Hypoglycemia occurs in diverse clinical conditions, and is a major problem for patients with insulin dependent diabetes mellitus (IDDM). Indeed, it is the limiting factor in attempts to achieve euglycemia and causes recurrent morbidity and even some mortality (estimated at 4% of deaths) in IDDM. Aside from the fact glucose transport into the brain becomes rate- limiting to brain metabolism and thus function as plasma glucose concentration falls to hypoglycemic levels, rather little is known about the factor that modulate glucose transport into the brain of humans. The development and availability of positron emission tomography (PET) will permit use to address several potential modulators of blood-brain barrier glucose flux including antecedent glycemia, cerebral blood flow and glucoregulatory hormones. We plan to utilize glucose clamp techniques (insulin infusion with glucose infusion at rates that achieve selected target plasma glucose concentrations), measurements of glucoregulatory hormones (including insulin, glucagon and epinephrine among others) and of metabolic substrates/intermediates, and symptom assessments coupled with measurements of forward unidirectional fractional extraction of glucose ([U-11C]glucose) and of regional cerebral blood flow (H215O) in normal subjects and patients with IDDM (and one subset of patients with cerebrovascular disease). We will test the hypothesis that: A. Unidirectional fractional glucose extraction by the human brain in inversely related to antecedent plasma glucose levels (hypoglycemia in one instance and relative hypoglycemia in the other). B. Progressive hypoglycemia leads to diminution of the regional cerebral blood flow (rCBF) responses to physiological stimuli, at plasma glucose concentrations at which forward flux of glucose becomes rate-limiting. C. Neither insulin nor glucose counterregulatory hormones (epinephrine, glucagon, cortisol, and growth hormone) affect glucose transport in normal humans. The effects of glucoregulatory hormones on glucose transport into the brain are altered in patients with IDDM. We anticipate that insight into the control of glucose delivery to the brain may lead to approaches to minimize hypoglycemic brain dysfunction and damage.
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