*5.2.3. Genetic and epigenetic regulation (activity dependent genes and epigenetic factors)*

The enhancement of memory by glucose might be related partly to the functions of activity dependent genes [90, 91], as well as epigenetic modifications (DNA methylation and histone modifications) by glucose or its metabolites [10, 91-94].

Since epigenetic profile of the cells play crucial role in glucose metabolism and neuronal cell functions, here, we would suggest that the initial epigenetic data (program) of the involved cells responsible for glucose memory facilitation are partly important for the differences reported in the literature. Epigenetic mechanisms of glucose metabolism and memory functions are regulated by the activity of transcription factors [10, 95]. Due to the importance of glucose in the functioning of the CNS [96], this regulation may be modulated by glucose molecule itself. For example, the data of Li et al. (2010) indicate that glucose regulates gene transcription in the liver by increasing the level of ATP, hence inhibiting AMP-activated protein kinase and inducing hepatocyte nuclear factor 4alpha to stimulate cytochrome P450 7A1 gene transcription. Glucose also increases histone acetylation and decreases H3K9 methylation in the cytochrome P450 7A1 chromatin [97].

Recent experiments show that glucose is involved in the regulation of functions even at the progenitor cell level. Metabolism-sensing factors have recently been implicated in the regula‐ tion of neural stem cell fate through epigenetics modification [92, 98]. Hayakawa et al. (2013) reported that in embryonic stem cell population, glucose metabolite induces switching from the inactive state by Ogt-Sirt1 to the active state by Mgea5, p300, and CBP at the Hcrt gene locus [92]. The many pathways of glucose metabolism allows for the inclusion of its metabolic products into numerous cellular activities. For example, substrates of glucose metabolic pathways (acetyl-CoA, ATP, NAD+, glutamine, UDP-N-acetyl-glucosamine, N-acetyl-D- mannosamine etc.) are candidates of epigenetic modifications. Acetyl-CoA is a donor of histone acetylation. NAD+regulates Sirt1, a member of the sirtuin family, which functions as histone deacetylase and is also a metabolic sensor [92] (for review see Hayakawa et al. 2013). Epigenetic regulation by glucose or its metabolites affects memory functions and glucose metabolism itself through a shift in the cellular concentrations of critical metabolites implicated in higher integrative brain functions and metabolism.

an integral process necessary for memory formation (especially long-term memory) [68, 69]. In fact, the NMDA receptor itself is implicated as one of the "alcohol receptors" [79]. Therefore, bi-directional effect of summation might occur through alcohol effect on neurotransmitter receptor systems, and glucose metabolism. The resultant effect is aggravation of memory

Since glucose is a metabolic product or must be involved in the cell's metabolic pathways before its usefulness is realized; therefore, it is necessary to assume that metabolic pathways, involving glucose molecule are those pathways crucial for memory formation or retrieval. Unfortunately, research in this aspect is scanty. A number of signaling pathways are involved in glucose metabolism, but there is no sufficient evidence on how they are associated with memory function [80]. The widely studied signaling pathways that have a relationship between glucose metabolism and memory functions [81, 82] include CREB pathway [83, 84], AMPK [85, 86], Notch signaling [87], mTOR pathway [88] etc. The mTOR pathway has been majorly implicated in both glucose and memory function. Importantly, it was reported that

glucose specifically affects memory through this pathway [84, 88, 89].

modifications) by glucose or its metabolites [10, 91-94].

methylation in the cytochrome P450 7A1 chromatin [97].

*5.2.3. Genetic and epigenetic regulation (activity dependent genes and epigenetic factors)*

The enhancement of memory by glucose might be related partly to the functions of activity dependent genes [90, 91], as well as epigenetic modifications (DNA methylation and histone

Since epigenetic profile of the cells play crucial role in glucose metabolism and neuronal cell functions, here, we would suggest that the initial epigenetic data (program) of the involved cells responsible for glucose memory facilitation are partly important for the differences reported in the literature. Epigenetic mechanisms of glucose metabolism and memory functions are regulated by the activity of transcription factors [10, 95]. Due to the importance of glucose in the functioning of the CNS [96], this regulation may be modulated by glucose molecule itself. For example, the data of Li et al. (2010) indicate that glucose regulates gene transcription in the liver by increasing the level of ATP, hence inhibiting AMP-activated protein kinase and inducing hepatocyte nuclear factor 4alpha to stimulate cytochrome P450 7A1 gene transcription. Glucose also increases histone acetylation and decreases H3K9

Recent experiments show that glucose is involved in the regulation of functions even at the progenitor cell level. Metabolism-sensing factors have recently been implicated in the regula‐ tion of neural stem cell fate through epigenetics modification [92, 98]. Hayakawa et al. (2013) reported that in embryonic stem cell population, glucose metabolite induces switching from the inactive state by Ogt-Sirt1 to the active state by Mgea5, p300, and CBP at the Hcrt gene locus [92]. The many pathways of glucose metabolism allows for the inclusion of its metabolic products into numerous cellular activities. For example, substrates of glucose metabolic pathways (acetyl-CoA, ATP, NAD+, glutamine, UDP-N-acetyl-glucosamine, N-acetyl-D-

dysfunction.

118 Glucose Homeostasis

*5.2.2. Metabolic signaling pathways*

A key mechanism for this epigenetic regulation is executed by the peripheral circadian oscillation [99]. However, importantly the peripheral clock and the central one could have some kind of metabolic associations. The concentration of NAD+/NADH plays critical link between metabolism and circadian rhythm [99]. Glucose and other metabolic substances may modulate the circadian rhythm by fluctuations in NAD+/NADH ratio. Compelling evidences now indicate that circadian misalignment could cause serious metabolic problems. In fact, transgenerational inheritance in metabolic alterations could be related to some mechanisms of epigenetic origin modulated by circadian clocks. Methylation of the leptin gene is associated with impaired glucose tolerance in the period of gestation [100]. This and many other discov‐ eries on transgenerational inheritance represent substantial contribution to understanding the pathogenesis of diabetes, obesity in children [100-102].

Epigenetic regulations are not only affected by metabolites, but also body mass index, intrauterine environment, exercise, and other environmental factors [101].

It might be possible that epigenetic dysregulation of cerebral glucose metabolism is the result of cognitive impairment since glucose metabolism is controlled by epigenetic mechanisms and is also associated with cognition. Emerging evidences indicate that metabolic regulation (through epigenetic mechanisms) might be involved in memory function disorders. Reports show that a major pathogenesis of the CNS disorder such as Alzheimer's disease involves metabolic alterations, especially in glucose metabolism and associated hormonal or peptide signaling. Metabolic disorders in CNS pathologies are associated with brain insulin signaling. For example, a substantial quantity of insulin receptors is located in the hippocampus (a brain region which is basically concerned with the acquisition, consolidation and recall of new information) [103]. Impaired brain insulin signaling is implicated in cognitive impairment. Moreover, cognitive impairment is associated with diabetes and obesity, which are metabolic disorders [104]. De la Monte (2009) reported that in the initial stage of Alzheimer's disease, cerebral glucose metabolism is reduced by 45% and cerebral blood flow approximately by 18% [104]. Earlier, Arnáiz et al. (2001) reported that among twenty patients with mild cognitive impairment, impaired cerebral glucose metabolism and cognitive functioning were able to predict deterioration in mild cognitive impairment [105]. Mild cognitive impairment is an important indicator of the development of Alzheimer's disease. Notably, impairment in cerebral glucose metabolism was even a better predictor (75%) compared to neurospcyholog‐ ical tests (65%) widely used in the assessment of cognitive impairment [105]. The authors further concluded that measures of temporoparietal cerebral metabolism and visuospatial function may aid in predicting the evolution to Alzheimer's disease for patients with mild cognitive impairment [105].

These data are very important especially when we consider the increasing prevalence of cognitive disorders. For instance, it is estimated that in 2030 years, the cases of Alzheimer's disease in relation to 2012 will double (35.6 million). No doubts, research in this direction is exceedingly necessary [106]. Previously other authors have also reported that impairment in cerebral glucose metabolism is associated with decline in cognition and memory functions. Schapiro et al (1988) studied the rate of cerebral metabolism for glucose with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in a 47 year-old man with trisomy 21 Down's syndrome and Alzheimer related dementia, and reported poorer general intelligence, visuospatial ability, language, and memory function compared with younger (19-33 years) patients with Down's syndrome [107]. Cerebral metabolism for glucose in the older patient was 28% less than in the younger patients. Besides, hypometabolism was reported in the parietal and temporal lobes of the brain cortices. Importantly, the study of Schapiro et al (1988) was probably one of the most comprehensive investigations to show the association between different diseases involving CNS disorder and their relationship with cerebral glucose metabolism [107]. Approximately a decade after Schapiro et al.'s (1988) work [107], Pietrini et al. (1997) reported another predictor method for Alzheimer's disease risk prior to dementia in patients with Down's syndrome who were above 40 years (mean of 50 years) of age [108]. Pietrini, et al. (1997) confirmed their hypothesis that despite normal cerebral glucose metab‐ olism at rest, an audiovisual stimulation (was used as a stress test) revealed abnormalities in cerebral glucose metabolism before the development of dementia in the parietal and temporal cortices which represent most vulnerable regions to Alzheimer's disease [108]. studied the rate of cerebral metabolism for glucose with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in a 47 year-old man with trisomy 21 Down's syndrome and Alzheimer related dementia, and reported poorer general intelligence, visuospatial ability, language, and memory function compared with younger (19-33 years) patients with Down's syndrome [107]. Cerebral metabolism for glucose in the older patient was 28% less than in the younger patients. Besides, hypometabolism was reported in the parietal and temporal lobes of the brain cortices. Importantly, the study of Schapiro et al (1988) was probably one of the most comprehensive investigations to show the association between different diseases involving CNS disorder and their relationship with cerebral glucose metabolism [107]. Approximately a decade after Schapiro et al.'s (1988) work [107], Pietrini et al. (1997) reported another predictor method for Alzheimer's disease risk prior to dementia in patients with Down's syndrome who were above 40 years (mean of 50 years) of age [108]. Pietrini, et al. (1997) confirmed their hypothesis that despite normal cerebral glucose metabolism at rest, an audiovisual stimulation (was used as a stress test) revealed abnormalities in cerebral glucose metabolism before the development of dementia in the parietal and temporal cortices which represent most vulnerable regions to Alzheimer's disease [108]. These CNS pathologies are now believed to be regulated by epigenetic mechanisms [109] and

**6. Glucose error commission depression effect: Cue to an overlapping bridge of neural error systems, memory and glucose metabolism?**

Our data and those of other authors show strong negative relations between glycemia and error commission. Whether this is due to the effect of glucose on memory or neural systems of error commission, is what is not exactly clear (see figure 2). There are no precise borders between the brain regions responsible for memory and error commission. Therefore, it is possible that the effect of glucose on error commission could be the resultant effect on the chief brain regions for memory function. Neural systems (or regions) of memory implicated in error commission have been linked to brain regions also involved in some aspects of memory function [115-117]. The brain systems concerned with error commission are referred to the error monitoring and processing system. The major regions of the brain concerned with error commission are the anterior cingulate cortex, basal ganglia, prefrontal cortex. These brain regions (especially the prefrontal cortex) are also implicated in memory function [45, 115, 117].

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**7. Effect of alcohol on glycemia and memory: More than just a bi-directional**

Alcohol is the most prevalent psychotic substance in the world. While alcohol affects glucose metabolism, memory also remains one of the most vulnerable functions of the brain that suffers from the negative effect of alcohol use [15, 16, 29, 30, 44, 45, 118]. Hence, there is the need to examine its effect on memory function and glucose regulatory mechanisms. Here, we view alcohol as a positive modulating factor for memory (especially at endogenous concentration), and as a psychopathological substance at blood concentrations higher than the normal

Glucose is the foremost energy substrate for neuronal functions (memory). It provides the energy bonds needed for the formation of memory and takes part in information retrieval from neural stores. Both glucose and its metabolites are involved in different stages of memory formation and retrieval. Several factors such as ethanol, some physiological indices, and other

competing factors modulate the effect of glucose on memory function.

**modulating effect**

physiological level.

**8. Conclusion**

**Author details**

M.O. Welcome and V.A. Pereverzev

Belarusian State Medical University, Minsk, Belarus

These CNS pathologies are now believed to be regulated by epigenetic mechanisms [109] and could have pretty good correlations with epigenetic mechanisms of cerebral glucose metabo‐ lism. Other CNS pathologies involving cognitive impairments such as epilepsy [110], schizo‐ phrenia [111, 112], Parkinson's disease [113], multiple sclerosis [114] had been associated with disturbances in glucose metabolism. could have pretty good correlations with epigenetic mechanisms of cerebral glucose metabolism. Other CNS pathologies involving cognitive impairments such as epilepsy [110], schizophrenia [111,112], Parkinson's disease [113], multiple sclerosis [114] had been associated with disturbances in glucose metabolism.

**Figure 2.** Interacting system (comprising of memory function, error monitoring and processing system, and modulators) of the reciprocability of neural systems of memory and the error monitoring and processing system. The modulators between the two reciprocals are glucose, other endogenous and exogenous substances/factors. N/B: Glucose can be an endogenous, as **Figure 2.** Interacting system (comprising of memory function, error monitoring and processing system, and modula‐ tors) of the reciprocability of neural systems of memory and the error monitoring and processing system. The modula‐ tors between the two reciprocals are glucose, other endogenous and exogenous substances/factors. N/B: Glucose can be an endogenous, as well as an exogenous factor; exogenous sources include per os administration of glucose, etc.; endogenous sources include gluconeogenetic production of glucose molecules, etc.

endogenous sources include gluconeogenetic production of glucose molecules, etc.

8

well as an exogenous factor; exogenous sources include per os administration of glucose, etc.;
