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Friday, 25 March 2016

“Type 3” Diabetes in Alzheimer’s, but maybe also in some Autism



Intranasal insulin, for cognitive enhancement in Alzheimer’s and …



Today’s post was sparked by another little experiment of mine; no, not intranasal insulin.

Recently I have been using a reduced number of therapies on Monty, aged 12 with ASD.  Some people think there are just too many pills.

I wrote many posts last year about something called PPAR gamma (Peroxisome proliferator-activated receptor gamma, PPAR-γ or PPARG, also known as the glitazone receptor).

As you can read in Wikipedia:-

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia andhyperglycemia. PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells. PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.
Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion.

What we found out in earlier posts that PPAR-gamma can be used to reduce microglial activation, which should turn down the body’s “immunostat”.  A key feature of many people’s autism appears to be an over-activated immune system, reflected by activated microglia.


PPAR-gamma agonists as regulators of microglial activation and brain inflammation.


The present review summarizes the several lines of evidence supporting that PPAR-gamma natural and synthetic agonists may control brain inflammation by inhibiting several functions associated to microglial activation, such as the expression of surface antigens and the synthesis of nitric oxide, prostaglandins, inflammatory cytokines and chemokines. 
Although most of the evidence comes from in vitro observations, an increasing number of studies in animal models further supports the potential therapeutic use of PPAR-gamma agonists in human brain diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease.



Experiment

The potent PPAR-gamma agonist drugs like Rosiglitazone, have side effects which I think make them unsuitable for autism.  I use a flavanol called Tangeritin, in the form of a supplement called Sytrinol.

For two months we have not used Sytrinol, but yesterday Monty had one pill after lunch.

The piano lesson was great and then Monty had three hours with his Assistant, doing academic work and then some more piano practice.

Before she went home, Monty’s Assistant spent ten minutes telling me, and Monty’s big brother, just how great the afternoon had been.

“Monty was amazing today”

“When he was doing math, it was like he wasn’t autistic”

(we live in a country where autism means strict definition autism, what in the US is called severe autism)

“Did you hear how he played the piano?”

I told Monty’s brother to make a mental note of this and tell it to Mum/Mom later.

The next day the effect of Sytrinol was not as profound.

This actually is a recurring theme, the effect of various interventions is the greatest at the beginning  and then, as the body’s feedback loops get involved, the effect reduces.  

The same is true with cinnamon, another food-based intervention, that also helps people with diabetes.  The effect in (some) autism is greatest when you start.

It would be great if it was possible to keep the full initial effect of both Sytrinol and Cinnamon, and avoiding the dampening reaction caused by feedback loops.

I think if this is possible, it will be via targeting the therapy directly at the brain, rather than the entire body.  This can be achieved via the intranasal route, as used with oxytocin.

What to put in the spray?  This would be a very personalizable solution, since different people have different dysfunctions and to varying degrees.  Some possibilities might include:-

·        Insulin  (read on to learn why)
·        IGF-1
·        T3 thyroid hormone
·        TRH
·        Type 2 iodothyronine deiodinase (D2) 
·        Oxytocin
  
Fine tuning Cognition

It is difficult to be certain what therapy is responsible for what effect.

I recently told one researcher/parent that interventions in autism seem to take effect very quickly and so you can pretty rapidly run through a series of mini-trials to see what helps, what makes things worse and what does nothing.  Being a researcher, his view is that you need to try things for much longer.

One problem of trials lasting months is that external factors may then change, that cause behavior to change and distort the result. This is why I try to avoid trials from May to October, the allergy season.

Many people do find that some supplements help a lot for a week or two and then make things worse.  This includes things like some B vitamins and carnitine.  For other people continued use keeps giving a positive effect.


Previous Experience with Sytrinol

Monty’s assistant at school last year thought Sytrinol made him cleverer.

She also thought the PAK inhibiting propolis (BIO 30) had a similar effect.  This propolis is quite expensive and I concluded the effect was small and this might be because it just was not potent enough. 

One reader of this blog is using a much more potent PAK inhibitor, FRAX486, and some people in the US use Ivermectin.

Ivermectin is an anti-parasite drug which also happens to be a PAK inhibitor.  It is not suitable for long term use.



 Why would Sytrinol improve cognition?

I have written a lot about PPAR gamma in the past, so today has a new angle on the subject.

I did a quick check on PPAR gamma and cognition.

I was surprised what I found.

  


  

PPARγ Recruitment to Active ERK during Memory Consolidation Is Required for Alzheimer's Disease-Related Cognitive Enhancement



Cognitive impairment is a quintessential feature of Alzheimer's disease (AD) and AD mouse models. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone improves hippocampus-dependent cognitive deficits in some AD patients and ameliorates deficits in the Tg2576 mouse model for AD amyloidosis. Tg2576 cognitive enhancement occurs through the induction of a gene and protein expression profile reflecting convergence of the PPARγ signaling axis and the extracellular signal-regulated protein kinase (ERK) cascade, a critical mediator of memory consolidation. We therefore tested whether PPARγ and ERK associated in protein complexes that subserve cognitive enhancement through PPARγ agonism. Coimmunoprecipitation of hippocampal extracts revealed that PPARγ and activated, phosphorylated ERK (pERK) associated in Tg2576 in vivo, and that PPARγ agonism facilitated recruitment of PPARγ to pERK during memory consolidation. Furthermore, the amount of PPARγ recruited to pERK correlated with the cognitive reserve in humans with AD and in Tg2576. Our findings implicate a previously unidentified PPARγ–pERK complex that provides a molecular mechanism for the convergence of these pathways during cognitive enhancement, thereby offering new targets for therapeutic development in AD.


Cognitive Enhancementwith Rosiglitazone Links the Hippocampal PPAR gamma and ERK MAPK Signaling Pathways



Pathogenesis of Alzheimer’s and Diabetes

The pathogenesis of a disease is the biological mechanism (or mechanisms) that lead to the diseased state.

I am not suggesting that autism leads to Alzheimer’s.  (We do though know that most people with Down Syndrome will develop early Alzheimer’s in their 40s or 50s)

Many complex diseases like Alzheimer’s, cancer and indeed autism have multiple biological mechanisms behind them.

By studying the molecular pathways involved in one disease it may help understand another disease.  This is why some readers of this blog follow the cancer/oncology research.

For some time I have been intrigued at the overlap between diabetes and autism.  What is good for autism really does seem to be good for diabetes and vice versa.


Alzheimer’s Disease as Type 3 Diabetes

I was surprised to learn that some clinicians now consider Alzheimer’s Disease as Type 3 Diabetes.           

You will recall that Type 1 diabetes is when your pancreas packs up making insulin and then you have to inject yourself with supplementary insulin.

Type 2 diabetes occurs in late middle age, often linked to obesity, and is characterized by high blood sugar, insulin resistance (insulin sensitivity), and relative lack of insulin.

Insulin resistance (IR) is generally regarded as a pathological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin. When the body produces insulin under conditions of insulin resistance, the cells in the body are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level. This often remains undetected and can contribute to a diagnosis of Type 2 diabetes.  Despite the ill-effects of severe insulin resistance, recent investigations have revealed that insulin resistance is primarily a well-evolved mechanism to conserve the brain's glucose consumption by preventing muscles from taking up excessive glucose.[

Eventually Type 2 diabetes may progress to Type 1 diabetes mellitus, where the body's own immune system attacks the beta cells in the pancreas and destroys them. This means the body can no longer produce and secrete insulin into the blood and regulate the blood glucose concentration. We saw how the use of Verapamil can stop beta cells being destroyed.

Some clinicians/researchers propose that diabetes of the brain should be called Type 3 diabetes.

The research does support the view that Alzheimer’s does incorporate this brain-specific type of diabetes.  But I know wonder if this applies to some autism.




Alzheimer’s disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.

Altogether, the results from these studies provide strong evidence in support of the hypothesis that AD represents a form of diabetes mellitus that selectively afflicts the brain

The human and experimental animal model studies also showed that CNS impairments in insulin/IGF signaling mechanisms can occur in the absence of T1DM or T2DM

Altogether, the data provide strong evidence that AD is intrinsically a neuroendocrine disease caused by selective impairments in insulin and IGF signaling mechanisms, including deficiencies in local insulin and IGF production.

At the same time, it is essential to recognize that T2DM and T3DM are not solely the end results of insulin/IGF resistance and/or deficiency, because these syndromes are unequivocally accompanied by significant activation of inflammatory mediators, oxidative stress, DNA damage, and mitochondrial dysfunction, which contribute to the degenerative cascade by exacerbating insulin/ IGF resistance.

Some of the most relevant data supporting this concept have emerged from clinical studies demonstrating cognitive improvement and/or stabilization of cognitive impairment in subjects with early AD following treatment with intranasal insulin or  a PPAR agonist



Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease


 Although many classes of drugs are now approved for management of diabetes, a primary focus of efforts to treat insulin-signaling dysfunction in AD has been the administration of exogenous insulin. There is abundant anecdotal evidence that insulin administration in people with diabetes may acutely affect mood, behavior, and cognitive performance.

Results of recent pilot studies of intranasal insulin in mild cognitive impairment (MCI) and AD have been encouraging. The most notable of these studies was a doubleblind, randomized trial of 104 older adults with MCI or AD who received placebo, low-dose (20 IU), or high-dose (40 IU) intranasal insulin for 4 months

In 2012, the U.S. National Institutes of Health allocated $7.9 million for a pivotal trial of intranasal insulin called the Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF; ClinicalTrials identifier: NCT01767909). This multicenter phase 2/3 study will be conducted by the ADCS. It is expected to recruit 250 participants with AD or MCI and to randomize them for 12 months to intranasal insulin or placebo, followed by an open-label extension of 6 months in which all participants will receive intranasal insulin. The study should be completed in late 2014.  The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF)

In preclinical studies, TZDs improved biomarkers of AD as well as memory and cognition (31). The first pilot studies in humans were also generally encouraging, including a study by Watson et al. (32) that showed improved memory and modulation of amyloid-b levels in CSF compared with placebo after 6 months of treatment with rosiglitazone. On the basis of these preliminary studies, the maker of rosiglitazone sponsored two adequately powered phase 3 studies of rosiglitazone in AD as monotherapy or as adjunctive therapy to acetylcholinesterase inhibitors in mild to-moderate AD. These larger trials failed to replicate the positive findings of the smaller pilot studies (33).

Many explanations have been proposed for why rosiglitazone does not appear to be effective as a treatment for AD in cognitively impaired adults. Perhaps the most convincing explanation is that rosiglitazone has only modest blood-brain barrier penetration, and in fact, rosiglitazone is actively pumped out of the brain by an endogenous efflux system (34). Therefore, rosiglitazone should be expected to have only a mild insulin-sensitizing effect in the human brain.





   


Conclusion

The type 2 diabetes drugs like Rosiglitazone/Pioglitazone have been trialed in both autism and Alzheimer’s.  The results in autism with pioglitazone were positive, in Alzheimer’s they used Rosiglitazone, due to the adverse side effects of pioglitazone, and the results were very mixed.  Rosiglitazone has only modest blood-brain barrier penetration so it looks a poor choice.

In the autism trial they measured "autism" rather than cognitive function.

Effect of pioglitazone treatment on behavioral symptoms in autistic children 

In a small cohort of autistic children, daily treatment with 30 or 60 mg p.o. pioglitazone for 3–4 months induced apparent clinical improvement without adverse events. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients.
Conclusion  Pioglitazone should be considered for further testing of therapeutic potential in autistic patients.

One to watch is the effect of the standard type 2 diabetes treatment Metformin on cognition in Alzheimer’s.  Nobody really knows the mode of action of Metformin.

Intranasal insulin is very interesting and not just in Alzheimer’s.


Intranasal insulin improves memory in humans


Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence





I will add it to my growing list of therapies for mild cognitive impairment, in case I need it in the future.

·        Nerve growth factor (NGF) eye drops
·        Lions Mane Mushrooms (that increase NGF)
·        Cocoa Flavanols (increase cerebral blood flow)
·        Intranasal insulin or just Tangeritin/Sytrinol

I do not know if intranasal insulin would be a safe long-term therapy for children, but it would be a good diagnostic tool.  Once large numbers of older people start using intranasal insulin for cognition, we will find out how well it is tolerated.  Older people seem far more prone to side effects than younger people.


For now I think Tangeritin/Sytrinol is the best choice.












19 comments:

  1. I know - magnesium does not solve everything - but just wanted to point out a couple connections. Also, I think it is interesting that you point out the link between autism and Alzheimer's, because just for fun in my spare time, I have been trying to find links between the two, (I realize people have done this before) and the TAU group of Israel has stated that there is a genetic link between the two, both having issues/mutations in the ADNP gene, which affects neuroprotection. Reading your post, it was coincidental that you posted about Diabetes type 3 and autism because I was just looking at that a few days ago - insulin thought not to be produced only in the pancreas but also in the brain. Up until a few days ago I had never heard of that concept before. I was wondering at the time how calcification or aluminum toxicity in the brain (both mg issues) and a lack of ionic magnesium specifically (the health benefits possibly being totally different for ionic magnesium) might contribute to Diabetes 3, and yes I agree that an individual with autism might be suffering from some degree of Diabetes 3 for sure. Magnesium is supposed to be crucial for both production and use of insulin, so it is no coincidence that black people have low magnesium, low insulin, and high rates of regressive type autism. Just out of interest, I had never heard of PPARgamma but I did find one study where PPARgamma was being tested - I found it interesting that, in order to create neurological vulnerability that would be responsive to PPARgamma, the researchers made the experimental mice magnesium deficient.

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    1. From my understanding, the inducing of magnesium deprivation is done to induce seizures which are then studied and this is a very common albeit probably standard method of doing so. Magnesium helps modulate NMDA receptor activity and depriving the receptors of magnesium causes them to be oversensitive to activity and if you do that throughout the brain or a whole brain region you get a cascade of uninhibited activity which can lead to seizures.

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  2. my high functioning son (11), makes very annoying "crazy" noises. Very disruptive to his peer/teachers. they are a combination of the movies he has watched, books read, computer games. I have read through your blog but not come across this issue.

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    1. This could be a kind of verbal stereotypy, or it could be a behavioral response. Does it only happen in school?

      If it is stereotypy it well worth trying NAC 600mg three or four times a day. You will know in a day or two if it works.

      It could be his way of dealing with anxiety, which is a big issue in Asperger's but not really in most classic autism. Anxiety in Asperger's seems to respond extremely well (70+% response rate) to Baclofen. It seems that 5-15 mg three times a day is what works. Baclofen seems to resolve many issues in Asperger's, so well worth trialing.

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  3. Thank you for your prompt reply.
    His desruptive noises are from the time he wakes till he goes to sleep! - not only in school.
    I think he has classic autism, not aspergers. I have come to the conclusion that what has been missing in his life is ABA therapy. He did have some back when he was first diagnosed at age 2.5 years. He had ABA for about 2 years. We saw wonderful gains. But he 'tricked' us to believe that it would be better for him to have a different variety of interventions as he is so high functioning. i.e. he is very articulate, completely verbal etc BUT he really is autistic to the core. We really have tried so many things and have not made much of a dent.
    I am understandabley very frustrated.
    We have tried homeopathy, supplements, and were even going to be participating in the drug study you mention above on Piogliatizone, but he did not give his consent and they did not allow it. He was 9 at the time!!

    What do you suggest if we were to try one or two of your recommendations? and how long will it take to see any results?

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    1. Debbie, if was classic autism he would not be articulate and would not be able to give consent to anything. All the autism terminology has been corrupted through over-use and over-diagnosis.

      The terminology does matter, because if he has normal IQ, Baclofen is likely to help. If has reduced cognitive functioning, then Bumetanide is a good place to start.

      Oxidative stress affects most people with a autism/asperger's and so NAC is well worth trying.

      Baclofen and Bumetanide are prescription drugs, NAC is a supplement. If NAC works, you will notice in a couple of days.

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  4. Peter... what kind of dosing do you expect for maximum benefit of sytrinol? Also, my son is a chewer... everything in his mouth... his stomach is very sensitive so high dose NAC has been tough... any ideas there for something that might help? TIA!

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    1. Sytrinol seems to help some people much more than others, I would start with 150 mg a day. See if you get a good effect and see if it continues.

      Pica, putting objects in your mouth, is common in autism. It can also be caused by some supplements, such as high dose vitamin B12.

      If he has GI issues you might well want to read the guest post on Verapamil. In addition to behavioral effects, it seems to make some people's GI problems disappear.

      http://epiphanyasd.blogspot.com/2016/03/verapamil-use-in-autism-request-for.html

      You may find that NAC capsules may cause more problems than mixing the NAC up in food/drink.

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  5. Thanks Peter.My son doesn't take high dose B12. Any other ideas on how to curb the Pica ?

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    1. There is quite a lot written about using behavioral strategies to reduce pica. You can download some resources here:

      https://www.autismspeaks.org/science/resources-programs/autism-treatment-network/atn-air-p-pica-guides?utm_source=social-media&utm_medium=text-link&utm_campaign=espeaks



      There probably is a biological cause/trigger to pica and this most likely varies from person to person.

      I think the behavioral approach is the best one to follow in this case.

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    2. Zinc helped my daughter's pica when she was very young.

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  6. Day 3 of sytrinol! babbling like crazy. Said MOMMA. so clearly. numerous times. A little wired at bed time though... went to be two hours later than normal... but he was so proud of all the noises he was making! Thank you Peter!

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    1. Great news, let us all know the longer term effect.

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  7. you had mentioned Sytrinol in earlier posts as having some of the benefits of NSAIDs such as Ibuprofen or Aleve without some of the longer term side effects. Is this benefit you are mentioning in this post for the same issues? Can you elaborate? thank you.

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    1. Sytrinol contains two citrus flavonoids tangeretin and nobiletin, both have interesting effects: anti-obesity, cholesterol lowering etc. Tangeretin is an agonist of peroxisome proliferator-activated receptors (PPARγ), nobiletin is not an agonist but does effect PPARγ signalling.

      PPARγ agonist drugs like Pioglitazone (brand name Actos) are prescription drugs used to treat type 2 diabetes. They have been trialled in autism with positive results. But these drugs also have multiple modes of action, which cause side effects. Actos is a big seller in the US, but was withdrawn from some countries because of the side effects.

      I wanted a safe PPARγ agonist for long term use. Sytrinol looks the best choice.

      Some NSAIDs like Ibuprofen are also PPARγ agonists, but they have other effects like inhibiting COX-1 and COX-2. The inhibition of COX-1 can cause damage to the mucus lining of the stomach, leading to the known GI side effects of NSAIDs.

      NSAIDs do seem to benefit many people with autism, and there are multiple possible reasons for this. Inhibiting COX-2 may be the major reason, but being a PPARγ agonist may also play a role. It may even vary from person to person.

      People who find NSAIDs helpful, but can only tolerate them for the short term, might want to trial Sytrinol to see if it is effective. They might also want to trial Montelukast (Singulair) a leukotriene receptor antagonist, which might also be effective and is usually well tolerated in children.

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    2. Thanks Peter. You said that some seem to respond to sytrinol better than others, i wonder if you know what the profile would be (behaviorally, etc) of the responders -- or non responders? You are always very helpful!

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    3. I think the only way is to buy some and try it. As you can see in the comment above from the mother whose son is now saying "Momma" on day 3 of her trial, the effect can be profound. For us Sytrinol is helpful, but not profound. It is safe and not so expensive and if it does not help, you can always give what is left to a friend/relative with elevated cholesterol.

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  8. So the effect has waned quite a bit ... After the initial excitement with all of his babbling ... It has tapered off almost back to where we were originally ... Would you suggest increasing sytrinol to two pills a day ? Or perhaps every other day? Or move on try something else:( so discouraged.

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    1. I would try experimenting, maybe two days with and then two days without. We see the same result, with the effect fading. Using higher and higher doses is not a good idea.

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