Non‐oxidative cerebral carbohydrate metabolism

Abstract

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 , or a metabolic ratio (OGI), calculated by , 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 (Siesjo, 1978). On the other hand, in normal resting volunteers, the arterial jugular venous difference for lactate (AVDlac) 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 AVDlac, 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 β2-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 13C-labelled glucose and lactate, are needed to further define and help answer these questions. In a recent paper by Dusick et al. (2007), [1,2-13C2]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.