Application of molecular genetics to the study of beta-cell function and diabetes mellitus

During the past decade molecular genetics has made major contributions to our understanding of beta-cell function in health and disease (IDDM, NIDDM). The beta-cell has the unique capacity to ''sense'' the extracellular glucose concentration and to respond to cellular signals generated by the ''glucose-sensor'' by secreting exactly the amount of insulin required to maintain glucose homeostasis. This regulated system of the beta-cell is very complex, and so far neither the exact molecular mechanisms of glucose-sensing nor the components of the signal transduction cascades linking it to insulin secretion are known in detail. Conventional methods for the molecular cloning of genes and for the direct analysis of gene expression in the beta-cell have already revealed many details of normal glucose regulation and about dysfunctions in different types of diabetes. In addition to these direct analytical methods, indirect approaches have proven their high potential for the study of the beta-cell during the past few years. We discuss in particular the results obtained by using linkage analysis and mutation scanning of candidate genes for diabetes mellitus. Novel gene transfer techniques useful for the molecular engineering of cells have also been developed recently. They are valuable for analytical applications and for the current attempts to construct ''artificial beta-cells'' using non-beta-cells as starting material. Efficient techniques for gene transfer in vivo have become available facilitating investigation of the consequences of overexpression of defined genes in animal models.