INTESTINAL MUCOSAL FUNCTION IN DIABETES

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Uncontrolled diabetes mellitus in the rat results in multiple alterations in the function of the brush border membrane of the enterocyte including the stimulation of active transport mechanisms and increases in a variety of membrane-bound hydrolases. Elucidation of the mechanisms involved may provide important insight into the patho-physiology of the human disease as well as into the nature of the regulation of brush border proteins. Our long term objective is to elucidate these mechanisms. Our specific aims are to answer the following questions: (1) is the increased rate of biosynthesis of sucrase- isomaltase in diabetic animals the result of transcriptional, translational, or posttranslational changes; (2) are the changes specific or is there altered regulation of all brush border hydrolases; (3) what are the mediators of altered regulation; (4) are alterations in hydrolases in other situations related to the diabetic changes. To answer these questions we will study the effects of diabetes and other conditions where hydrolase activity is altered on synthesis and intracellular processing of precursors of selected brush border hydrolases. This will be done by pulse/chase experiments followed by immune precipitation and SDS-polyacrylamide gel electrophoresis and fluorography and by immunoelectron microscopy. Effects on mRNA levels will be sought in cell free translational experiments, and the effects of several possible mediators on biosynthetic processes in organ- cultured intestine determined. Finally, since intracellular processing of these proteins is incompletely understood, we will, in the course of these experiments, define more clearly this processing in normal rat intestine and, in the case of several hydrolases, human intestine.