Mission and History

NIDDK's Mission

The National Institute of Diabetes and Digestive and Kidney Diseases conducts and supports research on many of the most serious diseases affecting public health. The Institute supports much of the clinical research on the diseases of internal medicine and related subspecialty fields as well as many basic science disciplines.

The Institute's Division of Intramural Research encompasses the broad spectrum of metabolic diseases such as diabetes, inborn errors of metabolism, endocrine disorders, mineral metabolism, digestive diseases, nutrition, urology and renal disease, and hematology. Basic research studies include biochemistry, nutrition, pathology, histochemistry, chemistry, physical, chemical, and molecular biology, pharmacology, and toxicology.

NIDDK extramural research is organized into divisions of program areas:

• Division of Diabetes, Endocrinology, and Metabolic Diseases
• Division of Digestive Diseases and Nutrition
• Division of Kidney, Urologic, and Hematologic Diseases

The Division of Extramural Activities provides administrative support and overall coordination. A fifth division, the Division of Nutrition Research Coordination, coordinates government nutrition research efforts.

The Institute supports basic and clinical research through investigator-initiated grants, program project and center grants, and career development and training awards. The Institute also supports research and development projects and large-scale clinical trials through contracts.

History of NIDDK

Important Events in NIDDK History

August 15, 1950 – President Harry S. Truman signed the Omnibus Medical Research Act into law establishing the National Institute of Arthritis and Metabolic Diseases (NIAMD) in PHS. The new institute incorporated the laboratories of the Experimental Biology and Medicine Institute and expanded to include clinical investigation in rheumatic diseases, diabetes, and a number of metabolic, endocrine and gastrointestinal diseases.

November 15, 1950 – The National Advisory Arthritis and Metabolic Diseases Council held its first meeting and recommended approval of NIAMD's first grants.

November 22, 1950 – Surgeon General Scheele established NIAMD.

1959 – Dr. Arthur Kornberg, former chief of the institute's enzyme and metabolism section, won the Nobel Prize for synthesizing nucleic acid.

The institute initiated an intramural research program in gastroenterology and launched an intramural research program in cystic fibrosis with the establishment of the Pediatric Metabolism Branch.

1961 – Laboratory-equipped, mobile trailer units began an epidemiological study of arthritis among the Blackfeet and Pima Indians in Montana and Arizona, respectively.

October 16, 1969 – The Nobel Prize was awarded to Dr. Marshall W. Nirenberg of the National Heart Institute who reported his celebrated partial cracking of the genetic code while an NIAMD scientist (1957-1962).

November 1970 – The institute celebrated its 20th anniversary. Secretary of Defense Melvin R. Laird addressed leaders in the department, representatives from voluntary health agencies and professional biomedical associations, as well as past and present institute National Advisory Council members.

May 19, 1972 – The institute name was changed to the National Institute of Arthritis, Metabolism, and Digestive Diseases.

October 1972 – Christian B. Anfinsen, chief of the institute's Laboratory of Chemical Biology, shared a Nobel Prize with two other American scientists for his demonstration of one of the most important simplifying concepts of molecular biology, that the three-dimensional conformation of a native protein is determined by the chemistry of its amino acid sequence. A significant part of this research cited by the award was performed while with NIH.

September 1973 – The institute's diabetes centers program was initiated with the establishment of the first Diabetes-Endocrinology Research Centers.

November 1975 – After 9 months of investigation into the epidemiology and nature of diabetes mellitus and public hearings throughout the United States, the National Commission on Diabetes delivered its report, the Long-Range Plan to Combat Diabetes, to Congress. Recommendations encompassed expansion and coordination of diabetes and related research programs; the creation of a diabetes research and training centers program; acceleration of efforts in diabetes health care, education, and control programs; and the establishment of a National Diabetes Advisory Board.

April 1976 – After a year of study and public hearings, the National Commission on Arthritis and Related Musculoskeletal Diseases issued the Arthritis Plan – its report to Congress. The report called for increased arthritis research and training programs; multipurpose arthritis centers; epidemiologic studies and data systems in arthritis; a National Arthritis Information Service and a National Arthritis Advisory Board.

October 1976 – Dr. Baruch Blumberg was awarded the Nobel Prize in Physiology or Medicine for research on the hepatitis B virus protein, the "Australia antigen," which he discovered in 1963 while at the institute. This advance has proven to be a scientific and clinical landmark in detection and control of viral hepatitis and led to the development of preventive measures against hepatitis and liver cancer.

April 19, 1977 – The director, NIH, established a trans-NIH program for diabetes, with lead responsibility in NIAMDD.

September 1977 – Over $5 million in grants was awarded to five institutions to establish Diabetes Research and Training Centers.

October 1977 – In response to the recommendation of the National Commission on Diabetes, the National Diabetes Data Group was established within the institute to collect, analyze, and disseminate data on this disorder to scientific and public health policy and planning associations.

December 1977 – Institute grantees Dr. Roger C.L. Guillemin and Dr. Andrew V. Shally shared the Nobel Prize in Physiology or Medicine with a third scientist, Dr. Rosalyn S. Yalow. Guillemin and Shally's prizes were for discoveries related to the brain's production of peptide hormones.

December 1978 – A study of cystic fibrosis focused on the need for future research activities, including increased support for clinical and basic research, expansion of specialized CF research resources, emphasis on training of scientific personnel, and coordination of public and private cystic fibrosis research activities.

January 1979 – Following 2 years of study and public hearings, the National Commission on Digestive Diseases issued its report, The National Long-Range Plan to Combat Digestive Diseases. Recommendations to Congress included the establishment of a National Digestive Diseases Advisory Board, an information clearinghouse, and increased emphasis on educational programs in digestive diseases in medical schools.

December 1979 – A task force completed its study and submitted the report, An Evaluation of Research Needs in Endocrinology and Metabolic Diseases.

September 1980 – Dr. Joseph E. Rall, director of NIAMDD intramural research, became the first person at NIH to be named to the distinguished executive rank in the Senior Executive Service. President Carter presented the award in ceremonies at the White House on September 9.

October 15, 1980 – NIAMDD celebrated its 30th anniversary with a symposium, "DNA, the Cell Nucleus, and Genetic Disease," and dinner at the National Naval Medical Center. Dr. Donald W. Seldin, chairman of the department of internal medicine, University of Texas Southwestern Medical School, Dallas, was guest speaker.

June 23, 1981 – The institute was renamed National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases.

April 1982 – HHS Secretary Richard S. Schweiker elevated NIADDK's programs to division status, creating five extramural divisions and the Division of Intramural Research.

November 1982 – Dr. Elizabeth Neufeld received a Lasker Foundation Award. She is cited, along with Dr. Roscoe E. Brady of NINCDS, for "significant and unique contributions to the fundamental understanding and diagnosis of a group of inherited diseases called mucopolysaccharide storage disorders (MPS)."

November 1984 – Grants totaling more than $4 million were awarded to six institutions to establish Silvio O. Conte Digestive Disease Research Centers. The research centers investigate the underlying causes, diagnoses, treatments, and prevention of digestive diseases.

April 8, 1986 – The institute's Division of Arthritis, Musculoskeletal and Skin Diseases became the core of the new National Institute of Arthritis and Musculoskeletal and Skin Diseases. The NIADDK was renamed the National Institute of Diabetes and Digestive and Kidney Diseases.

June 3, 1986 – The National Kidney and Urologic Diseases Advisory Board was established to formulate the long-range plan to combat kidney and urologic diseases.

August 1, 1987 – Six institutions were funded to establish the George M. O'Brien Kidney and Urological Research Centers.

December 25, 1987 – In response to congressional language on the FY 1988 appropriation for the NIDDK, the institute established a program of cystic fibrosis research centers.

September 16, 1990 – NIDDK celebrated its 40th anniversary. Dr. Daniel E. Koshland, Jr., editor of Science, was guest speaker.

June 1991 – The NIDDK Advisory Council established the National Task Force on the Prevention and Treatment of Obesity to synthesize current science on the prevention and treatment of obesity and to develop statements about topics of clinical importance that are based on critical analyses of the literature.

September 30, 1992 – Three Obesity/Nutrition Research Centers and an animal models core to breed genetically obese rats for obesity and diabetes research were established.

October 12, 1992 – Drs. Edwin G. Krebs and Edmond H. Fischer were awarded the Nobel Prize in Physiology or Medicine for their work on "reversible protein phosphorylation." They have received grant support from NIDDK since 1955 and 1956, respectively.

October 30, 1992 – In response to congressional language on the institute's FY 1993 appropriation, the NIDDK initiated a program to establish gene therapy research centers with emphasis on cystic fibrosis.

November 1, 1993 – The functions of the NIH Division of Nutrition Research Coordination, including those of the NIH Nutrition Coordinating Committee, were transferred to NIDDK.

October 10, 1994 – Dr. Martin Rodbell and Dr. Alfred G. Gilman received the Nobel Prize in Physiology or Medicine for discovering G-proteins, a key component in the signaling system that regulates cellular activity. Dr. Rodbell discovered the signal transmission function of GTP while a researcher in the National Institute of Arthritis and Metabolic Diseases, now NIDDK.

June 22, 1997 – Led by NIDDK, the NIH and the CDC announce the National Diabetes Education Program (NDEP) at the American Diabetes Association annual meeting in Boston. The NDEP's goals are to reduce the rising prevalence of diabetes, the morbidity and mortality of the disease and its complications.

June 2000 – In an effort to reduce the disproportionate burden of many diseases in minority populations, NIDDK initiates an Office of Minority Health Research Coordination.

November 16, 2000 – NIDDK celebrates its 50th Anniversary. Professional societies in eight U.S. locations and Canada sponsored scientific symposia and hosted an NIDDK exhibit "A New Century of Science…A New Era of Hope" is published to highlight research supported and conducted by NIDDK and concludes the year with a joint scientific symposium at the Society for Cell Biology's 40th Anniversary meeting in December.

NIDDK Legislative Chronology

December 11, 1947 – Under section 202 of P.L. 78-410 the Experimental Biology and Medicine Institute was established.

August 15, 1950 – Public Law 81-692, the Omnibus Medical Research Act, authorized establishment of NIAMDD to "... conduct researches relating to the cause, prevention, and methods of diagnosis and treatment of arthritis and rheumatism and other metabolic diseases, to assist and foster such researches and other activities by public and private agencies, and promote the coordination of all such researches, and to provide training in matters relating to such diseases...." Section 431 also authorized the Surgeon General to establish a national advisory council.

May 19, 1972 – President Nixon signed P.L. 92-305 to bring renewed emphasis to research in digestive diseases by changing the name of the institute to NIAMDD and by designating a digestive diseases committee within the institute's National Advisory Council.

August 29, 1972 – The National Cooley's Anemia Control Act (PL 92-414) authorized research in the diagnosis, treatment and prevention of this debilitating inherited disease, also known as thalassemia, occurring largely in populations of Mediterranean and Southeastern Asian origin.

July 23, 1974 – Public Law 93-354, the National Diabetes Mellitus Research and Education Act, was signed. The National Commission on Diabetes, called for by this act, was chartered on September 17, 1974, members were appointed by the HEW secretary. The act called for centers for research and training in diabetes and establishment of an intergovernmental diabetes coordinating committee, including NIAMDD and six other NIH institutes.

January 1975 – The National Arthritis Act of 1974 (P.L. 93-640) was signed into law to further research, education and training in the field of the connective tissue diseases. The HEW secretary appointed the mandated National Commission on Arthritis and Related Musculoskeletal Diseases, June 2. The act required centers for research and training in arthritis and rheumatic diseases and the establishment of a data bank, as well as an overall plan to investigate the epidemiology, etiology, control and prevention of these disorders.

October 1976 – P.L. 94-562, the Arthritis, Diabetes, and Digestive Diseases Amendments of 1976, established the National Diabetes Advisory Board charged with advising Congress and the HEW secretary on implementation of the "Long-Range Plan to Combat Diabetes" developed by the National Commission on Diabetes. The law also established the National Commission on Digestive Diseases to deal with many problems, including investigation into the incidence, duration, mortality rates, and social and economic impact of digestive diseases.

The National Arthritis Advisory Board, established by the same law, reviews and evaluates the implementation of the Arthritis Plan, formulated by the Arthritis Act of 1974. The board advises Congress, the HHS secretary, and heads of Federal agencies with respect to the plan and other Federal programs relating to arthritis.

December 1980 – Title II of the Health Programs Extension Act of 1980, P.L. 96-538, changed the institute's name to the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases. The act also established the National Digestive Diseases Advisory Board. The law authorized the National Diabetes Information Clearinghouse, the Diabetes Data Group, and the National Digestive Diseases Information and Education Clearinghouse. In addition, it reauthorized advisory boards for arthritis and diabetes research.

November 20, 1985 – The Health Research Extension Act of 1985, P.L. 99-158, changed the institute name to the National Institute of Diabetes and Digestive and Kidney Diseases. The act also established the National Kidney and Urologic Diseases Advisory Board. The law gave parallel special authorities to all institute operating divisions, including authorization of the National Kidney and Urologic Diseases Information Clearinghouse; National Kidney, Urologic, and Hematologic Diseases Coordinating Committee; National Kidney and Urologic Diseases Data System; National Digestive Diseases Data System; kidney and urologic diseases research centers; and digestive diseases research centers.

June 10, 1993 – The NIH Revitalization Act of 1993, P.L. 103-43, established NIDDK as the lead institute in nutritional disorders and obesity, including the formation of a research and training centers program on nutritional disorders and obesity.

It also provided for the directors of NIAMS, NIA, NIDR, and the NIDDK to expand and intensify programs with respect to research and related activities concerning osteoporosis, Paget's disease, and related bone disorders.

July 25, 1997 – A House report accompanying H.R. 2264 and Senate report with S. 1061, FY 1998 appropriations bills for Labor/HHS/Education, urged the NIH and NIDDK to establish a diabetes research working group to develop a comprehensive plan for NIH-funded diabetes research that would recommend future initiatives and directions. Dr. C. Ronald Kahn, diabetes research working group chairman, presented "Conquering Diabetes, A Strategic Plan for the 21st Century" to the Congress on March 23, 1999.

Biographical Sketch of NIDDK Director Allen M. Spiegel, M.D.

Allen M. Spiegel, M.D., was appointed Director of the NIDDK on November 15, 1999. As Director, he leads the national research effort to combat many of the nations most chronic and costly diseases. He promotes and supports the development of trans-NIH research initiatives to harness new developments in science and technology, and to acquire new knowledge essential to understanding, treating and preventing diseases within the NIDDK research mission. He also leads the Department's implementation of a special program of research initiatives on type 1 diabetes, which has been established by the Congress.

Spiegel has a long-standing and productive scientific association with the NIDDK. He joined the NIDDK's Endocrinology Research Training Program in 1973, after graduating cum laude from Harvard Medical School and completing an internship and residency in internal medicine at the Massachusetts General Hospital. He subsequently became a senior investigator and later Chief of the Molecular Pathophysiology Section, Metabolic Diseases Branch. In 1988, he was appointed Chief of that Branch. From 1990-1999, he served as Scientific Director of the NIDDK, with overall responsibility for guiding the research efforts of the Institute's many intramural labs and branches.

Spiegel is an internationally recognized endocrinologist whose research on signal transduction has helped to define the genetic basis of several endocrine diseases. His research established that inherited disease could be caused by defects in G proteins, which are intermediaries between hormone receptors and effectors. Spiegel and colleagues have identified mutations in G proteins that result in defective cell signaling and cause inherited disorders such as pseudohypoparathyroidism type Ia and McCune-Albright syndrome. He also participated in the successful, collaborative NIH effort to clone the tumor suppressor gene, which, when mutated, causes the inherited disease multiple endocrine neoplasia type 1 (MEN 1). Spiegel has received numerous awards in recognition of his accomplishments, including the Edwin B. Astwood Lecture Award from the Endocrine Society and the Komrower Memorial Lecture Award from the Society for the Study of Inborn Errors of Metabolism.

NIDDK Directors

Name	Date of Birth	In Office From	To
William Henry Sebrell, Jr.	1901	Aug. 15, 1950	Oct. 1, 1950
Russell M. Wilder	1885	Mar. 6, 1951	June 30, 1953
Floyd S. Daft	May 19, 1900	Oct. 1, 1953	May 3, 1962
G. Donald Whedon	July 4, 1915	Nov. 23, 1962	Sept. 30, 1981
Lester B. Salans	Jan. 25, 1936	June 17, 1982	June 30, 1984
Mortimer B. Lipsett	Feb. 20, 1921	Jan. 7, 1985	Sept. 4, 1986
Phillip Gorden	Dec. 22, 1934	Sept. 5, 1986	Nov. 14, 1999
Allen M. Spiegel	May 18, 1946	Nov. 15, 1999

Research Programs

Division of Intramural Research

The Division of Intramural Research conducts research and training within the Institute's laboratories and clinical facilities in Bethesda, Md., and at the Phoenix Epidemiology and Clinical Research Branch in Arizona.

The Division has ten Branches and ten Laboratories that cover a wide range of research areas. In addition, there is a section on veterinary sciences and an Administrative Management Branch.

Eight Branches engage in basic and clinical research on diabetes, bone metabolism, endocrinology, obesity, hematology, digestive diseases, kidney diseases and genetics. The Phoenix Branch develops and applies epidemiologic and genetic methods to the study of diabetes and obesity. The tenth branch addresses mathematical modeling of biological problems.

The Laboratories are engaged in fundamental research related to the institute's mission (e.g., molecular biology, structural biology, chemistry, cell biology, pharmacology, chemical physics, biochemistry, neuroscience, and developmental biology). The Laboratory Animal Science section provides research animal support and collaboration for institute research programs.

Division of Diabetes, Endocrinology and Metabolic Diseases

The DEMD supports research and research training related to diabetes mellitus, endocrinology, and metabolic diseases including cystic fibrosis. In addition, DEMD leads the administration of the Trans-NIH Diabetes Program and coordinates federally supported diabetes-related activities. The division also administers the Trans-NIH Cystic Fibrosis Program.

Diabetes Research Programs

The Therapeutic Approaches to Type 1 Diabetes Mellitus Program encompasses studies of therapeutic approaches to achieving euglycemia.

Specific areas of support include:

• Transplantation of pancreas, pancreatic endocrine cells (islets or beta cells) or beta cells in culture (including procedures to enhance tolerance or to improve transplant survival upon transplantation).

The Genetics of Type 1 Diabetes Program seeks to identify the genes that predispose to the development of type 1 diabetes and studies to determine their mechanism.

Specific areas of support include:

• Studies of animal models of type 1 diabetes such as the NOD mouse and the BB rat to identify genes responsible for the development of type 1 diabetes.
  
  
• Studies of the HLA region that contains the major genetic determinant for type 1 diabetes to understand its contribution to the development of diabetes.
  
  
• Studies of immune regulatory regions that may contribute to both type 1 diabetes as well as other autoimmune disorders.
  
  
• Development of genetic resources and patient samples for the studies on type 1 diabetes.
  
  
• Creation of animal models for therapeutic trials.

The Genetics of Type 2 Diabetes Program seeks to identify genes that contribute to the development of type 2 diabetes mellitus.

Specific areas of support include:

• Studies using animal models to identify diabetes genes.
  
  
• Studies using quantitative statistical methods to identify diabetes genes in human populations.
  
  
• Development of genetic resources, patient samples and methods for studying genetic linkage for diabetes.

The Clinical Research in Type 2 Diabetes Program will focus on patient-oriented research (i.e., clinical studies and small clinical trials) related to: pharmacologic interventions and/or lifestyle interventions to prevent or treat type 2 diabetes, including studies relevant to new drug development; development of surrogate markers for use in clinical trials for the prevention or treatment of type 2 diabetes; cellular therapies for the treatment of type 2 diabetes; improving the care of patients with type 2 diabetes.

The Autoimmunity/Viral Etiology of Type 1 Diabetes Program emphasizes support of investigator-initiated basic and clinical research relating to autoimmune endocrine diseases, including type 1 diabetes and autoimmune thyroid disease (AITD). Applications that address the etiology and pathogenesis of type 1 diabetes, immunology, and viral etiology of diabetes are included. Studies utilizing animal models to further our understanding of type 1 diabetes are of continuing interest to this program. Studies, which emphasize autoimmune thyroid disease, including Graves' disease, Hashimoto's thyroiditis, and their complications, are included. Humanized animal models of AITD are also included.

The Beta Cell Therapy Program focuses on research to develop alternative cell or tissue sources, as well as an understanding of the basic mechanisms that support regeneration or neogenesis of pancreatic islets. This program supports research in the following areas:

• Developing methods to expand pancreatic islets or beta cells for transplantation.
  
  
• Optimizing growth conditions for islet cell proliferation and differentiation.
  
  
• Deriving pancreatic islets from stem/precursor cells.
  
  
• Assessing alternative cell or tissue sources by transplantation.
  
  
• Animal models of islet regeneration and neogenesis.

The Epidemiology Type 1 Diabetes Research Program focuses on study of the distribution and determinants of type 1 diabetes in populations, including community-based groups and large patient populations. Specific areas of research include (1) epidemiologic studies on the genetic and environmental factors that determine type 1 diabetes; (2) geographic and temporal variations in the disease; (3) variations in disease frequency by race, socioeconomic status, metabolic factors, and other determinants; (4) studies on the etiology of diabetes including identification of risk factors determining susceptibility to diabetes and variations in the distribution of risk factors within populations and within individuals; (5) research on the etiology and pathogenesis of diabetes in well-defined populations; and (6) genetic, lifestyle, and environmental factors that predispose people to type 1 diabetes. Special emphasis is placed on epidemiologic studies of U.S. minority populations in which the prevalence and severity of diabetes and its complications are substantially elevated.

The Epidemiology Type 2 Diabetes Research Program focuses on study of the distribution and determinants of type 2 diabetes and gestational diabetes in populations, including community-based groups and large patient populations. Specific areas of research include (1) epidemiologic studies on the genetic and environmental factors that determine type 2 diabetes; (2) geographic and temporal variations in the disease and variations in disease frequency by race, socioeconomic status, metabolic factors, and other determinants; (3) studies on the etiology of diabetes including identification of risk factors determining susceptibility to diabetes and variations in the distribution of risk factors within populations and within individuals; (4) research on the etiology and pathogenesis of diabetes in well-defined populations; and (5) the genetic, lifestyle, and environmental factors that predispose people to type 2 diabetes. Special emphasis is placed on studies of U.S. minority populations in which the prevalence and severity of type 2 diabetes and its complications are substantially elevated.

The Type 2 Diabetes in the Pediatric Population Program encompasses research on the pathophysiology, prevention, and treatment of type 2 diabetes in children.

Specific areas of support include studies:

• To describe the epidemiology (incidence, prevalence, risk factors) of type 2 diabetes and its complications in children;
  
  
• To develop diagnostic criteria to distinguish type 1 and type 2 diabetes in children;
  
  
• To define the metabolic abnormalities (and the natural history of such abnormalities) in children with type 2 diabetes;
  
  
• To develop practical, effective strategies for the prevention and/or treatment of type 2 diabetes in children; and
  
  
• To understand the basis for race/ethnic disparities in the incidence of type 2 diabetes in the pediatric population.

The Glucose Sensors Program will contain projects aimed at developing or implementing glucose sensors that can determine glucose concentration in the plasma, interstitial fluid or other appropriate space in diabetic patients continuously or in repeated samples. This program also includes development of the necessary components of glucose sensors (such as biocompatible materials or fluorescent glucose ligands, new sampling systems, etc.), software, mathematical algorithms and circuitry designed for calibration or insulin pump control, and devices that combine these sensors with insulin delivery systems in a 'closed-loop' artificial pancreas.

The Prevention of Type 1 Diabetes Program includes studies on drug development, and cellular therapy that are being proposed to prevent type 1 diabetes.

Areas of particular interest are:

• Studies on drug development for type 1 diabetes treatment or prevention.
  
  
• Studies including the creation of animal models for therapy trials or humans to maintain normal blood glucose levels.
  
  
• Tolerance induction for prevention of type 1 diabetes.
  
  
• Immune intervention.
  
  
• "Humanized" mouse model (development of transgenic NOD with human HLA molecules on the T cells) for type 1 diabetes.
  
  
• Development of therapies for prevention of Impaired Glucose Tolerance (IGT) or interventions to prevent conversion of IGT to type 1 diabetes.
  
  
• Drugs designed to enhance peripheral glucose metabolism or reduce hepatic glucose production of type 1 diabetics.
  
  
• Therapies designed to increase insulin sensitivity of type 1 diabetics.

The Endocrine Pancreas Program includes projects to elucidate the basic biology of the endocrine cells of the pancreas, which include alpha, beta, delta, etc., cells within the islet. These include insulin or other hormone synthesis and secretion, coupling of nutrient sensing to insulin secretion, cell interactions, role of incretins, cytokines, other hormones, and enervation, studies of apoptosis and cell turnover in the adult organ, metabolism, basic signal transduction and regulation of gene transcription, especially as these areas relate to beta cell and islet function. This program also contains studies in cell culture to bioengineer glucose-responsive hormone secreting cells or islets for eventual treatment of diabetes.

This Hypoglycemia in Diabetes Program encompasses clinical and basic studies on the pathogenesis, prevention, treatment and sequelae (including hypoglycemia unawareness) of hypoglycemia in both type 1 and type 2 diabetes. Specific areas of research include studies to: identify the neuronal and hormonal systems involved in recognition and response to hypoglycemia; examine the interplay of counterregulatory endocrine responses; and ascertain the regulatory mechanisms for glucose homeostasis and the cells involved in this regulation.

The Diabetes Centers Program administers two types of center awards, the Diabetes Endocrinology Research Centers (DERC) and the Diabetes Research and Training Centers (DRTC). An existing base of high quality diabetes-related research is a primary requirement for establishment of either type of center. While not directly funding major research projects, both types of center grants provide core resources to integrate, coordinate and foster the interdisciplinary cooperation of a group of established investigators conducting research in diabetes and related areas of endocrinology and metabolism. The two types of centers differ in that the DERC focuses entirely on biomedical research while the DRTC has an added component in training and translation.

The Behavioral/Prevention Research Program encompasses individual, family, and community-based strategies aimed at prevention of diabetes and its complications through lifestyle modifications, education and other behavioral interventions. Particular emphasis is placed on development of culturally sensitive, lifestyle interventions to prevent or treat diabetes in diverse high-risk populations including African Americans, Hispanic Americans, and Native Americans. Specific areas of research include: 1) the link between behavior and physical health as it relates to diabetes and complications; 2) approaches to improving health-related behaviors and to enhancing diabetes self-management; and 3) other aspects of diabetes care.

The Type 1 Diabetes Clinical Trials Program supports large, multi-center clinical trials conducted under cooperative agreements or contracts. One primary prevention trial is underway. The Diabetes Prevention Trial Type-1 (DPT-1) is aimed at determining whether it is possible to prevent or delay the onset of type 1 diabetes in individuals determined to be at immunologic, genetic, and/or metabolic risk. It will also support future clinical trials of the Type 1 Diabetes TrialNet which will conduct intervention studies to prevent or slow the progress of type 1 diabetes, and natural history and genetics studies in populations screened for or enrolled in these studies. The program also supports the Epidemiology of Diabetes Interventions and Complications (EDIC) study, an epidemiologic follow-up study of the subjects previously enrolled in the Diabetes Control and Complications Trial (DCCT).

The Type 2 Diabetes Clinical Trials Program supports large, multi-center clinical trials conducted under cooperative agreements or contracts. One primary prevention trial is underway. The Diabetes Prevention Program (DPP) is focused on testing lifestyle and pharmacological intervention strategies in individuals at genetic and metabolic risk for developing type 2 diabetes to prevent or delay the onset of this disease.

The Glucose Transport Program encompasses all aspects of glucose transport in health and disease, especially as relating to glucose homeostasis in diabetes and obesity. Specific areas of support include: 1) kinetics and regulation of glucose uptake in muscle, liver, heart, gut, pancreas, kidney, etc.; 2) regulation and mechanism of glucose transporter (GLUT) storage, translocation to the membrane, and gene expression by insulin and other hormones, glucose, diet, exercise, and metabolic state (fasting, obesity); 3) structure of glucose transporter; and 4) kinetic and structural studies of the transport proteins and/or membrane channels of other nutrients, such as amino acids, ions and metals.

The Complications of Diabetes Program encompasses basic and clinical research related to acute (e.g., ketoacidosis and hyperosmolar coma) and chronic complications of type 1 and type 2 diabetes. Chronic complications include the vascular complications of diabetes and the effects of diabetes on any organ system. Clinical studies supported under this program include strategies to prevent or treat the complications of diabetes. Supported basic research examines the molecular and cellular mechanisms by which hyperglycemia mediates its adverse effects and the interrelationships among the mechanisms potentially involved in the pathogenesis of complications, including: increased polyol pathway flux; alterations of intracellular redox state; oxidative stress; glycation of structural and functional proteins; altered expression of growth factors; enhanced activity of PKC; impaired synthesis of nitric oxide and other vasoactive substances; and altered metabolism of fatty acids.

The Insulin Receptor/Structure/Function/Action Program encompasses studies of the structure, function and action of the insulin receptor. Specific areas of support include: 1) molecular analysis of ligand binding to receptor; 2) activation of the tyrosine kinase; 3) subsequent insulin receptor function in signal transduction by serving as a platform for the attachment of downstream signaling molecules involved in insulin action; and 4) the Insulin Receptor Signaling proteins (IRS)-1,2,3,4, and other proteins containing Src Homology Domains (e.g., SH2).

The Clinical Research in Type 2 Diabetes Program will focus on patient-oriented research (i.e., clinical studies and small clinical trials) related to: pharmacologic interventions and/or lifestyle interventions to prevent or treat type 2 diabetes, including studies relevant to new drug development; development of surrogate markers for use in clinical trials for the prevention or treatment of type 2 diabetes; cellular therapies for the treatment of type 2 diabetes; and improving the care of patients with type 2 diabetes.

The Adipocyte Biology Research Program encompasses research that addresses the development and physiology of the adipocyte cell. Specific areas of support include: 1) studies on the properties of transcription factors that regulate adipocyte differentiation; 2) research on the consequences of insulin action on adipocyte physiology; and 3) use of animal and tissue culture models to understand adipocyte biology.

The Diabetes Mellitus Interagency Coordinating Committee (DMICC), established in 1974 and chaired by the Director, DDEMD, includes representatives from all Federal departments and agencies whose programs involve health functions and responsibilities relevant to diabetes mellitus and its complications. Functions of the DMICC are 1) coordination of the research activities of the NIH and those activities of other Federal programs that are related to diabetes mellitus and its complications; 2) ensuring the adequacy and soundness of these activities; and 3) providing a forum for communication and exchange of information necessary to maintain coordination of these activities.

The National Diabetes Data Group (NDDG) serves as the major Federal focus for the collection, analysis, and dissemination of data on diabetes and its complications. Drawing on the expertise of the research, medical, and lay communities, the NDDG initiates efforts to: 1) define the data needed to address the scientific and public health issues in diabetes; 2) foster and coordinate the collection of these data from multiple sources; 3) identify important data sources on diabetes, and analyze and promulgate the results of these analyses to the scientific and lay public; 4) promote the timely availability of reliable data to scientific, medical, and public organizations and individuals; 5) modify data reporting systems to identify and categorize more appropriately the medical and socioeconomic impact of diabetes; 6) promote the standardization of data collection and terminology in clinical and epidemiologic research; and 7) stimulate development of new investigator-initiated research programs in diabetes epidemiology.

The National Diabetes Education Program (NDEP), co-sponsored by the NIDDK and the Centers for Disease Control and Prevention (CDC), is focused on improving the treatment and outcomes for people with diabetes, promoting early diagnosis, and ultimately preventing the onset of diabetes. The goal of the program is to reduce the morbidity and mortality associated with diabetes through public awareness and education activities targeted to the general public, people with diabetes and their families, health care providers, and policy makers and payers. These activities are designed to 1) increase public awareness that diabetes is a serious, common, costly, and controllable disease that has recognizable symptoms and risk factors; 2) encourage people with diabetes, their families, and their social support systems to take diabetes seriously and to improve practice of self-management behaviors; and 3) alert health care providers to the seriousness of diabetes, effective strategies for its control, and the importance of a team care approach to helping patients manage the disease. Toward these ends, the NDEP is developing partnerships with organizations concerned about diabetes and the health care of its constituents.

Endocrinology Research Programs

The Bone and Mineral Metabolism Research Program encompasses basic and clinical research on the hormonal regulation of bone and mineral metabolism in health and disease. Specific areas of support include: 1) endocrine aspects of disorders affecting bone, including osteoporosis, Paget's disease, renal osteodystrophy, and hypercalcemia of malignancy; 2) pathogenesis, diagnosis and therapy of parathyroid disorders, including primary or secondary hyperparathyroidism; 3) effects of parathyroid hormone (PTH), parathyroid hormone related protein (PTHrP), calcitonin, vitamin D, estrogen, retinoic acid, growth factors (e.g., IGF-I, etc.), glucocorticoids, thyroid hormone and other systemic or local-acting hormones and their receptors on bone metabolism; 4) bone active cytokines (e.g., TGF-b, BMPs, CSF-1); 5) studies of calcium homeostasis, absorption, metabolism, and excretion, including the calcium activated receptor (CaR); 6) basic and clinical studies of vitamin D; and 7) bone morphogenesis, including the roles of developmental factors in bone formation (e.g., hedgehogs, Hox genes).

The G-Protein Coupled Receptors Program encompasses studies on the G-protein coupled receptor superfamily. Specific areas of support include: 1) cell surface, or seven transmembrane domain (7-TM), receptors coupled to GTP-binding ("G")- proteins for signal transduction (e.g., beta-adrenergic receptor); 2) receptor structure; 3) receptor down-regulation (homologous desensitization); 4) role(s) of mutated receptors in disease; and 5) coupling of signaling through the receptor to other membrane-bound effectors and or regulators, such as adenylyl cyclase, ion channels, protein phosphatases or kinases, and other receptors. Signal transduction through GPCRs also includes mechanisms of regulation of gene expression through nuclear proteins such as the Cyclic Nucleotide Response Element Binding Protein (CREB) and the CREB binding protein (CBP).

The Nuclear Hormone Superfamily Program encompasses basic and clinical research on members of the steroid hormone superfamily (also known as the nuclear receptor superfamily). The program includes structure/function studies and the role in signal transduction and regulation of gene expression of the steroid hormones (glucocorticoids, mineralocorticoids, progesterone, estrogens, androgens (testosterone), DHEA) and the nuclear receptors including thyroid hormone, vitamin D, retinoids (RAR, RXR, vitamin A), PPARs, and orphan receptors (LXR, Nur77, COUP-TF, and others). Topics covered include receptor structure, interaction with cytoplasmic chaperones (e.g., Hsp90, Hsp70, etc.), interaction with ligand, nuclear translocation, binding to hormone response elements, interaction with nuclear accessory proteins (e.g., SRC-1, N-CoR, CBP, histone acetylase/deacetylase, GRIP1, etc.), and regulation of gene expression.

The Neuroendocrinology Program encompasses research on neuropeptides of the hypothalamus. Specific areas of research support include: 1) physiological response to stress through the hypothalamic-pituitary-adrenal axis; 2) neuropeptides and neuropeptide receptor signaling pathways; 3) gene regulation in the hypothalamus and pituitary gland; 4) diseases of the pituitary including neoplasia; 5) hypopituitary dwarfism; 6) identification and characterization of novel hypothalamic or pituitary hormones; 7) tissue specific and developmental expression of pituitary and hypothalamic genes; 8) pituitary hormone receptors and actions on target tissues (e.g., GH IGF-1 axis); 9) neuropeptide receptors in diagnosis and treatment of disease; and 10) neuroendocrine-immune interactions.

The Regulation of Energy Balance and Body Composition Program encompasses research on regulation of body composition by the hypothalamus and circulating factors. Specific areas of support include: 1) endocrinology of body composition including interactions between nutrition, exercise, and anabolic hormones; 2) neuropeptides and their receptors involved in regulatory pathways controlling feeding behavior, satiety, and energy expenditure; 3) interactions between hypothalamicpituitary adrenal axis and peripheral metabolic signals (for example, insulin), leptin, glucocorticoids); 4) hormones and cytokines involved in wasting syndromes (cancer, AIDS); 5) endocrine regulation of energy balance via uncoupling proteins; and 6) hypothalamic integration of peripheral endocrine and metabolic signals.

The Nonautoimmune Thyroid Disease Research Program is focused on normal thyroid physiology and non-autoimmune thyroid disease. Specific areas of research focus on: the physiologic regulation of the expression, processing, and secretion of thyroid hormones; dysfunctional regulation of thyroid hormones that results in disease; the etiology, pathogenesis, diagnosis, and therapy of thyroid disorders; the deiodinase enzymes that convert inactive thyroid hormone to active hormone; and neural cells that are targets of regulation by and feedback to the thyroid.

The Steroid Metabolism Program includes the biochemistry, molecular biology, intermediary metabolism, function and structure of steroids and similar molecules derived from cholesterol, including sex steroids and other hormones (glucocorticoids, mineralocorticoids), retinoids, cardiac glycosides, prostaglandins and eicosanoids, and bile acids. Structural and functional studies of the heme proteins, like mitochondrial cytochromes and cytochrome P450 are included in this program. It can also include enzyme structure and biology in activated nitrogen and oxygen species metabolism (nitric oxide, superoxide, hydrogen peroxide, and antioxidant enzymes).

The Mouse Metabolic Phenotyping Program contains a consortium of centers with the purpose of phenotyping mouse models of diabetes and its complications, obesity, or other chronic metabolic diseases. It will include the development of new tests for phenotyping mice, adaptation or miniaturization of existing tests, as well as the performance of these tests to more fully characterize new or existing models of disease. Emphasis is placed on non-invasive or minimally invasive technologies that can be used for longitudinal studies, but this program also includes high-throughput metabolic screens. Examples include glucose and insulin clamps, miniaturized assays for hormones, cytokines, nutrients or intermediary metabolites, kinetic measures of metabolic processes, immunological parameter, measurements of energy balance, body composition and activity, measures for metabolic, behavioral and physiologic abnormalities during disease progression.

The Developmental Biology Program includes grants dealing with developmental genetic screens for identifying mutations that affect the formation of tissue such as bone, adipose, endocrine pancreas or pituitary and grants dealing with signals, signaling pathway components and transcriptional factors that regulate pattern formation in the embryo, or control the fate, specifications, proliferation and differentiation of cells in the formation of tissues and organs.

The Intracellular Signal Transduction Research Program encompasses research aimed at understanding the structure and function of intracellular signal transducing molecules. Specific areas of support include: 1) intracellular kinases, phosphatases and anchoring proteins; 2) signaling mechanisms that have altered activity in response to protein phosphorylation, Ca++ and cAMP; 3) approaches to solving the three-dimensional structure of signaling proteins including crystallography and NMR; 4) functional analysis of these proteins including comparison of wild-type and naturally occurring or synthetic, mutant proteins or expression of dominant-negative forms of the proteins; 5) microscopic techniques to localize these proteins within cells; 6) the identification of substrates for these signaling proteins; and 7) the analysis of crosstalk among distinct signal transduction pathways.

The Hormone Distribution Program of the NIDDK makes available to the research community human and animal pituitary hormones, antisera to these hormones, and selected other hormonal and biological products. Currently, approximately 180 research materials are distributed through the National Hormone and Pituitary Program. Most of the products are unavailable commercially. Approximately 7,000 individual vials of human and animal hormones and antisera are awarded annually to investigators for immunochemical research. Frozen human pituitaries and rat hypothalami are also available for distribution to scientists attempting to isolate or characterize novel hormones and peptides or variants. Information about the distribution of these resources may be obtained from the Pituitary Hormones & Antisera Program.

Metabolic Diseases Research Programs

The Gene Therapy and Cystic Fibrosis Centers Program supports three types of centers: Gene Therapy Centers (P30), Cystic Fibrosis Research Center (P30), and Specialized Centers for Cystic Fibrosis Research (P50). Gene Therapy Centers provide shared resources to a group of investigators to facilitate development of gene therapy techniques and to foster multidisciplinary collaboration in the development of clinical trials for the treatment of cystic fibrosis and other genetic metabolic diseases. Cystic Fibrosis Research Centers (P30) and Specialized Centers for Cystic Fibrosis Research (P50) provide resources and support research on many aspects of the pathogenesis and treatment of cystic fibrosis.

The Cystic Fibrosis Research Program supports investigator-initiated research grants encompassing both fundamental and clinical studies of the etiology, molecular pathogenesis, pathophysiology, diagnosis, and treatment of cystic fibrosis and its complications. Particular areas of emphasis of the program include: 1) characterization of the cystic fibrosis gene, its mutations, and the molecular mechanisms by which mutations cause dysfunction; 2) studies of the cystic fibrosis transmembrane regulator (CFTR) protein encoded by the cystic fibrosis gene, including its processing, trafficking, and folding, and the mechanisms by which mutations alter CFTR trafficking and structure/function; 3) elucidation of the pathways of electrolyte transport in affected epithelia and the relationship between CFTR and other epithelial ion channels; 4) elucidation of the potential roles of CFTR in transport of molecules other than chloride, posttranslational processing of mucins and other proteins, exocytosis and recycling of cell membranes, subcellular organelle function, and other cellular processes; 5) studies of the relationship between genotype and phenotype in cystic fibrosis and identification of genetic or environmental factors which explain the variable clinical presentations and severity of disease; 6) delineation of the mechanisms underlying the inflammation and infection characteristic of cystic fibrosis and how mutations in the cystic fibrosis gene and alterations in CFTR function result in inflammation and infection; 7) research on other clinical manifestations of cystic fibrosis, including the pathophysiologic mechanisms underlying malnutrition and growth failure, impaired fertility, liver disease, and overall physical and psychosocial development, and approaches to ameliorate the complications of cystic fibrosis; 8) development of potential therapeutic approaches to modulating the transport defect in cystic fibrosis and to stabilize mutant CFTR and enhance its targeting and integration into the cell membrane; 9) development of safe and effective methods for gene therapy; 10) development of animal or cell models useful for study of cystic fibrosis and its therapy; and 11) evaluation of therapeutic interventions in cystic fibrosis in clinical studies or animal models.

The Gene Therapy Program encompasses research aimed at developing basic and applied gene therapy for genetic metabolic diseases. Specific areas of support include: 1) pilot and feasibility studies (R21) to improve gene delivery systems; 2) studies of the basic science of AAV, adenovirus, retrovirus and lentivirus vectors; 3) studies of non-viral methods of gene transfer such as liposomes or DNA-conjugates; 4) studies to target gene delivery to specific cell types; and 5) gene therapy of stem cells to treat a genetic metabolic disease.

The Inborn Errors of Metabolism Program encompasses research in the pathophysiology and treatment of genetic metabolic diseases. Specific areas of support include: 1) studies of etiology, pathogenesis, prevention, diagnosis, pathophysiology, and treatment of these diseases; 2) characterization of the genes, gene defects and regulatory alterations that are the underlying causes of these diseases; 3) studies of the mutant enzyme and its effect on the structure and function of the protein 4) the development of animal models for genetic disease; 5) development and testing of dietary, pharmacologic and enzyme replacement therapies; and 6) development of stem cell transplantation both prenatally and postnatally as a treatment for metabolic diseases.

The Metabolic Complications of HIV Program encompasses research on the endocrine and body composition abnormalities associated with HIV infection and its treatment.

Specific areas of support are:

• Studies of hormones and cytokines involved in wasting syndrome.
  
  
• Studies of changes in body composition in HIV patients.
  
  
• Studies of abnormalities of insulin sensitivity (and other components of the "Metabolic Syndrome" or "Syndrome X") in patients with HIV.

The Protein Trafficking/Secretion/Processing Research Program encompasses research aimed at understanding the mechanisms that account for the fate of proteins after their initial translation. Specific areas of support include: 1) protein folding; 2) post-translational modifications and the enzymes that catalyze them; 3) the movement of proteins in vesicles from the endoplasmic reticulum (ER) through the golgi and endosomes and their ultimate secretion; 4) mechanisms that account for vesicle formation (pinching off) and vesicle fusion which are paramount to understanding trafficking; 5) the movement of proteins in the direction opposite of secretion, including endocytosis and retrograde transport; 6) proteins and small molecules that regulate protein trafficking; and 7) proteasomes, ubiquitin conjugation, and the N-end rule.

The Molecular and Functional Imaging Program is comprised of projects that employ novel molecular and functional imaging techniques to visualize various aspects of diabetes and obesity, endocrinology, metabolism and metabolic diseases. The emphasis will be on in vivo techniques (PET, MRI, Ultrasound, CT, optical tomography, etc.) with applications serving to tag tissues and cells of interest; study biological processes in vivo; diagnose disease; or monitor progress during therapy. These will be studies either to monitor physiological or metabolic processes, rate of metabolism, blood flow, sites of hormone action, etc., using imaging and spectroscopic techniques or to identify cell types using molecular imaging probes. Another application might be the technology to develop a probe to identify in vivo the sites within the hypothalamus that control satiety.

The Proteomics in Diabetes, Endocrinology and Metabolic Diseases Program is comprised of grants that study the structure, mechanism, kinetics, and regulation of isolated purified proteins. This would include x-ray crystallography, mass spectroscopic, electron microscopic, nuclear magnetic resonance, and mutational studies of structure. It would include studies of subunit interactions and interactions with small regulatory ligands, substrates, intermediates, and products. Of special interest are new technologies for structure determination (especially membrane proteins), crystallization, identification of interacting molecules and proteins, and assignment of function to unknown gene products of interest to the fields of diabetes, endocrinology and metabolic diseases. High throughput methods are highlighted. All informatics associated with the field of proteomics are included.

The Metabolism and Insulin Resistance Program is comprised of grants that study intermediary metabolism and physiology on the whole body, organ, and cell level. These studies can be done in vivo, in isolated tissues or in cell culture. They have as a focus flux and regulation of either a single metabolic pathway, interacting pathways in a cell or organ, or interactions between organs in the whole body. Especially important are in vivo measurements of whole body flux, such as glucose production or turnover, or blood flow. Examples of important goals for these studies include an understanding of insulin resistance, regulation of gluconeogenesis and glucose disposal, protein turnover rate and regulation, cellular and whole body lipid fluxes, interaction between carbohydrate and lipid metabolism, rate of tricarboxylic acid cycle flux and energy production in the cell, transcriptional regulation of important flux regulating enzymes or transporters for a given pathway, etc.

Division of Digestive Diseases and Nutrition

This division supports research related to liver and biliary diseases, pancreatic diseases, gastrointestinal diseases, including neuroendocrinology, motility, immunology, and digestion in the GI tract, nutrient metabolism, obesity, eating disorders, and energy regulation. The division provides leadership in coordinating activities related to digestive diseases and nutrition throughout the NIH and with various other Federal agencies.

Digestive Diseases Programs

The Acquired Immunodeficiency Syndrome Program encourages research into the characterization of intestinal injury, mechanism of maldigestion, and intestinal mucosal functions, as well as hepatic and biliary dysfunction in AIDS. In addition, studies are supported on mechanisms of nutrient dysfunction, nutritional management in the wasting syndrome and other aspects of malnutrition related to AIDS.

Clinical Trials in Digestive Diseases. The Clinical Trials in Digestive Diseases is a prospective study on ten or more patients to evaluate one or more experimental intervention(s) in comparison with a standard treatment and/or placebo control among comparable groups of patients. Experimental interventions may include pharmacologic, nonpharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Areas of emphasis include nonalcoholic steatohepatitis (NASH); chronic hepatitis C; Helicobacter pylori; primary biliary cirrhosis; adult and adolescent obesity; inflammatory bowel disease; functional bowel syndrome and constipation; primary sclerosing cholangitis; pancreatitis; non-ulcer dyspepsia; prevention, management, and treatment of portal hypertension; and recurrent liver disease after transplantation. Either pilot studies or phase III trials may be appropriate. A phase III clinical trial usually involves several hundred or more comparable human subjects. The aim of the trial is to provide evidence for support of, or a change in, health policy or standard of care.

The Digestive Diseases and Nutrition Epidemiology and Data Systems was authorized by P.L. 99-158 for the collection, storage, analysis, retrieval, and dissemination of data derived from patient populations with digestive diseases and, where possible, data involving general populations to detect individuals with a risk of developing digestive diseases. The program emphasizes determining environmental and genetic risk factors, outcomes, and the public health impact of digestive and nutritional disorders.

The Digestive Diseases Research Core Centers (DDRCCs) in this program presently focus on liver diseases, gastrointestinal motility, absorption and secretion processes, inflammatory bowel disease, structure/function relationships in the gastrointestinal tract, neuropeptides and gut hormones, and gastrointestinal membrane receptors.

The Gastrointestinal Motility Program supports research on structure and function of gastrointestinal muscles, the biochemistry of contractile processes and mechanochemical energy conversion relations between metabolism and contractility in smooth muscle, extrinsic control of digestive tract motility, and fluid mechanics of gastrointestinal flow. Areas of interest include actions of drugs on gastrointestinal motility, intestinal obstruction, and diseases such as irritable bowel syndrome, colonic diverticular disease, swallowing disorders, and gastroesophageal reflux.

The Gastrointestinal Mucosa and Immunology Program. Research focuses on intestinal immunity and inflammation. Areas include: ontogeny and differentiation of gut-associated lymphoid tissue; migratory pathways of intestinal lymphoid cells; humoral antibody responses; cell-mediated cytotoxic reactions; genetic control of the immune response at mucosal surfaces; immune response to enteric antigens in both intestinal/extraintestinal sites; granulomatous inflammation; lymphokines and cellular immune regulation; leukotrienes/prostaglandin effects on intestinal immune responses; T-cell mediated intestinal injury; intestinal mast cells and their role in inflammation; approaches to optimal mucosal immunoprophylaxis, including viral, bacterial, and parasitic diseases; and diseases such as gluten sensitive enteropathy, inflammatory bowel disease, and gastritis.

The Gastrointestinal Neuroendocrinology Program supports both basic and clinical studies on normal and abnormal function of the enteric nervous system and the central nervous system elements that control the enteric nervous system. Research focuses on gastrointestinal hormones and peptides and studies on disease conditions associated with excessive or deficient secretions of neuropeptides.

The Gastrointestinal Transport and Absorption Program supports research on the process of food digestion in the gastrointestinal tract (GIT). Areas of research focus on the regulation of gene expression in the GIT; structure and function of the gut mucosa; cytoskeletal structure and contractility in brush border; growth and differentiation of gastrointestinal cells in normal and disease states; intestinal transplantation, storage, and preservation; and gastrointestinal tissue injury, repair, and regeneration.

The Liver and Biliary Program supports basic and clinical research into the normal function and the diseases of the liver and biliary tract. Areas of study include: Neurohormonal factors involved in the regulation of hepatic and biliary function, studies on receptors, and intracellular signal transducing pathways involved in hepatic response to different etiological factors; Post-translational mechanisms that account for the fate of proteins.

Studies of the biochemistry, etiology, pathogenesis, genetics, diagnosis, treatment and prevention of disorders of the liver and biliary tract, including chronic liver diseases and its sequelae, and liver diseases during pregnancy.

Studies on the natural history of infectious hepatitis, particularly viral Hepatitis C and B, its epidemiology, risk factors, preventive and therapeutic intervention; Studies on the interrelation of alcohol, viral hepatitis, HIV infections in the course of chronic liver diseases, cirrhosis and hepatic cancers; Basic and clinical studies on the etiology, molecular pathogenesis, pathophysiology, diagnosis, and treatment of hereditary liver diseases and its complications. Special emphasis is on characterization of the genes, gene defects and regulatory alterations that are the underlying causes of these diseases.

Developing an understanding of the basic underlying concepts and methodologies for gene therapy its application to the treatment of genetic liver diseases; Developmental of experimental models relevant of liver diseases; Studies on the isolation, characterization, culture of viable hepatocytes and stem cells for cell bioengineering and transplantation as support therapies for acute and chronic liver diseases.

The Pancreas Program encourages research into the structure, function, and diseases (excluding cancer and cystic fibrosis) of the exocrine pancreas. Research efforts focus on: Neurohormonal factors involved in the regulation of pancreatic exocrine function in response to pathophysiological stimuli; Studies on receptor and function of intra-cellular signal transducing molecules, coupling to downstream effectors; Compartmentalization of enzymes, substrates, and their effectors; Understanding post-translational mechanisms that account for the fate of proteins, including folding, trafficking and secretion. Understanding the properties and functions of intracellular and extracellular filamentous suprastructures that are involved in hormone signaling and exocrine pancreatic function.

Studies on the biochemistry, etiology, pathogenesis, genetics, epidemiology, diagnosis, treatment and prevention of disorders of the exocrine pancreas; Development of experimental models; Studies relating to development of the exocrine pancreas including the growth and differentiation factors involved in this process and the characterization, isolation, production and uses of pancreatic stem cells; Studies on organ collection, preservation and transplantation.

The Genetics and Genomics of Digestive Diseases supports research on identification of genes influencing predisposition to diseases of the gut, liver, and exocrine pancreas, as well as studies of control of gene expression during normal development and disease states of these organs.

Epidemiology and Clinical Trials Programs

The Clinical Trials Program in Digestive Diseases. The Clinical Trials in Digestive Diseases is a prospective study on ten or more patients to evaluate one or more experimental intervention(s) in comparison with a standard treatment and/or placebo control among comparable groups of patients. Experimental interventions may include pharmacologic, nonpharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Areas of emphasis include non-alcoholic steatohepatitis (NASH); chronic hepatitis C; Helicobacter pylori; primary biliary cirrhosis; adult and adolescent obesity; inflammatory bowel disease; functional bowel syndrome and constipation; primary sclerosing cholangitis; pancreatitis; non-ulcer dyspepsia; prevention, management, and treatment of portal hypertension; and recurrent liver disease after transplantation. Either pilot studies or phase III trials may be appropriate. A phase III clinical trial usually involves several hundred or more comparable human subjects, the aim of the trial being to provide evidence for support of, or a change in, health policy or standard of care.

The Clinical Trials Program in Obesity/Nutrition. This program includes prospective studies in nutrition and obesity that involve ten or more patients. In these studies, two forms of treatment, one which could be placebo or standard care, are to be compared. Areas of emphasis include adult and adolescent obesity, and nutrition areas such as eating disorders and wasting.

Either pilot studies or phase III trials may be appropriate. A phase III clinical trial usually involves several hundred or more comparable human subjects. The aim of the trial is to provide evidence for support of, or a change in, health policy or standard of care.

The Epidemiology and Data Systems Program was authorized by P.L. 99-158 for the collection, storage, analysis, retrieval, and dissemination of data derived from patient populations with digestive diseases and, where possible, data involving general populations to detect individuals with a risk of developing digestive diseases. The program emphasizes determining environmental and genetic risk factors, outcomes, and the public health impact of digestive and nutritional disorders.

Digestive Diseases and Nutrition Epidemiology and Data Systems was authorized by P.L. 99-158 for the collection, storage, analysis, retrieval, and dissemination of data derived from patient populations with digestive diseases and, where possible, data involving general populations to detect individuals with a risk of developing digestive diseases. The program emphasizes determining environmental and genetic risk factors, outcomes, and the public health impact of digestive and nutritional disorders.

Look AHEAD: Action for Health in Diabetes is a clinical trial recruiting 5000 obese individuals with type 2 diabetes into an 11.5 year study that will investigate the long term health consequences of interventions designed to achieve and sustain weight loss. The primary outcome of the trial is cardiovascular events: heart attack, stroke and cardiovascular death. The study also will examine impact of the interventions on cardiovascular risk factors, diabetes control, cost effectiveness, quality of life, and a number of additional measures. The Obesity Special Projects program also administers ancillary studies to Look AHEAD.

Nutritional Sciences Programs

Clinical Nutrition Research Units (CNRU). The CNRU is an integrated array of research, educational, and service activities focused on human nutrition in health and disease. It serves as the focal point for an interdisciplinary approach to clinical nutrition research and for the stimulation of research in improved nutritional support of acutely and chronically ill persons, assessment of nutritional status, effects of disease states on nutrient needs, and effects of changes in nutritional status on disease.

The Clinical Trials Program in Digestive Diseases. The Clinical Trials in Digestive Diseases is a prospective study on ten or more patients to evaluate one or more experimental intervention(s) in comparison with a standard treatment and/or placebo control among comparable groups of patients. Experimental interventions may include pharmacologic, nonpharmacologic, and behavioral interventions given for disease prevention, prophylaxis, diagnosis, or therapy. Areas of emphasis include non-alcoholic steatohepatitis (NASH); chronic hepatitis C; Helicobacter pylori; primary biliary cirrhosis; adult and adolescent obesity; inflammatory bowel disease; functional bowel syndrome and constipation; primary sclerosing cholangitis; pancreatitis; non-ulcer dyspepsia; prevention, management, and treatment of portal hypertension; and recurrent liver disease after transplantation. Either pilot studies or phase III trials may be appropriate. A phase III clinical trial usually involves several hundred or more comparable human subjects. The aim of the trial is to provide evidence for support of, or a change in, health policy or standard of care.

The Clinical Trials Program in Obesity/Nutrition. This program includes prospective studies in nutrition and obesity that involve ten or more patients. In these studies, two forms of treatment, one which could be placebo or standard care, are to be compared. Areas of emphasis include adult and adolescent obesity, and nutrition areas such as eating disorders and wasting.

Either pilot studies or phase III trials may be appropriate. A phase III clinical trial usually involves several hundred or more comparable human subjects. The aim of the trial is to provide evidence for support of, or a change in, health policy or standard of care.

The Nutrient Metabolism Program supports basic and clinical studies related to the requirement, bioavailability, and metabolism of nutrients and other dietary components. Specific areas of research interest include understanding of physiological function and mechanism of action/interaction of nutrients within the body; effects of environment, heredity, stress, drug use, toxicants, and physical activity on problems of nutrient imbalance and nutrient requirements in health and disease; and specific metabolic considerations relating to alternative forms of nutrient delivery and use such as total parenteral nutrition. The program also supports research to improve methods of assessing nutritional status in health and disease.

The Obesity and Eating Disorders Program emphasizes support of investigatorinitiated basic and clinical research relating to biomedical and behavioral aspects of obesity and eating disorders including anorexia nervosa, bulimia nervosa, and binge eating disorder. This research seeks to establish a clear understanding of the etiology, prevention, and treatment of these multifaceted conditions. Areas of research interest include investigations of molecular, physiological, metabolic, neuroendocrine, psychological, epidemiologic, and genetic factors that affect food choices, food intake, eating behavior, appetite, satiety, body composition, nutrient partitioning, and energy regulation. Studies include the effects of taste, smell, and gastric and humeral response in association with dietary intake and subsequent behavior. The roles of neural and hormonal factors, including leptin and its receptors, melanocortins and their receptors, Agouti-related peptide, MCH, urocortin, CRH, NPY, CART, orexin, CPE, and others from the molecular to the whole animal/human level are encompassed within this program if the primary goal of the investigations is to examine their role in the development or maintenance of obesity. The physiological and metabolic consequences of weight loss or weight gain, the effect of exercise on appetite and weight control, and the individual variability in energy utilization and thermogenesis (including the role of the uncoupling proteins and beta 3 adrenergic receptors in energy regulation) are contained within the specific research interests of this program. In addition, endocrine, metabolic, dietary, and other genetic and environmental determinants of the proliferation and control of adipocyte size, deposition and number, and the responsiveness of the adipocyte to various metabolic and pharmacological stimuli as they relate to the development of obesity are also specific topics. Investigations incorporating improved methods for assessment of body composition, examination of health risk factors with specific degrees of obesity or body composition, and determination of the effect of exercise on body composition also are supported.

The Obesity Special Projects Program administers the clinical trial Look AHEAD: Action for Health in Diabetes. Look AHEAD is recruiting 5,000 obese individuals with type 2 diabetes into an 11.5-year study that will investigate the long-term health consequences of interventions designed to achieve and sustain weight loss. The primary outcome of the trial is cardiovascular events: heart attack, stroke and cardiovascular death. The study also will examine impact of the interventions on cardiovascular risk factors, diabetes control, cost effectiveness, quality of life, and a number of additional measures. The Obesity Special Projects program also administers ancillary studies to Look AHEAD that were awarded under the RFA DK-00-017. Look AHEAD may potentially accept additional ancillary studies submitted as investigator-initiated applications, if they are approved in advance by the Look AHEAD Sub-studies and Ancillary Studies Committee to ensure that they do not impose an excessive burden on Look AHEAD participants or staff.

Obesity/Nutrition Research Center (ONRC). The ONRCs encourage collaboration among researchers and a multidisciplinary approach to the treatment and prevention of obesity. They will help to capitalize on emerging research opportunities in obesity and to enhance the translation of research findings to the public.

U.S. - Japan Malnutrition Panel. In 1965 President Lyndon B. Johnson and Japanese Prime Minister Eisaku Sato issued a joint communiqu� recognizing their mutual concern for the health and well being of all peoples of Asia. This led to the formation of the U.S.-Japan Cooperative Medical Science Program, which operates within a bilateral government framework. The malnutrition panel was established in 1966 to foster and support investigator-initiated research to help alleviate the serious problem of malnutrition.

Current topics of importance to the United States and Japan focus on consequences of changing dietary patterns on health, development of disease, and disease prevention. Specific research includes topics related to obesity and its co-morbidities with emphasis on the impact of body composition and regional deposition of adipose tissue on the development of physiologic abnormalities.

The Clinical Trials in Obesity/Nutrition Program includes prospective studies in nutrition and obesity, which involve ten or more patients. In these studies, two forms of treatment, one of which could be placebo or standard care, are to be compared. Areas of emphasis include adult and adolescent obesity, and nutrition areas such as eating disorders and wasting.

The Obesity Prevention and Treatment Program is designed to support research that focuses on the prevention and treatment of overweight and obesity in human populations. Prevention includes primary and secondary approaches to prevent the initial development of overweight/obesity through control of inappropriate weight gain and increases in body fat; weight maintenance among those at risk of becoming overweight, and prevention of weight regain once weight loss has been achieved. Treatment includes clinical trials evaluating approaches to lose weight or maintain weight loss, including, but not limited to, behavioral, pharmacological, and surgical approaches. This program also includes environmental-, policy-, and population-based approaches to the prevention and/or treatment of obesity.

Division of Kidney, Urologic and Hematologic Diseases

The division supports research on diseases of the kidney, genitourinary tract, and blood and blood-forming organs, and on the fundamental biology relevant to these organ systems. It funds training and professional development of investigators in disciplines critical for research in these areas.

Kidney Research

The Basic Renal Biology Program supports research on normal development, structure and function of the kidney. Areas of emphasis include glomerular function and cell biology, transport physiology and structure-function analysis of transport proteins, and integrated regulation of solute and water excretion. The program supports investigation of adverse effects of nephrotoxic drugs and environmental toxins and mechanisms of hypoxic renal cell injury.

A major area of strength is studies examining intracellular signal transduction for renal hormones and growth factors. In addition to study on mammalian systems, investigation is supported on transport function and development and genomic analysis of membrane transport proteins using simple systems such as bacteria C. elegans and zebrafish.

The Chronic Renal Diseases Program supports basic and clinical studies on the etiology, prevention, diagnosis and treatment of chronic renal diseases. Disease categories receiving particular emphasis include analgesic nephropathy, polycystic kidney disease, diabetic nephropathy, glomerulonephritis and other immune disorders of the kidney, hypertensive nephrosclerosis and HIV nephropathy. A major interest in this program is renal diseases that affect children and the effects of chronic renal insufficiency on growth and development of children.

The End-Stage Renal Disease Program supports investigation on the pathogenesis of the uremic state, on end-stage renal disease treatment by peritoneal and hemodialysis, and on nutrition in renal disease. Investigation on renal transplantation is supported with particular emphasis on nonimmunological renal injury and on methods of increasing organ availability, particularly in minority populations.

The Diabetic Nephropathy Program supports investigation into the pathogenesis, prevention and treatment of the kidney disease associated with diabetes mellitus. One major area of emphasis is the identification of genes associated responsible for the familial clustering of diabetic kidney disease, through sponsorship of the FIND consortium.

The Pediatric Nephrology Program supports basic and clinical research on the causes, treatments, and prevention of kidney diseases of children. Research efforts focus on inherited and congenital renal diseases; kidney disease of diabetes mellitus; IgA nephropathy; and kidney disease and hypertension, which starts in early childhood.

The Renal Epidemiology Program – Investigation into the incidence and prevalence of renal diseases, the factors associated with increased mortality and co-morbidity and cost-benefit assessment of prevention and treatment strategies are areas supported through the renal epidemiology program.

The U.S. Renal Data System (USRDS), an information resource for the epidemiology of end-stage renal disease, is supported through this program. USRDS investigation of cost factors in dialysis care is co-funded with the Centers for Medicare and Medicaid Services, formerly known as the Health Care Financing Administration.

Urology Research

The Basic Urology Program supports basic research on the normal and abnormal development, structure and function of the genitourinary tract. A major area of interest is investigation of the biology of bladder cells, including studies on transport properties, effects of obstruction on patterns of protein expression and examination of interactions between urinary pathogens and cells of the urinary tract. The program on prostate biology has particular strengths in investigation of prostate cell growth and mechanisms of growth factor signal transduction.

The Clinical Urology Program – The mission of this program is research that will increase the knowledge of etiology, diagnosis, pathophysiology, therapy and prevention of major pediatric and adult urological disorders. Non-malignant disorders of the bladder and prostate, including benign prostatic hyperplasia, interstitial cystitis, urinary tract infections, urinary incontinence and urolithiasis are areas of emphasis, as are the effects of systemic diseases such as diabetes mellitus, spinal cord injury, and multiple sclerosis on these organs. In addition, the program supports studies of diagnostic and therapeutic modalities such as 1) shock-wave and laser lithotripsy, 2) urolithiasis inhibitors, 3) bladder substitution procedures and devices, and 4) prostate growth inhibitor and reduction therapies.

The Urologic Diseases Epidemiology Program – The major emphasis of this program is to develop a source of epidemiological information that may further understanding of natural history, risk factors and health resource utilization for urologic conditions. Plans are to collect and analyze new and existing data on incidence, prevalence, morbidity, mortality and health resource utilization associated with various urologic conditions of high public health importance. The information will be presented in a planned publication tentatively titled "Urologic Diseases in America."

Hematology Research

The Hematology Program supports research into the fundamental processes underlying the normal and pathologic function of blood cells and the reticuloendothelial system. Major areas of interest include the genetic regulation of hemoglobin and other proteins of the blood; acquired and inherited anemias; cell membrane composition and regulatory processes; iron metabolism, storage, and transport; hematopoiesis and its regulation by growth factors, including erythropoietin; transcription and signaling factors such as the JAK/STAT pathway involved in hematopoietic cell differentiation; immunohematology; hematopoiesis, hematopoietic stem cell biology, and the expression of differentiation potential of hematopoietic stem cells; stem cell plasticity and the cellular, molecular, and genetic mechanisms that allow cells to express plasticity. Emphasis is on the application of fundamental knowledge to current issues such as gene transfer therapy and bone marrow transplantation, and disorders such as sickle cell anemia, thalassemia, hemochromatosis, iron deficiency anemia, thrombocytopenia and hemolytic anemia.

The Chelator Therapy Program – Research is supported on the development of new iron chelating drugs for the treatment of transfusion iron overload, such as in Cooley's anemia, sickle cell disease, and other instances of iron overload. A safe and inexpensive orally active iron chelator that effectively promotes iron excretion is needed urgently, since the only currently available drug, desferrioxamine B, is expensive and is painful and cumbersome to administer, leading to widespread non-compliance among the young adult patient population. Pre-clinical toxicity studies of potential iron chelating drugs are performed under the contract mechanism. Grant support is offered for basic research on the kinetics of iron chelation, the identity of the iron pools addressed, and ways to enhance the chelating activity and reduce the toxicity of known iron chelators.

The Hematopoietic Lineage Genomics Anatomy Program – This program has been initiated to merge the fields of hematopoietic cell biology, including erythroid cell physiology, with bioinformatics. The combination of these two fields will: 1) advance the ability to catalog and monitor genes that are expressed during normal and variant hematopoietic cell differentiation, 2) facilitate a more comprehensive understanding of the dynamics of molecular events that occur during differentiation, and most importantly, 3) develop a quantitative model that incorporates known gene expression data into a description of a red blood cell. This model could then be used to test novel expression patterns as they are discovered and also be used as a scaffold from which to devise models for other tissue and organ development.

Genomics Research

The Genomics Research Program encompasses research on genomics and related technologies in the study of kidney, genitourinary tract, and blood and blood-forming organs. This program also supports model organism genomics research, including the development of genetic tools for high-throughput functional genomics studies. One major programmatic area is the leadership of a major trans-NIH initiative to develop genomics of zebrafish, Danio rerio.

Office of the Director

Office of Minority Health Research Coordination. To address the burden of diseases and disorders that disproportionately impact the health of minority populations, the Director of the NIDDK created the NIDDK Office of Minority Health Research Coordination (OMHRC). The OMHRC will help implement the Institute's strategic plan for health disparities and build on the strong partnership with the National Center on Minority Health and Health Disparities at NIH. For more information, please contact: Office of Minority Health Research Coordination, 6707 Democracy Boulevard, Suite 901/933, Bethesda, MD 20892, phone: (301) 435-2988.

Advisory Council

National Task Force on Prevention and Treatment of Obesity. The task force was established in June 1991 to synthesize current scientifically based information on the prevention and treatment of obesity and to develop statements about topics of clinical importance that are based on critical analyses of the literature. It is composed of leading obesity researchers and clinicians who advise the institute on research needs and sponsor workshops on topics related to the prevention and treatment of obesity. Organizationally, it is placed under the auspices of the NIDDK Advisory Council.

Health Information and Education Services

National Diabetes Information Clearinghouse (NDIC)
National Digestive Diseases Information Clearinghouse (NDDIC)
National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC)

The three clearinghouses serve as information resources for patients, the public, and health professionals concerned with diabetes, digestive diseases, and kidney and urologic diseases. Each was authorized by Congress to increase knowledge and understanding about these areas through the effective dissemination of information. The NDIC was authorized by Congress in 1976, the NDDIC in 1980, and the NKUDIC in 1987.

The clearinghouses answer inquiries; develop, print and distribute publications; and work closely with professional and patient-advocacy organizations and U.S. Government agencies to coordinate informational resources about diabetes, digestive diseases, and kidney and urologic diseases.

The clearinghouses also develop and maintain relevant sections of the Combined Health Information Database – a free, online bibliographic database of references to books, journal articles, audiovisuals, directories, bibliographies, manuals, product descriptions, brochures and pamphlets, computer programs, monographs, newsletters, and other educational materials (http://chid.nih.gov/).

Addresses are:

NDIC, 1 Information Way, Bethesda, MD 20892-3560
phone: 1-800-860-8747;

NDDIC, 2 Information Way, Bethesda, MD 20892-3570
phone: 1-800-891-5389;

NKUDIC, 2 Information Way, Bethesda, MD 20892-3580
phone: 1-800-891-5390.

National Diabetes Education Program (NDEP)

The NDEP is sponsored by the NIDDK of the NIH and the Division of Diabetes Translation of the CDC and over 200 public and private organizations. The program's goal is to improve the treatment and outcomes for people with diabetes, to promote early diagnosis, and ultimately to prevent the onset of diabetes. The program's goal and objectives support a major Federal Government public health initiative, Healthy People 2010, which has established health objectives for reducing the burden of diabetes in the first decade of the 21st century. NDEP program audiences include people with diabetes and their families, with special emphasis on racial ethnic populations disproportionately affected by diabetes, health care providers, payer and purchasers of health care and health care systems, and the general public, including those people who are undiagnosed and people at risk for the disease.

NDEP publications are available through the NDEP home page at http://ndep.nih.gov/. The mailing address is 1 Diabetes Way, Bethesda, MD 20892-3600, phone 800-438-5383.

National Kidney Disease Education Program (NKDEP)

The NKDEP is a program of the National Institute of Diabetes and Digestive and Kidney Diseases to address the growing problem of kidney disease in this country and to reduce the morbidity and mortality caused by kidney disease and its complications. The program will raise awareness about the seriousness of kidney disease, the importance of prevention, early diagnosis and appropriate management of kidney disease, and the prevention and management of complications.

Weight-Control Information Network (WIN)

The Weight-control Information Network (WIN) is a national information service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH). WIN was established in 1994 to provide health professionals and consumers with science-based information on obesity, weight control, and nutrition. WIN has also developed the Sisters Together: Move More, Eat Better Media program that encourages Black women 18 and over to maintain a healthy weight by becoming more physically active and eating healthier foods.

WIN publications are available through the WIN home page at http://www.niddk.nih.gov/health/nutrit/nutrit.htm The mailing address is 1 WIN Way, Bethesda, MD 20892-3665, phone 1-877-946-4627.

NIDDK Appropriations – Grants and Direct Operations

Fiscal year	Total grants	Direct operations	Total
(Amounts in thousands of dollars)
1954	$3,621	$3,379	$7,000
1955	4,390	3,880	8,270
1956	5,910	4,930	10,840
1957	10,290	5,595	15,885
1958	13,837	6,548	20,385
1959	23,421	7,794	31,215
1960	38,553	8,309	46,862
1961	50,882	10,318	61,200
1962	69,809	12,022	81,831
1963	90,011	13,377	103,388
1964	99,914	13,765	113,679
1965	97,905	15,145	113,050
1966	104,393	18,810	123,203
1967	113,621	22,066	135,687
1968	116,160	22,738	138,898
1969	117,953	25,934	143,887
1970	118,959	27,660	146,619
1971	109,670	28,669	138,339
1972	122,309	31,016	153,325
1973	134,522	32,794	167,316
1974	125,622	33,825	159,447
1975	136,011	37,503	173,514
1976	138,612	40,904	179,516
1977	170,944	48,656	219,600
1978	202,719	57,534	260,253
1979	238,199	64,568	302,767
1980	274,088	67,118	341,206
1981	300,943	68,519	369,462
1982	296,898	71,293	368,191
1983	335,566	77,926	413,492
1984	384,080	79,946	464,026
1985	453,458	86,041	539,499
1986	461,890	85,483	547,373
1987	425,062	85,818	510,880
1988	442,618	91,741	534,359
1989	462,697	96,617	559,274
1990	474,455	105,529	579,984
1991	500,127	115,135	615,262
1992	539,913	121,533	661,446
1993	553,838	126,676	680,514
1994	598,885	125,737	715,622
1995	614,292	122,751	737,043
1996	636,295	132,058	768,353
1997	674,738	138,326	813,064
1998	723,738	146,493	869,686
1999	830,573	160,498	991,071
2000	954,437	185,678	1,140,115