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 pancreatic glucose clamps with basal insulin replacement in twenty-nine healthy young adults (34.5 years, SD = 10.1) we found 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 CMRglc during euglycemia. Surprisingly, hyperglycemia did not change regional cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2), or the blood-oxygen-level-dependent (BOLD) response. Correlation with existing regional gene expression data showed that brain regions where CMRglc increased have greater expression of hexokinase 2 (HK2). Simulations of glucose transport revealed that, unlike hexokinase 1, HK2 is not saturated at euglycemia, and thus can accommodate increased AG during hyperglycemia.
GruetterRUgurbilKSeaquistER.Steady-state cerebral glucose concentrations and transport in the human brain. J Neurochem1998;
70: 397–408.
2.
De GraafRAPanJWTelangF, et al.
Differentiation of glucose transport in human brain gray and white matter. J Cerebral Blood Flow and Metab2001;
21: 483–492.
3.
BarrosLFBittnerCXLoaizaA, et al.
A quantitative overview of glucose dynamics in the gliovascular unit. Glia2007;
55: 1222–1237.
4.
BlomqvistGGrillVIngvarM, et al.
The effect of hyperglycaemia on regional cerebral glucose oxidation in humans studied with [1-11C]-D-glucose. Acta Physiol Scand1998;
163: 403–415.
5.
HasselbalchSGKnudsenGMCapaldoB, et al.
Blood-brain barrier transport and brain metabolism of glucose during acute hyperglycemia in humans. J Clin Endocrinol Metab2001;
86: 1986–1990.
6.
KawasakiKIshiiKSaitoY, et al.
Influence of mild hyperglycemia on cerebral FDG distribution patterns calculated by statistical parametric mapping. Ann Nucl Med2008;
22: 191–200.
7.
BurnsCMChenKKaszniakAW, et al.
Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions. Neurology2013;
80: 1557–1564.
8.
IshibashiKKawasakiKIshiwataK, et al.
Reduced uptake of 18F-FDG and 15O-H2O in Alzheimer’s disease-related regions after glucose loading. J Cereb Blood Flow Metab2015;
35: 1380–1385.
9.
IshibashiKOnishiAFujiwaraY, et al.
Effects of glucose, insulin, and insulin resistance on cerebral 18F-FDG distribution in cognitively normal older subjects. PLoS One2017;
12: e0181400.
CranePKWalkerRHubbardRA, et al.
Glucose levels and risk of dementia. N Engl J Med2013;
369: 540–548.
12.
BiesselsGJStaekenborgSBrunnerE, et al.
Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol2006;
5: 64–74.
13.
NinomiyaT.Diabetes mellitus and dementia. Curr Diab Rep2014;
14: 487.
14.
van GilsVRizzoMCôtéJ, et al.
The association of glucose metabolism measures and diabetes status with Alzheimer’s disease biomarkers of amyloid and tau: a systematic review and meta-analysis. Neurosci Biobehav Rev2024;
159: 105604.
15.
KangJECirritoJRDongH, et al.
Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity. Proc Natl Acad Sci U S A2007;
104: 10673–10678.
16.
MacauleySLStanleyMCaesarEE, et al.
Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo. J Clin Invest2015;
125: 2463–2467.
17.
FoxPTRaichleME.Stimulus rate dependence of regional cerebral blood flow in human striate cortex, demonstrated by positron emission tomography. J Neurophysiol1984;
51: 1109–1120.
18.
SilettiKHodgeRMossi AlbiachA, et al.
Transcriptomic diversity of cell types across the adult human brain. Science2023;
382: eadd7046.
19.
SeekerLABestard-CucheNJäkelS, et al.
Brain matters: unveiling the distinct contributions of region, age, and sex to glia diversity and CNS function. Acta Neuropathol Commun2023;
11: 84–23.
20.
KrentzAJBoylePJMacdonaldLM, et al.
Octreotide: a long-acting inhibitor of endogenous hormone secretion for human metabolic investigations. Metabolism1994;
43: 24–31.
21.
DaiWGarciaDDe BazelaireC, et al.
Continuous flow-driven inversion for arterial spin labeling using pulsed radio frequency and gradient fields. Magn Reson Med2008;
60: 1488–1497.
22.
HackerCDLaumannTOSzramaNP, et al.
Resting state network estimation in individual subjects. Neuroimage2013;
82: 616–633.
23.
JenkinsonMBannisterPBradyM, et al.
Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage2002;
17: 825–841.
24.
JenkinsonMBeckmannCFBehrensTEJ, et al.
FSL. Neuroimage2012;
62: 782–790.
25.
AguirreGKDetreJAZarahnE, et al.
Experimental design and the relative sensitivity of BOLD and perfusion fMRI. Neuroimage2002;
15: 488–500.
26.
AlsopDCDetreJAGolayX, et al.
Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: a consensus of the ISMRM perfusion study group and the European Consortium for ASL in dementia. Magn Reson Med2015;
73: 102–116.
27.
MarkiewiczPJEhrhardtMJErlandssonK, et al.
NiftyPET: a high-throughput software platform for high quantitative accuracy and precision PET imaging and analysis. Neuroinformatics2018;
16: 95–115.
28.
RowlandDJGarbowJRLaforestR, et al.
Registration of [18F]FDG microPET and small-animal MRI. Nucl Med Biol2005;
32: 567–572.
29.
AvantsBBTustisonNJSongG, et al.
A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage2011;
54: 2033–2044.
30.
VaishnaviSNVlassenkoAGRundleMM, et al.
Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci U S A2010;
107: 17757–17762.
31.
FischlB.FreeSurfer. Neuroimage2012;
62: 774–781.
32.
PhelpsMEHuangSCHoffmanEJ, et al.
Tomographic measurement of local cerebral glucose metabolic rate in humans with (F‐18)2‐fluoro‐2‐deoxy‐D‐glucose: validation of method. Ann Neurol1979;
6: 371–388.
33.
RizzoGTurkheimerFEBertoldoA.Multi-scale hierarchical approach for parametric mapping: assessment on multi-compartmental models. Neuroimage2013;
67: 344–353.
34.
WuH-MBergsneiderMGlennTC, et al.
Measurement of the global lumped constant for 2-Deoxy-2-[18F]fluoro-D-glucose in normal human brain using [15O]water and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography imaging: a method with validation based on multiple methodologies. Mol Imaging Biol2003;
5: 32–41.
35.
HawrylyczMJLeinESGuillozet-BongaartsAL, et al.
An anatomically comprehensive atlas of the adult human brain transcriptome. Nature2012;
489: 391–399.
36.
PinheiroJCBatesDM.Mixed-Effects models in S and S-PLUS.
New York:
Springer, 2000.
37.
R Core Team. R: a language and environment for statistical computing [internet].
Vienna, Austria:
Author, 2018.
38.
GenoveseCRLazarNANicholsT.Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage2002;
15: 870–878.
39.
WinklerAMRidgwayGRWebsterMA, et al.
NeuroImage permutation inference for the general linear model. Neuroimage2014;
92: 381–397.
40.
SmithSMNicholsTE.Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage2009;
44: 83–98.
41.
LakensD.Equivalence tests: a practical primer for t tests, correlations, and meta-analyses. Soc Psychol Personal Sci2017;
8: 355–362.
42.
FoxPTRaichleMEMintunMA, et al.
Nonoxidative glucose consumption during focal physiologic neural activity. Science1988;
241: 462–464.
43.
HeegerDJRessD.What does fMRI tell us about neuronal activity?Nat Rev Neurosci2002;
3: 142–151.
44.
MintunMAVlassenkoAGRundleMM, et al.
Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. Proc Natl Acad Sci U S A2004;
101: 659–664.
45.
SperlingRABatesJFCocchiarellaAJ, et al.
Encoding novel face-name associations: a functional MRI study. Hum Brain Mapp2001;
14: 129–139.
46.
WilsonJE.Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol2003;
206: 2049–2057.
47.
WilsonJE.Regulation of mammalian hexokinase activity. In: Beitner R (ed.) Regulation of carbohydrate metabolism.
London:
CRC Press, 1985. p. 45,85.
48.
IshibashiKWagatsumaKIshiwataK, et al.
Alteration of the regional cerebral glucose metabolism in healthy subjects by glucose loading. Hum Brain Mapp2016;
37: 2823–2832.
49.
BlomqvistG.Effect of hyperglycemia on rCMRglc in rats. J Cereb Blood Flow Metab1995;
15: 349–351.
50.
HuangCWHuangCCChengJT, et al.
Glucose and hippocampal neuronal excitability: role of ATP-sensitive potassium channels. J Neurosci Res2007;
85: 1468–1477.
51.
BeroAWYanPRohJH, et al.
Neuronal activity regulates the regional vulnerability to amyloid-β 2 deposition. Nat Neurosci2011;
14: 750–756.
52.
IdoYChangKWilliamsonJR.NADH augments blood flow in physiologically activated retina and visual cortex. Proc Natl Acad Sci U S A2004;
101: 653–658.
53.
HuangC-WTsaiJ-JOuH-Y, et al.
Diabetic hyperglycemia is associated with the severity of epileptic seizures in adults. Epilepsy Res2008;
79: 71–77.
54.
DuckrowRBBeardDCBrennanRW.Regional cerebral blood flow decreases during hyperglycemia. Ann Neurol1985;
17: 267–272.
55.
IshibashiKKawasakiKIshiwataK, et al.
Reduced uptake of 18F-FDG and 15O-H2O in Alzheimer’s disease-related regions after glucose loading. J Cereb Blood Flow Metab2015;
35: 1380–1385.
56.
WolfTLindauerUVillringerA, et al.
Excessive oxygen or glucose supply does not alter the blood flow response to somatosensory stimulation or spreading depression in rats. Brain Res1997;
761: 290–299.
57.
GruetterRUğurbilKSeaquistER.Effect of acute hyperglycemia on visual cortical activation as measured by functional MRI. J Neurosci Res2000;
62: 279–285.
58.
MuziMFreemanSDBurrowsRC, et al.
Kinetic characterization of hexokinase isoenzymes from glioma cells: implications for FDG imaging of human brain tumors. Nucl Med Biol2001;
28: 107–116.
59.
HeikkiläOLundbomNTimonenM, et al.
Hyperglycaemia is associated with changes in the regional concentrations of glucose and myo -inositol within the brain. Diabetologia2009;
52: 534–540.
60.
MangiaSKumarAFMoheetAA, et al.
Neurochemical profile of patients with type 1 diabetes measured by 1 H-MRS at 4 T. J Cereb Blood Flow Metab2013;
33: 754–759.
61.
XiaH-GNajafovAGengJ, et al.
Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death. J Cell Biol2015;
210: 705–716.
62.
IrshadZXueMAshourA, et al.
Activation of the unfolded protein response in high glucose treated endothelial cells is mediated by methylglyoxal. Sci Rep2019;
9: 7889–14.
63.
HuYCaoKWangF, et al.
Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity. Nat Metab2022;
4: 1756–1774.
64.
LengLYuanZPanR, et al.
Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance. Nat Metab2022;
4: 1287–1305.
65.
LundgaardILiBXieL, et al.
Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nat Commun2015;
6: 6807.
66.
AskewKLiKOlmos-AlonsoA, et al.
Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep2017;
18: 391–405.
67.
AmorSMcNamaraNBGerritsE, et al.
White matter microglia heterogeneity in the CNS. Acta Neuropathol2022;
143: 125–141.
68.
Dos SantosSEMedeirosMPorfirioJ, et al.
Similar microglial cell densities across brain structures and mammalian species: Implications for brain tissue function. J Neurosci2020;
40: 4622–4643.
69.
JohkuraKNakaeYKudoY, et al.
Early diffusion MR imaging findings and short-term outcome in comatose patients with hypoglycemia. Ajnr Am J Neuroradiol2012;
33: 904–909.
70.
KangPYingCChenY, et al.
Oxygen metabolic stress and white matter injury in patients with cerebral small vessel disease. Stroke2022;
53: 1570–1579.
71.
FieldsMEGuilliamsKPRaganDK, et al.
Regional oxygen extraction predicts border zone vulnerability to stroke in sickle cell disease. Neurology2018;
90: e1134–44–e1142.
72.
MergenthalerPKahlAKamitzA, et al.
Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state. Proc Natl Acad Sci U S A2012;
109: 1518–1523.
73.
LeeHGKimHSonT, et al.
Regulation of HK2 expression through alterations in CpG methylation of the HK2 promoter during progression of hepatocellular carcinoma. Oncotarget2016;
7: 41798–41810.
74.
CheungECLudwigRLVousdenKH.Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc Natl Acad Sci U S A2012;
109: 20491–20496.
75.
ChédevilleALLourdusamyAMonteiroAR, et al.
Investigating glioblastoma response to hypoxia. Biomedicines2020;
8: 310.
76.
Abi-SaabWMMaggsDGJonesT, et al.
Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects : effects of hyperglycemia and hypoglycemia. Cereb Blood Flow Metab2002;
22: 271–279.
77.
GottsteinUHeldKSebeningH, et al.
Der glucoseverbrauch des menschlichen gehirns unter dem einfluß intravenöser infusionen von glucose, glucagon und glucose-insulin. Klin Wochenschr1965;
43: 965–975.
78.
WuLButlerNJMSwansonRA.Technical and comparative aspects of brain glycogen metabolism. In: DiNuzzoMSchousboeA (eds) Brain glycogen metabolism.
Cham:
Springer International Publishing, 2019, pp. 169–185.
79.
GoldbergNDO'TooleAG.The properties of glycogen synthetase and regulation of glycogen biosynthesis in rat brain. J Biol Chem1969;
244: 3053–3061.
80.
HutchinsDARogersKJ.Physiological and drug‐induced changes in the glycogen content of mouse brain. Br J Pharmacol1970;
39: 9–25.
81.
TakahashiSIzawaYSuzukiN.Astroglial pentose phosphate pathway rates in response to high-glucose environments. ASN Neuro2012;
4: 71–88.
82.
SoucekTCummingRDarguschR, et al.
The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Neuron2003;
39: 43–56.
83.
RobertsDJMiyamotoS.Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ2015;
22: 248–257.
84.
Garcia CorralesAVHaidarMBogieJFJ, et al.
Fatty acid synthesis in glial cells of the CNS. Int J Mol Sci2021;
22: 8159.
85.
ParhoferKG.Interaction between glucose and lipid metabolism: more than diabetic dyslipidemia. Diabetes Metab J2015;
39: 353–362.
86.
TangWHMartinKAHwaJ.Aldose reductase, oxidative stress, and diabetic mellitus. Front Pharmacol2012;
3: 87–88.
87.
DienelGACruzNFSokoloffL.Metabolites of 2-deoxy-[14C]glucose in plasma and brain: influence on rate of glucose utilization determined with deoxyglucose method in rat brain. J Cereb Blood Flow Metab1993;
13: 315–327.
88.
KweeILIgarashiHNakadaT.Aldose reductase and sorbitol dehydrogenase activities in diabetic brain: in vivo kinetic studies using 19F 3-FDG NMR in rats. Neuroreport1996;
7: 726–728.
89.
HwangJJJiangLHamzaM, et al.
The human brain produces fructose from glucose. JCI Insight2017;
2: e90508–6.
90.
FeldmanELNaveKArmin JensenTS, et al.
Review new horizons in diabetic neuropathy. Neuron2017;
93: 1296–1313.
91.
ChaudhuriJBainsYGuhaS, et al.
The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality. Cell Metab2018;
28: 337–352.
92.
WangD-QWangLWeiM-M, et al.
Relationship between type 2 diabetes and white matter hyperintensity: a systematic review. Front Endocrinol (Lausanne)2020;
111: 595962.
93.
ZhangTShawMCherbuinN.Association between type 2 diabetes mellitus and brain atrophy: a meta-analysis. Diabetes Metab J2022;
46: 781–802.
94.
HuangLZhangQTangT, et al.
Abnormalities of brain white matter in type 2 diabetes mellitus: a meta-analysis of diffusion tensor imaging. Front Aging Neurosci2021;
13: 693890.
95.
RabbaniNThornalleyPJ.Hexokinase-2 glycolytic overload in diabetes and ischemia–reperfusion injury. Trends Endocrinol Metab2019;
30: 419–431.
96.
RabbaniNXueMThornalleyPJ.Hexokinase-2-linked glycolytic overload and unscheduled glycolysis-driver of insulin resistance and development of vascular complications of diabetes. Int J Mol Sci2022;
23: 1–19.
97.
IrshadZXueMAshourA, et al.
Activation of the unfolded protein response in high glucose treated endothelial cells is mediated by methylglyoxal. Sci Rep2019;
9: 7889–14.
98.
XueMQianQAdaikalakoteswariA, et al.
Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes2008;
57: 2809–2817.
99.
XuFLiuPPascualJM, et al.
Acute effect of glucose on cerebral blood flow, blood oxygenation, and oxidative metabolism. Hum Brain Mapp2015;
36: 707–716.
100.
BorghammerPCummingPAanerudJ, et al.
Artefactual subcortical hyperperfusion in PET studies normalized to global mean: Lessons from Parkinson’s disease. Neuroimage2009;
45: 249–257.
101.
SokoloffLReivichMKennedyC, 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 Neurochem1977;
28: 897–916.
102.
SchuierFOrziFSudaS, et al.
Influence of plasma glucose concentration on lumped constant of the deoxyglucose method: effects of hyperglycemia in the rat. J Cereb Blood Flow Metab1990;
10: 765–773.
103.
van GolenLWHuismanMCIjzermanRG, et al.
Cerebral blood flow and glucose metabolism measured with positron emission tomography are decreased in human type 1 diabetes. Diabetes2013;
62: 2898–2904.
104.
HollenbeckCReavenGM.Variations in Insulin-Stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab1987;
64: 1169–1173.
105.
LarsenPBLinnebergAHansenT, et al.
Reference intervals for C-peptide and insulin derived from a general adult Danish population. Clin Biochem2017;
50: 408–413.
106.
TuYKGilthorpeMS.Revisiting the relation between change and initial value: a review and evaluation. Stat Med2007;
26: 443–457.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
