This proposal examines the effects of blood glucose on cerebral blood flow (CBF) and metabolism (M) of O2, glucose, ketones, lactate and pyruvate, emphasizing the changes with occur with acute hypoglycemia (HG) and with chronic hyperglycemia associated with Diabetes Mellitus (DM). First we will examine the mechanisms causing EEG flattening and loss of CBF vasoconstriction during moderate HG in combination with hypocapnia. Using 31p NMR we will measure intracellular pH (alkalosis) are severe enough to cause EEG flattening. We will concurrently investigate the roles of excitatory amino acid release, potassium release, and beta-adrenergic stimulation in the CBF/M and EEG changes associated with hypocapnia during moderate HG. Second, we will define how chronic hyperglycemia affects CBF/M . Using a canine diabetic model, CBF responses to CO2, hypoxia and hemorrhagic hypotension will be compared to acute hyperglycemia. Moreover, the effects of blood glucose control with insulin in DM will be studied by comparing tight control (fasting plasma glucose <200 mg/dl) vs. loose control (>300 mg/dl). In addition, the effects of acute onset of normoglycemia with insulin in chronically- hyperglycemic animals with loose control will be investigated to test whether CBF/M is affected in a manner analogous to acute HG in a non-DM animal. Third, we will examine the effect of acute vs. chronic hyperglycemia with and without tight glucose control on CBF/M following 30 minutes of incomplete cerebral ischemia using 31p NMR. We will determine if intracellular pH falls as much with controlled and uncontrolled chronic hyperglycemia as it does with acute hyperglycemia during ischemia. In summary, this proposal examines basic mechanisms of CBF/M changes associated with moderate HG, investigates the impact of CBF/metabolism of the important clinical problem of glucose control during DM, and then determines if chronic hyperglycemia is as detrimental as acute hyperglycemia during incomplete cerebral ischemia.
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