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Supplements for Vitiligo

Vitiligo is an autoimmune condition and as such certain dietary protocols as well as supplements can be used to support the immune system for those that experience the characteristic skin depigmentation. The scope of this article however is to discuss the supplements that have been shown in clinical trials to help the repigmentation of the skin.

In most cases supplementation was accompanied by the use of light therapy.

Khellin.

For thousand of years the treatment of “leukoderma” (vitiligo) involved the topical application or ingestion of seeds or plant extracts and the subsequent exposure to sunlight. Khellin is an extract from the seeds of the plant khella found in the eastern Meditteranean area. Supplementation of Khellin has been repeatedly shown (Abdel-Fattah, A. et al., 1982, Orecchia, G. et al., 1998, de LEEUW, J. et al., 2003) to improve the repigmentation of the skin.

 

There have been cases though (Ortel, B. et al., 1988) that after 4-6 weeks of khellin supplementation the elevation of transaminases was observed and for these individuals had to discontinue the treatment.

 

L-phenylalanine.

In search for re-pigmentation solutions for vitiligo, a group of scientists in Amsterdam – NL (Cormane R et al., 1985), noted that patients with phenylketonuria (who among other symptoms have lighter than normal skin) when administrated tyrosine and were incubated with UV-light had normal melanin production. Cormane’s team initially tried the tyrosine & UV-A protocol in a pilot study of 5 without any success. Sequentially they tried phenylalanine (a precursor of tyrosine) seeing improvement in 95% of the subjects after 6 to 8 months. The theory put forward on why phenylalanine benefits vitiligo patches was that it stops antibodies and allows sun radiation to stimulate melanocytes from other areas to migrate to the damaged ones (Camacho, F. and Mazuecos, J., 1999).

 

50 mg/kg of body weight per day of phenylalanine was administered 1 hour prior to UV A irradiation (twice per week). Of the 19 participants:

i. 5 noted dense re-pigmentation in 6 to 8 months

ii. 13 saw sparse re-pigmentation in the same period

iii. and 1 had no re-pigmentation even after 8 months.

Since the 1980’s there has been no more research examining the benefits of phenylalanine for vitiligo. All 3 studies combining the administration of the amino acid & UVA exposure as well as the 1 that used just the amino acid reported positive outcomes (Szczurko, O. and Boon, H.S., 2008).

 

Additional supplements.

PABA is an ingredient often used in sunscreen lotions. One study showed PABA to support repigmentation (Sieve B F, 1942) but currently there is limited research to confirm these findings. An 8 years old girl developed hemolytic anemia and hepatotoxicity after administration of PABA for 4 months. Symptoms were reversed 2 months after discontinuing the supplement (Tootoonchi, P., 2018). PABA has also been reported to cause depigmentation (Hughes, C. G., 1983)

 

Vitamin E (Szczurko, O. and Boon, H.S., 2008) and vitamin C have also been shown to support re-pigmentation potentially due to their antioxidant properties.

 

Conclusion.

The results in the above studies are very promising. However, as I mentioned already, in certain cases there have been adverse effects such as the development of cirrhosis which highlights the importance of complimentary testing and supervision.

 

 

References.

Abdel-Fattah, A., Aboul-Enein, M. N., Wasset, G. M., & El-Menshawi, B. S. (1982). An approach to the treatment of vitiligo by khellin. Dermatology165(2), 136-140.

 

Camacho, F. and Mazuecos, J., 1999. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Archives of dermatology, 135(2), pp.216-217.

 

Cormane, R.H., Siddiqui, A.H., Westerhof, W. and Schutgens, R.B.H., 1985. Phenylalanine and UVA light for the treatment of vitiligo. Archives of Dermatological Research, 277(2), pp.126-130.

 

de LEEUW, J., MAIERHOFER, G., & NEUGEBAUER, W. D. (2003). A case study to evaluate the treatment of vitiligo with khellin encapsulated in L‐phenylalanin stabilized phosphatidylcholine liposomes in combination with ultraviolet light therapy. European Journal of Dermatology13(5), 474-477.

 

Hughes, C. G. (1983). Oral PABA and vitiligo. Journal of the American Academy of Dermatology9(5), 770.

 

Szczurko, O. and Boon, H.S., 2008. A systematic review of natural health product treatment for vitiligo. BMC dermatology, 8(1), p.2.

 

Sieve, B. F. (1942). The clinical effects of a new B-complex factor, para-aminobenzoic acid, on pigmentation and fertility. South Med Surg104(135), 9.

 

Orecchia, G., Sangalli, M. E., Gazzaniga, A., & Giordano, F. (1998). Topical photochemotherapy of vitiligo with a new khellin formulation: preliminary clinical results. Journal of dermatological treatment9(2), 65-69.

 

Ortel, B., Tanew, A., & Hönigsmann, H. (1988). Treatment of vitiligo with khellin and ultraviolet A. Journal of the American Academy of Dermatology18(4), 693-701.

 

Tootoonchi, P. (2018). Hemolytic Anemia and Other Side Effects of Para-amino Benzoic Acid in an 8-Year-Old Girl. Iranian Journal of Pediatric Hematology & Oncology8(3).

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 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).

Reversing Vitiligo

(Updated: 17th Oct 2018)

Vitiligo (also called “leukoma”) is an autoimmune condition where loss of pigment from areas of the skin result in irregular white patches, the texture of which remain normal. Similar with all autoimmune disorders:

i. the body is attacking its own tissue. In the case of vitiligo the body is attacking the melanocytes (the cells responsible for skin colouring).

ii. the triggering cause may vary. I have seen 1 case where it started after a car accident at an early stage of life & another where it developed after a stressful period at late 40s.

iii. the development of the disease is the result of genetic predisposition as well as environmental factors.

iv. there is a higher than normal risk for the simultaneous presence of other autoimmune conditions.

 

Cease the Fire.

As an autoimmune condition vitiligo has to be treated as an immunological problem and not solely as a skin one. While the symptoms manifest in the skin it is the immune system that is over-reacting. This is the reason why in many cases immunosuppressive drugs are prescribed (Boone B., et al., 2007). Stopping the over-activity of the immune system may not be as straight forward as we wish. Foods, heavy metals, infections have been shown or speculated to be the root cause of this unfavourable behaviour of the immune system (IS).

In order to address each of the above one can:

i. follow an anti-inflammatory diet.

ii. remove any obvious toxic deposits in the body (i.e. mercury fillings, tattoos)

iii. get tested for carrying any of the common viruses associated with autoimmunity (i.e. Epstein Barr virus)

 

Test for other AI conditions.

While there are 100s of autoimmune conditions, Hashimoto’s & Celiac Disease have been shown to have a higher prevalence among patients of vitiligo. Hashimoto’s can be easily diagnosed through an inexpensive blood test for TPO (Thyroid peroxidase) & TgAB (Thyroglobulin) antibodies. The diagnosis of Celiac Disease requires a biopsy which is why a lot of patients with vitiligo decide to eliminate gluten from their diet without going through the hustle of testing.

 

If the body is attacking more than one of its own tissue it is best for all autoimmune cases to be supported at the same time.

 

Light Therapy.

For the depigmentation is of the “milky” patches the 2 versions of light therapy have been used successfully are: Narrowband UVB & Targeted light therapy (Grimers PE 2005).

 

Narrowband UV-B involves the use of UV lamps with a peak emission around 311 nm. It induces local immunosuppression while stimulating the production of melanocyte-stimulating hormone, and the increase of melanocyte proliferation and melanogenesis. In a study (Njoo M D et al., 2000) where 51 children with generalised vitiligo were treated with narrowband UV-B:

a) 53% achieved >75% of repigmentation

b) 29% had 26-50% of repigmentation

c) 18% had <25% of repigmentation

 

The main advantages of narrowband UV-B include:

a) safety for both adults & children

b) lack of systemic adverse effects

Source: Njoo M D et al., 1998

 

A number of supplements have been shown to help reverse vitiligo. Accompanying light therapy with supplementation is likely to amply its benefits.

 

Which Genes?

NLRP1 gene

NLRP1 is a gene involved in the production of proteins called inflammasomes. Inflammasomes participate in the regulation of the immune system & mutations in NLRP1 have been associated with the presence of autoimmune disorders. The rs6502867 variant of the NLRP1 gene (risky allele: T) was associated with vitiligo in an Indian study (Dwivedi M et al., 2013).

 

Phytonutrient (EGCG) in green tea has been shown to inhibit the action of the NLRP1 gene (Ellis L et al., 2010).

 

Methylation

Methylation is a process responsible for many functions in the body including cell replication and DNA repair. A study published among 80 individuals (40 with vitiligo & 40 controls) (Yasar, A et al., 2012) showed no correlation between mutations in MTHFR or the levels of serum folate & vitamin B12 among the patients. Had the study measured red blood cell folate and vitamin B12 their findings would have been more significant.

Both folate & vitamin B12 (which directly support the methylation pathway) have been used by vitiligo patients with positive outcomes.

 

Case Study.

The photos in the image above are from a female client in her 50’s. She was following the Wahls dietary protocol for 6 months as an anti-inflammatory / auto-immune friendly approach. The main adjustments in her diet where the increase of fats through nuts & seeds as well as progressing from 2 meals and 1 snack a day to a 16-8 hours fast and then to 1 meal a day (twice per week). Breathing exercises as well as progressive exposure to cold (through showers) were also part of her protocol.

 

References.

Boone, B., Ongenae, K., Van Geel, N., Vernijns, S., De Keyser, S. and Naeyaert, J.M., 2007. Topical pimecrolimus in the treatment of vitiligo. European Journal of Dermatology, 17(1), pp.55-61.

Dwivedi, M., Laddha, N.C., Mansuri, M.S., Marfatia, Y.S. and Begum, R., 2013. Association of NLRP1 genetic variants and mRNA overexpression with generalized vitiligo and disease activity in a Gujarat population. British Journal of Dermatology, 169(5), pp.1114-1125.

Ellis, L.Z., Liu, W., Luo, Y., Okamoto, M., Qu, D., Dunn, J.H. and Fujita, M., 2011. Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1β secretion. Biochemical and biophysical research communications, 414(3), pp.551-556.

Grimes, P. E. (2005). New insights and new therapies in vitiligo. Jama293(6), 730-735.

Njoo, M. D., Bos, J. D., & Westerhof, W. (2000). Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. Journal of the American Academy of Dermatology42(2), 245-253.

Njoo, M. D., Spuls, P., Bos, J. T. A., Westerhof, W., & Bossuyt, P. M. M. (1998). Nonsurgical repigmentation therapies in vitiligo: meta-analysis of the literature. Archives of dermatology134(12), 1532-1540.

Yasar, A., Gunduz, K., Onur, E. and Calkan, M., 2012. Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo. Disease markers, 33(2), pp.85-89.

 

 

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 why 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 synthesise 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.

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.

 

 

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.

 

  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.

🔑  Things to consider

👉🏻 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.

👉🏻 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.

👉🏻 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.

👉🏻 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 towards 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 all together. I have been consuming them freely. Two things that can help a lot in extending your fasting periods are:
👉🏻 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.

👉🏻 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 scientist at 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 balance 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 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. 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 disproportionate 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. Prioritises 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.

Magistretti PJ, Pellerin L, Rothman DL, Shulman RG. Energy on demand. Science 1999;283(5401):496–7.

Mobbs CV, Kow LM, Yang XJ. Brain glucose-sensing mechanisms: ubiquitous silencing by aglycemia vs. hypothalamic neuroendocrine responses. Am J Physiol Endocrinol Metab 2001;281(4):E649–54.

Molina PE, Abumrad NN. Contribution of excitatory amino acids to hypoglycemic counter-regulation. Brain Res 2001;899(1–2): 201–8.

Lazdunski M. ATP-sensitive potassium channels: an overview. J Cardiovasc Pharmacol 1994;24(4):S1–S5.

Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 1997;390(6659):521–5.

Stanley BG, Ha LH, Spears LC, Dee MG. Lateral hypothalamic injections of glutamate, kainic acid, D,L-alpha- amino-3-hydroxy- 5-methyl-isoxazole propionic acid or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats. Brain Res 1993; 613(1):88–95.

Ohno-Shosaku T, Sawada S, Yamamoto C. ATP-sensitive K . channel activators suppress the GABAergic inhibitory transmission by acting on both presynaptic and postsynaptic sites in rat cultured hippocampal neurons. Neurosci Lett 1993;159(1–2):139–42.

Yousef KA, Tepper PG, Molina PE, Abumrad NN, Lang CH. Differential control of glucoregulatory hormone response and glucose metabolism by NMDA and kainate. Brain Res 1994; 634(1):131–40.

What helps Histamine Intolerance?

Histamine is a hormone involved in digestion, immune & nervous system function. While anti-histamine drugs are often prescribed for asthma, they are also given to those with food allergies.

 

Anti-histamine drugs can be life saving in times of crisis. At the same time if one doesn’t deal with what causes the reaction at 1st place she/he is trying to put off a fire by removing the battery from the fire alarm.
Which raises the question “What helps histamine intolerance?”

 

What is Histamine Intolerance?

Histamine is a hormone with varying functions in different tissues.

 

Histamine intolerance symptoms are due to histamine’s relation with the immune system. Histamine activates immune cells (basophils & mast cells) while causing blood vessels to dilate so that immune cells can be quickly transferred to kill pathogens. In that sense you can think of histamine as a fire alarm.

“Histamine intolerance is a fire alarm going on when there is no fire.”

 

To be more precise histamine intolerance results from imbalance between accumulated histamine and the capacity to break it down. In most cases it is due to limited histamine breakdown capacity. Like all hormones histamine needs to be eliminated from the body when it has done its job. While it is broken down by a few different enzymes (HNMT, NAT1,2 & DAO), it is the DAO (Maintz, L. and Novak, N., 2007) responsible for the breakdown of ingested histamine.

 

Histamine’s link with Digestion.

Gastrointestinal problems are very common among those with histamine intolerance.

While histamine is necessary for proper gut function excess levels can cause digestive complications. Bellow are a few facts highlighting the link between histamine intolerance and gut health:

a. all 4 histamine receptors H1R-H4R are found in the digestive track and they have excitatory actions there (Breunig E. et al., 2007).

b. In a study conducted in Italy, 13 out of 14 subjects (with food intolerances) reported benefits in at least 1 food after DAO supplementation (Manzotti G. et al., 2015).

c. The capacity of both histamine breakdown pathways: HNMT and DAO have been reported to be reduced in those with food intolerances (Kuefner MA et al., 2004).

d. Elevated levels of histamine in the brain have been shown to suppress appetite. (Malmlöf, K. et al., 2005)

 

“Diet can help histamine intolerance in 2 ways: i. reduce the histamine load ii. support histamine breakdown”

 

Histamine Intolerance foods to avoid

 

There are 2 categories of foods those with histamine intolerance need to avoid: a. Those that contain histamine & b. those that can cause the release of histamine in the body although they don’t contain histamine (Maintz, L. and Novak, N., 2007)

#Foods to be avoided with Histamine IntoleranceContain HistamineLow in Histamine (but may trigger its release)DAO blockingVegetarianVeganFruits
Vinegar containing foods (ie pickles, mayonnaise, olives)XXX
Fermented foods (ie saurkraut, soy sauce, kombucha, kefir, yogurt)XXXX
Fermented foods (ie saurkraut, soy sauce, kombucha, kefir, yogurt)XX
Cured Meats (ie bacon, salami, hot dogs)X
Soured foods (ie sour cream, sour milk, buttermilk)XX
Dried fruitXXXX
Aged cheese (ie gouda, camembert, cheddar, goat cheese)XX
Nuts (walnuts, cashews, peanuts)XXX
Smoked fish & shellfishX
Chickpeas, soybeansXXX
Banana, Papaya, Pineapple, StrawberriesXXXX
ChocolateXXX
Cow's milkXX
TomatoesXXX
Black, green, mate teaXXX

 

Histamine Intolerance diet

The fresher the food the lower it is in histamine. Vitamin C supplementation has also been shown to reduce histamine levels (Hemilä, H., 2014).

#Diet for Histamine IntoleranceVegetarianVegan
Fresh cooked meat, poultry
Fresh caught fish
EggsX
Gluten free grains: rice, quinoaXX
Fresh fruits (ie mango, pear, watermelon, apples)XX
Fresh veggies (except: tomatoes, eggplant, spinach, avocado)XX
Dairy substitutes (ie coconut m rice, hemp, almond milk)XX
Cooking oils (olive & coconut)XX
Herbal teasXX

 

Blood sugar regulation and Histamine Intolerance

The link between histamine and diabetes goes back to the 1950 (Pini A et al., 2016).

Plasma histamine was shown to reduce after insulin administration in diabetic rats (Hollis T. et al., 1985). Two of the mechanisms through which insulin and histamine interact was that the activation of histamine 3 receptors (H3R) in pancreatic beta cells was shown to: a. inhibit insulin secretion (Nakamura T et al., 2014) b. reduce glucagon production in non-hyperglycemic state (Nakamura T et al., 2015). While the mechanisms of interaction between diabetes and histamine intolerance are currently not clear the correlation appears to be positive (Pini A et al., 2016).

To that extent a state of insulin resistance should be addressed in cases of histamine intolerance together with any other protocol.

 

How to test for Histamine Intolerance

Prior to treating any condition it is wise to diagnose it first. By measuring the levels of DAO enzyme in your blood you can assess your body’s capacity to breakdown histamine. The cut off level of serum DAO activity (for probable histamine intolerance) is <10 U/mL (Manzotti G. et al., 2015)

 

Labs that offer this service are:

Smart Nutrition in UK

ImmunoPro in Australia

Dunwoody Labs in US & UK (via Invivo clinical)  – In my opinion the best test for gut integrity currently available.

 

23andme results & Histamine Intolerance

23andme results can be useful in identifying potential blockages in the pathway of histamine. At the same time it is dangerous to drive conclusions solely from one’s genetic make up, let alone one gene. In many cases a person may have no SNPs in the gene that produces the DAO enzyme (AOC1 gene) and at the same time experience histamine-like reactions after the consumption of red wine for instance. The case bellow is such an example.

The woman is in her mid 40s, vegetarian with a more or less healthy lifestyle. She carries only 1 homozygous polymorphism in the AOC1 gene which has been shown to be beneficial.

 

Source: Opus23

 

While there seems to be no burden on the production of DAO if you look at the entire pathway you will see that she carries SNPs in the HNMT and MAOB genes. Both of which can tax DAO’s function.

 

Source: Opus23

 

How can this information be useful? 

For this woman supporting the function of HNMT and MAOB can help with histamine symptoms. For HNMT methylation support as well Salacia Oblonga (Oda, Y et al., 2015)  can be used while for MAOB vit B2.

 

Source: Opus23

 

This Nutrigenomics analysis would not be possible without access to Opus23 analytics.

 

 

References

Breunig, E., Michel, K., Zeller, F., Seidl, S., Weyhern, C.W.H.V. and Schemann, M., 2007. Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors. The Journal of physiology583(2), pp.731-742.

 

Hemilä, H., 2014. The effect of vitamin C on bronchoconstriction and respiratory symptoms caused by exercise: a review and statistical analysis. Allergy, Asthma & Clinical Immunology10(1), p.58.

 

Hollis, T.M., Kern, J.A., Enea, N.A. and Cosgarea, A.J., 1985. Changes in plasma histamine concentration in the streptozotocin-diabetic rat. Experimental and molecular pathology, 43(1), pp.90-96.

 

Kuefner, M.A., Schwelberger, H.G., Weidenhiller, M., Hahn, E.G. and Raithel, M., 2004. Both catabolic pathways of histamine via histamine-N-methyltransferase and diamine oxidase are diminished in the colonic mucosa of patients with food allergy. Inflammation Research, 53, pp.S31-S32.

 

Malmlöf, K., Zaragoza, F., Golozoubova, V., Refsgaard, H.H.F., Cremers, T., Raun, K., Wulff, B.S., Johansen, P.B., Westerink, B. and Rimvall, K., 2005. Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight. International journal of obesity, 29(12), pp.1402-1412.

 

Manzotti, G., Breda, D., Di Gioacchino, M. and Burastero, S.E., 2015. Serum diamine oxidase activity in patients with histamine intolerance. International journal of immunopathology and pharmacology, p.0394632015617170.
Maintz, L. and Novak, N., 2007. Histamine and histamine intolerance. The American journal of clinical nutrition, 85(5), pp.1185-1196.

 

Pini, A., Obara, I., Battell, E., Chazot, P.L. and Rosa, A.C., 2016. Histamine in diabetes: is it time to reconsider?. Pharmacological research111, pp.316-324.

 

Nakamura, T., Yoshikawa, T., Noguchi, N., Sugawara, A., Kasajima, A., Sasano, H. and Yanai, K., 2014. The expression and function of histamine H3 receptors in pancreatic beta cells. British journal of pharmacology, 171(1), pp.171-185.

 

Nakamura, T., Yoshikawa, T., Naganuma, F., Mohsen, A., Iida, T., Miura, Y., Sugawara, A. and Yanai, K., 2015. Role of histamine H 3 receptor in glucagon-secreting αTC1. 6 cells. FEBS open bio, 5, pp.36-41.

 

Oda, Y., Ueda, F., Utsuyama, M., Kamei, A., Kakinuma, C., Abe, K. and Hirokawa, K., 2015. Improvement in Human Immune Function with Changes in Intestinal Microbiota by Salacia reticulata Extract Ingestion: A Randomized Placebo-Controlled Trial. PloS one, 10(12), p.e0142909.

 

 

 

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.

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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].

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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.

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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  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 ageing [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.

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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.

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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 in the beginning of the disease [22]. Reduced ATP production leads to the activation of erk36 & erk40 [23] and subsequently tau hyperphosphorylation [24].

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

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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 in the presence of Cu2+. Studies in cybrid cells demonstrated 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)****

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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]

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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 depolarisation of mitochondrial inner membrane [44]

2. increases CoQ9 antioxidant  [44]

3. modulates glutathione redox cycle [127]

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

5. promotes clearance of Aβ [13]

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“ 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 been 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 defence mechanism against brain’s degeneration in AD?

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* 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 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]

8. References

1. Qiu, W.Q. and Folstein, M.F., 2006. Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer’s disease: review and hypothesis. Neurobiology of aging, 27(2), pp.190-198.

2. Kahn SE, Andrikopoulos S, Verchere CB. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 1999;48:241–53

3. Bennett RG, Duckworth WC, Hamel FG. Degradation of amylin by insulin-degrading enzyme Identification and isolation of a cytosolic proteolytic complex containing insulin degrading enzyme and the multicatalytic proteinase. J Biol Chem 2000;275:36621–5.

4. Runyan K, Duckworth WC, Kitabchi AE, Huff G. The effect of age on insulin-degrading activity in rat tissue. Diabetes 1979;28:324–5

5. Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer’s disease. Int J Biochem Cell Biol 2003;35:1505–35.

6. Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R. Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 2002;22:RC221.

7. Runyan K, Duckworth WC, Kitabchi AE, Huff G. The effect of age on insulin-degrading activity in rat tissue. Diabetes 1979;28:324–5.

8. Frolich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Turk A, Hoyer S, Zochling R, Boissl KW, Jellinger K, Riederer P. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 1998;105:423–38.

9. Gibson, G.E. Petersen, C. and Jenden, D.J. (1981) Brain acetylcholine synthesis decline with senescence. Science, 213, 674-676.

10. Selkoe DJ. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis 2001;3:75–80.

11. Westermark P, Wilander E. The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus. Diabetologia 1978;15:417–21.

12. Nicolls, M.R., 2004. The clinical and biological relationship between Type II diabetes mellitus and Alzheimer’s disease. Current Alzheimer Research,1(1), pp.47-54.

13. Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogenactivated protein kinase signaling. J Neurosci 2001;21:2561–70.

14. Schubert, M., Gautam, D., Surjo, D., Ueki, K., Baudler, S., Schubert, D., Kondo, T., Alber, J., Galldiks, N., Küstermann, E. and Arndt, S., 2004. Role for neuronal insulin resistance in neurodegenerative diseases. Proceedings of the National Academy of Sciences of the United States of America, 101(9), pp.3100-3105.

15. Mandelkow EM, Drewes G, Biernat J, Gustke N, Van Lint J, Vandenheede JR, et al. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett 1992;314:315–21.

16. Henneberg N, Hoyer S. Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)? Arch Gerontol Geriatr 1995;21:63–74

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18. Kish SJ. Brain energy metabolizing enzymes in Alzheimer’s disease: alpha-ketoglutarate dehydrogenase complex and cytochrome oxidase. Ann N Y Acad Sci 1997;826:218–28.

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The ROSE Method

Do you care about your body composition?

Although I cannot see your face I can guess your response: “WHAT A STUPID QUESTION? OF COURSE I…” and some of you will say “DO” and some will say “DON’T”. For me to ask this question and have developed a method for it I obviously consider it a significant one. Not because I think that everyone needs to look like the cover model of a fashion magazine but because body composition is a great indication of health.

Science has shown body composition to be linked with the development of certain diseases (cancer been one [1]) but not others (like inflammatory bowel disease [2]). So if you are health conscious you should be only partly concerned if you have low muscle tone or excess fat, correct?

OK I suggest we keep it real. Low muscle tone and/or excess body fat is as bad for health as it is for self esteem. The view of a person with a low % of muscle mass and high % of body fat is almost the opposite of a sick one!

 

What can you do to improve your body composition then?

You want to learn more?