Continue to Full Report of Participants in the Trans-NIH Symposium
Diabetes Mellitus: Challenges and Opportunities
Final Report and Recommendations
Overview-Part 2
Summary of Research Recommendations from the NIH-Sponsored
Symposium "Diabetes Mellitus: Challenges and Opportunities" September 4-5, 1997,
Bethesda, Maryland
Within the context of diabetes research accomplishments,
gaps, and opportunities, the scientific experts at the trans-NIH diabetes symposium made
recommendations for new research initiatives and other actions that should be pursued to
exploit and capitalize on research progress and momentum, as well as to address pressing
issues and questions in diabetes research. Recommendations are summarized below, clustered
according to working groups. In each of the working groups, cross-cutting issues were
identified that related to the broad research agenda in diabetes and to the research
enterprise of the entire NIH. These types of recommendations-many of which relate to
research resources, infrastructure and training, and mechanisms such as clinical
trials-have been extracted from the individual working group recommendations,
consolidated, and presented under the title "cross-cutting recommendations" at
the beginning of this overview, in order to avoid redundancy. The complete report from the
symposium is provided at the end of this document.
Cross-Cutting Recommendations
Expand research resources and facilities to give
diabetes investigators the tools they need to combat diabetes
- Gain insights into diabetes disease processes through
expansion of animal models and other systems and facilities.
- Foster promising genetic studies through creation of DNA
and tissue repositories.
- Search for important clues to diabetes through
establishment of research databases. Facilitate combining the results of all completed
genetic analyses for diabetes into a single database.
- Accelerate research progress in diabetes through support of
protein and antibody production and/or distribution systems.
- Spur diabetes research by increasing the availability of
sophisticated, high-technology instrumentation for regional or national use.
- Encourage the Human Genome Project to prioritize the
sequencing of genetic regions sharing significant linkage to diabetes.
Develop new research methods and measures to foster diabetes research
- Conduct additional methodological research into approaches
for establishing genetic linkage analyses.
- Develop methods for reliable and affordable typing of
genes.
- Develop better surrogate endpoints to identify subjects for
genetic analysis at earlier points.
- Standardize surrogate endpoints for sensory function in
humans.
- Develop delivery systems to target emerging therapies for
diabetic nerve disease, such as neurotropin therapy.
- Develop new and better methods for evaluation of ß-cell
function, including noninvasive techniques.
- Develop methods to identify peptides in insulin-producing
ß-cells that may play a role in the destruction of these cells in type 1 diabetes.
- Develop technologies for delivering drugs selectively to
the eye, particularly drugs aimed at preventing or reducing the proliferation of diabetic
eye disease.
- Develop innovative approaches such as
"telemedicine" technologies for more effective screening of diabetic eyes by
primary care physicians.
Pursue the development of new clinical trials
- Assess the effects of interventions on the prevention of
heart disease and on its progression in patients with diabetes, including the impact of
high levels of glucose and insulin on the heart and the effect of drug, dietary, and
surgical interventions.
- Identify agents that prevent, stabilize, or reverse
complications in animals.
- Pursue the most promising drug treatments through
establishment of a national database of consenting patients, updated with regard to
diabetes and complication status.
- Identify and validate sensitive and specific indicators of
developing diabetic kidney disease.
- Follow short-term studies in diabetic patients with a
long-term, multicenter, primary prevention/secondary intervention study with clinically
significant endpoints to establish the therapeutic potential of promising agents.
Ensure a cadre of talented diabetes researchers by intensifying
research training and career development efforts
- Develop mechanisms to attract highly talented M.D.s and
Ph.D.s to careers in diabetes research.
- Attract to the field of diabetes research talented
investigators with expertise in other fields such as engineering, genetics, certain
clinical specialties, and biostatistics.
- Emphasize clinical research training, including the
development of novel training programs.
- Devise mechanisms to encourage cross-training among M.D.s
and Ph.D.s.
Foster translational research to enhance the timely transfer of important advances in
diabetes research to the practice of medicine
- Train more clinical researchers in order to remove one of
the major rate-limiting steps in translating diabetes research into clinical practice.
- Increase the role of Diabetes Research and Training Centers
and other mechanisms conducive to encouraging translational research.
- Enhance enthusiasm for translational research by ensuring
appropriate expertise in this field on NIH peer review panels.
Develop new modes of interaction to foster diabetes research
- Increase interaction among academia, NIH, and industry.
- Develop new modes of interaction to foster research between
industry and academia and between NIH and academia, as well as new or modified grant
mechanisms to foster and increase public support for diabetes research.
Continue planning process for diabetes research
- Establish a working advisory group of extramural scientists
who will work with the program officers and the Director of NIDDK to continue the process
of brainstorming and to develop practical mechanisms to stimulate diabetes research
through both programmatic and support efforts.
- Establish a coordinating focus for research on diabetic
nerve disease at NIH to evaluate, promote, and be responsible for multidisciplinary
approaches to diabetic nerve disease.
- Convene workshops and conferences to help guide program
planning efforts and to develop standardized research measures and assays. Specific
actions to be taken include the following:
-Help catalyze a consensus regarding numbers and
characteristics of patient populations to be studied and samples to be collected, and spur
the development of appropriate analytic tools.
-Design an interinstitutional linkage study of the
genetics of obesity.
-Validate assays for testing cells involved in the immune
response in type 1 diabetes.
-Consider "vaccination" trials using key
autoantigens and establishing approaches to modulate autoimmune responses.
-Develop a multidisciplinary strategy for identifying
diabetes and obesity susceptibility genes in various ethnic populations and characterizing
their role in diabetes.
Summary Recommendations of Work Group on Etiology and Pathophysiology of Type 1
Diabetes
Co-Chairs: Daniel W. Foster, M.D., and Ake Lernmark,
Ph.D.
Major recommendation: Pursue research initiatives
to achieve a better understanding of the mechanisms involved in the causes, genetics, and
disease processes of type 1 diabetes, with a goal of developing more effective treatments
and ways to prevent onset of the disease.
- Undertake rigorous studies of known and unknown
infectious agents and their relationship to islet autoimmunity in order to gain insights
into the roles of environmental factors, in combination with genetic susceptibility, in
the initiation of the disease process in type 1 diabetes.
Seek better reporting of type 1 diabetes in children and young
adults and expand registries of new-onset patients with collection of blood, DNA, and
tissue when possible.
Initiate rigorous study of environmental risks, both
infectious and noninfectious.
- Seek to determine the genetic risk for type 1 diabetes
and the possible environmental factors that trigger its development into overt disease
through studies of autoimmunity.
Continue
exploration of genetic susceptibility, with specific emphasis on understanding the role of
Class II human leukocyte antigen (HLA) function in the disease process.
Summary Recommendations of Work Group on Etiology and Pathogenesis of Type 2 Diabetes
Co-Chairs: Jerrold M. Olefsky, M.D., and Kenneth S.
Polonsky, M.D.
Major recommendation: Pursue research initiatives
to achieve a better understanding of the causes and progression of type 2 diabetes through
intensified study of insulin secretion, insulin action/resistance, genetics, and obesity-a
major risk factor for this disease.
- Understand and find ways to intervene in the processes
of insulin secretion, insulin action, and insulin resistance, and to understand, treat,
and prevent obesity.
Determine the factors
responsible for growth and development of the insulin-producing cells of the pancreas.
Define the molecular elements that compromise the
insulin-signaling pathway and the defects in this pathway that contribute to insulin
resistance.
Determine whether there are identifiable stages of type 2
diabetes and/or insulin resistance that can be described and differentiated on the basis
of altered expression of sets of genes or other criteria.
Summary Recommendations of the Work Group on Therapy of Diabetes
Co-Chairs: David M. Nathan, M.D., and James Gavin,
M.D., Ph.D.
Major recommendation: Pursue research initiatives
to improve treatment of diabetes through behavioral approaches to foster adherence to
therapy, and through development of innovative biologic, mechanical, and pharmacologic
approaches to therapy.
- Improve adherence to therapy based on behavioral
approaches.
Maximize the ability of patients and
providers to implement recommended therapy and achieve desirable outcomes, and maximize
adoption and maintenance of a healthy lifestyle.
- Develop innovative therapies for type 1 diabetes, with
emphasis on biologic and mechanical approaches for achieving and maintaining metabolic
control in type 1 diabetes.
Develop new biologic
or cellular approaches for achieving and maintaining metabolic control in type 1 diabetes,
including approaches that focus on the biology of ß cells, modulation of the immune
system, and the therapeutic transplantation of cells and whole organs.
Develop new mechanical approaches to metabolic control,
including more effective glucose sensors, as well as bioengineered insulin delivery
devices.
- Develop innovative pharmacologic approaches to the
treatment of diabetes.
Initiate studies on the
biology of ß-cells, the expression of the insulin gene, and the development of imaging
methods to assess ß-cell biology. Conduct a wide range of studies on important issues
such as insulin resistance, genes involved in diabetes, obesity as a risk factor for
diabetes, prevention of elevated blood glucose levels in intensive therapy, and diabetes
in pregnancy.
Summary Recommendations of the Work Group on Microvascular Complications
Co-Chairs: Michael Brownlee, M.D., and Daniel Porte,
Jr., M.D.
Major recommendation: Pursue research initiatives
to achieve better understanding, treatment, and prevention of damage to the small blood
vessels of the eye, kidney, and nerves, which leads to major disease complications of
diabetes.
- Undertake studies to pinpoint interrelationships among
signaling pathways affected by high blood glucose levels, their molecular elements, and
interventions for modifying these pathways.
Determine
the sequence of events in the onset and progression of tissue injury induced by high
levels of glucose in the blood.
- Understand and discover ways to intervene in the genetic
underpinnings of microvascular complications of diabetes.
Conduct systematic studies of familial/ethnic aggregation of
proliferative diabetic eye and diabetic nerve disease.
- Understand and find ways to treat diabetic eye disease
effectively and to prevent or delay its onset.
Expand
basic studies on mechanisms of initial injury in laboratory studies of diabetic eye
disease.
- Understand and find ways to treat diabetic kidney
disease effectively and to prevent or delay its onset.
Pursue investigations of the fundamental cellular mechanisms
involved in kidney dysfunction induced by high levels of glucose in the blood.
Initiate collaborative multicenter studies of the genetic
basis of diabetic kidney disease in both type I and type 2 diabetes.
- Understand and find ways to treat diabetic nerve disease
effectively in the extremities and in the brain, to prevent or delay its progression to
brain dysfunction or amputations of the extremities, and to prevent or delay its onset.
Investigate the fundamental cellular mechanisms involved in the
nerve dysfunction diabetic patients may experience in their hands, legs, and feet.
Systematically study the mechanisms by which chronic,
repeated high and/or low glucose levels cause damage to the central nervous system.
Summary Recommendations of the Work Group
on Macrovascular Disease
Co-Chairs: Willa A. Hsueh, M.D., and Antonio M. Gotto,
Jr., M.D.
Major recommendation: Pursue research initiatives
to achieve a better understanding of the underlying process of heart disease as a
complication of diabetes and to seek means to develop and test potential interventions for
effective treatment and prevention through diet, exercise, and pharmacologic or genetic
manipulation.
- Develop and study animal models to gain insights into
the processes underlying the damage that diabetes does to the large blood vessels of the
heart, resulting in serious morbidity and mortality.
Investigate hyperglycemia and glycation effects that alter cellular
responses to diabetes-induced injury to the heart.
Characterize insulin action in vascular cells, at the
molecular level, and in organs.
Evaluate the impact of specific alterations in circulating
lipids on the development and expansion of heart disease, and the interaction of lipids
with the wall of the heart vessels.
Determine the role of inflammation and its enhancement in
the diabetic state.
Assess the importance of increased oxidation in insulin
resistance and in mechanisms of diabetes leading to heart disease.
Determine the effects of antidiabetic agents on the
development, progression, and mortality of diabetes-associated heart disease.
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