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

Three Major Areas of Interest  Diabetes & Metabolic Disease NIDDK, NHLBI, NIA, NICHD, NIAID, NCI, NIBIB, etc.  Obesity Trans-NIH  NIH Roadmap Trans-NIH

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 $1.14 billion for FY FY 2008 Diabetic Complications  Common to type 1 and type 2 diabetes  Heart disease/atherosclerosis, microvascular disease / neuropathy, retinopathy, nephropathy

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

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

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

Type 1 Diabetes Resources  Collaborative Projects on Proteomics & Metabolomics For Type 1 Diabetes & its Complications Clearinghouse for tissue samples for proteomics/metabolomics analysis  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

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

Current & Future Diabetes Initiatives Current: RFA-DK receipt: March 17, 2005 Collaborative Studies on Angiogenesis and Diabetic Complications RFA-DK receipt: 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)

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

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

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

Obesity Research (from the NIH Point of View) NIH Obesity Taskforce established April, ICs and offices, co-chaired by the Directors of NIDDK and NHLBI 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.

NIDDK Office of Obesity Research “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

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

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 receipt: July 19, 2005 Ancillary Studies to Obesity-Related Clinical Trials

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

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

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

Recent NIH Obesity Workshops Women and Obesity November 4, 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

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

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

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

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

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

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

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.)

2005 RM Initiatives (from 16 total) Building Blocks, Biological Pathways RM receipt2/22/05 National Technology Centers for Networks and Pathways Molecular Libraries RM receipt 3/10/05 Cheminformatics Research Centers RM receipt 2/14/05 Assay Technology Development RM receipt 2/15/05 Pilot-Scale Libraries for High-Throughput Screening Structural Biology RM receipt 1/24/05 Membrane Protein Production and Structure Determination

2005 RM Initiatives (cont’d.) Interdisciplinary Research RM receipt 2/11/05 Short Programs for Interdisciplinary Research Training RM receipt 2/11/05 Interdisciplinary Health Research Training: Behavior, Environment and Biology High Risk Research NIH Director's Pioneer Awards

Other Funding Mechanisms for Partnerships  BRP Bioengineering Research Partnerships files/PAR html  R24 Interactive Partnerships NIGMS or NIDDK Grantees, Collaboration between funded investigators $300K/yr for 4 yrs, non-renewable For consortium activities files/PA html files/PA html

Contact Information Maren R. Laughlin, Ph.D. Senior Advisor for Integrative Metabolism NIDDK, NIH 6707 Democracy Blvd., MSC 5460 Bethesda, MD &