Non-oxidative cerebral carbohydrate metabolism
1
J Physiol 587.1 (2009) p 9 9 PERSPECTIVES Non-oxidative cerebral carbohydrate metabolism Thomas Glenn Department of Neurosurgery, University of California at Los Angles, Box 957039, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7039, USA Email: [email protected] Kety and Schmidt’s application of the Fick Principle in the 1940s has served as the technical basis for the human cerebral metabolic studies still in use today. In this technique, arterial and jugular venous blood samples are collected, analysed for oxygen, glucose and lactate, and an arterial-jugular venous difference (AVD) is calculated. The cerebral metabolic rate is then calculated as the product of the AVD and the simultaneous measurement of cerebral blood flow. To further understand the relationship between the cerebral metabolic components, an oxygen–carbohydrate index (OCI), calculated by CMR O2 (CMR glucose + 1 / 2CMR lactate ), or a meta- bolic ratio (OGI), calculated by CMR O2 /CMR glucose , is used to determine how much fuel substrate is oxidized, where a value of 6 represents the complete oxidation of glucose. Glucose is considered to be the preferred cerebral oxidative fuel source under normal resting conditions, with 90% of brain glucose used oxidatively. The remaining 10% of glucose goes to non-oxidative uses, such as glycogen formation and other metabolic processes (Siesj¨ o, 1978). On the other hand, in normal resting volunteers, the arterial jugular venous difference for lactate (AVD lac ) is negative, indicating that the brain is producing and releasing lactate primarily through glycolysis. However, strenuous exercise or traumatic brain injury studies reveal that the brain has a positive AVD lac , 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 brain activation or brain insult, with values dropping significantly due to a greater uptake of glucose and lactate relative to oxygen. In this issue of The Journal of Physiology , Larsen et al. (2009) have examined the role that the catecholamines adrenaline and noradrenaline may play in cerebral carbohydrate uptake and metabolism in normal healthy subjects. This work is a continuation of earlier studies, which found that the non-selective β-adrenergic antagonist propranolol blocked the reduction of the OCI in exercising humans (Larsen et al. 2008). In Larsen’s current study, subjects were infused with either adrenaline or noradrenaline, and arterial and jugular venous blood was sampled at fixed times, allowing for the calculation of variables such as AVD, OGI and OCI. The overall findings of the current study revealed that adrenaline caused an increase in glucose uptake and a small uptake of lactate. On the other hand, noradrenaline caused an increase in glucose uptake alone, and only at the lower doses. Furthermore, adrenaline, but not noradrenaline, caused a decrease in both OCI and OGI. Therefore, their results indicate that a β 2 -adrenergic mechanism is responsible for the increased carbohydrate uptake. In conclusion, several important questions are raised by this research. Does adrenaline cross the blood brain barrier? As the authors suggest, are the changes in cerebral metabolism from earlier brain activation studies of Fox et al. (1988) caused by a catecholamine stress response? And ultimately, what is the fate of the excess carbohydrate uptake, i.e. where is the lactate going and through which pathways is glucose being metabolized? As the authors state, studies using stable isotopes, such as 13 C-labelled glucose and lactate, are needed to further define and help answer these questions. In a recent paper by Dusick et al. (2007), [1,2- 13 C 2 ]glucose was infused into traumatically brain injured patients and normal subjects. In this study, the pentose phosphate cycle activity was significantly increased in the trauma patient group as compared to normal controls, accounting in part for the increased glucose uptake seen during decreased OGI. Thus, Larsen’s current study has important implications for understanding catecholamine induced cerebral responses, extending beyond exercise physiology. In disease states, such as trauma, where catecholamine levels are elevated, these findings may shed new light on the complexity of cerebral carbohydrate metabolism. References Dalsgaard MK (2006). J Cereb Blood Flow Metab 26, 731–750. Dusick JR, Glenn TC, Lee WN, Vespa PM, Kelly DF, 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, McArthur DL, 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 Appl Physiol 87, 1604–1608. Larsen TS, Brassard P, Jorgensen TB, Hamada AJ, Rasmussen P, Quistorff B, Secher NH & Nielsen HB (2009). J Physiol 587, 285–293. Larsen TS, Rasmussen P, Overgaard M, Secher NH & Nielsen HB (2008). J Physiol 586, 2807–2815. Siesj¨ o BK (1978). Brain Energy Metabolism, 1st edn, 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
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Transcript of Non-oxidative cerebral carbohydrate metabolism
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: [email protected]
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
