J Physiol 587.1 (2009) p 9 9

PERSPECT IVES

Non-oxidative cerebralcarbohydrate metabolism

Thomas GlennDepartment of Neurosurgery, Universityof California at Los Angles, Box 957039,David Geffen School of Medicine at UCLA,Los Angeles, CA 90095-7039, USA

Email: tglenn@mednet.ucla.edu

Kety and Schmidt’s application of the FickPrinciple in the 1940s has served as thetechnical basis for the human cerebralmetabolic studies still in use today. In thistechnique, arterial and jugular venous bloodsamples are collected, analysed for oxygen,glucose and lactate, and an arterial-jugularvenous difference (AVD) is calculated. Thecerebral metabolic rate is then calculatedas the product of the AVD and thesimultaneous measurement of cerebralblood flow. To further understand therelationship between the cerebral metaboliccomponents, an oxygen–carbohydrateindex (OCI), calculated by CMRO2

(CMRglucose + 1/2CMRlactate), or a meta-bolic ratio (OGI), calculated byCMRO2/CMRglucose, is used to determinehow much fuel substrate is oxidized,where a value of 6 represents the completeoxidation of glucose.

Glucose is considered to be the preferredcerebral oxidative fuel source under normalresting conditions, with 90% of brainglucose used oxidatively. The remaining10% of glucose goes to non-oxidative uses,such as glycogen formation and othermetabolic processes (Siesjo, 1978). On theother hand, in normal resting volunteers,the arterial jugular venous difference forlactate (AVDlac) is negative, indicating thatthe brain is producing and releasing lactateprimarily through glycolysis. However,

strenuous exercise or traumatic brain injurystudies reveal that the brain has a positiveAVDlac, and is therefore taking up lactate(Ide et al. 1999; Glenn et al. 2003; Soustiel &Sviri, 2007; Dalsgaard, 2006). Furthermore,the OCI/OGI can be influenced by brainactivation or brain insult, with valuesdropping significantly due to a greateruptake of glucose and lactate relative tooxygen.

In this issue of The Journal of Physiology,Larsen et al. (2009) have examined therole that the catecholamines adrenalineand noradrenaline may play in cerebralcarbohydrate uptake and metabolism innormal healthy subjects. This work isa continuation of earlier studies, whichfound that the non-selective β-adrenergicantagonist propranolol blocked thereduction of the OCI in exercising humans(Larsen et al. 2008). In Larsen’s currentstudy, subjects were infused with eitheradrenaline or noradrenaline, and arterialand jugular venous blood was sampled atfixed times, allowing for the calculationof variables such as AVD, OGI and OCI.The overall findings of the current studyrevealed that adrenaline caused an increasein glucose uptake and a small uptake oflactate. On the other hand, noradrenalinecaused an increase in glucose uptake alone,and only at the lower doses. Furthermore,adrenaline, but not noradrenaline, caused adecrease in both OCI and OGI. Therefore,their results indicate that a β2-adrenergicmechanism is responsible for the increasedcarbohydrate uptake.

In conclusion, several important questionsare raised by this research. Does adrenalinecross the blood brain barrier? As theauthors suggest, are the changes in cerebralmetabolism from earlier brain activationstudies of Fox et al. (1988) caused bya catecholamine stress response? Andultimately, what is the fate of the excesscarbohydrate uptake, i.e. where is the lactategoing and through which pathways is

glucose being metabolized? As the authorsstate, studies using stable isotopes, such as13C-labelled glucose and lactate, are neededto further define and help answer thesequestions. In a recent paper by Dusick et al.(2007), [1,2-13C2]glucose was infused intotraumatically brain injured patients andnormal subjects. In this study, the pentosephosphate cycle activity was significantlyincreased in the trauma patient group ascompared to normal controls, accountingin part for the increased glucose uptakeseen during decreased OGI. Thus, Larsen’scurrent study has important implicationsfor understanding catecholamine inducedcerebral responses, extending beyondexercise physiology. In disease states, suchas trauma, where catecholamine levels areelevated, these findings may shed new lighton the complexity of cerebral carbohydratemetabolism.

References

Dalsgaard MK (2006). J Cereb Blood Flow Metab26, 731–750.

Dusick JR, Glenn TC, Lee WN, Vespa PM, KellyDF, Lee SM, Hovda DA & Martin NA (2007).J Cereb Blood Flow Metab 27, 1593–1602.

Fox PT, Raichle ME, Mintun MA & Dence C(1988). Science 241, 462–464.

Glenn TC, Kelly DF, Boscardin WJ, McArthurDL, Vespa P, Oertel M, Hovda DA,Bergsneider M, Hillered L & Martin NA(2003). J Cereb Blood Flow Metab 23,1239–1250.

Ide K, Horn A & Secher NH (1999). J ApplPhysiol 87, 1604–1608.

Larsen TS, Brassard P, Jorgensen TB, HamadaAJ, Rasmussen P, Quistorff B, Secher NH &Nielsen HB (2009). J Physiol 587, 285–293.

Larsen TS, Rasmussen P, Overgaard M, SecherNH & Nielsen HB (2008). J Physiol 586,2807–2815.

Siesjo BK (1978). Brain Energy Metabolism, 1stedn, p. 104. John Wiley & Sons, New York.

Soustiel JF & Sviri GE (2007). Neurol Res 29,654–660.

C© 2009 The Author. Journal compilation C© 2009 The Physiological Society DOI: 10.1113/jphysiol.2008.166876