In vivo Magnetic Resonance Spectroscopy of cerebral glycogen metabolism in animals and humans

Abstract

Glycogen serves as an important energy reservoir in the human body. Despite the abundance of glycogen in the liver and skeletal muscles, its concentration in the brain is relatively low, hence its significance has been questioned. A major challenge in studying brain glycogen metabolism has been the lack of availability of non-invasive techniques for quantification of brain glycogen in vivo. Invasive methods for brain glycogen quantification such as post mortem extraction following high energy microwave irradiation are not applicable in the human brain. With the advent of 13C Magnetic Resonance Spectroscopy (MRS), it has been possible to measure brain glycogen concentrations and turnover in physiological conditions, as well as under the influence of stressors such as hypoglycemia and visual stimulation. This review presents an overview of the principles of the 13C MRS methodology and its applications in both animals and humans to further our understanding of glycogen metabolism under normal physiological and pathophysiological conditions such as hypoglycemia unawareness.

Revisiting Glycogen Content in the Human Brain

“…The primary limitation of our study is the small sample size dictated by the substantial expense associated with these studies and the several-day long experimental design [17,18]. Similarly, we studied an all-male cohort due to challenges with recruitment for these long experiments; however we have not detected any appreciable differences between males and females in our prior studies investigating glycogen metabolism [19,20,28]; therefore the conclusions obtained in this cohort should be generalizable to both genders.…”

“…This method was further refined to eliminate label turnover as a variable in the determination of glycogen concentration and resulted in estimates of ~5–6 µmol/g glycogen content in the rat brain [15,16]. To date, 13 C MRS in conjunction with intravenous (IV) administration of [1- 13 C]glucose to isotopically label glycogen remains the only method to detect glycogen and estimate its content and turnover rate in the living human brain [17,18]. Using this method, we have previously reported 3.5–4.3 µmol/g for glycogen content of the healthy human brain [19,20].…”

Carbohydrate and Amino Acid Metabolism as Hallmarks for Innate Immune Cell Activation and Function

“…Glucose can also polymerize to form larger polysaccharides such as glycogen [17]. Glycogen has been extensively studied in hepatocytes, muscle cells, and neuronal tissue in which it serves as an intracellular cytosolic carbon reservoir [18][19][20][21]. A number of enzymes are required for the synthesis of glycogen in cells.…”

Experimental strategies for in vivo 13 C NMR spectroscopy

“…Hence a two-step labeling strategy was recently proposed, starting with an oral [1-13 C]glucose administration to reach isotopic steady-state, followed by infusion of doubly labeled glucose ([1,6-13 C 2 ]glucose) so that fractional enrichment is maintained at position C1 of glycogen, which can be used to track concentration variations, while the dynamics of 13 C enrichment at position C6 of glycogen (relative to C1) will reflect turnover rates [33]. For a more comprehensive review about glycogen labeling strategies, we refer to these two recent reviews [34,35].…”