Normalization of blood glucose levels via intensive insulin therapy reduces the incidence of diabetic complications. However, the benefits of such treatment regimens remain limited by frequent and severe bouts of hypoglycemia. These episodes diminish the brain's capacity to detect hypoglycemia and to activate counterregulatory defenses, further increasing the risk of subsequent hypoglycemia. As a result, hypoglycemia can occur without warning symptoms or during sleep, underscoring the need for preventive strategies and of minimizing its potential adverse consequences like seizures, coma and permanent injury. This issue is of particular concern in type 1 diabetes (T1DM) where recent studies suggest that severe and recurrent hypoglycemia occurring early in a patient's life can result in cognitive impairment and lasting brain damage. Previously we found that transport and metabolism of the monocarboxylic acid acetate was upregulated in T1DM and in a recurrent hypoglycemia rat model indicating that enhanced alternate fuel consumption plays a major role in hypoglycemia unawareness. However, when we studied the more relevant alternate fuel lactate, we found to our surprise that enhanced lactate transport did not go hand in hand with increased lactate utilization, but stimulated brain glucose metabolism instead. Our observations in rodents have since been confirmed by a recent study in T1DM subjects. These findings support the concept of lactate having a dual role during hypoglycemia in T1DM, as both a substrate and as an activator of glucose metabolism. We have recently gained additional insight into this lactate paradox through its impact on neuronal pyruvate dehydrogenase (PDH) complex activity. Our preliminary results suggest that PDH is inhibited during hypoglycemia, and that this inhibition can be reversed by plasma lactate. If this model is correct the preserved glucose metabolism in T1DM, which may play an important role in hypoglycemia unawareness, is due to elevated transport raising brain lactate levels and preventing inhibition of PDH. Thus, the overall goal of this proposal is to define the interplay of brain lactate and glucose metabolism in the context of recurrent hypoglycemia to establish the molecular mechanism by which T1DM patients sustain brain metabolism (and function) and become unaware of hypoglycemia. We are going to use NMR spectroscopy to define the contributions of 13C-labeled glucose and lactate to brain metabolism in the setting of recurrent hypoglycemia. In addition we will use pharmacologic and siRNA knockdown approaches to determine the role of PDH inhibiting kinases in the suppression of PDH flux under hypoglycemia. The human relevance of these findings will be tested by NMR spectroscopy in T1DM patients with hypoglycemia unawareness and matched controls using 13C-glucose and lactate.
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. These could then be used to sustain normal brain metabolism under hypoglycemia and would thereby allow for tighter glucose control with better protection from long-term diabetic related complications.
|De Feyter, Henk M; Herzog, Raimund I; Steensma, Bart R et al. (2018) Selective proton-observed, carbon-edited (selPOCE) MRS method for measurement of glutamate and glutamine 13 C-labeling in the human frontal cortex. Magn Reson Med 80:11-20|
|Ryu, Changwan; Sun, Huanxing; Gulati, Mridu et al. (2017) Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 196:1571-1581|
|Tricò, Domenico; Di Sessa, Anna; Caprio, Sonia et al. (2017) Oxidized Derivatives of Linoleic Acid in Pediatric Metabolic Syndrome: Is Their Pathogenic Role Modulated by the Genetic Background and the Gut Microbiota? Antioxid Redox Signal :|
|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|
|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|
|Tricò, Domenico; Prinsen, Hetty; Giannini, Cosimo et al. (2017) Elevated ?-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents. J Clin Endocrinol Metab 102:2473-2481|
|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|
|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|
|de Graaf, Robin A; Prinsen, Hetty; Giannini, Cosimo et al. (2015) Quantification of (1)H NMR Spectra from Human Plasma. Metabolomics 11:1702-1707|
|Herzog, Raimund I; Jiang, Lihong; Herman, Peter et al. (2013) Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. J Clin Invest 123:1988-98|