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Molecular mechanisms of insulin resistance in non-insulin dependent diabetes mellitus

Objective

Objectives:
Current understanding of the pathogenesis of insulin resistance involves environmental factors combined with a marked inherited component, however, no major NIDDM genes could be identified so far. This relates to the incomplete knowledge of the insulin signaling cascade and the lack of any demonstrated influence of NIDDM-associated environmental factors on genes encoding key insulin signaling proteins. The concerted research plan of five European laboratories aims to fill this gap of knowledge with the ultimate goal to establish novel approaches for diagnosis, prevention and treatment of NIDDM.

Non-insulin dependent diabetes mellitus (NIDDM) is a chronic disease affecting around 5% of the total European population. Due to its prevalence and marked risk for enhanced morbidity and mortality, NIDDM must be considered as a major socio-economic burden of the European community. Insulin resistance to muscle glucose uptake and utilisation has been recognised as one of the earliest abnormalities leading to NIDDM. Early detection of insulin resistance and detailed knowledge of the mechanisms leading to this deregulation would provide the key to prevention, treatment and improved prognosis of NIDDM. Current understanding of the pathogenesis of insulin resistance involves environmental factors combined with a marked inherited component, however, no major NIDDM genes could be identified so far. This relates to the incomplete knowledge of the insulin signalling cascade and the lack of any demonstrated influence of NIDDM-associated environmental factors on genes encoding key insulin signalling proteins. The concerted research plan of five European laboratories, as described in the present proposal, aims to fill this gap of knowledge with the ultimate goal to establish novel approaches for diagnosis, prevention and treatment of NIDDM.

Molecular, cellular, genetic, physiological and clinical research and expertise of the participating groups will be combined at the European level with three major objectives: I) Analysis of critical insulin signalling intermediates and correlation to environmental factors; II) Search for potential candidate genes by targeted analysis of gene expression, and; III) Analysis of candidate genes in NIDDM and high risk patients.

Molecular studies on rodent muscle tissue and cell cultures will provide new insights into insulin signalling pathways and potential mechanisms of dysregulation including altered expression of critical genes. These studies will then be extended to human skeletal muscle and correlated to environmental factors and the action of new antidiabetic drugs. Finally, different populations of patients will be available in the different European laboratories allowing mutational analysis, genetic epidemiology and detection of high-risk patients. This project will contribute to the development of new strategies for diagnosis and treatment of NIDDM and thus helps to improve the health and quality of life of European citizens.

Funding Scheme

CON - Coordination of research actions

Coordinator

Deutsche Diabetes Forschungsgesellschaft e.V.
Address
65,Auf'm Hennekekamp
40225 Düsseldorf
Germany