The objective of this proposal is to investigate whether intestinal basement membrane (BM) pathology in diabetes mellitus plays a role in the development of precocious epithelial maturation and nutrient hyperabsorption. Although this hypothesis has not thus far been explored, this proposal is founded on a large body of preliminary data supporting its formulation. The first phase of this study will be a rigorous analysis of immediate and long-term intestinal adaptive changes in steptozocin-treated, diabetic rats. Specific issues that have been ambiguous in the past such as time course of development, reversibility with insulin, and underlying causative cellular mechanisms will be addressed. Ultrastructural, biochemical, morphometric, functional and molecular findings will be correlated. In the second phase of these studies, the role of basement membrane in diabetic intestinal adaptation will be examined. The immediate and chronic effects of diabetes on morphological, biochemical, compositional and regional features of BM will be defined and correlated with the developments of intestinal adaptive events. How specific modifications of BM or BM constituents seen in diabetes might affect intestinal cell (rat IEC-6 crypt) growth and differentiation will be investigated. Finally, how diabetes might alter specific cellular and molecular mechanisms for 1) biosynthesis and maintenance of BM, and 2) the expression of mature intestinal cell function. With respect to the latter, the level of gene expression of Na-dependent glucose transport and alkaline phosphatase will be investigated by measuring steady state mRNA concentrations. 3) Expression of the laminin receptor, a potentially important component of intestinal epithelial maturation. These studies are significant because they address a previously unexplored mechanism for diabetic intestinal adaptation. In addition, the process of diabetic intestinal adaptation may be a useful paradigm for understanding basic mechanisms of cellular growth and morphogenesis. Such knowledge may be of potential significance to future strategies for treating malabsorption states, where induction of such adaptive processes would be of great benefit. In addition, they may provide insight into mechanisms of neoplastic development and its regulation.
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