By identifying new genes and mechanisms involved in diabetes mellitus, European teams are opening the way to better prevention and treatment of this disease. Background Non-insulin-dependent diabetes mellitus (diabetes mellitus type 2 , NIDDM) affects some 90 million people worldwide. This number is expected to double in the next ten tears, by which time treatment of the disease and its complications is likely to account for 10% to 15% of all medical costs globally. Factors implicated in the spectacular progression of NIDDM include industrialisation, obesity and lack of exercise. However, predisposing genetic factors also exist. To help explain these factors and provide new tools for prevention and therapy, six European teams have joined forces in a Biomed project: 'Identification of the genes involved in the pathogenesis of non-insulin-dependent diabetes mellitus: a paradigm for multifactorial diseases'. Description, impact and results Although some cases of NIDDM are due to a mutation in a single gene, the disease usually has many causes, arising when adverse effects of lifestyle (over-eating, insufficient exercise) combine with the presence of several genes favouring high energy storage, high food intake, insulin resistance, or low insulin production. To identify predisposing gene variants and help understand how the disease develops, the project partners 'collect' families with several known cases of the disease, characterise their disease phenotypes, explore entire genomes to find diabetes-linked gene combinations, and clone and study candidate genes. This work has cast light on a network of nuclear transcription factors (regulators of gene expression) produced by the pancreas and important in its formation. These factors control energy expenditure and blood glucose levels in response to metabolic signals. Transcription-factor mutations appear linked to some forms of NIDDM. In other forms, the transcription factors become down-regulated as the disease progresses, a mechanism which may partly explain why diabetes evolves unfavourably even when treatment is initially successful. Such findings offer new prospects for treatment, if drugs can be found that enhance the action of these factors or prevent their down-regulation. The project partners, from EU research institutes and universities, played a leading role in the first global genetic study of NIDDM, based on data from 5 000 families, which led to the discovery of a new 'diabetes locus' on chromosome 20. The next step is to identify the genes concerned - knowledge of diabetes genes will make it possible to screen for susceptibility to NIDDM and take early preventive measures. In addition, it will open the way to new therapeutic approaches, including gene therapy. And the methodology developed here can also be used to study other major multifactorial diseases, such as hypertension. Working partnerships The research has brought together a unique combination of experts in diabetology, human genome mapping, statistical genetics, bioinformatics and databases, the analysis of genetic diseases, metabolic endocrinology, and animal models of diabetes. Now six new partners have launched a new project under Biomed to continue this valuable work.