Diabetic complications can be reduced by normalization of blood glucose levels via intensive insulin therapy. This treatment, while effective, bears the risk of an increased incidence of recurrent hypoglycemia. It blunts the central counterregulatory response to low blood glucose (counterregulatory failure) and thereby magnifies the risk of severe hypoglycemia and brain injury. This proposal is aimed at characterizing the CNS complications of intensive insulin therapy in type 1 diabetes;specifically, abnormalities in brain metabolism and its adaptations to recurrent hypoglycemia, the major cause of hypoglycemia unawareness. Previous data from our group from type 1 diabetic patients showed an increased ability of the brain to utilize alternate fuels under hypoglycemia, likely due to increased transporter protein expression. Preliminary in vivo NMR spectroscopy data from our animal model of recurrent hypoglycemia confirmed these findings since we found that infused monocarboxylic acids such as acetate and lactate could serve as energy substrates other than glucose and support brain metabolism under hypoglycemia. Antecedent recurrent hypoglycemia enhances these effects via a functional increase in alternate fuel transport into the brain. When testing lactate as an alternative fuel, we made the surprising observation that even though its uptake following exposure to recurrent hypoglycemia was enhanced, it still did not contribute significantly to overall brain oxidative capacity. Together this led us to hypothesize that recurrent hypoglycemia enhances uptake of monocarboxylic acids into the brain, which could be taken advantage of to support neuronal metabolism if a candidate fuel would not be subject to the same limitations as lactate. Because it does not depend on the potentially limiting step of pyruvate dehydrogenase conversion, beta-hydroxy-butyrate is one such fuel. Thus, we are proposing to determine the ability of the neuronal fuel beta-hydroxy-butyrate to support metabolic fluxes and to support human brain energy homeostasis under hypoglycemia. In a crossover study design, we will characterize brain ketone metabolism by carbon-13 NMR spectroscopy in healthy control and type 1 diabetic subjects during eu- and hypoglycemic clamp studies. By providing an alternate fuel when glucose is in limited supply, we will then be in the position to determine the contribution of ketones to overall brain metabolism. We will also characterize the ketone effect on neurotransmitter homeostasis. Our data will refine our understanding of brain monocarboxylic acid metabolism and will have important implications for creating new therapies to reduce brain dysfunction, injury and even death from hypoglycemia. Perhaps more importantly, this novel therapy may provide the opportunity to achieve tighter glucose control of type 1 diabetic patients, with reduced risk of brain injury from severe hypoglycemia, thus allowing more aggressive treatment and decreasing long term complications.

Public Health Relevance

Understanding the changes of brain energy substrate transport and metabolism in intensively treated type 1 diabetic patients will provide the basis for the identification of novel therapeutic approaches that could protect the brain from hypoglycemia-induced injury. This in turn could then sustain normal brain metabolism under hypoglycemia and would further allow for tighter glucose control with better protection from long-term diabetic related complications. Here we are testing the ability of the ketone body -hydroxybutyrate to support brain metabolism under hypoglycemia in healthy human subjects and type 1 diabetic patients with frequent exposure to low blood sugar.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code
Tricò, Domenico; Herzog, Raimund I (2017) Metabolic brain adaptations to recurrent hypoglycaemia may explain the link between type 1 diabetes mellitus and epilepsy and point towards future study and treatment options. Diabetologia 60:938-939
Goldberg, Emily L; Asher, Jennifer L; Molony, Ryan D et al. (2017) ?-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Rep 18:2077-2087
Belinsky, Glenn S; Sreekumar, Bharath; Andrejecsk, Jillian W et al. (2016) Pigment epithelium-derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI via Wnt3a blockade. FASEB J 30:2837-48
de Graaf, Robin A; Prinsen, Hetty; Giannini, Cosimo et al. (2015) Quantification of (1)H NMR Spectra from Human Plasma. Metabolomics 11:1702-1707
Xiang, Yaozu; Cheng, Jijun; Wang, Dandan et al. (2015) Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood 125:3377-87