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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS001380-04
Application #
3084374
Study Section
Neurological Disorders Program Project Review A Committee (NSPA)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1992-09-01
Budget End
1993-08-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sieber, F E (1997) The neurologic implications of diabetic hyperglycemia during surgical procedures at increased risk for brain ischemia. J Clin Anesth 9:334-40
Sieber, F E; Traystman, R J; Martin, L J (1997) Delayed neuronal death after global incomplete ischemia in dogs is accompanied by changes in phospholipase C protein expression. J Cereb Blood Flow Metab 17:527-33
Sieber, F E; Martin, L J; Brown, P R et al. (1996) Diabetic chronic hyperglycemia and neurologic outcome following global ischemia in dogs. J Cereb Blood Flow Metab 16:1230-5
Sieber, F E; Palmon, S C; Traystman, R J et al. (1995) Global incomplete cerebral ischemia produces predominantly cortical neuronal injury. Stroke 26:2091-5;discussion 2096
Palmon, S C; Sieber, F E; Brown, P R et al. (1995) Poor hemodynamic and metabolic recovery after global incomplete cerebral ischemia associated with short-term diabetes in dogs. J Cereb Blood Flow Metab 15:673-80
Feldman, E L; Stevens, M J; Thomas, P K et al. (1994) A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17:1281-9
Sieber, F E; Koehler, R C; Brown, P R et al. (1994) Diabetic chronic hyperglycemia and cerebral pH recovery following global ischemia in dogs. Stroke 25:1449-55
Sullivan, K A; Feldman, E L (1994) Immunohistochemical localization of insulin-like growth factor-II (IGF-II) and IGF-binding protein-2 during development in the rat brain. Endocrinology 135:540-7
Feldman, E L; Randolph, A E (1994) Regulation of insulin-like growth factor binding protein synthesis and secretion in human retinal pigment epithelial cells. J Cell Physiol 158:198-204
Sieber, F E; Brown, P R; Wu, Y et al. (1993) Cerebral blood flow responsivity to CO2 in anesthetized chronically diabetic dogs. Am J Physiol 264:H1069-75

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