Hyperglycemia Selectively Increases Cerebral Non-oxidative Glucose Consumption Without Affecting Blood Flow

Overview

Journal bioRxiv

Date 2024 Sep 24

PMID 39314314

Authors

Tyler Blazey

John J Lee

Abraham Z Snyder

Manu S Goyal

Tamara Hershey

Ana Maria Arbelaez

Marcus E Raichle

Affiliations

Soon will be listed here.

Abstract

Multiple studies have shown that hyperglycemia increases the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter. This observation remains unexplained. Using positron emission tomography (PET) and euinsulinaemic glucose clamps, we found, for the first time, that acute hyperglycemia increases non-oxidative CMRglc (i.e., aerobic glycolysis (AG)) in subcortical white mater as well as in medial temporal lobe structures, cerebellum and brainstem, all areas with low euglycemic CMRglc. Surprisingly, hyperglycemia did not change regional cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO), or the blood-oxygen-level-dependent (BOLD) response. Regional gene expression data reveal that brain regions where CMRglc increased have greater expression of hexokinase 2 (). Simulations of glucose transport revealed that, unlike hexokinase 1, is not saturated at euglycemia, thus accommodating increased AG during hyperglycemia.

References

de Graaf R, Pan J, Telang F, Lee J, Brown P, Novotny E . Differentiation of glucose transport in human brain gray and white matter. J Cereb Blood Flow Metab. 2001; 21(5):483-92. DOI: 10.1097/00004647-200105000-00002. View

Wolf T, Lindauer U, Villringer A, Dirnagl U . Excessive oxygen or glucose supply does not alter the blood flow response to somatosensory stimulation or spreading depression in rats. Brain Res. 1997; 761(2):290-9. DOI: 10.1016/s0006-8993(97)00354-5. View

Hacker C, Laumann T, Szrama N, Baldassarre A, Snyder A, Leuthardt E . Resting state network estimation in individual subjects. Neuroimage. 2013; 82:616-633. PMC: 3909699. DOI: 10.1016/j.neuroimage.2013.05.108. View

Hasselbalch S, Knudsen G, Capaldo B, Postiglione A, Paulson O . Blood-brain barrier transport and brain metabolism of glucose during acute hyperglycemia in humans. J Clin Endocrinol Metab. 2001; 86(5):1986-90. DOI: 10.1210/jcem.86.5.7490. View

Borghammer P, Cumming P, Aanerud J, Gjedde A . Artefactual subcortical hyperperfusion in PET studies normalized to global mean: lessons from Parkinson's disease. Neuroimage. 2008; 45(2):249-57. DOI: 10.1016/j.neuroimage.2008.07.042. View

Larsen P, Linneberg A, Hansen T, Friis-Hansen L . Reference intervals for C-peptide and insulin derived from a general adult Danish population. Clin Biochem. 2016; 50(7-8):408-413. DOI: 10.1016/j.clinbiochem.2016.12.004. View

Lundgaard I, Li B, Xie L, Kang H, Sanggaard S, Haswell J . Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nat Commun. 2015; 6:6807. PMC: 4410436. DOI: 10.1038/ncomms7807. View

van Golen L, Huisman M, IJzerman R, Hoetjes N, Schwarte L, Lammertsma A . Cerebral blood flow and glucose metabolism measured with positron emission tomography are decreased in human type 1 diabetes. Diabetes. 2013; 62(8):2898-904. PMC: 3717848. DOI: 10.2337/db12-1159. View

Amor S, McNamara N, Gerrits E, Marzin M, Kooistra S, Miron V . White matter microglia heterogeneity in the CNS. Acta Neuropathol. 2021; 143(2):125-141. DOI: 10.1007/s00401-021-02389-x. View

10.

Siletti K, Hodge R, Mossi Albiach A, Lee K, Ding S, Hu L . Transcriptomic diversity of cell types across the adult human brain. Science. 2023; 382(6667):eadd7046. DOI: 10.1126/science.add7046. View

11.

Hutchins D, Rogers K . Physiological and drug-induced changes in the glycogen content of mouse brain. Br J Pharmacol. 1970; 39(1):9-25. PMC: 1703027. DOI: 10.1111/j.1476-5381.1970.tb09551.x. View

12.

Kang P, Ying C, Chen Y, Ford A, An H, Lee J . Oxygen Metabolic Stress and White Matter Injury in Patients With Cerebral Small Vessel Disease. Stroke. 2021; 53(5):1570-1579. PMC: 9038643. DOI: 10.1161/STROKEAHA.121.035674. View

13.

Heeger D, Ress D . What does fMRI tell us about neuronal activity?. Nat Rev Neurosci. 2002; 3(2):142-51. DOI: 10.1038/nrn730. View

14.

Johkura K, Nakae Y, Kudo Y, Yoshida T, Kuroiwa Y . Early diffusion MR imaging findings and short-term outcome in comatose patients with hypoglycemia. AJNR Am J Neuroradiol. 2012; 33(5):904-9. PMC: 7968806. DOI: 10.3174/ajnr.A2903. View

15.

Ishibashi K, Kawasaki K, Ishiwata K, Ishii K . Reduced uptake of 18F-FDG and 15O-H2O in Alzheimer's disease-related regions after glucose loading. J Cereb Blood Flow Metab. 2015; 35(8):1380-5. PMC: 4527997. DOI: 10.1038/jcbfm.2015.127. View

16.

Smith S, Nichols T . Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage. 2008; 44(1):83-98. DOI: 10.1016/j.neuroimage.2008.03.061. View

17.

Kawasaki K, Ishii K, Saito Y, Oda K, Kimura Y, Ishiwata K . Influence of mild hyperglycemia on cerebral FDG distribution patterns calculated by statistical parametric mapping. Ann Nucl Med. 2008; 22(3):191-200. DOI: 10.1007/s12149-007-0099-7. View

18.

Gruetter R, Ugurbil K, Seaquist E . Effect of acute hyperglycemia on visual cortical activation as measured by functional MRI. J Neurosci Res. 2000; 62(2):279-85. DOI: 10.1002/1097-4547(20001015)62:2<279::AID-JNR12>3.0.CO;2-3. View

19.

Irshad Z, Xue M, Ashour A, Larkin J, Thornalley P, Rabbani N . Activation of the unfolded protein response in high glucose treated endothelial cells is mediated by methylglyoxal. Sci Rep. 2019; 9(1):7889. PMC: 6536510. DOI: 10.1038/s41598-019-44358-1. View

20.

Abi-Saab W, Maggs D, Jones T, Jacob R, Srihari V, Thompson J . Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects: effects of hyperglycemia and hypoglycemia. J Cereb Blood Flow Metab. 2002; 22(3):271-9. DOI: 10.1097/00004647-200203000-00004. View