Brain glycogen metabolism and hypoglycemia

Glycogen in the brain is the single most concentrated storage of carbohydrate in the brain. Despite its importance to normal brain function very little is known about the function of glycogen in the brain. Dr. Gruetter's group has pioneered the technological advances to enable the non-invasive measurement of brain glycogen using NMR spectroscopy. This is especially important because measurement of brain glycogen in tissue extracts is difficult due to rapid agonal glycogenolysis. To achieve a complete non-invasive measurement of brain glycogen, a new pulse sequence that takes into account the short relaxation times of the glycogen signal had to be devised, which was extensively tested and verified, yielding high-resolution information on amino acid turnover in the brain:

Accurate localization of the method was demonstrated by the elimination of the lipid signals (which originate from the subcutaneous tissue) in vivo at 30.5 ppm (see above). Furthermore, accurate localization was demonstrated with the elimination of the glycogen signal when applying the localization method to the post-mortem rat brain:

Following these studies, 13C glucose was administered and it was demonstrated that label incorporation into glycogen was faster than label wash-out, using a pulse-chase experiment. These experiments provided further evidence for an action of plasma insulin/glucose on brain glycogen metabolism:

In a recent study, it was demonstrated that when brain glucose concentrations approached the Km of hexokinase (50µM), cerebral blood flow was acutely increased and brain glycogen degradation started. This points to brain glucose being an important signal that mobilizes defense mechanisms endogenous to the brain.

Our working hypothesis is that brain glycogen acts as an important endogenous reservoir to maintain cellular function with a bulk turnover that is very slow, on the order of a few % of resting metabolism. Currently we are expanding these experiments to hypoglycemia and to the human brain, where nothing is known about brain glycogen and its metabolism.