FUNCTIONAL-EFFECTS OF TRANSGENIC EXPRESSION OF CHOLERA-TOXIN IN PANCREATIC BETA-CELLS

Investigation of intracellular pathways of stimulus-secretion signalin g in vivo is possible by transgenic expression of agents known to infl uence specific biochemical interactions in the cells. The objective of the present study was to establish an experimental model for analyzin g signal transduction mechanisms in pancreatic beta-cells in vivo, by expressing the cholera toxin Al subunit under control of the insulin p romoter, intending a constant activation of the G(s)-protein, and ther eby constant generation of cAMP. Surprisingly, the transgenic mice dem onstrated mild hyperglycemia and hypoinsulinemia in vivo, and diminish ed glucose-induced insulin release from the in vitro perfused pancreas , whereas the pancreatic insulin content was normal. These observation s suggest a deficiency in either the insulin release mechanisms or glu cose recognition. Although the translated cholera toxin Al subunit was biologically active, there was no increase in the islet content of cA MP. We conclude that the observed phenotype in the cholera toxin trans genic mice may be caused by a deleterious effect of the transgene itse lf on beta-cell function, or that counter regulatory mechanisms may co mpensate for the transgene-induced changes in intracellular enzymatic pathways.