The Brain Hypometabolism Hypothesis Part 59: A Summary of Posts to Date

glucose_2

This post summarises the previous posts on the Brain Hypometabolism Hypothesis. The post summarises the hypothesis and then looks at physiological principles relating to cerebral glucose metabolism and how this is impacted with age. Broadly speaking there are four main sections

  1. An examination of the relationship between Diabetes and neurodegeneration
  2. An examination of the GLUT receptors
  3. An examination of the consequences of Hypoxic Ischaemic Brain Injury (HIBI)
  4. An examination of the key metabolites in energy metabolism pathways

Brain Hypometabolism Hypothesis

The Brain Hypometabolism Hypothesis focuses on energy metabolism. More specifically the hypothesis states that

Energy hypometabolism in the brain leads to neuropathology

What is the value for Brain Glucose Metabolism?

One of the key concepts in understanding brain glucose metabolism is the cerebral metabolic rate of glucose. This was calculated by comparing the glucose content of cerebral arterial and cerebral venous blood. When this difference is calculated it can be combined with the cerebral blood flow values to estimate the rate of glucose metabolism by the brain.

The value given in the article is (see Appendix A for calculations)

6–7 mg/100 g/min

or approximately

31 μmol/100 g/min

 

Is there a Link Between Alzheimer’s Disease and Brain Glucose Metabolism?

In their 2016 paper, Cunnane and colleagues outline several supporting lines of evidence as the basis for their paper

(i) Lower glucose uptake in the frontal cortex of older adults

(ii) Regional deficits in brain glucose uptake in younger adults at risk of Alzheimer’s Type Dementia

(iii) Preservation of ketone uptake in the brain

(iv) Evidence from ketone based studies.

Is there Lower Glucose Uptake in the Frontal Cortex of Older Adults?

Cannane and colleagues published a paper on brain metabolism and aging based on a database they had compiled using radioactive tracers for glucose and ketone metabolism in the brain.

fnmol-09-00053-g002

Figure 2 from Cunnane and colleagues, CC BY

Is Insulin Resistance a Risk Factor?

The Rotterdam study looked at insulin resistance in a large prospective cohort. Researchers found a correlation between insulin resistance and incident Alzheimer’s Type Dementia but only within the first three years.

However we know from Kuhn’s work on ‘The Structure of Scientific Revolutions‘ that central paradigms are successful even if there are lines of evidence that do not support the paradigm (as models are approximations to reality).

A Review of ‘The Structure of Scientific Revolutions’

Is Diabetes a Risk Factor for Dementia?

Gudala and colleagues published a meta-analysis of prospective observational studies in 2013 looking at the relationship between Diabetes and the risk of Dementia. The researchers screened 67,083 papers and identified 28 papers for inclusion. The papers included are found in Table 1 and include the Rotterdam study.

Demographic Chart

The meta-analysis included 1,148,041 patients and of these 89,708 had a diagnosis of Diabetes (although I couldn’t see a distinction between NIDDM and IDDM).

In people with Diabetes the relative risk of Dementia was:-

(1) Alzheimer’s Type Dementia: Pooled RR 1.56 (95% CI 1.41–1.73)

(2) Vascular Dementia: Pooled RR 2.27 (95% CI 1.94–2.66)

The researchers suggested several mechanisms that may lead to the increased risk including advanced glycation end-products.

Is Insulin Dependent Diabetes a Risk Factor for Dementia?

The question of whether Insulin Dependent Diabetes Mellitus (IDDM) is associated with an increased risk of Dementia was asked in one study that was presented at the Alzheimer’s Association International Conference in 2015. There are two sources for the presentation here and here.

There were 490,344 persons aged >= 60 years and followed up over 12 years. During this time 16% of people with IDDM developed Dementia compared to 12% of those without IDDM. However after adjustment for other risk factors the hazards ratio for Dementia with IDDM compared to Dementia without IDDM was 1.83 (95% confidence interval [CI], 1.3 – 2.5).

Is There a Diabetes Type 3?

There is a concept of a Type 3 Diabetes where the pathology occurs in the brain and is described in this paper by Dr Suzanne de la Monte.

To the best of my knowledge this subject has been on the periphery of research into Alzheimer’s Disease. The concept of Diabetes Type 3 is not widely accepted and looking at the ICD-11 Browser Beta (not final) version I couldn’t find any reference to this diagnosis as a specific category.

At this stage, this looks to be an emerging discussion but I am not clear on whether it will become an established diagnosis. It is still useful to know about this concept because even if it does not become established it involves various models of glucose metabolism in the brain.

The concept appears to date back to 2005 and from the paper above, the 2 initial papers are here and here. I will refer to this from here on in as the Type 3 Diabetes model (T3DM).

The key molecules in the T3DM are Insulin and Insulin-like Growth Factors. In the 2014 paper Dr de la Monte outlines the various important functions that Insulin has in the brain ranging from anti-apoptosis through to growth, plasticity and metabolism. Although the model is more nuanced I will summarise this as

Insulin and Insulin-like Growth Factor Dysfunction Leads to Neuropathology

The dysfunction is not clear but reframing this we can say that in this model the actions of Insulin and Insulin-like Growth Factor are not as expected.

The video above is from the NDSU Virtual Cell Animations collection and illustrates the intracellular mechanism of action of Insulin.

Dr de la Monte refers to the effects of glucose uptake and underutilisation in the brain as three-fold

(a) Oxidative stress

(b) Impaired homeostasis

(c) Cell death

The paper elaborates on the GLUT4 receptors:-

(1) Insulin regulates both the expression of the receptors and the transfer of the receptors to the cell membrane

(2) GLUT4 receptors are expressed in the medial temporal lobe

(3) The GLUT4 receptors are not reduced in Alzheimer’s Type Dementia

(4) There may possibly be a reduced transfer of GLUT4 to the cell membrane

Does atrophy in a brain region account for brain hypometabolism?

Cunnane and colleagues answer this question in two ways.

Firstly there is a specific research methodology that is able to answer this question – correction for atrophy. In their 2011 paper, Cunnane and colleagues review the literature on brain glucose metabolism studies in Alzheimer’s Type Dementia and summarise the results in Table 1 in the paper.

They note that in some studies, there is correction for atrophy and in those studies there is still a preservation of the relationship between Alzheimer’s Type Dementia and brain glucose hypometabolism.

Secondly Cunnane and colleagues also answer this question by referencing risk factors for Alzheimer’s Type Dementia where brain glucose hypometabolism occurs even in the absence of cognitive impairment

  • Pre-senilin-1 mutation,
  • Apolipoprotein E4 carrier status
  • Matrilinear AD
  • Cognitively healthy aging
  • Insulin resistance

There are five lines of evidence for further investigation of the question above. However the relationship cited above looks at cognitive impairment. Cognitive impairment is a proxy marker. The key question is whether there is brain atrophy which is causing the brain hypometabolism.

So the question can be asked for each of the five risk factors identified above.

What is the Mechanism for Glucose Uptake in the Brain?

In their 2011 paper, Cunnane and colleagues note that there are three separate isoforms of GLUT1 that facilitate glucose uptake in the brain

(1) One isoform facilitates glucose uptake across the blood-brain barrier

(2) Another isoform facilitates glucose uptake in astrocytes

(3) A third isoform facilitates glucose uptake in neurons

There are however other mechanisms for glucose uptake in the brain.

What are the GLUT’s?

GLUT’s are short for Glucose Transporters. They constitute a set of molecules which transport substrates across cell membranes. They play a central role in Glucose transport and hence the name. However their role is not limited to the transport of Glucose.

Professors Bernard Thorens and Mike Mueckler have written a review titled ‘Glucose Transporters in the 21st Century’. In terms of a Brain Hypometabolism Hypothesis, it is important to understand how Glucose is handled in the brain. Thorens and Mueckler reference 14 Glucose Transporters but not all of them are expressed in the brain.

In the article they note that the glucose transporters (members of the GLUT family) are part of the Major Facilitator Superfamily of Membrane Transporters (e.g. see this paper).

This superfamily of membrane transporters is responsible for transporting a large variety of compounds across the cell membrane and along an electrochemical gradient.

In their paper they also note that Glucose not just a source of energy but is also a signalling molecule. Thus they state that Glucose influences various processes including

(a) The activity of neurons that regulate Glucose (e.g. see this paper)

(b) Gene transcription

(c) Enzyme activity

In this paper it is noted that the GLUT family are divided into three classes.

Class I – GLUT1, GLUT2, GLUT3, GLUT4, GLUT14

Class II – GLUT5, GLUT7, GLUT9, GLUT11. Fructose is a subtrate for Class II GLUT’s.

Class III – GLUT6, GLUT8, GLUT10, GLUT12, GLUT13

This paper goes into some of the more subtle nuances of the GLUT’s.

GLUT 1

Addressing GLUT1, Thorens and Mueckler refer to this as the most intensively studied of this family.

GLUT1 is expressed in the endothelial cells that constitute the blood brain barrier. There is an emerging discussion about how GLUT1 specifically might be involved in neurodegenerative conditions such as Alzheimer’s Type Dementia (e.g. see this paper).

GLUT 2

In the paper they note that there is evidence that GLUT 2 plays a role in glucose ‘sensors’ in the central nervous system and the periphery.

There are a number of papers on GLUT2 and the brain including this one on a possible drug interaction with GLUT2 and this one on Ghrelin and the Hypothalamus.

GLUT 3

In their paper, Thorens and Mueckler note that GLUT 3 is the main glucose transporter in the brain but also plays an important role in embryogenesis.

GLUT 4

In their paper, Thorens and Mueckler note that GLUT 4 is one of the most well studied Glucose transporters and is linked to Glucose homeostasis throughout the body. There are various studies that have examined GLUT 4 in the brain including this one which looks at synaptic activity.

GLUT 5

In their paper, Thorens and Mueckler note that GLUT 5 specialised for Fructose transport and expressed predominantly in the intestine although also in other tissues including the brain.

Does the brain metabolise fructose? There is evidence presented in this paper.

GLUT 6

In their paper, Thorens and Mueckler note that there is little data on GLUT 6.

GLUT 7

In their paper, Thorens and Mueckler note that there is little data on GLUT 7 other than to say it is similar in structure to GLUT 5 and is not very effective for either Glucose or Fructose as a transporter. Therefore Thorens and Mueckler suggest it is effective for another substrate. The suggestion of another substrate is reiterated in this paper.

GLUT 8

In their paper, Thorens and Mueckler note that GLUT8 has been linked to neuronal proliferation in the Hippocampus. This paper implicates GLUT8 in both Hippocampal neuroproliferation and also an increase in the atrial p-wave duration.

GLUT 9

In their paper, Thorens and Mueckler discuss evidence to suggest that GLUT 9 is a urate transporter and is implicated in hyperuricaemia which can lead to Gout and is also seen in Lesch-Nyhan syndrome.

In terms of a hypothesis about metabolism this may not be relevant. Urate is an end-product of Purine metabolism and is usually excreted. Possibly the only significance here is that there is a conserved mechanism for molecular transport that is shared by metabolites such as Glucose. Nevertheless there is this paper which suggests that Urate may be neuroprotective (although high levels can also cause neuronal damage). There are also lines of evidence suggesting a possible interaction between Insulin and Urate.

As with other substrates the body has elegant mechanisms for homeostasis.

GLUT 10

Mutations in GLUT 10 are linked to Arterial Tortuosity Syndrome. A more recent literature search reveals a number of other papers in relation to ATS as well as a study looking at peripheral vascular disease in Diabetes. At the time of writing, the NIH Gene Database describes the gene as playing a role in glucose homeostasis.

GLUT 11

Thorens and Mueckler note in their 2009 paper that not much is known about GLUT 11 other than an affinity for both Glucose and Fructose. A 2017 medline search using the search term “GLUT11” retrieved only 14 results and for “SLC2A11” also. Few of these papers post-dated the 2009 review and there was little discussion about the brain. This does not discount the possibility of a significant role in brain metabolism but it looks as though this is not an area of active research.

GLUT 12

This paper suggests properties of the GLUT12 transporter that differ from other members of the GLUT family and hint at an as yet undiscovered substrate. The authors note that previously it has been proposed as an ancestor of GLUT4 with ancillary function. They identify complex aspects of its action and also transport to the plasma membrane. They suggest that GLUT12 is involved in Glucose homeostasis throughout the body.

GLUT 13

In their paper, Professors Bernard Thorens and Mike Mueckler note that GLUT 13 is

  1. A myoinositol transporter
  2. A symporter
  3. Expressed mainly in the brain

As of April 2017 there is no solved structure for GLUT 13 according to PhosphoSite Plus.

GLUT 13 is described as a symporter

What is a Symporter?

A symporter is a membrane protein that transports more than one substance across the membrane in the same direction. This contrasts with the antiporter (which transports substances in opposite directions) and a uniporter which transports a single substance.

Inositol_structure

Myo-Inositol by Edgar181

What is Myo-Inositol?

Myo-Inositol is a molecule derived from Glucose-6-phosphate. Inositol is a substrate of GLUT 13 (one of the GLUT’s). Inositol plays a role in energy metabolism and is relevant to a discussion of the Brain Hypometabolism Hypothesis.

GLUT 14

Professors Bernard Thorens and Mike Mueckler have written a review titled ‘Glucose Transporters in the 21st Century’. In terms of a Brain Hypometabolism Hypothesis, it is important to understand how Glucose is handled in the brain. Thorens and Mueckler reference 14 Glucose Transporters but not all of them are expressed in the brain.

In their paper, Professors Bernard Thorens and Mike Mueckler note that GLUT 14 is not primarily expressed in the brain and also that the role of GLUT 14 in glucose metabolism is not characterised.

The Context of Hypoxic Ischaemic Brain Injury

Sekhon, Ainslie and Griesdale have written an open access article on hypoxic ischaemic brain injury titled “Clinical Pathophysiology of Hypoxic Ischemic Brain Injury after Cardiac Arrest:A “two-hit” Model“. This paper can be used as a starting point for discussion of the events that lead to brain injury following hypoxia. This in turn is relevant to the question of energy usage in the Brain Hypometabolism Hypothesis.

Sekhon, Ainslie and Griesdale posit a simple two stage model of brain injury following cardiac arrest in which injury results from

  1. Primary cerebral hypoxia
  2. Secondary mechanisms after return of cerebral perfusion

In Sekhon, Ainslie and Griesdale’s model they discuss primary and secondary brain injury following a cardiac arrest.

Primary Brain Injury after Hypoxia

Looking more closely at the primary brain injury they state that with a reduction in cerebral oxygen ATP production decreases and there is a switch to anaerobic respiration. This in turn leads to a reduction in ATP dependent ion channel action. There are three main effects

  1. Accumulation of Na+ ions
  2. Accumulation of lactate with acidosis
  3. An influx of Calcium ions into the cells

Secondary Brain Injury after Hypoxia

Sekhon, Ainslie and Griesdale identify 7 factors associated with secondary brain injury after hypoxia in their two stage model. These 7 factors are

  1. Microvascular Dysfunction
  2. Cerebral Oedema
  3. Anaemia
  4. Impaired Cerebral Autoregulation
  5. Carbon Dioxide
  6. Hyperoxia
  7. Hyperthermia

Human_Metabolism_-_Pathways

Human Metabolism by Frozen Man (CC BY 4.0)

What is Metabolism?

Metabolism can be defined as the chemical processes that occur in living organisms. There are three types of metabolic processes

(a) Generation of energy

(b) Generation of basic chemicals including fatty acids, amino acids and sugars

(c) Elimination of Nitrogen waste products

Glycolysis

Glycolysis

Glycolysis by Dr Thomas Shafee (CC BY 4.0)

Glycolysis is one of the key pathways for energy metabolism in the human body. In this metabolic pathway the molecule Glucose is converted into Pyruvate. This pathway generates energy in the form of ATP. This pathway however does not use oxygen although the products generated are metabolised using oxygen. This is relevant to the bigger picture of energy metabolism in the brain.

1024px-Acetyl-CoA-3D-vdW

Acetyl CoA Space Filling Molecule by Benjah-bmm27 (Public Domain)

Acetyl Coenzyme A is an important molecule for many pathways involved in energy metabolism. Acetyl Coenzyme A is derived from

(a) Glucose via the Glycolysis pathway

(b) Amino acids via Acetoacetyl-CoA, Pyruvate and directly through multiple pathways

(c) Fatty acids via Beta-oxidation

Vitamin B5 is required for the synthesis of Acetyl CoA.

The Citric Acid Cycle

The Citric Acid Cycle (CC BY 3.0) by Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins, Wadester16

The Citric Acid Cycle is one of the main energy metabolism pathways in humans. Acetyl Co-A which is generated from other pathways is utilised in the Citric Acid Cycle. The Citric Acid Cycle has a number of properties

  1. Generation of energy in the form of ATP
  2. Generating NADH which is utilised in oxidative phosphorylation
  3. Citric Acid is regenerated
  4. Carbon Dioxide is produced

The Citric Acid Cycle takes place in the Mitochondria.

The Citric Acid Cycle is important for the discussion of the Brain Hypometabolism Hypothesis where we have already discussed the metabolism of Glucose.

Appendix A – Calculations for Unit Conversion

A mole is 6 x 10²³ molecules.

The molecular weight for glucose is 180.1559 g per mole.

Therefore 31 μmol of glucose is equivalent to 180.1559 g x 31/1000000

= 0.00558 g

= 5.58 mg

which is in the range described above.

There is also a conversion calculator here.

References

Ashrafi G, Wu Z, Farrell RJ, Ryan TA. GLUT4 Mobilization Supports Energetic Demands of Active Synapses.Neuron. 2017 Feb 8;93(3):606-615.e3. doi: 10.1016/j.neuron.2016.12.020. Epub 2017 Jan 19.

Barros LF, San Martín A, Ruminot I, Sandoval PY, Fernández-Moncada I Baeza-Lehnert F, Arce-Molina R, Contreras-Baeza Y, Cortés-Molina F, Galaz A, Alegría K.J Neurosci Res. 2017 Feb 2. doi: 10.1002/jnr.23998. [Epub ahead of print]Near-critical GLUT1 and Neurodegeneration.

Bell S, Kolobova I, Crapper L, Ernst C, Lesch-Nyhan Syndrome: Models, Theories, and Therapies. Mol Syndromol 2016;7:302-311

De la Monte SM. Type 3 Diabetes is Sporadic Alzheimer’s disease: Mini-Review. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2014;24(12):1954-1960. doi:10.1016/j.euroneuro.2014.06.008.

Ebert K, Ludwig M, Geillinger KE, Schoberth GC, Essenwanger J, Stolz J, Daniel H, Witt H.Reassessment of GLUT7 and GLUT9 as Putative Fructose and Glucose Transporters.
J Membr Biol. 2017 Jan 12. doi: 10.1007/s00232-016-9945-7. [Epub ahead of print]

Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: A meta‐analysis of prospective observational studies. Journal of Diabetes Investigation. 2013;4(6):640-650. doi:10.1111/jdi.12087.

Meaney E, Alva F, Moguel R, Meaney A, Alva J, Webel R. Formula and nomogram for the sphygmomanometric calculation of the mean arterial pressure. Heart. 2000 Jul;84(1):64.

Membrez M, Hummler E, Beermann F, et al. GLUT8 Is Dispensable for Embryonic Development but Influences Hippocampal Neurogenesis and Heart Function. Molecular and Cellular Biology. 2006;26(11):4268-4276. doi:10.1128/MCB.00081-06.

Mypinder S. Sekhon, Philip N. Ainslie and Donald E. Griesdale
Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model. Critical Care. 2017. 21:90. DOI: 10.1186/s13054-017-1670-9

Oppelt SA, Zhang W, Tolan DR.Specific regions of the brain are capable of fructose metabolism. Brain Res. 2017 Feb 15;1657:312-322. doi: 10.1016/j.brainres.2016.12.022. Epub 2016 Dec 27.

Pao SS, Paulsen IT, Saier MH. Major Facilitator Superfamily. Microbiology and Molecular Biology Reviews. 1998;62(1):1-34.

Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM.
Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005 Dec;8(3):247-68.

Spindelboeck W, Gemes G, Strasser C, Toescher K, Kores B, Metnitz P, Haas J, Prause G. Arterial blood gases during and their dynamic changes after cardiopulmonary resuscitation: A prospective clinical study.Resuscitation. 2016 Sep;106:24-9. doi: 10.1016/j.resuscitation.2016.06.013. Epub 2016 Jun 18.

Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimers Dis. 2005 Feb;7(1):63-80.

Thorens B, Mueckler M. Glucose transporters in the 21st Century. American Journal of Physiology – Endocrinology and Metabolism. 2010;298(2):E141-E145. doi:10.1152/ajpendo.00712.2009.
Tomioka NH, Tamura Y, Takada T, Shibata S, Suzuki H, Uchida S, Hosoyamada M. Immunohistochemical and in situ hybridization study of urate transporters
GLUT9/URATv1, ABCG2, and URAT1 in the murine brain. Fluids Barriers CNS. 2016 Dec 12;13(1):22.

Index: There are indices for the TAWOP site here and here

Twitter: You can follow ‘The Amazing World of Psychiatry’ Twitter by clicking on this link.

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Responses: If you have any comments, you can leave them below or alternatively e-mail justinmarley17@yahoo.co.uk.

Disclaimer: The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

Conflicts of Interest: *For potential conflicts of interest please see the About section”

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