Diabetes mellitus is one of the most common endocrine diseases in all populations and all age groups. It is a syndrome of disturbed intermediary metabolism caused by inadequate insulin secretion or impaired insulin action, or both.

Diabetes is crudely grouped into the two types - insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus. Both types are associated with excessive morbidity and mortality.

Relative mortality in people with insulin dependent diabetes is between 10 and 30 (equal to a 5-10 year reduction in life expectancy), depending on the age at diagnosis, current age, the duration of the disease, and the year of diagnosis.

Non-insulin dependent diabetes is associated with an overall age adjusted mortality that is about twice that of non-diabetic populations; life expectancy is reduced by 5 to 10 years in middle aged patients with this type of diabetes.

The world has over 100 million diabetics, having an enormous adverse impact on people who are afflicted. This burden also amounts as a staggering economic cost to the countries involved - for example, in the US there has been estimated that diabetes costs to the society approximately $92 billion annually, which includes direct medical costs and indirect costs such as disability, work loss, and premature mortality. About one third of these people are unaware that they have diabetes. There are 1,700 new cases of diabetes diagnosed every day and 625,000 new cases diagnosed every year. The worldwide prevalence of diabetes is expected to more than double between 1994 and 2010, to 239 million people.

Most of the increase will be in type 2 diabetics and is resulting from increasing obesity and inactivity. Also important is low birth weight, predisposing people to develop diabetes.

Serious health complications result from diabetes, including eye, heart, kidney, and nerve damage. Diabetes is the leading cause of new cases of blindness among adults 20 to 74 years of age: 12,000 to 24,000 new cases each year. It is the leading cause of end-stage renal disease (ESRD), accounting for 19,790 new cases in 1992. Additionally, over half of lower limb amputations in the United States occur among persons with diabetes. The number of amputations among persons with diabetes averaged 54,000 from 1989 to 1992. A disproportionate share of that burden is borne by racial and ethnic minorities.

Basic research underpins many therapies developed for diabetes: insulin pumps, various forms of insulin, and strategies for treating type 1 diabetes and numerous medications for type 2 diabetes. Even with these therapies, diabetes remains an exceedingly difficult disease to control. The health complications that result from uncontrolled or poorly controlled diabetes are largely responsible for the toll diabetes takes on human health and on the health care system. Thus, effectively treating and preventing diabetes and its complications are major goals of research.

Significant recent advances have been made in this field, including the cloning of leptin (ob), the leptin receptor (db), and the other rodent single gene obesities: agouti signaling protein (Ay), carboxypeptidase E (fat), and tubby (tub). All of these genes have human homologs whose role in human obesity is under intense investigation. Several measures have been used to identify subtle lowering of energy expenditure in children and adults destined to become obese and in the formerly obese: (1) the identification of PPAR transcription factor and identification of troglitazone as a ligand that modifies insulin sensitivity; (2) molecular cloning of new uncoupling proteins that may play an important role in human energy homeostasis; (3) refined measures of energy expenditure in humans, including hood and chamber calorimetry; and (4) longer term measures in free living subjects using the differential excretion of heavy isotopes of water.

Specific areas of research opportunities include the following:

- Understand the close causal link that epidemiologic and physiologic studies show between obesity (and body fat distribution) and type 2 diabetes. The molecular mechanisms for this causal relationship are not completely understood, but existence indicates that the prevention or reduction of obesity would eliminate or alleviate up to 70 percent of instances of type 2 diabetes. Thus, research on obesity should be regarded as a major vehicle for ultimately controlling the growing prevalence of type 2 diabetes.

- Elucidate the molecular bases for the imbalance between energy intake and expenditure that is responsible for obesity in order to identify prophylactic and therapeutic targets for obesity and type 2 diabetes. Obesity results from a long-term imbalance of energy intake and expenditure. Physiologic studies in humans indicate that reduced energy expenditure (and diminished fat oxidation) precede the development of obesity. The formerly obese also show diminished energy expenditure, suggesting that loss of body fat returns the obese individual to the metabolic status that preceded weight gain. A substantial portion of the difference in energy expenditure is the result of changes in skeletal muscle metabolism. This, in turn, could be a result of changes in sympathetic nervous activity or effects of reduced body fat on primary metabolic processes. A major breakthrough relates to the discovery that the system for regulating energy intake and expenditure is coordinately and potently regulated by a newly discovered peripheral hormone, leptin (LEP).

- Achieve a better understanding of leptin physiology, including the following:

-- Elucidate the rate-limiting steps for leptin action in obese individuals
-- Determine central and peripheral mechanisms by which leptin influences insulin action
-- Better define the central "wiring diagram" for the hypothalamic control of energy intake and expenditure.

- Identify the genes that contribute to body fat content, including those that mediate food intake within the CNS (such as NPY), energy expenditure in peripheral tissues (such as UCPs), and the partitioning of energy stores between lean and fat tissue (such as LEP). The identification of all genes making clinically relevant contributions to regulation of body fat should proceed along several lines:

-- Use animal single- and multigene models of obesity to clone and characterize such genes
-- Identify candidate genes for body weight regulation by prospective scanning of the literature and relevant databases for genes whose functions or map positions suggest a role in energy homeostasis
-- Identify new obesity genes in human populations by linkage analysis.

- Identify the genes involved in energy homeostasis that interact with each other and the environment to produce behavioral and metabolic phenotypes.

- Identify nominally significant sequence variants in human subjects, and examine their effects prospectively by identifying children or young adults who have the mutation/sequence variant but are not yet obese.

- Clarify the mechanisms by which excess body fat compromises glucose metabolism. Effects of excessive body fat are protean and involve pancreatic ß-cell performance, skeletal muscle insulin sensitivity, and hepatic gluconeogenesis. Some of these effects are apparently conveyed by free fatty acids, but the mechanisms are unknown.

- Enhance understanding of the molecular physiology of adipocyte development.

- Convene a group of obesity physiologists, geneticists, and statistical geneticists to design an interinstitutional linkage study of the genetics of obesity.

- Develop complex measures of metabolic physiology, such as energy expenditure, food intake, body composition, substrate flux, neurochemistry, and neurophysiology, to work out the molecular physiology of energy homeostasis.

- These studies require special equipment and expertise. Facilities for such studies in rodents and humans should probably be identified and developed in a few specialized centers to which all investigators would have access on a collaborative basis.