Obligatory role of endoplasmic reticulum in brain FDG uptake
- 284 Downloads
The endoplasmic reticulum (ER) contains hexose-6P-dehydrogenase (H6PD). This enzyme competes with glucose-6P-phosphatase for processing a variety of phosphorylated hexoses including 2DG-6P. The present study aimed to verify whether this ER glucose-processing machinery contributes to brain FDG uptake.
Effect of the H6PD inhibitor metformin on brain 18F-FDG accumulation was studied, in vivo, by microPET imaging. These data were complemented with the in vitro estimation of the lumped constant (LC). Finally, reticular accumulation of the fluorescent 2DG analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2NBDG) and its response to metformin was studied by confocal microscopy in cultured neurons and astrocytes.
Metformin halved brain 18F-FDG accumulation without altering whole body tracer clearance. Ex vivo, this same response faced the doubling of both glucose consumption and lactate release. The consequent fall in LC was not explained by any change in expression or activity of its theoretical determinants (GLUTs, hexokinases, glucose-6P-phosphatase), while it agreed with the drug-induced inhibition of H6PD function. In vitro, 2NBDG accumulation selectively involved the ER lumen and correlated with H6PD activity being higher in neurons than in astrocytes, despite a lower glucose consumption.
The activity of the reticular enzyme H6PD profoundly contributes to brain 18F-FDG uptake. These data challenge the current dogma linking 2DG/FDG uptake to the glycolytic rate and introduce a new model to explain the link between 18-FDG uptake and neuronal activity.
KeywordsBrain imaging PET/CT FDG H6PD Endoplasmic reticulum Glucose metabolism
The authors are indebted with Proff. Antonio De Flora, Alessandro Morelli and Alberto Pupi for the enthusiastic support and criticisms.
This study was funded by the program “Ricerca Corrente,” line “Guest-Cancer Interactions,” by Compagnia di San Paolo (project ID Prot.: 2015.AAI4110.U4917).
Compliance with ethical standards
All procedures involving animals were performed in respect of the current National and International regulations and were reviewed and approved by the Licensing and Animal Welfare Body of the IRCCS Ospedale Policlinico San Martino, Genoa, Italy and by the Italian Ministry of Health.
Conflict of interests
No author has any conflict of interest to declare.
- 1.Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, et al. The 14C-deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem. 1977;28:897–916.CrossRefGoogle Scholar
- 3.Sols A. Substrate specificity of brain hexokinase. J Biol Chem. 1954;210:581–95.Google Scholar
- 12.Moreira PI. Metformin in the diabetic brain: friend or foe? Ann Transl Med. 2014;2:2–4.Google Scholar
- 14.Blumrich EM, Dringen R. Metformin accelerates glycolytic lactate production in cultured primary cerebellar granule neurons. Neurochem Res. 2017:1–12. https://doi.org/10.1007/s11064-017-2346-1.
- 15.Westhaus A, Maria E, Dringen R. The antidiabetic drug metformin stimulates glycolytic lactate production in cultured primary rat astrocytes. Neurochem Res. 2015;123:1–16.Google Scholar
- 16.Buschiazzo A, Cossu V, Bauckneht M, Orengo A, Piccioli P, Emionite L, et al. Effect of starvation on brain glucose metabolism and 18F-2-fluoro-2- deoxyglucose uptake: an experimental in-vivo and ex-vivo study. EJNMMI Res. 2018. https://doi.org/10.1186/s13550-018-0398-0.
- 19.Graham MM, Muzi M, Spence AM, O'Sullivan F, Lewellen TK, Link JM, et al. The FDG lumped constant in normal human brain. J Nucl Med. 2002;43:1157–67.Google Scholar
- 20.Noll T, Mühlensiepen H, Engels R, Hamacher K, Papaspyrou M, Langen KJ, et al. A cell-culture reactor for the on-line evaluation of radiopharmaceuticals: evaluation of the lumped constant of FDG in human glioma cells. J Nucl Med. 2000;41:556–64.Google Scholar
- 24.Fiske CH, Subbarow Y. The colorimetric determination of phosphorus. J Biol Chem. 1925;66:375–400.Google Scholar
- 25.Cura AJ, Carruthers A. Role of monosaccharide transport proteins in carbohydrate assimilation , distribution, metabolism , and homeostasis. Compr Physiol. 2012;2:863–914.Google Scholar
- 32.Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Neurobiology. 1994;91:10625–9.Google Scholar