This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypoglycemia unawareness is a complication of intensive insulin therapy often encountered in patients and normal subjects after episodes of iatrogenic hypoglycemia. The mechanisms by which the brain detects low blood sugar concentrations are uncertain. The brain contains approximately 3 mM glycogen that may serve as a fuel during moderate hypoglycemia. In most tissues, including the brain, glycogen metabolism is insulin- and glucose-sensitive. Brain glycogen thus provides an aspect of cerebral carbohydrate metabolism that is sensitive to alterations in glucose homeostasis such as those seen in diabetic patients. The long-term goal of this project is to explore the effect of hypoglycemia on brain glycogen metabolism and the potential role of glycogen metabolism in mediating hypoglycemia unawareness. To date, brain glycogen concentrations and metabolism have not been measured in the live human brain. We recently were the first to demonstrate methods that can achieve this goal using noninvasive 13C NMR spectroscopy. Therefore, the aim of this project is to generate the preliminary data and demonstrate the feasibility of measurinig brain glycogen in humans. The long-term hypotheses of this project are that human brain glycogen metabolism under normal conditions is very slow and that the brain glycogen concentrations are higher than the euglycemic free brain gluose concentrations, with the specific aim to determine the brain glycogen content in the conscious human brain. This aim will be achieved in human brain using localized 13C NMR spectroscopy while infusing 13C labeled glucose. Administration of the glucose infusions and blood sampling as well as GCMS analysis requires the support of the GCRC