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Category: Mental health

Few people would argue that mental health is not important. Mental health can be subdivided to :

• Behavioral health (ie. Depression)

• Personality disorders (ie. Bipolar, Psychophrenia)

• Developmental disorders (ie. ADHD)

• Degenerative conditions (ie. Alzheimers, Parkinson’s Disease)

A lot of us identify who we are with our brain’s functions. Mental health was the reason I started studying Nutritional Therapy as someone close to me had such challenges.

Articles in this category:

What is the selfish brain theory?

The link between Type 2 Diabetes & Alzheimers Disease

 

Ice baths

Cold exposure : 3 benefits

The popularity of cold exposure has increased since 2017 in continental Europe, US & Australia through the work of Wim Hof. Whether it is through cryotherapy or cold water immersion more and more people practice and hashtag: #coldexposure. Cold therapy has its roots back in South East Asian yogic traditions and Eastern European-Scandinavian cultures. In this article I will cover 3 benefits training with cold has for those of us living a modern lifestyle.

 

How old is cold therapy?

The moment you ask this question you realise that cold has been accompanying humans from the very start of our existence. As temperatures in nature constantly fluctuate, humans have been exposed to cold : voluntarily or not for a long time.

 

As from a therapy stand point, cold exposure is listed in “The Edwin Smith Papyrus” dated 3,500 BC (Wang H et al., 2006). In certain parts of the globe (ie. Russia, Bulgaria, Scandinavian countries) cold training has been part of the culture, practiced in banya or plunge pools, as well as a standard procedure in hospitals to prevent further damage in patients with cardiovascular (Ref) and neurological conditions (Ref).

 

In recent years Wim Hof (a dutchman Guinness record holder) popularised cold training through his workshops across the globe. It was my training with Wim in 2016 that initiated my journey in cold exposure.

 

1. Cold exposure improves Circulation & Cardiovascular Function

Think of cold exposure as a workout for the circulatory system.

Most people think of cardio when it comes to improving their cardiovascular function. Cold exposure though offers a unique way to strengthen one’s cardiovascular system (cvs).

Our cardiovascular system is surrounded by epithelial muscles which facilitate the circulation of the blood. At low temperatures the epithelial muscles surrounding the veins and arteries of our extremities constrict – preserving the blood and the nutrients carried in it for the more vital organs in the trunk and the head. When the body returns to higher temperatures the epithelial muscles in our extremities dilate again allowing for the blood to flow freely there. In a similar way that our biceps get stronger as they contract during bicep curls (or chaturangas) our cardiovascular system can get stronger through cold exposure.

 

 

Good circulation means no athletes foot, no cold extremities, better cognitive function, ability to heal/recover faster and perform better in sports.

 

2. Cold exposure as a meditation technique

Those that practice cold water immersions for some time report a sensation of stillness in mind (usually 30 seconds to a minute after the initial exposure). A friend of mine Luke Wills (founder of the Optimal Health Method) said he reached a similar state of mind in his 2nd ice bath, with that on the 7th day of a vipassana meditation retreat. Anecdotal evidence like this were confirmed to be valid in a study published in May 2018 titled “Brain over Body“.  In this study participants with no previous experience in cold exposure and Wim Hof, were interchangeably exposed to cold and neutral temperatures. One of the most striking differences between the inexperienced subjects and Wim was the Dutchman’s ability to reduce activity in the insular cortex part of the brain during cold exposure. Insular cortex is an area involved in emotional attachment to external stimuli and self-reflection. Activity in this part of the brain has been shown to be linked with meditation and control in emotional eating.

 

Meditation is the 5th of the 8 limbs of yoga. Cold exposure is one of the many ways to enter into a state of meditation.

 

3. Cold exposure helps overcome fears

Cold exposure is demanding on many levels:

• the adrenal glands

• musculoskeletal system

• circulation and

• the brown fat tissue are activated at low temperatures.

Aside though the multiple biochemical adaptations in the rest of the body:

our brain also changes when we are exposed to cold.

The initial response is that of: “fight or flight”. A small area of the brain called amygdala (Greek word for almond) – activates the HPA (Hypothalamic Pituitary Adrenal) axis – signalling a stress response to the rest of the body. While this initial stage is universal the way one deals with cold thereafter depends on his/her experience and ability to use her breath.

By training the body to deal with a stressful situation (ie. a cold immersion) in a controlled environment (such as a shower or a bath) we can reprogram our mind to deal with stressful situations which are out of our control. Our main tool is our breath. Dealing with fear was the focus of a workshop I gave in 2017 to a group of actors.

 

 

Conclusion

The list above is not exhaustive of the benefits one can get from cold exposure :

• Controlling pain perception [Ref]

• Generation of Brown Fat [Ref]

• Strengthening of the immune system [Ref] • Improved tolerance to cold [Ref]

are also good reasons for modern “over-civilised” humans to train with cold.

 

 


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How to test for Celiac Disease?

The only way you can get a definite YES or a NO for Celiac Disease (CD) is by doing an intestinal biopsy. As this is an invasive and expensive procedure, many prefer measuring serum antibodies as an initial screening process. When someone decides to test for antibodies against gluten it is necessary to keep in mind:

a) that the gluten protein is fairly complex and thus all antibodies need to be tested

b) that the blood test is not a substitute for the biopsy.

Whichever assessment method one decides to use it is important to know that:

For CD, early diagnosis means early intervention with treatment and prevention of long-term complications, including the development of severe and irreversible phenotypes and of other autoimmune disorders.” (Ventura A et al., 2010)

 

Intestinal biopsy is the golden standard for diagnosing Celiac Disease.

 

An individual is classified as celiac when a biopsy of the duodenal mucosa is taken which detects:

a) a reduction or disappearance of intestinal villi &

b) intraepithelial lymphocytes (IELs) higher than 25/100 enterocytes (Sapone A. et al., 2012).

Individuals presenting with significant villous atrophy are classified as CD March stage III, whereas normal villi but increased number of intraepithelial lymphocytes are classified as Marsh I or II (Hill ID et al., 2005). Marsh type II may also suffer from CD but positive serological tests is needed to strengthen the diagnosis (Hill ID et al., 2005). When only elevated IELs are observed but no damage of the intestinal lining, it is difficult to diagnose CD (Kakar eta l., 200). In literature this state is usually referred to as latent CD (Dewar et al., 2005) and further testing is required.

 

Can elevated IELs be due to a different cause other than Celiac Disease?

The presence of IELs can be due to gastrointestinal inflammation caused by H. pylori (Memeo et al., 2005) or tropical sprue (Ross et al., 1981). Unexplained neurological or psychiatric disorders such as autism, schizophrenia, and cerebellar ataxia (Cascella N et al., 2009, Burk K et al., 2009, Genuis S and Bouchard T, 2010) are also linked with elevated IELs and no mucosal damage.

 

Can a blood test confirm Celiac Disease?

No. However, a lot of the time serum antibody testing is used in the screening process. The ones necessary are: anti-DGP IgG & anti-tTG IgA

 

Antibodies for the diagnosis of Celiac Disease

Antibodies

Accurate

Not affected by IgA deficiency

Not prone to interpretation

Cheap

Appropriate for children <2 years old

AGA IgA

AGA IgG

EMA IgA

tTG IgA

DGP IgG

Anti-Actin IgA

 

 

classic Anti-gliadin (AGA) antibody IgA

Pros:

1. relatively cheap

Cons:

1. found in healthy individuals (Bizzaro N et al., 2012)

2. May fluctuate within the first 2 years of age (Simell et al., 2007)

3. relatively insensitive (Fasano A, 2013)

 

AGA-IgG

Pros:

1. useful for pediatric patients with CD who test negative for anti-tTG (Carlsson A et al. 2001, Lagerqvist C et al., 2008).

2. useful in patients with IgA deficiency (Villalta D et al., 2007).

3. reasonably cheap

3. Same results where obtained with the DGP IgG test (Liu E et al., 2007, Agardh D 2007, Basso D et al., 2009, Naiyer A et al., 2009).

4. Remains constant the first 2 years of age (Simell et al., 2007)

Cons:

1. relatively insensitive (Fasano A, 2013)

 

EmA (Endomysial Antibodies – antigliadin) IgA (unless IgG requested)

Pros:

1. It is equally specific with the anti-tTG antibodies, meaning it recognizes the same antigens (Hill 2005)

Cons:

1. It is prone to subjective interpretation

2. It is less sensitive than the anti-tTG (Biagi F et al., 2001, Baudon J et al., 2004, Lock et al., 2004, Kaukinen K et al., 2007).

3. Not accurate in patients with selective IgA deficiency.

4. May fluctuate within the first 2 years of age (Simell et al., 2007)

5 *The IgG version has inferior sensitivity (Fasano A, 2013)

 

anti-tTG (antihuman tissue transglutaminase) IgA (unless IgG requested)

Pros:

1. As it is quantitative, automated and not prone to subjective interpretation

2. high diagnostic sensitivity (95%) specificity (97%) (Tozzoli et al., 2010)

Cons:

1. Anti-tTG IgA is not sensitive enough to be used alone and the addition of the anti-DGP IgG test would increase the accuracy for CD especially in children (Niveloni S et al., 2007, Villalta D et al., 2007, Volta U et al., 2010, Tonutti E et al., 2009, Villalta et al., 2010, Maglio M et al., 2010)

2. May fluctuate within the first 2 years of age (Simell et al., 2007)

3 *The IgG version has inferior sensitivity (Fasano A, 2013)

 

DGP antibodies IgG (deamidated gliadin peptide)

Pros:

1. antibodies comparable sensitivity and specificity to anti-tTG and EMA (Sugai E et al., 2006)

2. Remains constant the first 2 years of age (Simell et al., 2007)

3. DGP IgG test positive in 80% of cases of CD patients with IgA deficiency as compared to 40% for AGA IgG ( Villalta et al., 2010)

 

ANTI-ACTIN IgA

Pros: can evaluate the severity as it is related to the severity of intestinal damage (Granito A et al., 2004, Carroccio A et al., 2005)

Cons: limited usefulness for diagnosis

 

In monitoring of patients on a gluten-free diet, positivity with a low titer of anti-DGP antibodies suggests that the diet should be reassessed, even if the anti-tTG test is negative” (Tursi et al., 2006)

 

Interpretation of serological and biopsy test results

Biopsy

+

Serology

+

CD

Absence of CD and possible false-positive blood test. A negative genetic test can strengthen the negative diagnosis.

This result is treated as CD. However, inflammation in the lining can be due to other causes, including intolerances to other foods.

No CD. However, in the presence of other autoimmune conditions or genetic predisposition, future monitoring may be appropriate.

 

Which other blood biomarkers are available?

While the tests above are the ones most commonly done there is evidence that more thorough testing may be needed for those with negative results and positive symptoms. A complete antibody screening should include: Alpha gliadin, Omega gliadin, Gamma gliadin, Deamidated gliadin, TG2, TG3, TG6.

 

Deamidation is an acid or enzymatic treatment used by the food processing industry to make wheat, water-soluble so it mixes with other foods. It has been shown to cause severe immune responses to people (Leduc V et al., 2003).

Gliadin is broken down to alpha, omega and gamma fractions. If a lab tests only for alpha gliadin antibodies the results may be misleading (Quartesn H et al. 2001).

Elevated antibodies of TG2 indicated a reaction against the intestinal track (Thomas H et al., 2011). Transglutaminase 3 (TG3) is found in the skin. An autoimmune reaction to skin may lead to skin disorder known as dermatitis herpetidormis, which presents as itchy red blisters found usually in the knees, elbows, buttocks but can appear anywhere on the body (Stamnaes I et al., 2010). Elevated antibodies to transglutaminase 6 indicate an immune response against the nervous system (Alessio et al., 2012).

How to detect vitamin B12 deficiency?

Vitamin B12 is common and unfortunately one cannot rely on serum vitamin B12 to detect a deficiency. Vitamin B12 is carried in the blood by either of 2 proteins: haptocorrin and holotranscobalamin. While the majority of vitamin B12 is carried by haptocorrin, this vitamin B12 is considered inactive* [1]. A serum vitamin B12 test cannot differentiate between the active and inactive form and as a result while the level may appear healthy, the active form of vitamin B12 may be significantly low.

 

WHICH TEST IS BEST TO IDENTIFY VITAMIN B12 DEFICIENCY?

The most direct way to detect vitamin B12 deficiency is to measure your active form of B12: holotranscobalamin. Biolab in UK offers that test.

If that test is not available to you, your 2nd best option is to measure your homocysteine levels. Homocysteine is a protein humans synthesize in their body and it’s considered one of the most significant biomarkers of cardiovascular health. Its production relies on the availability of vitamin B12, folate & protein.

detect vitamin B12 deficiency

source: PMID 16702348 [4]

As multiple other factors though affect the levels of Homocysteine, one cannot drive conclusive results for her vitamin B12 just knowing her homocysteine level.

detect vitamin B12 deficiency detect vitamin B12 deficiency detect vitamin B12 deficiency detect vitamin B12 deficiency

 

 

Which symptoms indicate vitamin B12 deficiency?

Vitamin B12 plays a critical role in the methylation cycle [3] (which consists of the folate & methionine cycle). As a result, any problems associated with methylation may be driven due to:

  1. low vitamin B12 intake (important for vegans and vegetarians)
  2. poor absorption (relevant for those with poor gastrointestinal function) [2] or
  3. compromised metabolism (possibly due to MTR & MTRR polymorphisms)

 

 

* due to the fact that haptocorrin receptors are found mainly in the liver.

 

References

  1. Morkbak, A.L., Poulsen, S.S. and Nexo, E., 2007. Haptocorrin in humans. Clinical Chemical Laboratory Medicine, 45(12), pp.1751-1759.
  2. Schjønsby, H., 1989. Vitamin B12 absorption and malabsorption. Gut, 30(12), p.1686.
  3. Miller, A., Korem, M., Almog, R. and Galboiz, Y., 2005. Vitamin B12, demyelination, remyelination and repair in multiple sclerosis. Journal of the neurological sciences, 233(1), pp.93-97.
  4. Refsum, H., Nurk, E., Smith, A.D., Ueland, P.M., Gjesdal, C.G., Bjelland, I., Tverdal, A., Tell, G.S., Nygård, O. and Vollset, S.E., 2006. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. The Journal of nutrition, 136(6), pp.1731S-1740S.

Fasting Diet: progressions

 

Updated: 26 Sep 2018

 

This article is written with deep respect in the process of fasting and consciousness that its epigenetic effects are far reaching. Fasting in my opinion is something we all need to be comfortable with. There are many disputes on what the healthiest diet is, with advocates of the different diets often trying to support their view using ethnological and ancestral data. It is clear though to everyone that our ancestors had to survive periods of fasting independent of their diet (whether the famine was caused due to lack of game or a disaster in the crops).

My Journey with the Fasting Diet

I have been following a Fasting Diet on and off since September 2009. In my first attempt to fast (after reading my first book on nutrition called: Food Governs your Destiny) I set x3 2hour slots in the day during which I allowed myself to eat. Outside these windows I would consume only liquids. I stayed on the diet for 6 months, during which I:

?? reduced my waist circumference from 34 to 29 inches.

?? lost 7.5 kilos.

?? achieved mental clarity I have never experienced before.

During a big part of these 6 months I was vegetarian.

In 2016 I decided that as a way of monitoring my metabolism I would like to measure the production of ketones in my body. Between October 2016 and February 2017 I monitored my Blood Glucose (BG) and Ketone Bodies (KB) – beta-hydroxybutyric acid on a daily basis. Monitoring can be useful:

?? as feedback for one’s response to food / exercise.

?? for compliance when BG & KB targets are set.

During this period there were weeks of following a vegetarian diet but most days I consumed meat.

Fast Diet: Progressions

Bellow I share what I consider to be a natural progression of fasting. Of course everyone’s starting point is different: not everyone starts with a: 3 meals and 2 snacks diet and neither do we all have the same tolerance to the changes each step requires. I imagine you have not been eating the same way all your life, after all. If you are not sure how quickly you should progress from one stage to the next I suggest you err on the safe side. Most people will find progressions comfortable if they spend 1-2 months on each stage. Those with a healthy relationship to food will evolve our fasting practice over our lifespan.

⏱ Time restrict your eating

I consider the 16-8h type-diet to be an easy one for most people to adopt. During this diet you restrict your caloric intake over an 8 hour window. The remaining 16 hours one is allowed to have non-caloric drinks such as water, coffee and tea. The easiest way to get into it, is to prolong the overnight fast. Assuming one sleeps for 8 hours and stops eating 4 hours prior to going to bed, she / he can achieve the 16/8h fast by eating 4 hours after waking up. If the idea still feels daunting here are a few tips to ease your way into it:

?? Start with a 12-12h diet and gradually increase the fasting window. The danger here is not to be consistent. Decide which window schedule suits you and stick to it for at least 1 week before increasing the fasting phase.

?? Take days off if you find the idea of doing it daily suffocating. However have the days scheduled before hand and do not change them. You know you are ready to proceed when you have completed 4 consecutive weeks with 5 days per week on your “Time Restricted Eating” schedule.

🌞 Eat while the sun is up

While I acknowledge that many people working in offices have more physically active evenings than mornings; the body’s biological clock will not flip upside down because you signed up at the 20:30 CrossFit class. Neither your sleeping time can accommodate all the digestion you wish just because your gym class finishes at 22:00. As a next step to a “Time Restricted Eating” I consider to be the swift of the eating window earlier in the day. How early is early? – you decide. My suggestion is to finish eating prior to the sunset and ideally by midday. As you can see in the infographic from a 2018 paper [1], time restricting food to the earlier part of the day causes an number of beneficial effects:

Actions that helped me with this transition:

?? Exercise earlier in the day.

?? Make sure the quality of my sleep is not compromised. Supplements as well as breathing practices can support a good night sleep. Initially prolonged fasts can lead to elevated cortisol levels which will mess up with sleep. Poor sleep leads to tiredness and erratic appetite the next day.

⏰ Set your eating times

That stage could also be called: Stop snaking. Most of us (living a western lifestyle) have constant access to food and numerous stressors during our day. The combination of the two in many cases lead to binging / snaking. Whether you call it comfort food or not, every extra meal (and by meal let’s call anything containing more than 20 calories) requires the activation of the pancreas and the subsequent release of insulin. Insulin is a hormone with multiple roles in our biochemistry other than food metabolism. With that in mind I don’t find strange that hormonal imbalances are common in those with erratic eating patterns.

If one attempts to “Set her Eating Times” while she is eating during daytime only, I expect this transition not to be a big challenge. On the other hand shifting from a 16-8h fast to a “Set Eating Times” schedule can be a bigger step.

Setting the times when someone eats is a personal issue and can be scheduled around her lifestyle. My suggestion is to schedule no more than 3 meals a day and if for whatever reason a meal is lost not to be replaced.

☝ Eat once a day

If you have been following the progression described above I would be surprised if you are eating more than twice a day by now. Eating once can be something you want to try occasionally based on your energy expenditure & mood.

😶 Eat only when hungry & as much as you need

Even when I eat once a day I sometimes find hard not to overeat. I consider our relationship with food complex and the addictive aspect of it multidimensional. We can be addicted to:

?? certain foods.

?? the sensation of fullness.

Whatever the addiction is it will always manifest to emotions which make it hard to break loose off. To that extent I would like to clarify that:

“I consider eating one of the big joys of life & fasting can only enhance this sensation.”

Fasting works as a challenge for the body. This doesn’t mean it makes it makes the body weaker. In the same way that you would not assume a runner to be doing harm to her body just because her legs are weak at the end of a training session, don’t be afraid of fasting.

Fast Diet: Considerations

Most people when they consider fasting, they are worried about their energy levels and muscle mass maintenance. The energy levels may fluctuate initially: that is due not to lack of energy but to poor hormone regulation. Even if you have 9% of body fat, there is enough energy stored in your body to keep you alive for days. Fluctuations in energy levels can be caused because your metabolism has no access to your fat. If you are concerned with maintaining muscle mass I suggest you keep your protein intake high when you eat (~x1.6 gr of protein per body weight in kg)

Those that depend on constant energy supply (ie. 3 meals a day + 2 snacks) are the ones that would benefit the most from fasting.

4 Things to consider

1 Always keep your (AME) Appetite, Mood and Energy levels in check. If one of them is not under control adjustments may be necessary. In most cases soon after one gets out of control the other 2 follow.

2 Our life changes constantly and so will our mood, circadian cycle, appetite, needs for nutrients etc. I hope this article works as a road map not an itinerary.

3 Food composition can affect your Blood Glucose and consequently your fasting phases. Fibre, fat, protein can slow down your meals’ metabolism which is necessary initially.

4 Metabolism is complex and its efficiency depends on many factors including oxygen availability & insulin sensitivity. Practicing yoga, breathing exercise and cold exposure can be very useful for improving metabolic efficiency and supporting a fasting practice.

Things to consume while fasting

In order to maintain the calories low during fasting my suggestion is to limit your liquid intake to coffee & teas. If stimulants play havoc in your metabolism & appetite you should avoid caffeinated drinks altogether. I have been consuming them freely. Two things that can help a lot in extending your fasting periods are:
1 Water – in particular carbonated. I think it is easier if one takes sips during the day aiming for 1-3 litters as opposed to drinking 3 glasses when filling peckish.

2 Magnesium Citrate powder (I like the one from Designers for Health). Its sweet taste can help deal with a sweet tooth while the Magnesium supports the adrenals & promotes gut mobility.

?? Brushing teeth after eating. Making sure mouth hygiene is in check can help in 2 ways: 1. some associate a clean mouth with the end of eating 2. food leftovers will stop triggering taste buds receptors.

 

References:

1. Sutton, E. F., Beyl, R., Early, K. S., Cefalu, W. T., Ravussin, E., & Peterson, C. M. (2018). Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metabolism.

What is the Selfish Brain Theory?

According to the Selfish Brain theory our brain has a series of (hierarchically ordered) mechanisms in place to maintain constant supply of energy at a certain concentration.

Despite weighing only ~2% of body weight, the brain consumes a disproportionate high amount of energy: ~20%. Knowing that, it should come as no surprise that many physical symptoms linked with poor metabolism (incl. muscular fatigue, obesity, taxed liver function possibly due to alcoholism) are linked with compromised brain function (i.e. migraines, forgetfulness, irritability).

The Selfish Brain theory was put forward by scientists at the University of Luebeck in Germany in 2004 and is likely to bring a swift in the way we understand and treat metabolic & personality disorders in the future. [ The theory has its roots in some earlier research in 1997 on addiction (DuPont RL 1997) ]

In clinical practice I consider 3 qualitative markers as a sign of good health: Energy, Mood & Appetite (EMA). When all 3 in are balanced the body is 95% of the time thriving. The Selfish Brain theory offers a “simple” model of their intimate relationship.

1. The brain’s unique role in energy management

How the human body manages energy supply to different organs is key for treating chronic illness including obesity, PCOS, cardiovascular disease & cancer. Energy metabolism is dependent on:
i. energy supply
ii. energy allocation

The brain plays a key role in this process. What gives the brain a unique role in the body’s metabolism?

i. It carries important functions for the rest of the body.
Together with the heart the brain is responsible for processes that run on an ongoing basis. The shortage of energy supply to these 2 organs can be life-threatening.

ii. It consumes a lot of energy.
Despite its small weight (~2% of total body weight), it consumes a disproportionately high amount of energy ~20%, partly due to the energy needs of neurotransmitter transmission (Attwell D and Laughlin S 2001).

iii. It has low energy storage capacity.
In contrast to most other organs it depends almost entirely on glucose for energy but has limited capacity to store glucose. The liver and (to a lesser extent) the muscles are the body’s main glucose reserves (in the form of glycogen).

iv. It’s access to the blood supply is controlled.
The brain comes in contact with the blood (cardiovascular system) in 2 areas only: the Blood Brain Barrier (BBB) where astrocytes (neuron cells) serve as a filter wall and the Hypothalamus. Due to the high amounts of toxins and pathogens circulating in the blood there may be an evolutionary benefit in this physical protection of the brain.

v. It is able to monitor other organs and affect their function.
Through the Peripheral Nervous System (PNS) the brain is able to record information from other organs as well as control their function.

Accounting for the above idiosyncratic functions, the Selfish Brain theory suggests that the brain:

i. Prioritizes its own energy supply before other organs by using the stress system when there is an energy deficit (Allocation)

ii. It subsequently alters appetite to alleviate stress and return to balance (Appetite -> Food intake)

The model has the shape of a fishbone to illustrate the hierarchically structure of the pathway.

2. How does the brain sense if it has enough energy?

Cells in the brain as well as skeletal muscles (Lazdunski M. 1994) sense the levels of energy intracellularly through: ATP-sensitive potassium (Katp) channels. ATP & ADP (the body’s energy currencies) bind on these channels and this way signal availability or lack of energy. In an excitatory neutron adequate levels of ATP (by binding on Katp channels) will trigger the release of glutamate or brain-derived neurotrophic factor (BDNF) while elevated ADP will silence it.

A key feature of the Selfish Brain theory is that the brain has 2 types of Katp channels: high & low affinity. When a cell has relatively low ATP concentrations, high affinity Katp channels are still occupied. On the other hand low affinity Katp channels require high ATP concentration to get occupied. The high affinity Katp channels are found mostly in excitatory neurones (releasing glutamate & Brain-Derived Neurotrophic Factor (BDNF)) while low affinity ones are in inhibitory neurones (releasing γ-amino-butyric acid / GABA) (Ohno-Shosaku T et al., 1993). Both types of are found in the human neocortex (Jiang C et al., 1997).

With low ATP concentrations the glutamateric neurones are dominantly active while at high ATP concentrations the GABA-eric neurones predominate.

It is worth mentioning that at critically reduced ATP both excitatory & inhibitory neurones are inactive – a phenomenon referred to as “global silencing” (Mobbs CV et al., 2001).

3. How does the brain maintain a constant energy level?

The brain according to the Selfish Brain theory has 2 ways to maintain a set energy level. One via moderating the allocation on the currently available energy from the peripheral tissue to itself and a 2nd by demanding more energy from the environment by controlling eating behaviour.

3.1 Brain’s “energy on demand”

In order for the brain to access glucose (energy) available in the blood it needs to “open” the blood-brain barrier (BBB). Glutamate activates the glucose receptors (GLUT1 in the astrocytes) of the BBB and sequentially the glucose enters the brain (Magistretti PJ et al., 1999). GABA on the other hand does not have the same impact in the BBB (Chatton JY et al., 2003).

Glutamate* was also shown to activate the limbic-hypothalamic-pituitary-adrenal (LHPA) axis (Yousef KA et al., 1994). LHPA axis is commonly referred to as the stress or the flight or flight response. By activating the LHPA axis glutamate is able to restrict glucose supply to other organs and preserve it for the brain. The steps are as follows:

Glutamate signals the limbic system that the body is in a stressful state. The limbic system stimulates the sympathetic nervous system (NS) through the Ventromedial part of the Hypothalamus (VMH) resulting in the release of CRH & vasopressin hormones. In this way it tells the pituitary to release ACTH hormone. ACTH is released in the blood and stimulates the production of cortisol from the adrenals. Cortisol finally inhibits the production of insulin from pancreatic β cells and thus the uptake of glucose for certain organs making it available for the brain (Jansen AS et al., 1997). In the Selfish Brain model the allocation of energy takes place in the VMH.

In a state of high energy GABA (a calming neurotransmitter) is also released counteracting glutamate’s excitatory effects. The sympathetic system is not activated and the junctions in the BBB remain tightly closed.

In summary the brain can moderate the allocation on the currently available energy from the peripheral tissue to itself as follows:

When there is low energy in brain, glutamate is released in relatively higher levels than GABA causing 2 effects:
1. the BBB opes and increases the intake of glucose from the blood stream to the brain
2. the Limbic Hypothalamic Pituitary Adrenal (LHPA) axis is activated restricting the supply of glucose in peripheral tissue.

3.2 Requesting energy from the environment

Lateral Hypothalamus (LH) is a key area of the brain where appetite is controlled (Anand BK, Brobeck JR. 1951), although not the only one. Glutamate can stimulate the LH to increase appetite [13]. With the increase of food intake, energy from the environment is enters the body (Stanley BG et al., 1993)

According to the Selfish Brain theory the Neocortex acts at the primary regulatory system for energy and the LHPA axis functions as a secondary. xxx Many more hormones (i.e. Leptin hormone signals the hypothalamus that energy has been stored in the fat tissue (Spanswick D et al., 1997)) can be added to the graph without affecting its hierarchy.

The Selfish Brain theory demonstrates how the brain manipulates the stress response mechanism to moderate energy supply. That’s worth keeping in mind when dealing with mental or eating disorders.

 

 

 

* in particular through glutamate receptors of N-methyl-D-aspartate (NMDA) subtype (Molina PE, Abumrad NN 2001).

 

 

 

References

Anand BK, Brobeck JR. Hypothalamic control of food intake in rats and cats. Yale J Biol Med 1951;24:123–46.

Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab. 2001;21:1133-45.

Chatton JY, Pellerin L, Magistretti PJ. GABA uptake into astrocytes is not associated with significant metabolic cost: Implications for brain imaging of inhibitory transmission. Proc Natl Acad Sci USA 2003;12456–61.

DuPont RL. The selfish brain: learning from addiction. Center City, Minnesota: Hazelden; 1997.

Jansen AS, Hoffman JL, Loewy AD. CNS sites involved in sympathetic and parasympathetic control of the pancreas: a viral tracing study. Brain Res 1997;766(1–2):29–38.

Jiang C, Haddad GG. Modulation of K . channels by intracellular ATP in human neocortical neurons. J Neurophysiol 1997;77(1): 93–102.

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Type 2 Diabetes & Alzheimer's

The link between type 2 diabetes and Alzheimers Disease

THE LINK BETWEEN TYPE 2 DIABETES AND ALZHEIMERS DISEASE

The 1st case of Alzheimer’s Disease (AD) was reported in 1906 in Germany [53]. According to Alzheimer’s Association (www.alz.org) as of Oct 2016 there are more than 5 mil. Americans living with AD while in 2017 it is estimated to cost US $274 billion.

Over the last decade there has been a lot of research associating the development of Alzheimer’s Disease with Type 2 Diabetes.

There are 2 ways in which T2D influences the risk of AD:

1. by contributing to small vessel disease. T2D can disrupt the healthy function of brain vasculature and lead to dementia and AD [47]

2. by interacting with key proteins & pathways (such as Aβ and tau), T2D influences the development of AD.

In this article I will discuss the 2nd link.

 

 

1. THE HALLMARKS OF T2D AND AD

Alzheimer’s Disease (AD) is a neurodegenerative disease characterised by selective neuronal cell death. Two hallmarks of AD are:

– the intracellular neurofibrillary tangles (NFTs)

– extracellular amyloid deposits forming senile plaques.

The accumulation of neurotoxin amyloid β peptide (Aβ) in the hippocampus and cerebral cortex appears to be a major pathological step in the progression of AD [1, 10]. Based on the tau hypothesis excess phosphorylation of tau proteins result in the transformation of normal tau proteins to NFTs.

ad1

Diabetes mellitus is a metabolic disorder characterised by hyperglycaemia. In type 2 diabetes (T2D) the main effect is insulin resistance causing relative insulin deficiency. Pancreatic β-cells co-secrete insulin and amylin (also known as islet amyloid polypeptide IAPP). One of the hallmarks of T2D is:

– β-cell loss [11] due to amyloid deposits (composed primarily of amylin) [2].

Similar with AD in T2D degeneration of pancreatic islets has been associated with NFTs formation [12].

ad2

 

2. INSULIN’S IMPLICATIONS IN Aβ BREAKDOWN

Both Aβ peptide and insulin are amyloidogenic peptides sharing a common sequence recognition motif. Together with other amyloidogenic proteins (i.e. glucagon and amylin) they are degraded by Insulin Degrading Enzyme (IDE)* [3, 13]. IDE highest expression is in the liver, testes, muscles and brain [4]. Aβ is also broken down through Neprilysin (NEP) [5].

Both Aβ peptide and insulin compete with each other not only for their degeneration through IDE but also for binding to insulin receptors [6].

Insulin plays a key role in the healthy metabolism of Aβ peptides. It up regulates the transport of AβPP/Aβ from trans-Golgi to cellular membrane [13] promoting the transport of Aβ outside the cell [13] and has been shown through different mechanisms to contribute to the increase of extracellular Aβ levels and decrease of intracellular Aβ levels [13].

As I will discuss later insulin seems to counteract many of the toxic effects of Aβ in the mitochondria.

ad3

In the only study so far that measured insulin levels in the brain** it was shown that insulin reduces with age in both healthy subjects and patients with AD [8] indicating that low brain insulin is not a direct cause of AD pathology. On the other hand though there is consistency in the findings of insulin resistance in AD patients [49].

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The following mechanism has been speculated to contribute to that:

1. IDE expression decreases with aging [7] reducing the breakdown capacity of Aβ peptides; leading to higher intracellular Aβ levels.

2. Sequentially the relatively higher levels of Aβ 1-40 & Aβ 1-42 peptides by binding on insulin receptors reduce insulin’s binding capacity and promote insulin resistance [5].

The fact that insulin resistance is not specific to insulin in AD brain is supported by the fact that both insulin-like growth factor (IGF) I & II (50,51) and lectin (52) are reported to be lower.

Type 2 Diabetes & Alzheimer's

 

3. OTHER LINKS THROUGH WHICH INSULIN RESISTANCE CAN CONTRIBUTE TO ALZHEIMER’S

Insulin also regulates the phosphorylation of tau proteins with insulin resistance been shown to cause [14] tau hyper-phosphorylation [15] and the formation of NFTs.

Type 2 Diabetes & Alzheimer's

 

4. HYPOMETABOLISM OF GLUCOSE (IN CEREBRAL CORTEX)

In areas of the brain with high glucose demand and insulin resistance, AD patients have been shown to have compromised glucose metabolism [16]. 44% reduction in cerebral glucose metabolism has been reported in the early onset of AD [5].

Hypo metabolism of glucose leads to:

A. the inhibition of glutamine synthase, creatine kinase, aconitase, pyruvate dehydrogenase & α-ketoglutarate dehydrogenase [17,18,19] Sequentially the lower levels of pyruvate dehydrogenase lead to lower levels of acetyl-CoA, the compromised production of acetylcholine [20] and the decreased formation of intracellular cholesterol [21] (which is necessary for normal cell function).

B. reduced ATP production. In sporadic AD patients*** there is a 50% ATP decrease at the beginning of the disease [22]. Reduced ATP production leads to the activation of erk36 & erk40 [23] and subsequently tau hyperphosphorylation [24].

Glucose hypometabolism of early-onset AD was shown to be much more severe than in late-onset patients [25].

Type 2 Diabetes & Alzheimer's

 

5. IMPAIRED DETOXIFICATION & COMPROMISED Ca2+ BUFFERING (MITOCHONDRIA)

Aβ42 protein was shown to inhibit cytochrome oxidase in human mitochondria in a dose depended manner [26]. The effect was dependent on the presence of Cu2+. Studies in cybrid cells demonstrated a deficit of cytochrome oxidase in AD platelets as well as impaired intracellular calcium buffering and elevated basal cytosolic calcium concentration in AD [27,28]

Mitochondria serve as a high capacity Ca2+ sinks, supporting cellular Ca2+ homeostasis [33]. Excess Ca2+ uptake in the mitochondria has been shown to [34, 35, 36]:

1. Increase ROS production

2. inhibit ATP synthesis

3. release cytochrome c

4. induce mitochondrial permeability transition (MPT)****

Type 2 Diabetes & Alzheimer's

The maintenance of Ca2+ homeostasis represents a major expenditure within neutrons [40]. In high oxidative stress there is an increase in cytoplasmatic Ca2+ [37].  MTP is enhanced by increased Ca2+, oxidative stress, and low membrane potential, while Mg2+, ADP, high membrane potential [38, 39], CoQ10, vitamin E, reduced glutathione, melatonin and nicotine oppose that effect [41, 42].

Diabetes decreases the capacity of mitochondria to accumulate Ca2+ thus leading to MPT opening [31, 32]

Type 2 Diabetes & Alzheimer's

 

6. INSULIN’S PROTECTIVE MECHANISM IN THE PRESENCE OF Aβ (MITOCHONDRIA)

Insulin has been shown to support mitochondrial function in skeletal muscles [43]. It seems to impact the function of neuronal mitochondria in multiple ways [40]:

1. prevents the depolarization of mitochondrial inner membrane [44]

2. increases CoQ9 antioxidant  [44]

3. modulates glutathione redox cycle [127]

4. increases the capacity of mitochondria to accumulate Ca2+ [40]

5. promotes clearance of Aβ [13]

Type 2 Diabetes & Alzheimer's

“ Although insulin does not affect basal mitochondria function, in the presence of Aβ  insulin prevents a drastic decline in mitochondrial OXPHOS efficiency and avoids an increase in the oxidative stress, improving and/or preserving the function of neurons under adverse conditions.” [40]

 

7. CONCLUSION

While genetics indisputably play a role in the development of AD; with 50% of patients being carriers of the APOE4 gene [1], there is enough research showing the link between T2D and AD. Non-APOE4 carriers have 535% (1.4 -> 7.5%) more chances of developing AD if their fasting blood insulin is > 89.4 pmol/l [54, 55].

The relationship between T2D and AD is intricate though if you consider the following:

1. One of the hallmarks of T2D is insulin resistance causing elevated insulin levels.

2. One of the hallmarks of AD is elevated Αβ peptides.

3. Insulin counteracts many of the toxic effects of the Aβ peptides in the brain of patients with AD.

3. Aβ peptides appear to contribute to the development of insulin resistance independent of insulin’s action, by binding on insulin receptors.

AD -> high Aβ peptides -> Insulin Resistance / T2D -> elevated insulin -> Protect from Aβ toxicity

Could T2D be a defense mechanism against the brain’s degeneration in AD?

Type 2 Diabetes & Alzheimer's

 

* IDE is a zinc-metallopeptidase. It is also known as insulysin.

** It is not clear if insulin is produced in the brain or transferred there through the bloodstream [48]

*** Sporadic AD are the patients without a genetic predisposition to develop AD

**** The mitochondrial permeability transition (MPT) is the sudden increase of inner mitochondrial membrane permeability to solutes with a molecular mass less than 1500 Da [29,30]

 

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