a coalescing of scientific ideas and insights painstakingly accumulated over decades of basic and clinical biomedical research, from the initial discovery that type 1 diabetes results from a defect in pancreatic insulin production, to more recent advances in transplantation and modulating the immune system. A major insight into the causes of diabetes came in 1889, when researchers who removed the pancreas of a dog found that the dog developed severe diabetes. Spurred by this finding, another group of scientists developed a way to extract from pancreatic tissue a substance that could treat diabetes -- insulin. This research dramatically changed the lives of people with type 1 diabetes, for whom the onset of disease, generally in childhood, had once meant imminent death. Insulin could now be administered to patients to lower the dangerously high blood glucose (sugar) levels characteristic of this disease. For their discovery and purification of insulin, the scientists won the Nobel Prize. Several decades later, recombinant DNA technology revolutionized biological science and led to significant improvements in the treatment of type 1 diabetes. Previously, cow- and pig-derived insulins were the only sources of this therapy. Although these animal insulins were highly effective, they sometimes produced side effects, such as allergic reactions. Now, with recombinant (genetically-engineered) human insulin, researchers could diminish these side effects. Subsequent research led to the development of insulin with improved characteristics. These include quickacting formulations that can be taken with a meal to bring down blood sugar levels rapidly, and long-acting forms that give steady control over glucose levels throughout an entire day. Additional technological advances have also affected the lives of people with diabetes. A recent NIH-supported study found that improved long-term survival for patients with type 1 diabetes roughly correlated with the introduction of glucose self-monitoring devices, better methods of assessing glucose control, and advances in blood pressure therapy in the 1980s. While insulin therapy has dramatically extended and improved the lives of patients, it is a treatment, not a cure, and its success requires both extreme vigilance in monitoring blood glucose levels and daily doses of insulin. The critical importance of intensive therapy, guided by frequent glucose monitoring, was demonstrated in the landmark Diabetes Control and Complications Trial, an NIH-supported study. This study showed that intensive glucose control dramatically reduces the risk of microvascular complications of diabetes, including diabetic retinopathy (eye disease), Clinical Trials and Clinical Research of Critical Importance 99 Story of Discovery nephropathy (kidney disease), and neuropathy (disorders affecting nerve function). A follow-up study to the DCCT showed that the limited period of improved glucose control during the trial yielded benefits that persisted long after the trial ended, with dramatic reductions in complications of diabetes continuing for at least seven years. However, this intensive insulin therapy was also associated with an increased risk of severe hypoglycemia, dangerously low blood sugar. Because of the burden and difficulty of trying to maintain optimal blood glucose control with externally-supplied insulin, researchers have redoubled their efforts to search for a cure -- a transplant that would allow people with diabetes to make their own insulin. This proved to be a far greater challenge than originally imagined. As one method for trying to cure diabetes, doctors can transplant an entire pancreas into a diabetic patient. Since this procedure is technically demanding and poses significant risks to the patient, it is usually limited to people who are undergoing a simultaneous kidney transplant. The idea of transplanting only the islet cells of the pancreas, a potentially simpler procedure, arose a number of years ago. Islets are little clusters of cells that contain insulin-producing cells. In 1972, an NIH-supported scientist first reported that islet transplantation could cure diabetes in rats. Until recently, however, attempts at islet transplantation to help patients with diabetes fared poorly. The success rate for islet transplantation has now improved dramatically. Drawing upon lessons learned from extensive, previous research, a group of scientists in Edmonton, Canada, devised a new procedure for islet transplantation and published very promising results. Research conducted and supported by the NIH, including the initial islet transplant studies in rats, as well as other important discoveries, had laid important groundwork for the Edmonton advance. For example, islets require very delicate handling, but after years of experimentation, researchers improved islet isolation techniques and ways to assess islet function. An NIH grantee refined the method for isolating islets from pancreatic tissue so that larger numbers of human islets could be obtained from donor pancreata. Another avenue of research, the investigation of drugs that modulate the immune system, also contributed to the success in Edmonton. The body's immune system is designed to attack foreign invaders, such as viruses and bacteria. Unfortunately, however, the immune system can also perceive transplanted cells and organs from a donor as foreign,
The stem cell has the potential to develop into all the cell types that make up an islet, including the insulin-producing beta cells. Research to find ways to coax stem cells to become islets could remedy the current shortage of human islets for transplantation. Illustration: Donald Bliss, Medical Arts and Photography Branch, NIH. 100 Conquering Diabetes: Extraordinary Research Opportunities On the Road to a Cure: From Identification of Insulin to Islet Transplantation and attack these too. This problem has long plagued the field of transplantation research, because agents that suppress the immune system to prevent transplant rejection could also leave a patient more vulnerable to infection and other complications. An added layer of complexity exists in type 1 diabetes, as the underlying cause of the deficiency in insulin production is an immune system gone awry. The immune cells of people who develop this disease mistakenly attack and destroy the body's own insulin-producing beta cells in the islets. Many of the islet transplants attempted previously had used glucocorticoids as immununosuppressive agents, but research suggested these agents could be particularly problematic. The Edmonton researchers thus developed a glucocorticoid-free immunosuppressive strategy with several different immunosuppressive agents, including a substance called FK-506, now known as tacrolimus. An NIH-supported scientist, who is one of the world's premier liver transplant researchers, had pioneered the use of FK-506 years earlier to prevent immune rejection of transplants. In the year 2000, 50 years after President Truman established the NIH Institute tha