Simply stated the Brain Hypometabolism Hypothesis (BHH) is
‘Brain hypometabolism leads to neuropathology’
This is a very simple but broad statement which is a starting point for elaboration.
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
31 μmol/100 g/min
What is the 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) Further evidence on consequences of ketone based interventions.
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.
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.
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 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.
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.
Appendix B – Citations
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.
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.
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.
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.
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