Altered Plasticity of Glycogen Phosphorylase in Forebrain Gliosomes Obtained from Insulinoma Patients

J Mol Neurosci. 2015 Sep;57(1):21-7. doi: 10.1007/s12031-015-0573-y. Epub 2015 May 7.

Abstract

We investigated a control model of hypoglycemia-exposed brain tissues from a small series of patients with insulinoma, immediately dissect them, and perform a differential cold centrifugation to obtain gliosomes and examine alterations of glycogenolytic mechanisms. The BB as well as MM isoforms of glycogen phosphorylase enzymatic protein expression remained unaltered between insulinoma and control subjects within the gliosomes. However, the glycogen phosphorylase remained in a form that was potentially activated several folds on placing the gliosomes in a glucose-free medium. This was examined by its increased interaction with protein kinase A. Inhibitors of glycogen phosphorylase was used as controls. Furthermore, we demonstrated that glucose-depleted medium enhanced production of both ATP and lactate by the gliosomes. It is possible that a portion of glucose obtained from glycogen breakdown was circuited through glycolytic pathways to generate ATP. It has been reported earlier that ATP within gliosomes plays a major role in glutamate uptake, thus potentially preventing seizure during active bouts of hypoglycemia. Lactate shuttle from astrocytes is a potential mechanism to balance neuronal bioenergetics during events of hypoglycemia. Newer approaches to pharmacologically modulate glycogen phosphorylase may prove to be rational approach for neuroprotective therapy in this common clinical syndrome of hypoglycemia.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aged
  • Astrocytes / metabolism*
  • Case-Control Studies
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytoplasmic Granules / metabolism*
  • Glucose / metabolism
  • Glycogen Phosphorylase / genetics
  • Glycogen Phosphorylase / metabolism*
  • Humans
  • Hypoglycemia / metabolism*
  • Insulinoma / metabolism*
  • Lactic Acid / metabolism
  • Middle Aged
  • Neurons / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Prosencephalon / cytology
  • Prosencephalon / metabolism*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism

Substances

  • Protein Isoforms
  • Lactic Acid
  • Adenosine Triphosphate
  • Glycogen Phosphorylase
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose