title: Brain glycogen and its role in supporting glutamate and GABA homeostasis in a type 2 diabetes rat model.
abstract: The number of people suffering from diabetes is hastily increasing and the condition is associated with altered brain glucose homeostasis. Brain glycogen is located in astrocytes and being a carbohydrate reservoir it contributes to glucose homeostasis. Furthermore, glycogen has been indicated to be important for proper neurotransmission under normal conditions. Previous findings from our laboratory suggested that glucose metabolism was reduced in type 2 diabetes, and thus we wanted to investigate more specifically how brain glycogen metabolism contributes to maintain energy status in the type 2 diabetic state. Also, our objective was to elucidate the contribution of glycogen to support neurotransmitter glutamate and GABA homeostasis. A glycogen phosphorylase (GP) inhibitor was administered to Sprague-Dawley (SprD) and Zucker Diabetic Fatty (ZDF) rats in vivo and after one day of treatment [1-¹³C]glucose was used to monitor metabolism. Brain levels of ¹³C labeling in glucose, lactate, alanine, glutamate, GABA, glutamine and aspartate were determined. Our results show that inhibition of brain glycogen metabolism reduced the amounts of glutamate in both the control and type 2 diabetes models. The reduction in glutamate was associated with a decrease in the pyruvate carboxylase/pyruvate dehydrogenase ratio in the control but not the type 2 diabetes model. In the type 2 diabetes model GABA levels were increased suggesting that brain glycogen serves a role in maintaining a proper ratio between excitatory and inhibitory neurotransmitters in type 2 diabetes. Both the control and the type 2 diabetic states had a compensatory increase in glucose-derived ¹³C processed through the TCA cycle following inhibition of glycogen degradation. Finally, it was indicated that the type 2 diabetes model might have an augmented necessity for compensatory upregulation at the glycolytic level.
authors.affiliation: Dept. of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark. hellesickmann@hotmail.com
authors.forename: Helle Mark
authors.initials: HM
authors.lastname: Sickmann
authors.forename: Helle Sønderby
authors.initials: HS
authors.lastname: Waagepetersen
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.forename: Andrew James
authors.initials: AJ
authors.lastname: Benie
authors.forename: Stephan Daniel
authors.initials: SD
authors.lastname: Bouman
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000502:physiology*; D006003:Glycogen / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors; D006706:Homeostasis / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010654:Phenylbutyrates / Q000494:pharmacology; D011766:Pyruvate Carboxylase / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: C504712:3-(5-chloroindole-2-carbonyl)amino-2-hydroxy-4-phenylbutyric acid N-methyl-N-methoxyamide; D007211:Indoles; D010654:Phenylbutyrates; D011768:Pyruvate Dehydrogenase Complex; D001224:Aspartic Acid; D019344:Lactic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D006003:Glycogen; D024981:Glycogen Phosphorylase; D011766:Pyruvate Carboxylase; D005947:Glucose