MRS Studies of Brain Metabolic Adaptations in Diabetes

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DESCRIPTION (provided by applicant): In intensively treated subjects with T1DM during hypoglycemia there is often a loss of both the counterregulatory response and the mild cognitive symptoms prior to severe cognitive dysfunction. Both of these adaptations are believed to contribute significantly to hypoglycemic unawareness, which increases the risk of severe hypoglycemia. Using a novel method combining 13C MRS and [2-13C] acetate infusion we found that cortical monocarboxylic acid transport (MCT) and metabolism is up regulated 2-fold in patients with intensively treated T1DM. In Aim 1 we will assess whether increased usage of lactate, the monocarboxylic acid (MCA) with the highest concentration in blood during hypoglycemia, plays a significant role in preserving neuronal energy metabolism in subjects with intensively treated T1DM. In Aim 2 we will assess whether MCT upregulation is specifically caused by recent exposure to extended hypoglycemia. The detailed understanding provided by these studies of cortical metabolic adaptations to hypoglycemia should aid in the development of strategies for counteracting them, which may help restore awareness of hypoglycemia in such patients. In Aim 3 we will use a novel 1H MRS method for measuring brain glucose transport to assess upregulation of glucose transport in intensively treated TIDM. In Aim 4 we will use an animal model to validate our interpretation that the increase in acetate transport and metabolism due to repeated hypoglycemia is due to upregulation of blood brain barrier MCT activity. Finally in Aim 5 we will further assess in the animal model whether the upregulation of MCT activity can potentially protect against hypoglycemic energy failure. If MCAs or alternatively medium chain fatty acids can protect against hypoglycemic energy failure they may potentially be administered as a protective therapy for nocturnal hypoglycemic episodes.