Hypoglycemia is the major factor limiting the use of effective insulin treatment regimens in type I diabetes (T1DM). In some patients the severity as well as the inability to detect hypoglycemia (hypoglycemia unawareness) has sufficient clinical impact to warrant consideration for islet transplantation, the primary indication for the procedure. Little is known about the CNS adaptations that influence brain metabolism and cognitive function in response to hypoglycemia in unaware patients. This proposal is a multicenter, multidisciplinary clinical trial that brings together a group of clinical and basic scientists at Yale with a strong track record of research in the area of hypoglycemia and brain metabolism and a group of the most experienced islet transplant surgeons in North America. The primary goal is to better define the impact of recurrent hypoglycemia and hypoglycemia unawareness on CNS function and metabolism in T1DM patients with severe hypoglycemia unawareness being considered for islet transplantation. For this purpose, we will apply state-of-the-art MRS techniques to study patients selected to undergo islet cell transplantation because of a history of severe hypoglycemia and hypoglycemia unawareness at the University of Alberta, Edmonton, the University of Miami, and the University of Minnesota. We will test the hypothesis, based on our preliminary data in intensively treated T1DM patients and rodent models, that these patients show upregulation of monocarboxylic acid transport which serves to protect basic brain functions, but may be inadequate for optimal cognitive performance during acute hypoglycemia. The specific aims are: 1) To determine the long-term effect of severe recurrent hypoglycemia and hypoglycemia unawareness in patients with T1DM on: a) brain metabolism, including monocarboxylic acid transport, brain glucose levels and TCA cycle activity; b) cognitive function, and c) counterregulatory hormone secretion and symptoms during acute hypoglycemia. These data will provide new insights into changes in brain metabolism in T1DM patients with hypoglycemia unawareness, and would set the stage for future studies designed to assess the impact of restoring normoglycemia (via islet transplantation) on these.