1. Diabetes, Obesity & Metabolism Research in the Early 21 st Century* (*from the NIH Point of View) December, 2004 Maren R. Laughlin, Ph.D. Senior Advisor for Integrative Metabolism National Institute of Diabetes & Digestive and Kidney Diseases National Institutes of Health

2. Three Major Areas of Interest  Diabetes & Metabolic Disease NIDDK, NHLBI, NIA, NICHD, NIAID, NCI, NIBIB, etc.  Obesity Trans-NIH http://www.obesityresearch.nih.gov/ http://www.niddk.nih.gov/welcome/org/OD/OOR/OOR.htm  NIH Roadmap Trans-NIH www.nihroadmap.nih.gov

3. Diabetes & Metabolic Disease* (*from the NIH Point of View) Type 2 Diabetes  Incidence: ~18M Americans  Healthcare burden: $132B in 2002  Recently found in children and young people as well as older adults  Major focus of NIDDK research efforts Type 1 Diabetes Special Statutory Funding Program for Type 1 Diabetes Research http://www.niddk.nih.gov/fund/diabetesspecialfunds/funding.htm $1.14 billion for FY 1998 - FY 2008 Diabetic Complications  Common to type 1 and type 2 diabetes  Heart disease/atherosclerosis, microvascular disease / neuropathy, retinopathy, nephropathy

4. Multi-pronged Approach to Diabetes Research  Investigator Initiated Grants  Treatment and Prevention Trials  Epidemiology  Genetics studies  Requests for Applications: NIH Initiated Grants  Resources, such as Animal models Tissue sources Standards Reagents and technologies  Community Organization (consortia, collaberations, workshops, etc)  Training

5. Type 2 Diabetes Resources  Diabetes Centers: DERCs and DTRCs Provides core resources to foster interdisciplinary research in diabetes and related areas  International Type 2 Diabetes Linkage Analysis Consortium  Mouse Metabolic Phenotyping Centers (MMPC) Mice are shipped to a Center for in-depth phenotyping  Nuclear Receptor Signaling Atlas to gather and organize information relating to key aspects of orphan nuclear receptor biology

6. Type 1 Diabetes Resources cont’d.  Islet Cell Resource Centers (ICR) Human Pancreatic Islets Available for Non-Clinical Research ($0.10 / islet)  Availability of pancreas-specific microarrays Mouse PancChip 5.0 and Human PancChip 1.0  Beta Cell Biology Consortium Reagents for study of islet development & cell replacement therapies

7. Type 1 Diabetes Resources  Collaborative Projects on Proteomics & Metabolomics For Type 1 Diabetes & its Complications Clearinghouse for tissue samples for proteomics/metabolomics analysis www.niddk.nih.gov/fund/diabetesspecialfunds/proteomics/  Access to samples from major clinical trials (DCCT, DPP)  Type 1 Diabetes-Rapid Access to Intervention Development (T1D-RAID) Resources to aid in pre-clinical development of new drugs  Type 1 Diabetes Mouse Repository at the Jax Labs  Animal Models of Diabetic Complications Consortium Mice and pig models

8. Growth in Basic Biology Programs  Beta cell developmental biology: (stem cells and transcription factors, toward cell therapy)  Islet transplantation and engineering  Imaging the pancreatic beta cell  Adipocyte as endocrine organ  Immunology of diabetes  Mechanisms of insulin resistance  Neurobiology of energy balance  Proteomics and metabolomics of diabetes: Biomarkers of disease  Diabetic Complications Hypoglycemia unawareness Molecular mechanisms

9. Current & Future Diabetes Initiatives Current: RFA-DK-04-022receipt: March 17, 2005 Collaborative Studies on Angiogenesis and Diabetic Complications RFA-DK-05-001receipt: February 24, 2005 Preventing Mitochondrial Oxidative Stress in Diabetes and Obesity Coming Soon:  Beta Cell Regeneration for Diabetes Therapy (RFA)  Pilot and Feasibility Program in Human Islet Biology (RFA)  Mouse Metabolic Phenotyping Centers (RFA)

10. Special Emphasis Program Announcements  PA-04-092 Long-Term Weight Maintenance: Basic and Clinical Studies  PA-04-088 Non-Invasive Methods for Diagnosis and Progression of Diabetes, Kidney, Urological, Hematological, and Digestive Diseases  PA-04-081 Proteomics: Diabetes, Obesity, and Endocrine, Digestive, Kidney, Urologic, and Hematologic Diseases  PAR-04-078 Ancillary Studies to Major Ongoing NIDDK Clinical Research Studies  PA-04-074 Health Disparities in NIDDK Diseases  PA-04-068 Development Assays for High Throughput Drug Screening  PA 04-033 Diet Composition and Energy Balance

11. Diabetes Program Announcements  PA 03-052 Proteomics in Diabetes and Other Endocrine and Metabolic Diseases  PA 02-077 Secondary Analyses in Diabetes, Digestive and Kidney Diseases  PA03-0156 Insulin Signaling and Receptor Cross-Talk  PA-04-033 Diet Composition and Energy Balance  PA-04-098 Heterogeneity of Fat Depots: Underlying Basis and Association with Morbidity  PA 03-150 Erythroid Lineage Molecular Toolbox  PA 03-145 Ubiquitin and Ubiquitin-Like Modification Regulating Disease Processes  PA 02-161 Development of the Endocrine Pancreas  PA 02-117 Racial & Ethnic Differences in the Etiology of Type 2 Diabetes in United States  PA 01-117 Liver and Pancreatic Disease in HIV Infection  PA 01-112 The Role of Antioxidants in the Prevention of Diabetic Complications  PA 02-100 Complex Formation in Hormonal Regulation of Gene Expression  PA 02-094 Ancillary Studies on Control Groups in Clinical Trials

12. NIDDK Initiative Concepts for 2006  Development of Biomarkers for Disease  Animal Models of NIDDK-Relevant Diseases  Imaging Fibrosis in Kidney, Liver and Bladder  Potential Therapeutic Agents for Diseases of Protein Misprocessing or Misfolding  Genetic Longitudinal Studies of Obesity-Related Phenotypes  Translation of Invertebrate Obesity Genetics to Mammals  Planning or Implementation of New Clinical Studies of Interest to NIDDK

13. Obesity Research (from the NIH Point of View) NIH Obesity Taskforce established April, 2003 25 ICs and offices, co-chaired by the Directors of NIDDK and NHLBI http://www.obesityresearch.nih.gov/ Strategic Plan: Research toward preventing and treating obesity through lifestyle modification. Research toward preventing and treating obesity through pharmacologic, surgical, or other medical approaches. Research toward breaking the link between obesity and its associated health conditions. Cross-cutting research topics, including health disparities, technology, fostering of interdisciplinary research teams, investigator training, translational research and education/outreach efforts.

14. NIDDK Office of Obesity Research http://www.niddk.nih.gov/welcome/org/OD/OOR/OOR.htm “Right hand” of NIH Obesity Task Force comprised of NIDDK staff serves to assist the Director, NIDDK in identifying research opportunities, initiatives, and advances identify and plan appropriate workshops and conferences

15. Clinical Trials in Obesity Action to Control Cardiovascular Disease Risk in Diabetes (ACCORD) test best ways to lower risk of heart disease and stroke in adults with type 2 diabetes BARI 2 Bypass Angioplasty Revascularization Investigation 2 Diabetes Determine the best therapies for people with type 2 diabetes and heart disease Longitudinal Assessment of Bariatric Surgery (LABS) conducting coordinated clinical, epidemiological, and behavioral research in the field of bariatric surgery SEARCH for Diabetes in Youth Study determine the prevalence of diabetes in children in six areas of the U.S. and help clarify trends in the development of diabetes in youth TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) identify the best treatment of type 2 diabetes in children and teens

16. Clinical Samples for Obesity & Diabetes Researchers NIDDK Central Repositories: Biosamples, Genetics, Data Established to store biosamples and data collected in designated NIDDK-funded clinical studies. Purpose is to expand the usefulness of these studies by allowing a wider research community to access collected materials RFA-DK-03-022receipt: July 19, 2005 Ancillary Studies to Obesity-Related Clinical Trials

17. Current Obesity Research Solicitations RFA-DK-05-0receipt: February 24, 2005 Preventing Mitochondrial Oxidative Stress in Diabetes and Obesity RFA-HL-04-022receipt: February 16, 2005 Bioengineering Approaches to Energy Balance and Obesity (measure energy balance, food intake, activity, etc.) PA-04-156receipt:Feb 1, June 1, Oct 1 Bioengineering Approaches to Energy Balance and Obesity (SBIR/STTR) RFA-ES-04-003receipt: Dec. 17, 2004 Obesity and the Built Environment RFA-DK-03-018receipt: March 17, 2005 Genetic Studies of Obesity-Related Traits in Model Organisms (Drosophila, C elegans, zebrafish)

18. Obesity Program Announcements Basic Research  PA-04-124: Studies of Energy Balance and Cancer in Humans  PA-04-098: Heterogeneity of Fat Depots: Underlying Basis & Association with Morbidity  PA-04-081: Proteomics: Diabetes, Obesity, and Endocrine, Digestive, Kidney, Urologic & Hematologic Diseases  PA-04-033: Diet Composition and Energy Balance

19. Clinical and Behavior Research  PA-04-092: Long-Term Weight Maintenance: Basic and Clinical Studies  PAR-03-009: Improving Diet and Physical Activity Assessment  PAR-04-082: Small Clinical Grants in Digestive Diseases, Nutrition and Obesity  PA-04-121: Understanding Mechanisms of Health Risk Behavior Change in Children & Adolescents  PAR-03-060: Planning Grants for Translational Research for the Prevention and Control of Diabetes  PA-02-153: Translational Research for the Prevention and Control of Diabetes  PA-02-159: Enhancing Adolescent Health Promotion Across Multiple High Risk Behaviors  PA-05-009: Research on the Economics of Diet, Activity, and Energy Balance  PA-04-145: School-Based Interventions To Prevent Obesity Obesity Program Announcements

20. Recent NIH Obesity Workshops Women and Obesity November 4, 2004 1-3 p.m. Obesity and the Built Environment: Improving Public Health Through Community Design May 24-26, 2004 Lipids and the Pathophysiology of Obesity May 10-11, 2004 From clinical trials to community: The science of translating diabetes and obesity research January 12-13, 2004 Adipose Tissue Secretory Function and Its Role in Obesity-Associated Co-Morbidities December 11-13, 2003 Phenotyping Obesity for Human Genetic Studies October 28-30, 2003

21. NIH Roadmap* (* from the NIH Point of View)  Theory NIH institutes working together to serve the unique needs of 21 st century American biomedical science  Practice Research themes, projects and resources that no one institute could support because of limited budgets and defined missions 28 initiatives & 171 awards to date  Resources $237M in FY05, projected to ~ $500M by FY09

22. The NIH Roadmap and Obesity PI: JAY D. HORTON Title: Task force for Obesity Research at UT Southwestern RFA: Exploratory Centers for Interdisciplinary Research Goals:  Taskforce combines neuroendocrinology, genetics, lipid metabolism, intermediary metabolism, and clinical epidemiology  Brain regulation of food intake and energy expenditure  Dysregulation of glucose and lipid metabolism in the liver

23. PI: BARRY M. POPKIN Project Title: An Interdisciplinary Strategy for Obesity RFA: Exploratory Centers for Interdisciplinary Research Goals:  Inter-Disciplinary Obesity Center (IDOC)  Nutrition, epidemiology, health behavior, urban planning, health economics, physiology, psychology, genetics, and clinical medicine  Find effective interventions for prevention and treatment of obesity The NIH Roadmap and Obesity

24. The NIH Roadmap & Metabolic Disease PI: HENRI BRUNENGRABER Title: Dynamic Metabolomics via Isotopomer Analysis RFA: Metabolomics Technologies Development Goals:  Identify, measure and interpret the complex time-related concentration, activity and flux of endogenous metabolites  instrumentation to increase sensitivity  Carbon-labeled substrates and 2 H 2 O to measure fluxes in metabolic networks via mass isotopomer analysis  Models and multivariate statistics to provide new avenues for understanding metabolic diseases

25. NIH Roadmap Themes ( & 13 Implementation Committees ) New Pathways to Discovery Building Blocks, Biological Pathways, and Networks Molecular Libraries & Molecular Imaging Structural Biology Bioinformatics and Computational Biology Nanomedicine Research Teams of the Future High-Risk Research Interdisciplinary Research Public-Private Partnerships Re-engineering the Clinical Research Enterprise Clinical Research Networks/NECTAR Clinical Research Policy Analysis and Coordination Clinical Research Workforce Training Dynamic Assessment of Patient-Reported Chronic Disease Outcomes Translational Research

26. New Pathways to Discovery Projects SMALL MOLECULES Metabolomics Technology Development Projects tools to measure metabolites and their dynamic fluctuations within cells Molecular Libraries Screening Center Network (MLSCN) high throughput screening of chemically diverse small molecules (500,000) with the hope of providing new reagents for research (activators / inhibitors / markers) MOLECULAR IMAGING technologies and reagents for imaging of molecules or molecular events within single cells and whole organisms PROTEINS National Technology Centers for Networks and Pathways tools to measure the activity, translocation, and interactions of intracellular protein molecules Innovation in Membrane Protein Production Centers to prepare membrane proteins for structural studies

27. Research Teams of the Future Projects HIGH RISK RESEARCH: 9 Pioneer Awards $500K/yr for 5 yrs to encourage creative, outside-the-box thinkers to pursue exciting and innovative ideas in biomedical research INTERDISCIPLINARY RESEARCH Exploratory Centers (P20) for Interdisciplinary Research Large series of training initiatives in IR TRANSLATIONAL RESEARCH RAID: Rapid Access to Intervention Development resources for pre-clinical development of drugs (toxicology, dosing, manufacture, etc.)

28. 2005 RM Initiatives (from 16 total) http://nihroadmap.nih.gov/grants/index.asp Building Blocks, Biological Pathways RM-04-019 receipt2/22/05 National Technology Centers for Networks and Pathways Molecular Libraries RM-04-027 receipt 3/10/05 Cheminformatics Research Centers RM-05-011 receipt 2/14/05 Assay Technology Development RM-05-014 receipt 2/15/05 Pilot-Scale Libraries for High-Throughput Screening Structural Biology RM-04-026 receipt 1/24/05 Membrane Protein Production and Structure Determination

29. 2005 RM Initiatives (cont’d.) http://nihroadmap.nih.gov/grants/index.asp Interdisciplinary Research RM-04-008 receipt 2/11/05 Short Programs for Interdisciplinary Research Training RM-05-010 receipt 2/11/05 Interdisciplinary Health Research Training: Behavior, Environment and Biology High Risk Research NIH Director's Pioneer Awards

30. Other Funding Mechanisms for Partnerships  BRP Bioengineering Research Partnerships http://grants2.nih.gov/grants/guide/pa- files/PAR-04-023.html  R24 Interactive Partnerships NIGMS or NIDDK Grantees, Collaboration between funded investigators $300K/yr for 4 yrs, non-renewable For consortium activities http://grants2.nih.gov/grants/guide/pa- files/PA-03-127.html http://grants2.nih.gov/grants/guide/pa- files/PA-03-127.html

31. Contact Information Maren R. Laughlin, Ph.D. Senior Advisor for Integrative Metabolism NIDDK, NIH 6707 Democracy Blvd., MSC 5460 Bethesda, MD 20892 301-594-8802 Maren.laughlin@nih.gov www.nih.gov & www.niddk.nih.gov