Brain activity energy metabolism and neurotransmitter cycling

Epidemiological, cross-sectional and prospective associations between T2DM and moderate cognitive impairment of memory and executive functions have been discovered and were reviewed by Pasquier et al. (2006). Both vascular and non-vascular factors were found to be the reasons for dementia in diabetes (Stewart & Liolitsa 1999). Direct study using functional BOLD MRI of brain activation has shown that hypoglycaemia induced impairment of brain function is associated with task specific localised reduction in brain activation (Rosenthal et al. 2001). Higher increase of deoxygenation, depicted as higher BOLD signal in active brain areas, can help to overcome the energy shortage caused by hypoglycaemia (Rosenthal et al. 2001) or micovascular damage in type 1 diabetic patients (Wessels et al. 2006) with retinopathy. Certain overcompensation mechanisms can be observed in 31P and 1H MR spectroscopic observation of energy metabolism in type 1 diabetic patients, where, in contrast to healthy volunteers, no decrease of energy buffer - phosphocreatine (Bischof et al. 2004) - and neurotransmitter - glutamine (Bischof et al. 2006) - has been observed in acute hypoglycaemia. In a similar population of type 1 diabetic patients with unawareness of hypoglycaemia, increased transport of glucose between plasma and brain tissue was detected in controlled conditions of hyperglycaemia by direct :H MR spectroscopic measurement of brain glucose (Criego et al. 2005a,b). These studies were based on previous results in which a linear relationship between plasma and brain glucose was established and validated (Gruetter et al. 1998; Choi et al. 2001; Seaquist et al. 2001). In order to increase glucose transport, in vivo studies in rat brain suggested that a mechanism of hypoglycaemia induced brain glycogen overcompensation could protect brain tissue from acute energy shortage during and following hypoglycaemia (Choi et al. 1999, 2003; Choi & Gruetter 2003). These measurements apply a robust 13C MR signal localisation technique (Choi et al. 2000; Gruetter et al. 2003) that enables brain glycogen quantification, which was recently validated against biochemical measurements (Morgenthaler et al. 2006). First study in human brain (Oz et al. 2006) confirmed that brain glycogen stores exceed those of free glucose and that brain glycogen metabolism is very slow under normal conditions.

Several studies on healthy volunteers have characterised and measured fluxes in the glutamate/glutamine neurotransmitter cycle, which is critical to normal brain function and protection against excitotoxicity (Rothman 2001; de Graaf et al. 2003; Shulman et al. 2004). Using 13C NMR measurements to follow 13C-labeled glucose molecules into the glutamine and glutamate pool of neurons and glia (Shen et al. 1999; Gruetter et al. 2001; Lebon et al. 2002), the rates of neuronal and astroglial TCA cycle and glutamine synthesis anaplerosis could have been quantified. Most of these studies have been conducted using MR systems with higher magnetic field strengths (>2 T) and steady state physiological conditions, as well as steady state isotopic enrichment of blood plasma (Shen et al. 1999; Gruetter et al. 2001; Lebon et al. 2002), but a clinical approach using simple infusion of [1-13C]glucose (Bluml et al. 2001; Moreno et al. 2001) and/or [1-13C]acetate solution (Bluml et al. 2002) and a clinically available 1.5 T MR system also successfully assessed brain glucose metabolism (Bluml et al. 2001; Moreno et al. 2001) and astroglial TCA cycle (Bluml et al. 2002). Using this simpler approach, defect abnormalities in the 13C enrichment pattern of brain metabolites were observed in pediatric patients with leukodystrophies and mitochondrial disorders (Bluml et al. 2001) and disturbed neurotransmitter glutamate/glutamine cycling in chronic hepatic encephalopathy (Bluml et al. 2001). Even though direct 13C MRS provides excellent spectral resolution, allowing for detailed 13C enrichment analysis, its inherent low sensitivity limits the signal detection to relatively large volumes. Several combined :H-13C MR techniques, which take advantage of magnetisation transfer between highly abundant and highly sensitive protons and 13C nuclei in specific 13C-labeled chemical bounds, provide tissue specific localisation of neurotrasmitter studies (Mason et al. 1999, 2003; Shen et al. 1999; Chen et al. 2001; Gruetter et al. 2001; Lebon et al. 2002; Pan et al. 2002). Using this approach in functional studies, some experiments have been designed and performed to measure TCA cycle activity in healthy cortex during visual stimulation (Chen et al. 2001; Chhina et al. 2001). These experiments provided evidence for almost 50% increase of oxidative glucose consumption in the visual cortex during activation. However, none of these elaborate techniques have been applied in human studies focusing on acute or chronic effects of hypo- or hyperglycaemia.

Diabetes Sustenance

Diabetes Sustenance

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