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Identification of the genes involved in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) : a paradigm for multifactorial diseases

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Complementary strategies to identify diabetes genes will be applied, such as 1) random mapping of the total human genome from several hundred well-characterized NIDDM families, with highly informative DNA markers for a systematic search for chromosomal regions co-segregating in subtypes of NIDDM, 2) positional cloning in cases where chromosomal localization does not reveal known candidate genes, 3) cloning of a series of candidate genes and screening of these genes for disease-causing mutations, 4) identification of new NIDDM candidate genes by mRNA-differential display in muscle biopsies from insulin resistant NIDDM-patients, 5) genetic studies of animal modes, eg. the GK-rat, and extrapolation of the results to human NIDDM and 6) studies of early onset NIDDM families (MODY) which are negative for linkage to glucokinase or adenosine deaminase genes. Defining the nature of the NIDDM genes will allow early identification of high risk individuals who may benefit from early medical intervention and thereby the prevention of NIDDM in many cases. Knowledge of the genetics of NIDDM will also give the basis for the development of specifically targeted antidiabetic drugs and/or gene therapy in some cases.

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