The """"""""polyol pathway"""""""" is that series of reactions whereby glucose is metabolized to sorbitol and fructose as opposed to direct metabolism through the glycolytic pathway via glucose 6-phosphate. Recent studies have suggested that this pathway may serve both a physiologic role in cellular adaption to hyperosmolarity and a pathophysiologic role in those tissues susceptible to end-organ damage in diabetes mellitus--including the kidney. Observed decreases in cellular levels of myo-inositol which parallel changes in sorbitol have led many investigators to speculate that the polyphosphoinositide pathway is altered under such conditions. However, clear documentation that such derangements occur in the kidney and cogent explanations based on experimental observations of those mechanisms which may serve as the basis for such derangements are not yet available. In this context the following questions are to be addressed: 1.What contributions do polyols play in the generation of renal phospholipids including phosphoinositides and both acyl and ether-linked phospholipids? 2.What is the composition and source of diglyceride in renal tissue under basal, hyperosmolar, hormone stimulated, hyperglycemic and insulinopenic conditions? 3.What alterations in renal inositol phosphate and inositol lipid production occur under hyperosmolar and diabetic conditions? 4.What are the properties of phosphatidyl inositol synthase in renal mesangial and inner medullary collecting tubule cells? Can changes in inositol lipid metabolism be explained on the basis of such properties and the observed levels of polyols and their metabolism? 5.Do inositol phosphates modulate polyol metabolism via renal aldolase type B and does the binding of inositol phosphates to aldolase explain the observed disparity between measured levels inositol trisphosphate and those concentrations required for the mobilization of intracellular calcium?
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