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Showing posts with label Diabetes. Show all posts
Showing posts with label Diabetes. Show all posts

Thursday, 6 September 2018

Ketones and Autism Part 4 – Inflammation, Activated Microglia, CtBP, the NLRP3 Inflammasome and IL-1β




This series of posts on ketones and the ketogenic diet (KD) is nearly finished and I am glad that I made favourable comments about the KD earlier on in this blog, before I knew all the nitty-gritty of the science. (no re-editing required)




Inflammasome Inhibition: Putting Out the Fire                                                                                                                       


There is more than one anti-inflammatory mechanism involved in the ketogenic diet (KD); in Part 3 we covered Niacin Receptor HCA2, today in Part 4 we look at NLRP3 and CtBP.
The reason I am going into all this detail is because if you knew why someone responds to ketones in a favourable way, there might actually be an even more potent therapy using an entirely different substance.
CtBP represses the transcription of certain tumour supressing genes and some other genes involved in the development of cancer, i.e. they promote tumorigenesis.  CtBP is often overexpressed in certain cancers and indicates a worse prognosis. In these cancers you would want to inhibit CtBP.
Just to complicate matters, CtBP also supresses the activity of certain inflammatory genes. So, in certain diseases like diabetes you might benefit from keeping CtBP permanently in its active state. In particular, this would apply to when the microglia are activated, which is the case in much autism.
The coconut oil doctors have the idea that the key problem in autism is activated microglia in the brain.  Microglia mediate immune responses in the central nervous system, clearing cellular debris and dead neurons via a process called phagocytosis. These doctors propose coconut oil to calm the microglia.
Microglia can be in a resting or activated state, the research suggests that in much autism the microglia are permanently activated.
Some research suggests that microglia act like an “immunostat” reflecting not just what is going on in the brain, but elsewhere in the body.  I favour this view.
A small trial using a drug to calm the microglia did not impact autism.
Personally, I believe that microglia being activated is not a good thing, but that it is part of a much more complex picture than the coconut doctors suggest. 
As we learn later in this post, to get the CtBP benefit to microglia, it appears that you need the kind of ketosis you achieve only in the full ketogenic diet, not the transient mild ketosis that you achieve from two heaped tablespoons of coconut oil, or any of the keto supplements. 

NLRP3 inflammasome
The complicated-sounding NLRP3 inflammasome relates to diseases where the proinflammatory cytokine IL-1β is elevated; this includes Alzheimer’s, MS, Inflammatory Bowel Disease (IBD) and often autism.
For the details of how NLRP3 works see below; the important thing to note is that the result is elevated levels of IL-1β, which, at least in blood, is easy to measure.  It is an open question whether this represents the level inside the brain.  If your child has elevated IL-1β then it is worth studying NLRP3.




Schematic illustration of the NLRP3 inflammasome activation. Upon exposure to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), Toll-like receptors (TLRs) are phosphorylated and subsequently activate NF-κB. In the nucleus, NF-κB promotes the transcription of NLRP3, proIL-1β, and proIL-18, which, after translation, remain in the cytoplasm in inactive forms. Thus, this signal (depicted in red as “Signal 1”) is a priming event. A subsequent stimulus (shown as “Signal 2” in black) activates the NLRP3 inflammasome by facilitating the oligomerization of inactive NLRP3, apoptosis-associated speck-like protein (ASC), and procaspase-1. This complex, in turn, catalyzes the conversion of procaspase-1 to caspase-1, which contributes to the production and secretion of the mature IL-1β and IL-18. Three models have been proposed to describe the second step of inflammasome activation: (1) Extracellular ATP can induce K+/potassium efflux through a purogenic P2X7-dependent pore, which, leads to the assembly and activation of the NLRP3 inflammasome. Calcium flux is also involved in this process. (2) PAMPs and DAMPs trigger the generation of ROS that promote the assembly and activation of the NLRP3 inflammasome. (3) Phagocytosed environmental irritants form intracellular crystalline or particulate structures leading to lysosomal rupture (magenta box) and release of lysosomal contents like cathepsin B. These induce NLRP3 inflammasome assembly and activation. In addition, other factors and mechanisms have been implicated in the assembly and activation of the NLRP3 inflammasome, including mitochondrial damage, autophagic dysfunction, and thioredoxin-interacting protein (TXNIP).



Proinflammatory cytokine IL-1β 
My public enemy number 1 cytokine is actually IL-6, today we primarily look at IL-1β, which for many people with a neurological disorder is a big part of their problem. IL-6 and IL-1β are actually interrelated, as we see later.
For a summary of the role of this cytokine in autism, I will leave it to Paul Ashwood:-  


Interleukin (IL)-1B

IL-1Β is an inflammatory cytokine expressed very early in immune responses. In tissue, IL-1Β propagates inflammation by activating local immune cells and the vascular endothelium. Systemically, IL-1Β stimulates IL-6 production and eventually an acute phase response in the liver. Systemic IL-1Β can cross the blood brain barrier and stimulate its own expression in the hypothalamus, which leads to neuroendocrine changes associated with fever and sickness behavior . IL-1Β receptors are structurally related to toll-like receptors (TLRs), and signaling is achieved through NF-κB and MAP kinase (MAPK) signaling cascades. IL-1Β belongs to an evolutionarily conserved family of proteins that function beyond immunity. It shares structural homology with fibroblast growth factors, which are critical in embryonic neurodevelopment, and are implicated in autism and schizophrenia.
Genes for IL-1Β, its receptor, and its receptor-associated proteins are associated with intellectual disability, schizophrenia, and autism. Children and adults with autism have increased plasma IL-1Β and skewed cellular IL-1Β responses following stimulation. Compared to controls, monocytes from children with ASD produce excessive IL-1Β following LPS exposure, and lower levels following exposure to TLR 9 agonists. The IL-1 antagonist, IL-1ra, is also increased among ASD subjects. IL-1ra reduces inflammation by competing for the IL-1Β receptor, and increased levels may represent an attempt to counteract inflammation in ASD. Postmortem brains from ASD subjects had normal IL-1Β levels, but given that peripheral IL-1Β can enter the brain, increased systemic levels could directly impact neurological processes
IL-1Β disruption can have a variety of neurological consequences relevant to autism. The cytokine and its receptors are found throughout the nervous system during critical developmental periods. IL-1Β induces neural progenitor cell proliferation in some CNS regions, while inhibiting it in others. This could contribute to the region-specific overgrowth and undergrowth observed in the ASD brain. Excitatory synapse formation is partially mediated by the IL-1 receptor and receptor-associated proteins.
Altering these proteins can tip the balance between excitatory and inhibitory signaling, which might underlie neurological features of autism. Increased IL-1ra in autism suggests an attempt to counterbalance IL-1Β and may or may not be beneficial. Following brain injury, IL-1ra upregulation serves a neuroprotective role by dampening excessive inflammation. However, if administered during critical windows of neurodevelopment, IL-1ra can negatively impact neurogenesis, brain morphology, memory consolidation, and behavior. This shows that some level of IL-1B signaling is essential during development. In adulthood, IL-1Β is implicated in CNS disorders like Alzheimer’s disease and the advancement of amyloid-containing plaques. While excessive IL-1B contributes to pathology in some cases, it may have a protective role in others. For example, IL-1Β limits neuronal damage following excitotoxic exposures, and mice lacking IL-1Β fail to undergo remyelination following experimental autoimmune encephalitis (EAE) induction. IL-1Β is involved in higher order brain processes and is induced in the hippocampus during learning processes, and is critical for maintenance of long-term potentiation (LTP) Both over expression and under expression of IL-1 beta are associated with impairments in memory and learning.



At the table in the kitchen, there were three bowls of porridge.  Goldilocks was hungry.  She tasted the porridge from the first bowl.
"This porridge is too hot!" she exclaimed.
So, she tasted the porridge from the second bowl.
"This porridge is too cold," she said
So, she tasted the last bowl of porridge.
"Ahhh, this porridge is just right," she said happily and she ate it all up. 

In summary, IL-1Β participates in neurological processes, and appears to have a role in both CNS pathology and healing. Normal, homeostatic levels of IL-1Β and its antagonist IL-1ra are necessary for proper brain development and function. This “Goldilocks” state is typical of many cytokines, where too much or too little is not desirable. Alterations in IL-1Β systems due to genetic mechanisms or environmental exposures may contribute to autism. 


CtBP (C-terminal-binding protein) 
In 2017 research led by Dr Raymond Swanson, a professor of neurology at the University of California, San Francisco, suggested CtBP as an additional possible mechanism by which the ketogenic diet can reduce brain inflammation.   CtBP activation turns off key inflammatory genes.
In the case of CtBP, I doubt that the very partial ketosis achieved with BHB and C8 supplements will be enough, I think you would need the full ketogenic diet. 
Restricting the glucose metabolism with the ketogenic diet lowers the NADH/NAD+ ratio which activates CtBP. There is no direct role played by ketones in this process, it is just the presence of large amounts of ketones reduces the role of glucose.



Factors that reduce glucose flux through glycolysis, such as reduced glucose availability or glycolytic inhibitors, reduce NADH levels and thereby reduce NADH:NAD+ ratio, whereas factors that inhibit oxidative metabolism, such as hypoxia and mitochondrial inhibitors, have the opposite effect. Glutamine provides ketone bodies (α-ketoglutarate) to fuel mitochondrial ATP production in the absence of glycolysis. Lactate dehydrogenase (LDH) maintains the lactate:pyruvate ratio in equilibrium with the cytosolic NADH:NAD+ ratio.


BHB is not directly a CtBP activator.
A drug that acts as an CtBP activator would be great for diabetes and anyone with brain inflammation.
Using BHB and C8 you would need to create enough ketones in your blood to reduce the glucose metabolism substantially, not by a trivial amount.
The easy to read version:- 

New research uncovers and replicates the mechanism by which a ketogenic diet curbs brain inflammation. The findings pave the way for a new drug target that could achieve the same benefits of a keto diet without having to actually follow one.

A keto state lowers brain inflammation
A keto diet changes the metabolism, or the way in which the body processes energy. In a keto diet, the body is deprived of glucose derived from carbs, so it starts using fat as an alternative source of energy.

In the new study, Dr Swanson and his colleagues recreated this effect by using a molecule called 2-deoxyglucose (2DG).
The 2DG molecule stopped glucose from metabolizing and created a ketogenic state in rodents with brain inflammation as well as in cell cultures. Levels of inflammation were drastically reduced - almost to healthy levels - as a result.
"We were surprised by the magnitude of our findings," said Dr Swanson. "Inflammation is controlled by many different factors, so we were surprised to see such a large effect by manipulating this one factor. It reinforces the powerful effect of diet on inflammation."
The restricted glucose metabolism lowered the so-called NADH/NAD+ ratio
"Cells convert NAD+ to NADH, as an intermediary step in generating energy from glucose, and thus increase the NADH/NAD+ ratio," he added.
When this ratio is lowered, the CtBP protein gets activated and attempts to turn off inflammatory genes. As Dr. Swanson told us, "CtBP is a protein that senses the NADH/NAD ratio and regulates gene expression depending on this ratio."
So, the scientists designed a molecule that stops CtBP from being inactive. This keeps the protein in a constant "watchful" state, blocking inflammatory genes in an imitation of the ketogenic state. Dr. Swanson said, "Our findings show that it is [...] possible to get the anti-inflammatory effect of a ketogenic diet without actually being ketogenic
The findings could apply to other conditions that are characterized by inflammation. In diabetes, for example, the excessive glucose produces an inflammatory response, and the new results could be used to control this dynamic.
"[The] ultimate therapeutic goal would be to generate a [drug] that can act on CtBP to mimic the anti-inflammatory effect of [the] ketogenic diet," Dr. Swanson concluded. 

Full Paper:- 


The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.

One way that CtBP regulates gene transcription is through interactions with the histone acetyltransferase HDAC1. 

Taken together, our findings indicate that metabolic influences that alter the cytosolic NADH:NAD+ ratio regulate NF-κB transcriptional activity through an NADH-dependent effect on CtBP dimerization. Conditions that reduce glycolytic flux, such as ketogenic diet and caloric restriction, can thereby suppress NF-κB activity, while conditions that increase glycolytic flux may increase it. These interactions provide a mechanism for the suppressive effects of ketogenic diet and caloric restriction on brain inflammation after brain injury. By extension, these interactions may also contribute to the pro-inflammatory states associated with diabetes mellitus and metabolic syndrome. 



Inhibiting NLRP3 and/or activating CtBP

You do not need to be a genius to see that inhibiting NLRP3 and/or activating CtBP, using the ketogenic diet, is likely to benefit some people with autism.
On the flipside, someone with colon cancer, where CtBP is over-expressed to the point where the cancer depends on it for growth, certainly would not want the ketogenic diet.
This cancer flipside we have seen before, antioxidants like NAC and Sulforaphane (via activating the redox switch Nrf2) are chemoprotective for healthy people, but bad for you if you have developed cancer.  Oxidative stress is very damaging to cancer cells and so it becomes a good thing. Some people who develop cancer then choose to improve their diet to include new healthy foods, sadly for some people this may actually be counterproductive.
Estrogen is another case in point, it has many positive effects and has been suggested to be one reason why women like longer than men. If you develop estrogen positive breast cancer, more estrogen is the last thing you would want.  

Other NLRP3 inhibitors 

                          

Coll et al. (2015) discovered that MCC950, a diarylsulfonylurea-containing compound known to inhibit caspase-1-dependent processing of IL-1β, also inhibits both canonical and non-canonical activation of the NLRP3 inflammasome. MCC950 inhibits secretion of IL-1β and NLRP3-induced ASC oligomerization in mouse and human macrophages. It reduces secretion of IL-1β and IL-18, alleviating the severity of EAE and CAPS in mouse models. Coll et al. (2015) further showed that MCC950 acts specifically on the NLRP3 inflammasome

Note that MCC950 is the new name for a drug Pfizer originally called CP-456773 or CRID3, which was not successful as a treatment for arthritis, but now has a second chance

Youm et al. (2015) discovered that the ketone metabolite β-hydroxybutyrate (BHB), but not acetoacetate or the short-chain fatty acids butyrate and acetate, reduced IL-1β, and IL-18 production by the NLRP3 inflammasome in human monocytes. Like MCC950, BHB appears to block inflammasome activation by inhibiting NLRP3-induced ASC oligomerization. Their in vivo experiments showed that BHB or a ketogenic diet alleviate caspase-1 activation and caspase-1-mediated IL-1β production and secretion, without affecting the activation of NLRC4 or AIM2 inflammasomes. BHB inhibits NLRP3 inflammasome activation independently of AMP-activated protein kinase, ROS, autophagy, or glycolytic inhibition. These studies raise interesting questions about interactions among ketone bodies, metabolic products, and innate immunity. BHB levels increase in response to starvation, caloric restriction, high-intensity exercise, or a low-carbohydrate ketogenic diet. Vital organs such as the heart and brain can exploit BHB as an alternative energy source during exercise or caloric deficiency. Future studies should examine how innate immunity, particularly the inflammasome, is influenced by ketones and other alternative metabolic fuels during periods of energy deficiency 
Although both MCC950 and BHB inhibit NLRP3 inflammasome activation, their mechanisms differ in key respects. BHB inhibits K+ efflux from macrophages, while MCC950 does not. MCC950 inhibits both canonical and non-canonical inflammasome activation, while BHB affects only canonical activation. Nevertheless both inhibitors represent a significant advance toward developing therapies that target IL-1β and IL-18 production by the NLRP3 inflammasome in various diseases. 

Type I Interferon (IFN) and IFN-β

In contrast to these newly described, NLRP3-specific inflammasome inhibitors, type I interferons (IFNs), including IFN-α and IFN-β, have been used for some time to inhibit the NLRP3 and other inflammasomes in various auto-immune and auto-inflammatory diseases. These diseases include multiple sclerosis, systemic-onset juvenile idiopathic arthritis caused by gain-of-function NLRP3 mutations, rheumatic diseases and familial-type Mediterranean fever.

These studies highlight the efficacy of type I IFN therapy and the need for future studies to elucidate the mechanisms of NLRP3 inflammasome inhibition. This work may improve clinical approaches to treating multiple sclerosis and other auto-immune and auto-inflammatory diseases.

Other Kinds of NLRP3 Inflammasome Inhibitors
Several additional ways for inhibiting the NLRP3 inflammasome have opened up in recent years. Autophagy, a self-protective catabolic pathway involving lysosomes, has been shown to inhibit the NLRP3 inflammasome, leading researchers to explore the usefulness of autophagy-inducing treatments  

Cannabinoid receptor 2 (CB2R) is an already demonstrated therapeutic target in inflammation-related diseases (Smoum et al., 2015). Work from our own laboratory (Shao et al., 2014) has shown that autophagy induction may help explain why activation of the anti-inflammatory CB2R leads to inhibition of NLRP3 inflammasome priming
Thus CB2R agonists similar to the HU-308 used in our work may become an effective therapy for treating NLRP3 inflammasome-related diseases by inducing autophagy.
Several other microRNAs have been reported to be involved in the activation of the NLRP3 inflammasome, including microRNA-155, microRNA-377, and microRNA-133a-1. Reducing the levels of these factors may be useful for treating inflammasome-related disease 


Conclusion regarding NLRP3 inhibitors

At this point in time BHB is clearly the best choice; at some point it would be expected that Pfizer will commercialize MCC950. 

 Further relevant papers: 

Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3”. The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors. 

NLRP3-inflammasome activates caspase-1 and processes pro-IL-1β and pro-IL-18 into the active cytokines. Two recent studies describe specific inhibitors of NLRP3 inflammasome that inhibit IL-1β release and inflammation. The specificity and potency of these compounds gives hope that a targeted approach to inhibit NLRP3-driven inflammation may be just around the corner



Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer’s disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targeting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS + Aβ-induced caspase 1 activation in microglia and this was accompanied by IL-1β release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aβ phagocytosis in vitro, and it reduced Aβ accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function. 

Scientists say new treatments for inflammatory diseases could be on the way

New treatments for inflammatory diseases could be on the way thanks to a significant discovery made by an international group of scientists, including some at Trinity College Dublin. 
The treatments could be used for a whole range of inflammatory disease including arthritis, Alzheimer's, multiple sclerosis, Parkinson's, gout, asthma and Muckle-Wells syndrome.

The researchers have found that a molecule, previously developed and then abandoned by a multinational pharmaceutical company, can block one of the key drivers of a plethora of inflammatory conditions.
The molecule, MCC950, was produced by Pfizer two decades ago as a possible treatment for arthritis.
However, the company discontinued its efforts to bring the drug to market, and the intellectual property rights on it subsequently lapsed.
Around eight years ago, scientists at Trinity's Biomedical Sciences Institute led by Professor of Biochemistry Luke O'Neill came across the compound and began to explore its potential uses.
They subsequently discovered that it could effectively block the NLRP3 inflammasome.
Inflammasomes are a complex of molecules that trigger inflammation when exposed to infection or stress.
They have been identified as promising therapeutic targets for researchers in recent years.
The NLRP3 inflammasome has been found to be a common activator of a key process in certain inflammatory diseases.
The discovery by the research team, details of which are published in the journal Nature Medicine, confirms that all inflammatory diseases share a common process, although the part of the body which experiences the inflammation might differ.
The scientists subsequently carried out trials on mice and found that the molecule stopped the progression of multiple sclerosis and sepsis.
They also carried out testing on samples taken from humans with Muckle-Wells syndrome, a rare auto-inflammatory disorder, and discovered it was equally effective.
The scientists also say that it is likely the drug could produce fewer common side-effects, such as susceptibility to infection, than other anti-inflammatory drugs, and could prove cheaper and capable of being administered orally.
The next stage will involve testing the compound on humans and a wider group of diseases.
The researchers say for certain conditions, like Muckle-Wells syndrome and asthma, such trials could take place as early as two to three years from now, as the drug had already undergone some human testing by Pfizer.
However, even if the trials prove the drug is safe and effective, they stress that it could be ten-15 years before it could be fully approved for use in humans for the treatment of more complex diseases like multiple sclerosis or Alzheimer's.
They also stress that while the molecule could become an effective treatment, it will not be a cure, though it is possible it could be effective in undoing some of the damage done by well progressed cases of certain diseases.
Prof O'Neill and his team now plan to form a company to further develop and test the compound.
MCC950 is also currently being tested on mice in the US for anti-ageing properties, as there is a growing school of thought that inflammation is responsible for much of the ageing process - a theory which has come to be known as "inflammaging".
The study, part funded by Science Foundation Ireland and the European Research Council, was carried out by a collaboration of six institutions, including the Universities of Queensland, Michigan, Massachusetts and Bonn. 

Conclusion

I am amazed at all the potentially good things that ketones and KD can do for many people’s health and it is all based on science from very serious institutions. 






Thursday, 19 July 2018

Ketones and Autism Part 2 - Ketones as a Brain Fuel to treat Alzheimer’s, GLUT1 Deficiency and perhaps more



Today’s post looks at the role ketones can play as a fuel for the brain.

The research has already shown that in young babies there is insufficient glucose to fuel their power-hungry growing brains and so ketones provide up to 40% of the fuel to their brains.
Glucose or Ketones at the pump?

This does show any sceptics that you can indeed safely combine two sources of fuel at the same time in humans; we have all done it.
This process works in tiny babies because their diet is rich in medium chain fatty acids, which become the ketones.
Only mitochondria in your brain and your muscles can be fuelled by ketones; some elite athletes take advantage of this.
People who are overweight have excess adipose tissue (fat) and when in ketosis, fatty acids from this tissue are released into your blood and travel to the liver where they produce ketones. Mitochondria can also burn fatty acids directly. People losing weight on the ketogenic diet are burning fat and ketones as their main fuel source. To lose weight you do have to be in calorie deficit, you cannot just eat unlimited fat.
Athletes want to improve their performance and some use ketones to achieve this. The fat they are burning is from diet, not from accumulated over-eating.
Ketones as a brain fuel is a niche subject, but a growing one.

Low brain glucose uptake
Low brain glucose uptake is a feature or Alzheimer’s disease and also of a rare inborn condition called GLUT1 deficiency, which appears as epilepsy, MR/ID and with features of autism. Infants with GLUT1 deficiency syndrome have a normal head size at birth, but growth of the brain and skull is slow, in severe cases resulting in an abnormally small head size (microcephaly).

GLUT1, GLUT3 and GLUT4
GLUT1 (glucose transporter 1) occurs in almost all tissues, with the degree of expression typically correlating with the rate of cellular glucose metabolism. It is expressed in the endothelial cells of barrier tissues such as the blood brain barrier.
Glucose delivery and utilization in the human brain is mediated primarily by GLUT1 in the blood–brain barrier and GLUT3 in neurons.
GLUT3 is most known for its specific expression in neurons and was originally designated as the neuronal glucose transporter.
GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues (fat) and striated muscle (skeletal and cardiac), but also in the brain.
So, in neurological disorders it is important to optimize GLUT1, GLUT3, GLUT4 and insulin.  In GLUT1 deficiency, as the name suggests, there is an inadequate supply of glucose crossing the blood brain barrier. In people with insulin resistance (T2 diabetes, Alzheimer’s etc) GLUT4 may be impaired.

Insulin resistance in the brain
Insulin resistance in the brain is highly complex and only partially understood; but it does lead to numerous problems. Glucose in the blood does not get taken up adequately into neurons which then become starved of fuel. We will see how this can be overcome by reverting to ketones as an alternative fuel.
At this point I digress a little into the detail of insulin resistance and glucose transport.                                                                             

Insulin resistance is a condition in which cells fail to respond normally to the hormone insulin. The body produces insulin when glucose starts to be released into the bloodstream from the digestion of carbohydrates  in diet. Under normal conditions of insulin reactivity, this insulin response triggers glucose being taken into body cells, to be used for energy, and inhibits the body from using fat for energy, thereby causing the concentration of glucose in the blood to decrease as a result, staying within the normal range even when a large amount of carbohydrates is consumed. During insulin resistance, excess glucose is not sufficiently absorbed by cells, even in the presence of insulin, causing an increase in the level of blood sugar.

The following paper is very interesting, if you can access the full text version


Considerable overlap has been identified in the risk factors, comorbidities and putative pathophysiological mechanisms of Alzheimer disease and related dementias (ADRDs) and type 2 diabetes mellitus (T2DM), two of the most pressing epidemics of our time. Much is known about the biology of each condition, but whether T2DM and ADRDs are parallel phenomena arising from coincidental roots in ageing or synergistic diseases linked by vicious pathophysiological cycles remains unclear. Insulin resistance is a core feature of T2DM and is emerging as a potentially important feature of ADRDs. Here, we review key observations and experimental data on insulin signalling in the brain, highlighting its actions in neurons and glia. In addition, we define the concept of 'brain insulin resistance' and review the growing, although still inconsistent, literature concerning cognitive impairment and neuropathological abnormalities in T2DM, obesity and insulin resistance. Lastly, we review evidence of intrinsic brain insulin resistance in ADRDs. By expanding our understanding of the overlapping mechanisms of these conditions, we hope to accelerate the rational development of preventive, disease-modifying and symptomatic treatments for cognitive dysfunction in T2DM and ADRDs alike. 

Sources of insulin in the brain. Insulin levels in cerebrospinal fluid (CSF) are much lower than in plasma but these levels are correlated, indicating that most insulin in the brain derives from circulating pancreatic insulin. Insulin enters the brain primarily via selective, saturable transport across the capillary endothelial cells of the blood–brain barrier (BBB).
Despite glucose being the major energy source for the brain, the uptake, transport and utilization of glucose in neurons is only influenced by insulin and is not dependent on it
The insulinindependent glucose transporter GLUT3 is the major glucose transporter in neurons and is present in very few other cell types in the body. The density and distribution of GLUT3 in axons, dendrites and neuronal soma correlates with local cerebral energy demands. Insulin is not required for GLUT3mediated glucose transport; instead, NMDA receptormediated depolarization stimulates consumption of glucose, which prompts glucose uptake and utilization via GLUT3. 
Although most glucose uptake in neurons occurs via GLUT3, insulinregulated GLUT4 is also coexpressed with GLUT3 in brain regions related to cognitive behaviours — at least in rodents. These regions include the basal forebrain, hippocampus, amygdala and, to lesser degrees, the cerebral cortex and cerebellum. 
Activation by insulin induces GLUT4 translocation to the neuron cell membrane via an AKTdependent mechanism and is thought to improve glucose flux into neurons during periods of high metabolic demand, such as during learning. Interestingly, GLUT4 is also expressed in the hypothalamus, a key area for metabolic control. Deletion of GLUT4 from the CNS in mice results in impaired glucose sensing and tolerance, which might be due in part to an absence of GLUT4 in the hypothalamus.

Brain insulin resistance definition. Insulin resistance in T2DM has been defined as “reduced sensitivity in body tissues to the action of insulin”. Similarly, brain insulin resistance can be defined as the failure of brain cells to respond to insulin. Mechanistically, this lack of response could be due to downregulation of insulin receptors, an inability of insulin receptors to bind insulin or faulty activation of the insulin signalling cascade. At the cellular level, this dysfunction might manifest as the impairment of neuroplasticity, receptor regulation or neurotransmitter release in neurons, or the impairment of processes more directly implicated in insulin metabolism, such as neuronal glucose uptake in neurons expressing GLUT4, or homeostatic or inflammatory responses to insulin. Functionally, brain insulin resistance can manifest as an impaired ability to regulate metabolism — in either the brain or periphery — or impaired cognition and mood 

Studies have yet to show whether T2DMassociated cognitive impairment and brain neuroimaging findings are a consequence of brain insulin resistance or are due to other factors that cooccur with systemic insulin resistance. Common comorbidities of systemic insulin resistance in T2DM — such as hyperglycaemia, advanced glycation end products, oxidatively dam aged proteins and lipids, inflammation, dyslipidaemia, athero sclerosis and microvascular disease, renal failure and hypertension — all have their own complex effects on brain function through a variety of mechanisms independent of insulin signalling. Furthermore, evidence suggests that systemic insulin resistance or high circulating levels of insulin affects the function of the BBB by downregulating endothelial insulin receptors and thus decreasing permeability of the BBB to insulin. This change in permeability is potentially of great importance as it could lead to decreased brain insulin levels and decreased insulinfacilitated neural and glial activity40. On the other hand, T2DM can lead to damage of the BBB, which results in increased permeability to a variety of substances

Brain insulin resistance in ADRDs
• Increasing age is associated with decreasing cortical insulin concentration and receptor binding in older adults without dementia 
•Brain tissue from those with Alzheimer disease (AD) shows major abnormalities in insulin signalling, including - Decreased insulin, insulin receptor and insulin receptor substrate 1 (IRS1) mRNA and/or protein expression levels
Decreased activation of insulin pathway molecules (for example, IRS1 and AKT) with ex vivo stimulation
Increased basal phosphorylation levels of multiple insulin–IRS1–AKT pathway molecules
 Positive correlation between phosphorylated IRS1 and other pathway molecules and AD pathology 
• Intranasal insulin administration improves cognitive functioning in humans with AD or mild cognitive impairment and improves measures of insulin signalling, amyloid-β and cognitive behaviours in AD model mice 
Brain insulin resistance might be a feature of other neurodegenerative diseases

Insulin receptor expression is decreased and AKT signalling is abnormal in the substantia nigra in Parkinson disease
Abnormal phosphorylated IRS1 expression is observed in tauopathies but is not seen in synucleinopathies or TDP-43 proteinopathies
Aside from treatment with insulin itself, insulinsensitizing medicines commonly used in T2DM have attracted growing interest as potential therapies for brain insulin resistance in ADRD. For instance, investigators have begun testing of metformin, the most commonly prescribed drug for T2DM, in nondiabetic individuals with MCI or early dementia due to AD, with some signs of benefit. In addition, thiazolidinedionebased nuclear peroxisome proliferatoractivated receptorγ (PPARγ) agonists, which were originally developed as insulin sensitizers for T2DM, have shown numerous beneficial neural effects in animal models of neuro degenerative diseases

Autism and GLUT1 deficiency:


Another excellent paper:-  


Brain energy metabolism in Alzheimer’s disease (AD) is characterized mainly by temporo-parietal glucose hypometabolism. This pattern has been widely viewed as a consequence of the disease, i.e. deteriorating neuronal function leading to lower demand for glucose. This review will address deteriorating glucose metabolism as a problem specific to glucose and one that precedes AD. Hence, ketones and medium chain fatty acids (MCFA) could be an alternative source of energy for the aging brain that could compensate for low brain glucose uptake. MCFA in the form of dietary medium chain triglycerides (MCT) have a long history in clinical nutrition and are widely regarded as safe by government regulatory agencies. The importance of ketones in meeting the high energy and anabolic requirements of the infant brain suggest they may be able to contribute in the same way in the aging brain. Clinical studies suggest that ketogenesis from MCT may be able to bypass the increasing risk of insufficient glucose uptake or metabolism in the aging brain sufficiently to have positive effects on cognition.

Push-pull: two distinct strategies to supply the brain with energy substrates. Glucose is the brain’s main fuel and is taken up by the brain in relation to demand. Hence, this is a “pull” strategy because glucose is pulled into the cell following neuronal activation and the subsequent decrease in neuronal glucose concentrations. Ketones are the brain’s main alternate fuel to glucose and are taken up by the brain in relation to their presence in blood. Hence, this is a “push” strategy because ketones are pushed into the brain in direct proportion to their concentrations in the blood.

5 Cognitive benefits of increasing brain ketone supply


Since brain ketone uptake is still normal in mild to moderate AD and the problem of low brain glucose uptake appears to be contributing to declining cognition in AD, it is reasonable to hypothesize that providing the brain with more ketones may delay any further cognitive decline. This hypothesis has been supported by results from acute and chronic studies in AD patients and in the prodromal condition to AD – mild cognitive impairment. Other trials with ketogenic supplements in AD are ongoing. Conditions involving acute or long-term cognitive problems including post-insulin hypoglycemia and epilepsy also respond to a ketogenic diet or supplement.

One of the reasons that type 2 diabetes is such an important risk factor for AD may be due to insulin resistance. The brain has long been thought to function independently of insulin, but this is now being challenged. Insulin resistance not only affects glucose uptake by peripheral tissues but it also blocks ketogenesis, thereby limiting production of ketones to be taken up by the brain. Indeed, if the insulin resistance of type 2 diabetes in some way impairs brain glucose metabolism, brain energy supply is in fact in double jeopardy because insulin excess also blocks ketogenesis from long chain fatty acids stored in adipose tissue thereby restricted access not just of the brain’s primary fuel (glucose) but its main back-up fuel (ketones) as well. One potential solution is that ketogenesis from MCFA appears to be independent of insulin, in which case a ketogenic MCFA supplement should still be able to supply the brain with ketones despite the presence of insulin resistance or type 2 diabetes. This is an active area of research.  

6 Ketones and infant brain development


Raising plasma ketones is commonly viewed as risky, primarily because ketosis is associated with uncontrolled type 1 diabetes, i.e. an acute and severe absence of insulin. However, pathological ketosis needs to be distinguished from nutritional ketosis: the former is associated with metabolic ketoacidosis, i.e. plasma ketones exceeding 15 mM, which is medically serious condition requiring rapid treatment. In contrast, the latter is associated with plasma ketones below 5 mM and can be safely induced by short- or long-term dietary modification. The very high fat ketogenic diet induces nutritional, not pathological ketosis. It has been used for nearly 100 years as a standard-of-care for intractable childhood epilepsy and is rarely associated with serious side-effects despite producing plasma ketones averaging 2–5 mM for periods commonly exceeding 2 years. Its mechanism of action is still poorly understood but the efficacy of this dietary ketogenic treatment for intractable epilepsy is greater in younger infants suggesting a possible link the well-established but often overlooked importance of ketones in infant brain development.

During lactation, the human infant brain metabolises >50% of the fuel provided, despite the brain representing only 12–13% of body’s weight. Glucose supplies about 30% of the late term fetus’s brain energy requirements and about 50% of the neonate’s brain energy requirements; the difference is provided by ketones. Therefore, ketones are an obligate brain fuel during an infant’s development, as opposed to being an alternative brain fuel in the adult human, i.e. only needed when glucose is limiting. Ketones are more than just catabolic substrates (fuel) for the developing brain – they are also important anabolic substrates because they supply the majority of carbon used to synthesize brain lipids such as cholesterol and long chain saturated and monounsaturated fatty acids. 


                                        

Unique route of medium chain fatty acid (MCFA) absorption compared to other common long chain dietary fatty acids. The lymphatic and peripheral circulation1 distribute most common long chain fatty acids as chylomicrons throughout the body, whereas MCFA are mostly absorbed directly via the portal vein to the liver2  

MCFA are more rapidly absorbed from the gut directly to the liver via the portal vein compared to long chain fatty acids which are absorbed primarily via the lymphatic duct and into the peripheral circulation. MCFA are also more easily β-oxidized in mitochondria because they do not require activation to CoA esters by carnitine. Both the rapid absorption and β-oxidation of MCFA suggest these fatty acids have a physiologically important function. Theoretically, this function could include elongation to long-chain fatty acids but, in practice, is probably limited to ketogenesis, especially in infancy which is the only period when it is normal to be regularly consuming MCFA.

Long chain fatty acids are the main alternate fuel to glucose for most tissues. They can also be taken up by the brain but the reason they are not a useful fuel for the brain is because their rate of uptake is insufficient to meet the demand for energy once glucose becomes limiting. However, MCFA such as octanoate (caprylic acid) can be taken up rapidly and be metabolized by the brain. Whether MCFA have direct effects on the brain or are principally metabolized to ketones before exerting any effect as fuels, lipid substrates or lipid signalling molecules remains to be seen. 



Ketones for Alzheimer’s? AC1202/4 
A lot of money is being spent on developing variants of caprylic acid (C8) as a medical food to treat one feature of Alzheimer’s. This medical food market has even attracted Nestle, the Swiss chocolate to baby food giant, to invest in ketones.
Even though clinical trials have not yet been successfully completed, American doctors are already prescribing a product called Axona to people with Alzheimer’s.
It looks like there are plenty of sceptics, but it looks like plenty of people are paying $80 a month for their Axona (>95% C8 oil). One packet of Axona powder, contains 20 grams MCTs almost exclusively C8.
You can see from the clinicals trials that Accera have been comparing the effectiveness of generic (unpatentable) C8 vs their two proprietary powders called AC-1202 and AC-1204. Clearly Accerra want to maximize plasma BHB, but in a way that has patent protection.
Since C8 is not so expensive when bought in bulk, the obvious alternative is just to drink C8 and in the way that best promotes its absorption and the production of ketones, which would seem to be when you wake up and before you have eaten anything.


http://www.about-axona.com/us/en/cgp/how-axona-could-help/how-axona-works.html



CNS therapeutics company Accera's AC-1204 has failed to demonstrate a positive outcome in the Phase III trial for the treatment of patients with mild-to-moderate Alzheimer's disease. 
AC-1204 is a small-molecule drug compound designed to leverage the physiological ketone system in order to address the deficient glucose metabolism in Alzheimer's. 
The ketones are thought to have a potential to restore and improve neuronal metabolism, resulting in better cognition and function.
The trial results indicated that the drug did not show a statistically significant difference at week 26 when compared with placebo, as measured by the Alzheimer's disease assessment scale-cognitive subscale test (ADAS-Cog). 
"The formulation of the drug was changed between the Phase II and Phase III studies."
The double-blind, randomised, placebo-controlled, parallel-group Phase III (NOURISH AD) trial evaluated the effects of daily administration of AC-1204 in the subjects for 26 weeks.
Accera research and development vice-president Samuel Henderson said: "The formulation of the drug was changed between the Phase II and Phase III studies. 
"Unfortunately, this change in formulation had the unintended consequence of lowering drug levels in patients. We are confident that our newly developed formulation will provide increased exposure and allow a more conclusive test of drug efficacy." 
The primary and key secondary endpoints of the trial are the measure of AC-1204 effects on memory, cognition and global function. 
While the drug was found to be safe with high levels of tolerability, a detailed pharmacokinetic analysis showed that the modified formulation used in the study led to a decrease in drug plasma levels when compared to prior formulations. 


FDA hit Accera with a warning letter in 2013 on the grounds its marketing materials caused Axona to be classed as a drug. Accera continues to market Axona as a medical food for Alzheimer’s but has tweaked its website since the warning letter.
Axona and AC-1204 both provide patients with a source of caprylic triglyceride—also known as fractionated coconut oil—that is intended to increase the availability of ketones to the brain. The potential of the therapeutic approach has enabled Accera to pull in more than $150 million from backers including Nestlé, according to SEC filings.

Ketones for GLUT1 deficiency?  C7 Triheptanoin
It looks like the star clinician/researcher for people with GLUT1 deficiency is Dr. Juan Pascual, Associate Professor of Neurology and Neurotherapeutics, Pediatrics, and Physiology at UT Southwestern Medical Center.
As we saw earlier you need the transporter GLUT1 for glucose to cross the blood brain barrier and then provide fuel for the mitochondria in the brain. 
It has been known for some time that people with GLUT1 deficiency make improvements on the ketogenic diet.  Now in the previous post we saw how the effect on epilepsy of the KD comes via a change in the mix of bacteria in the gut; this eventually leads to a sharp increase in the ratio of GABA/Glutamate in the brain. This reduces seizures, which are a feature of GLUT1 deficiency.
Dr Pascual wants a second benefit from the ketogenic diet, having got the benefit from the gut bacteria he wants to benefit from the ketones as a fuel, just like some Alzheimer’s researchers.
This time though he has picked another MCT (medium chained triglyceride) he picked C7.
C7 is not something you can pick up from your specialist ketone supplier. It is still very much a research chemical.
Dr Pascual did not start with C8 because he has done his homework.  He actually wants some help for his GLUT1 deficient patients from some C5 ketones and a good way to produce them is from C7.
Using C7 oil Dr Pascual is also going to produce BHB (beta-hydroxybutyrate) and acetoacetate, just like all those athletes, body builders, slimmers and older people with Alzheimer’s are doing with the KD, C8 and BHB.




           Metabolism of glucose, C7-derived heptanoate and 5-carbon (C5) ketones in the brain

Glial metabolism is distinct from neuronal metabolism. Glucose can access both glia (via GLUT1) and neurons (via GLUT3), fueling the TCA cycle (CAC). In glia, pyruvate is converted into oxaloacetate (OAA) via carboxylation, donating net carbon to the TCA cycle (anaplerosis). This reaction can be impaired in G1D. Like glucose, the C7 derivative heptanoate and related metabolites (i.e., the 5-carbon ketones beta-ketopentanoate and beta-hydroxypentanoate) also generate acetyl-coenzyme A (Ac-CoA) but, unlike the 4-carbon ketone bodies beta-hydroxybutyrate and acetoacetate, they can also be incorporated into succinyl-coenzyme A (Suc-CoA) via propionyl-CoA (Prop-CoA) formation, supplying net, anaplerotic carbon to the cycle. In addition to 5-carbon (C5) ketones, the 4-carbon ketone bodies beta-hydroxybutyrate and acetoacetate are also metabolites of C7.




Dr. Pascual led the JAMA study that relied on data from a worldwide registry he created in 2013 for Glut1 deficiency patients. The research tracked 181 patients for three years, finding that a modified Atkins diet that includes less fat and slightly more carbohydrates than the standard ketogenic diet helped reduce seizures and improved the patients' long-term health. The study also found earlier diagnosis and treatment of the disease improved their prognosis.
In addition, Dr. Pascual is overseeing national clinical trials that are testing whether triheptanoin (C7) oil improves the intellect of patients by providing their brains an alternative fuel to glucose. The trials will last five years and are funded with more than $3 million from the National Institutes of Health.

So far, the nearly 40,000 Americans potentially living with the disease have had only one primary option for treating symptoms: a high-fat, low-carbohydrate ketogenic diet that can limit seizures. The diet works in about two-thirds of patients but does not improve their intellect and carries long-term risks such as kidney stones and metabolic abnormalities.

Dr. Pascual expects the modified diet from the JAMA study and the C7 oil will prove at least as effective as the ketogenic diet in preventing seizures - without the health risks - while feeding the brain vital fuel to improve learning.


Background: Ketones are the brain's main alternative fuel to glucose. Dietary medium-chain triglyceride (MCT) supplements increase plasma ketones, but their ketogenic efficacy relative to coconut oil (CO) is not clear.

Objective: The aim was to compare the acute ketogenic effects of the following test oils in healthy adults: coconut oil [CO; 3% tricaprylin (C8), 5% tricaprin (C10)], classical MCT oil (C8-C10; 55% C8, 35% C10), C8 (>95% C8), C10 (>95% C10), or CO mixed 50:50 with C8-C10 or C8.

Methods: In a crossover design, 9 participants with mean ± SD ages 34 ± 12 y received two 20-mL doses of the test oils prepared as an emulsion in 250 mL lactose-free skim milk. During the control (CTL) test, participants received only the milk vehicle. The first test dose was taken with breakfast and the second was taken at noon but without lunch. Blood was sampled every 30 min over 8 h for plasma acetoacetate and β-hydroxybutyrate (β-HB) analysis.

Results: C8 was the most ketogenic test oil with a day-long mean ± SEM of +295 ± 155 µmol/L above the CTL. C8 alone induced the highest plasma ketones expressed as the areas under the curve (AUCs) for 0–4 and 4–8 h (780 ± 426 µmol h/L and 1876 ± 772 µmol h/L, respectively); these values were 813% and 870% higher than CTL values (P < 0.01). CO plasma ketones peaked at +200 µmol/L, or 25% of the C8 ketone peak. The acetoacetate-to-β-HB ratio increased 56% more after CO than after C8 after both doses.

Conclusions: In healthy adults, C8 alone had the highest net ketogenic effect over 8 h, but induced only half the increase in the acetoacetate-to-β-HB ratio compared with CO. Optimizing the type of MCT may help in developing ketogenic supplements designed to counteract deteriorating brain glucose uptake associated with aging. This trial was registered at clinicaltrials.gov as NCT 02679222. 

Brain glucose uptake is lower in Alzheimer disease (AD). This problem develops gradually before cognitive symptoms are present, continues as symptoms progress, and becomes lower than the brain glucose hypometabolism occurring in normal aging. In contrast to glucose, brain ketone uptake in AD is similar to that in cognitively healthy, age-matched controls. For ketones to be a useful energy source in glucose-deprived parts of the AD brain, the estimated mean daily plasma ketone concentration needs to be >200 μmol/L (21). With a total 1-d dose of 40 mL C8, plasma ketones peaked at 900 μmol/L and the day-long mean was 363 ± 93 μmol/L, whereas with the same amount of CO, they peaked at 300 and 107 ± 57 μmol/L, respectively. Our 2-dose test protocol (breakfast and midday) generated 2 peaks of plasma total ketones throughout 8 h, with the second dose inducing 3.5 and 2.4 times higher ketones with C8 than with CO, respectively. The first dose taken with a meal would be a more typical pattern but resulted in less ketosis that without a meal. One limitation of this study design is that the metabolic study period was only 8 h. A longer-term study lasting several weeks to months would be useful to assess the impact of regular MCT supplementation on ketone metabolism.




Conclusion
I hope Dr Pascual has read the UCLA study on bacteria mediating the effect of the ketogenic diet on seizures. I think this has big implications for how to best manage people with GLUT1 deficiency.
I can see why Nestlé are investing in C8 products to treat Alzheimer’s. It does makes sense to optimize bioavailability, but in the meantime drinking regular liquid C8 would seem a smart idea.

While C8 is being proposed for Alzheimer's as a means of compensating for reduced glucose uptake in the brain, it has other benefits.  In the next post we will look at the anti-inflammatory benefits of the ketone BHB; these benefits are very relevant to Alzheimer's, where we know that the pro-inflammatory cytokine IL-1B is over-expressed. We will discover how BHB reduces expression of IL-1B. 
The amount of C8 required to start partially fuelling the brain is trivial, just 40ml a day. If combined with BHB itself, you would need even less and if I was Nestlé that is what I would develop.
Unless you have GLUT1 deficiency I do not see why C7 is better than C8 as a brain fuel.
In autism you would only benefit from ketones as a brain fuel if you have reduced glucose uptake, reduced insulin sensitivity or a mitochondrial disorder. Clearly, some people diagnosed with autism should benefit from ketones as a secondary brain fuel to glucose. If intranasal insulin helps, ketones are particularly likely to help.