This project is concerned with evaluating 2 hypotheses: (1) that the basal phosphatidylinositol (PI) turnover, which is demonstrable in most resting tissues, plays a significant role in metabolic regulation; and, (2) that the defect in maintaining normal levels of myo-inositol (MI) in specific tissues that results from experimental diabetes can induce metabolic alterations by affecting PI turnover in small rapidly-turning-over pools that are involved in metabolic regulation. Basal PI turnover (as assessed by the incorporation into, and release of (2-3H)MI and (1-14C0 arachidonic acid from prelabelled PI) and the resting rate of energy utilization with glucose as substrate, will be studied in incubated preparations of rabbit aortic intima-media (AIM) and endoneurium.
The aim i s to demonstrate that in both tissues there is a component of resting energy utilization that is reversibly inhibited either by omitting MI from the medium or by depletion of endogenous free AA with defatted albumin, and that this inhitition is associated with the loss of a specific component of basal PI turnover. We will attempt to demonstrate that the loss of this component of basal PI turnover is associated with a decrease in the percent of the basal O2 uptake that is inhibitable by ouabain to demonstrate that the energy requiring processes regulated through basal PI turnover in these tissues includes a component of Na+ K+ ATPase activity. We will determine whether perturbations that should increase the activity of this enzyme selectively increase a specific component of basal PI turnover, which can be identified because it is inhibited either by omitting MI from the medium or by depleting free AA and is not dependent on medium Ca++. In endoneurium we will determine whether the decreased basal rate of O2 uptake and the decreased tissue MI concentration that result from experimental diabetes is associated with a decrease in the same component of basal PI turnover and in the percent of the basal O2 uptake that is inhibitable by ouabain. We will detemine whether the alterations in metabolism and in basal PI turnover in diabetic endoneurium are both corrected when the tissue MI is raised to normal levels by incubation for a relatively prolonged period in medium containing a high MI concentration.
| Simmons, D A; Winegrad, A I (1991) Elevated extracellular glucose inhibits an adenosine-(Na+,K+)-ATPase regulatory system in rabbit aortic wall. Diabetologia 34:157-63 |
| Simmons, D A; Winegrad, A I (1989) Mechanism of glucose-induced (Na+, K+)-ATPase inhibition in aortic wall of rabbits. Diabetologia 32:402-8 |
