Turmeric powder, only in food, modified the SLC6A15 gene
I know that most readers of this blog want to treat autism with supplements and/or diet.
Many supplements and herbal medicines do show promise in the laboratory, when tests are conducted in vitro, but very often when tests are made in humans the results are much weaker, or just not present.Turmeric/Curcumin is a perfect example; in the test tube it has a wide range of potent benefits, but due to low absorption into humans (bioavailability) it does not show such conclusive results in human studies.
One researcher a while back did send me a study that reviewed all the turmeric/curcumin trials and it concluded that curcumin has no beneficial effect in humans.
In modern medicine anecdotal evidence does not count. Some anecdotes are genuine, but some are coincidence and some are placebo.
Mini trial of Turmeric at three UK Universities
There is a remarkably good medical program produced by the BBC in the UK, called Trust me I’m a Doctor, where the doctor presenters team up with universities to test practical medical hypotheses.
In one study they took 100 people to assess whether turmeric has any measurable medical benefit. They teamed up with Newcastle University, Leeds University and a clever genetic researcher at University College London (UCL).
They showed that eating turmeric in your food modified a specific gene (SLC6A15) associated with certain cancers, asthma/eczema and depression.
Taking turmeric as a supplement pill or taking a placebo pill had no effect on the gene.
The researcher at UCL was measuring the epigenetic tags attached to the genes. He showed that methylation of this gene was increased by dietary turmeric. Changing the methylation of this gene will change when it turns on/off.
Anecdotally, we know that people who eat a lot of turmeric tend to have less cancer, less asthma and less eczema.
Given that this gene is also associated with depression, you might expect big eaters of turmeric to have either less, or more, depression. Probably nobody has researched this.
SLC6 Gene Family
It is true that asthma and eczema (atopic dermatitis) are common in people with autism, but variations in the broader SLC6 family of genes are known to affect people with ADHD, Fragile X, Tourette’s and broad autism.
SLC transporters encompass approximately 350 transporters organized into 55 families. The SLC6 family is among the largest SLC families, containing 20 genes that encode a group of highly similar transporter proteins. These proteins perform transport of amino acids and amino acid derivatives into cells.
In humans, the SLC6 family of transporters defines one of the most clinically relevant protein groups with links to orthostatic intolerance, attention deficit hyperactivity disorder (ADHD), addiction, osmotic imbalance, X-linked mental retardation , Hartnup disorder, hyperekplexia, Tourette syndrome, schizophrenia, Parkinson disease (PD), autism and mood disorders such as depression, anxiety, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD).
This review will focus on the structure-function aspects of the mammalian SLC6 transporters, their regulation by both classical as well as emerging epigenetic/transgenerational mechanisms and what impact these properties may have on disease and the use of biomarkers to detect these proteins in disease states
Solute carrier 6 (SLC6) is a gene family of ion-coupled plasma membrane cotransporters, including transporters of neurotransmitters, amino acids, and osmolytes that mediate the movement of their substrates into cells to facilitate or regulate synaptic transmission, neurotransmitter recycling, metabolic function, and fluid homeostasis. Polymorphisms in transporter genes may influence expression and activity of transporters and contribute to behavior, traits, and disease. Determining the relationship between the monoamine transporters and complex psychiatric disorders has been a particular challenge that is being met by evolving approaches. Elucidating the functional consequences of and interactions among polymorphic sites is advancing our understanding of this relationship. Examining the influence of environmental influences, especially early-life events, has helped bridge the gap between genotype and phenotype. Refining phenotypes, through assessment of endophenotypes, specific behavioral tasks, medication response, and brain network properties has also improved detection of the impact of genetic variation on complex behavior and disease.
Amino acids are very important and it is not just that you need them, but you need them in the right place at the right time.
It appears that one of the many effects of defective amino acid/derivative transport into cells is on behaviour.
Improving amino acid transmission is therefore a potential therapy to correct aberrant behaviour, including depression but likely much more.
Conclusion
Modern clinical trials are often hugely expensive, but as the BBC keeps showing with its TV series, you can carry out very meaningful research without breaking the bank.
You would think that cancer researchers would now look at the modified versions of turmeric that claim higher bioavailability and see if these pills can also modify this cancer gene, since they can easily repeat the UCL laboratory analysis. I doubt this will happen any time soon.
It has long been known that turmeric is not well absorbed, but just one teaspoon a day added to food was enough to modify the gene.
Indians have a low incidence of cancer and a high consumption of turmeric. Turmeric should particularly limit breast cancer.
The above chart, where blue is best, shows India does well, as do some other turmeric eating countries (South Asia and the Middle East). Clearly longevity and quality of healthcare also matter, so beware Africa. Europe, Russia, Argentina, Uraguay, Oz, NZ and North American might want to up their turmeric intake.
We can say that turmeric is a potential epigenetic therapy for at least one important gene (SLC6A15) and possibly more, because turmeric does not just affect methylation. It has several other better documented epigenetic properties.
Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.
Only a few reports have so far investigated the effect of curcumin on DNA methylation. Molecular docking of the interaction between curcumin and DNMT1 suggested that curcumin covalently blocks the catalytic thiolate of DNMT1 to exert its inhibitory effect on DNA methylation. However, a more recent study showed no curcumin-dependent demethylation, which suggested that curcumin has little or no pharmacologically relevant activity as a DNMT inhibitor. To clarify these contradictions, more research is urgently needed.
Given that 5-azacitidine and decitabine, two FDA-approved hypomethylating agents for treating myelodysplastic syndrome, have a demonstrated ability to sensitize cancer cells to chemotherapeutic agents, it would be worthwhile to explore whether the hypomethylation effect of curcumin can also induce cancer cell chemosensitization. Interestingly, a phase 1 trial with curcumin administered several days before docetaxel in patients with metastatic breast cancer resulted in 5 partial remissions and stable disease in 3 of 8 patients. This unexpected high response might have resulted from the clever sequential delivery of these two agents, which capitalized on and maximized curcumin’s epigenetic activity for cancer treatment.
Docetaxel is a 20 year old chemotherapy drug produced using extracts from the leaves of the European yew tree, perhaps best taken with root (rhizome) of the Asian Curcuma Longa plant.
The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly. It exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells.
One key issue for most people with more severe autism (DSM5 level 3, any DSM3, or just SDA – Strictly Defined Autism) is getting them to fully use their capacity to communicate.
Many such people do learn to talk, but often this is a very matter of fact kind of speech, that is limited to answering questions and making requests.
Often the limiting factor is not vocabulary, grammar or vocalization. Many can put ideas in words on paper, they can sing and read aloud; but something is lacking when it comes to conversation.
You can use behavioral therapy (like Verbal Behavior, VB) and some of the more relevant parts of speech therapy to encourage more extensive speech, but it is a real slog. When you spend less time on 1:1 “speech training”, in order to develop academic school work, you end up with less speech.
I was discussing this with Monty’s assistants, the need to take a step back and refocus on speech as a skill, in addition to regular school work.It is good to be able to master algebra, but in any social situation communication remains number one.
I have long wondered if it is a behavioural problem, a structural brain problem or a treatable biological problem. I do see parallels with how typical people speak foreign languages. For example, if I was on a train in Germany and somebody wanted to talk to me in German, I would keep my answers short and simple; I would not be trying to keep the conversation going. My German is very rusty, but I can read it aloud and yes, I could sing in it. I would not make small talk in German.
I do consider people like Monty, now aged 15 with autism, not to have a first language; silence is their first language and their mother tongue is like a second language. Some readers of this blog are exceptions, but most people are pretty weak in their second language. For them it never becomes intuitive, you have to painfully learn what preposition takes what case and how to decline nouns and conjugate verbs. You can make a strong case that people who do not begin to speak until 4 years old have missed a critical window in how the brain develops and so when language does slowly begin to come, it can never become truly fluent, a bit like my German.
I do have a broader interest in how you acquire language. Monty's big brother is bilingual and also pretty fluent in Russian and German and chatty in French. This all came with minimal effort, but being exposed from birth to two languages and then learning more languages in the conventional way.
Many readers of autism forums ask about what pill can you take to promote speech. I always thought this was rather wishful thinking, in that you cannot target such a specific aspect of someone’s autism. Just like there may be no magic pill for algebra.
Writing before talking?
One idea I had to promote more prolonged “conversation” was to first have Monty write about the subject.I agreed with Monty’s assistants one new exercise, which is to have him write a daily diary of his day and then later on have him retell the day’s events, but without reference to the diary.
It does indeed work, having written about the subject, when later asked to talk about it, there is a much longer and more detailed conversation.
No pills required.
The Ketone BHB
The reason for all the recent posts in this blog about ketones and autism is that perhaps there actually is a “pill” you can take to promote speech.
Our reader Agnieszka in Poland has been experimenting with ketones for some time and since her son responds to most of the things in Monty’s PolyPill, I assume that there is a good chance that anything new that works for her son might also work for Monty.
One area that the ketone BHB seems to help in Agnieszka’s case is promoting speech and BHB does indeed have the very same effect in Monty.
One effect of sulforaphane/broccoli was increased verbalization. If your child is four years old, increased verbalization would be something to celebrate, but by 15 years old you want relevant speech (for some people sulforaphane does indeed produce increased relevant speech).Very encouragingly, BHB seems to deliver an increase in intelligent, relevant, spontaneous speech. These are things that Monty could write but would not say, unprompted.
There are big gaps in the scientific data about ketone supplements in humans. These supplements are only widely available in North America, even though it looks like most commercial products are repackaged from Chinese bulk chemical producers.
It appears that the most effective therapy is a combination of a precursor to ketones (C8) and a salt of the BHB ketone (Sodium, Calcium, Magnesium or Potassium Beta-Hydroxybutyrate).
According to one Chinese bulk producer, the Calcium salt of BHB is not very effective, they recommend Sodium and/or Magnesium.
By using a salt of BHB, you are going to consume significant amounts of sodium, calcium, magnesium or potassium. This may be unwise for some people.
The objective is to raise the amount of BHB in your bloodstream.
You can measure BHB in urine inexpensively, but the more reliable blood testing equipment is more expensive.
The study below evaluated one widely available commercial supplement:-
Figure 1b: mean, standard deviation of D-βHB (mmol/L) level in serum of all subjects () within a time period of 5.5 h after intake of βHB salt mixture (0.5 g/kg BW).
The supplement used was Ketosports KetoCaNa Orange.
In fact the dose of Ca/Na Betahydroxybutyrate was very high, 0.5g per Kg. In the case of a typical adult that might be 40g per day.
That would contain:-
·23g of BHB
·2.6g of sodium
·2.3g of calcium
That is quite a lot of sodium and calcium.
Some products are exclusively Potassium Betahydroxybutyrate, in those for each 23g of BHB you would get 8,700 mg of potassium, which is way too much to take at once. I am amazed it has not been banned.
When it comes to data on the use of C8 MCT oil in humans to produce BHB, we have the following study. The chart they produced is the total of BHB and another ketone, acetoacetate (AcAc), but we can extract the data on BHB itself.
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.
Plasma concentration and summed daily means (far right) during the metabolic study days for total ketones (β-HB and AcAc) obtained without an added test oil (CTL; ●) or after taking two 20-mL doses of CO alone (▵), C10 alone (□), medium-chain TGs (C8-C10; ★), or C8 alone (⋄).The open arrow indicates when the breakfast plus test oil was consumed; the solid arrow indicates when the test oil alone was consumed without an accompanying meal at midday. Data for metabolic study days on which CO+C8-C10 and CO+C8 were tested are not shown here for clarity, but their AUC data are shown in Figure 2. Values are means ± SEMs; n = 9/point. *Different from CTL, P < 0.05. AcAc, acetoacetate; CO, coconut oil; CTL, control; C8, tricaprylin; C10, tricaprin; β-HB, β-hydroxybutyrate.
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.
In summary, C8 was the most ketogenic MCT tested in this acute 8-h study and its ketogenic effect was significantly higher in the absence of an accompanying meal. Despite a low net ketogenic effect, CO may still be of interest because of its effect on plasma acetoacetate-to-β-HB ratio. With the help of positron emission tomographic imaging and the ketone tracer 11C-acetoacetate (2, 18, 20), it is now possible to investigate the impact on tissue ketone uptake of various ketogenic interventions.
Areas Under the Curve = AUC
Plasma concentration and summed means of 0- to 4-h and 4- to 8-h AUCs for plasma total ketones (i.e., AcAc and β-HB combined) (A) and for the mean AcAc-to-β-HB ratio (B). Bars represent no test oil consumed (CTL) or values after taking 2 doses of CO alone, C10 alone, medium-chain TGs (C8-C10), C8 alone, CO+C8-C10 (50:50), or CO+C8 (50:50). Values are means ± SEMs; n = 9. The AUC for 0–4 h was significantly different from the AUC for 4–8 h under all conditions. Labeled means without a common letter differ (a < b < c < d < e and A < B < C < D < E), P < 0.05. AcAc, acetoacetate; CO, coconut oil; CTL, control; C8, tricaprylin; C10, tricaprin; β-HB, β-hydroxybutyrate.
If we assume AcAc/BHB from C8 oil is 0.8 and that taking C8 without foode gives a total peak ketone (AcAc + BHB) of 0.5 mmol/L in blood. That implies we can approximate peak BHB as 0.28 mmol/L and peak AcAc as 0.22 mmol/L.
The jumbo dose of 23g of BHB produced peak BHB of 0.6 mmol/L in adults.
If the BHB level in blood is linearly related to the dose of BHB supplement, the we might assume that 15ml of Ketoforce produces 0.15 mmol/L (3.9*1.5/23*0.6).
If the Chinese are right that calcium BHB is not effective, then 15ml of Ketoforce likely produces a bit more than 0.15mmol/L., since it contains sodium BHB and potassium BHB.
So we might assume that my 20ml of C8 and 15ml of Ketoforce would producea peak BHB in the bloodstream of about 0.5 mmol in a 55kg boy and that slightly more is coming from the C8 than the BHB salt.
As you can see from the chart 0.5 is not very much and just at the lower edge of nutritional ketosis. With supplementation 0.5 is the peak level; it will rapidly fall back to the starting level.
So via supplementation we have a brief period of mild nutritional ketosis.
Anyone who has done their homework on Ketones will have come across Dominic D’Agostino.He is a researcher with a big interest in ketones. He has published interesting research and has his own blog on the subject.
I saw his advice that suggested starting with 10ml of C8 and 10ml of KetoForce.
The producer suggests 30ml a day of Ketoforce in adults.
10 ml of Ketoforce contains
·3.9 g of BHB
·533 mg of Potassium
·533 mg of Sodium
Even 500mg of potassium is going increase potassium levels in your blood.
If you happen to be taking bumetanide for autism, you will be losing potassium and likely taking a potassium supplement. Depending on your bumetanide dosage and potassium supplement, you may well be able to make some adjustments and cope with 10 ml of Ketoforce.
Speech and C8/Ketoforce Dosage
Our reader Agnieszka was very scientific and tried different BHB supplements and measuredBHB in urine. She found Ketoforce the most effective at producing BHB in urine; speech was one big area of improvement, but not the only one.
I took the advice of Dr D’Agostino, the ketone guru, and combined Ketoforce with C8 in my experiment.
Starting with 10ml of C8 and 10ml Ketoforce, it did produce a marginal change in Monty, but increasing to 20ml of C8 and 15ml of Ketoforce produced a clear increase in spontaneous speech.
Work in progress
Clearly this is a work in progress. Ideally I would want to get all the BHB from C8, since then I do not need to worry about sodium and potassium.
Ketoforce is pretty expensive in the US and very expensive in Europe. C8 is not cheap, but much more reasonable.
Other MCT oils and coconut oil may be cheaper, but are very much less potent, so C8 is the most cost effective MCT oil to produce the ketone BHB.
A naturopathic physician in the US, called Dr Bruce Fife, has written extensively about “reversing autism” with coconut oil; that kind of language will make many people wary. He does suggest the mode of action is calming microglia, which is something BHB should be doing. Regular coconut oil will produce BHB, but you would have to eat a great deal of it.Coconut oil it is not cheap and so it is more cost effective to use C8 oil. The effect of coconut oil (CO) was shown earlier on in this post, in the above line graph, where the triangle represents coconut oil.
Coconut oil, counter intuitively, actually lowers your blood cholesterol, so it actually is a healthy oil, but if it is the ketone BHB you are after, it does not look the best choice.
It is possible that coconut oil does something clever that is unrelated to BHB.
Underlying Mode of Action
By investigating all the modes of action of BHB, this may lead to a more effective therapy. BHB is a signalling molecule and if you know which of its many effects is the key one, you may find an alternative signalling molecule that gives a more potent result.
I have a good effect from C8/Ketoforce, but I would like more of the same; but without the full ketogenic diet and not causing a problem with excess sodium, potassium, calcium or magnesium. In the coming posts we will look into BHB's other modes of action. It will get quite interesting and we will see how one might even treat psoriasis and Multiple Sclerosis with BHB, because it is an activator of the niacin receptor HCA2. There is a potent HCA2 agonist drug, dimethyl fumarate.
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 transporterfound 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 carbohydratesin 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 insulin‑independent 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 GLUT3‑mediated glucose transport; instead, NMDA receptor‑mediated depolarization stimulates consumption of glucose, which prompts glucose uptake and utilization via GLUT3.
Although most glucose uptake in neurons occurs via GLUT3, insulin‑regulated GLUT4 is also co‑expressed 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 AKT‑dependent 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 T2DM‑associated cognitive impairment and brain neuroimaging findings are a consequence of brain insulin resistance or are due to other factors that co‑occur 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 insulin‑facilitated 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, insulin‑sensitizing 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, thiazolidinedione‑based nuclear peroxisome proliferator‑activated receptor‑γ (PPARγ) agonists, which were originally developed as insulin sensitizers for T2DM, have shown numerous beneficial neural effects in animal models of neuro‑ degenerative diseases
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.
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 isDr. 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.
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.
Source: https://vizhub.healthdata.org/gbd-compare/
