Metabolic Syndrome & Autism

Today’s post is not just about autism.

Having written 370 posts in this autism blog, I sometimes feel that I am becoming a bit of an expert on diabetes (and COPD), which you might think has nothing to do with autism.

I was talking to a friend of mine who has type 2 diabetes; he was telling me about all the other things that are going wrong with him, because he actually has “metabolic syndrome”.

What exactly is metabolic syndrome?  It really is not a very good name. Sure you can have a metabolic system, but there are going to be many different ones.  It looks like in the world of medicine there is just one.

The common problem is that in late middle age many people get overweight around their waist, they also have increased blood pressure, high blood sugar and abnormal cholesterol, or triglyceride levels. This combination of symptoms is called metabolic syndrome and it increases your risk of heart disease, stroke, diabetes and much more. (see chart above, even high uric acid/gout is there)

The clever way to treat metabolic syndrome would be to treat the underlying molecular biology, rather than each symptom one by one.  This is not as hard as it may sound, just from reading about the biology of autism, I was telling my friend lots of things he could suggest to his doctor.

If you are going to take a drug to lower blood pressure, why not take the one that also protects your beta cells, the ones that produce insulin, from dying? If you are going to take an ACE inhibitor, why not take the one that will also improve your insulin sensitivity. Instead of taking a glitazone drug that is effective at lowering blood glucose, but has not been shown to reduce the long-term complications of diabetes (such as heart disease and stroke), why not take a single drug that does all three?

Metabolic Syndrome & Autism

It is not surprising to me that research shows that parents who develop metabolic syndrome have an increased likelihood of already having children with autism.

Nor is it a surprise that people with autism, or schizophrenia, have themselves a tendency to various kinds of metabolic syndrome; in fact I would suggest that autism is a metabolic syndrome, just not always the same kind.

It is not a surprise that the drugs produced to treat the classic metabolic syndrome seem to provide such a good hunting ground for autism drugs.

We know that glitazone drugs, being PPAR gamma agonists, should help some kinds of autism and also that PPAR delta agonists may help some with mitochondrial disease. The issue I have with glitazone drugs is their safety in long term use.  Another glitazone autism trial is underway in Canada. Glitazone drugs are used to improve insulin sensitivity in type 2 diabetics.

Bezafibrate is getting a well-deserved trial for mitochondrial disease. Through its action on PPAR, where it is a “pan-agonist”, it is thought that Bezafibrate should trigger biogenesis of mitochondria. Bezafibrate is an old drug to lower cholesterol.

One very interesting candidate drug for autism is Telmisartan which will be covered in a coming post on Angiotensin II in the brain.  Telmisartan is an Angiotensin AT1 agonist, which means it will lower blood pressure, but it does numerous other things. It happens also to be a PPAR gamma/delta agonist.  It improves insulin sensitivity and lower blood glucose levels.  It also modifies the immune system by reducing Il-17a, an important inflammatory cytokine found elevated in both autism and schizophrenia. It also reduces leptin release and prevents leptin resistance. Leptin levels are high in autism and leptin resistance is feature of obesity.

One of the drugs often prescribed to people with metabolic syndrome is Atorvastatin, which some readers of this blog have found improves the application of cognitive ability in their case of autism.

If I had metabolic syndrome, after losing weight, I would choose Atorvastatin, Verapamil and Telmisartan as my top three drugs; none of which are prescribed to that friend of mine. I would also add a glass of beetroot juice which is vasodilating; it is not a drug, but should do plenty of good. I would use an antioxidant like ALA (alpha-lipoic acid) and use sulforaphane to activate the body’s antioxidant genes via Nrf2; many side effects of metabolic syndrome are caused/aggravated by oxidative stress.

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes

 

In recent posts we have looked at PPARα (Peroxisome proliferator-activated receptor alpha) and PEA (Palmitoylethanolamide), which activates it.  Both appeared to me to have some very interesting properties.  PPARα has siblings - PPARβ, and PPARγ.  It may not come as a surprise that one of these is currently at the centre on clinical trials for autism.  But is it the right one?

Thiazolidinediones (TZDs) are agonists of PPAR gamma (PPARγ), a nuclear hormone receptor which modulates insulin sensitivity, and have been shown to induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. The TZD pioglitazone (Actos) is an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile. Pioglitazone is currently in Phase 2 trials for autism.

Dose Finding Study of Pioglitazone in Children With Autism Spectrum Disorders (ASD)

The full version of the earlier study was:-

Effect of pioglitazone treatment on behavioral symptoms in autistic children

Conclusion

In view of its established safety profile, the current results provide the rationale or further testing of pioglitazone in autism and other forms of ASD. 

It is interesting that  PPARγ agonists are currently used in type 2 (non-insulin dependent) diabetes because in my earlier post is was shown that activating PPARα could treat a nasty side effect of both type 1 and type 2 diabetes, Peripheral Neuropathy;  this is damage to the peripheral nervous system.  An example is sharp pain in the sole of your feet, even when lying down.

 

Fibrates

Fibrates are a class of drug identified in the 1930s and are used in accessory therapy in many forms of hypercholesterolemia, usually in combination with statins. Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore indicated only in those not tolerant to statins.

Although less effective in lowering LDL and triglyceride levels by increasing HDL levels and decreasing triglyceride levels, they seem to improve insulin resistance when the dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes type 2). They are therefore used in many hyperlipidemias. Fibrates are not suitable for patients with low HDL levels.

In the 1990s, the mechanism of action was discovered;  fibrates activate PPARα.

Fibrates are the main PPARα activating drugs in use, but there do seem to be various problematic side effects.  In an earlier post we did discover a naturally occurring PPARα activator that seems to have no side effects or contraindications, PEA (Palmitoylethanolamide).

Heart Disease

Heart disease is the leading cause of death in developed countries and so is very well researched.  What is remarkable is how closely related autism is to heart disease.

Almost all of the ingredients in my autism Polypill are actually drugs normally given to people with heart disease and of course people with autism are known to be prone to heart disease.

Atherosclerosis is a chronic inflammatory disease as well as a disorder of lipid metabolism.  So is autism.

Let’s look what we can learn from research into PPARs in heart disease.

 

PPARs in atherosclerosis: the clot thickens

"Atherosclerosis is a chronic inflammatory disease as well as a disorder of lipid metabolism. The accumulation of cholesterol-rich lipoproteins in the artery wall results in the recruitment of circulating monocytes, their adhesion to the endothelium, and their differentiation into tissue macrophages. Lipid-loaded macrophages play an important role in the production of chemokines, cytokines, and reactive oxygen species in the early stages of lesion formation. Therefore mechanisms that limit macrophage cholesterol accumulation and/or prevent the production of inflammatory mediators all have the potential to inhibit lesion development.

The PPAR family is comprised of 3 different proteins: PPARα, PPARβ, and PPARγ. Natural ligands for these receptors include fatty acids and oxidized fatty acids. The relevance of PPAR pathways to metabolic disease is underscored by the use of the fibrates (PPARα agonists) and thiazolidinediones (PPARγ agonists) to treat hyperlipidemia and type 2 diabetes, respectively."

 

 

"PPAR signaling pathways influence macrophage gene expression and foam-cell formation. Ligand activation of PPARα and PPARγ, but not PPARβ/δ, inhibits the development of atherosclerosis in LDLR_/_ mice. Both systemic and local mechanisms might contribute to these beneficial effects. Previous studies have suggested that PPARα and PPARγ increase LXRα expression in macrophages and promote expression of ABCA1, which mediates cholesterol efflux to apoAI. Results from the study in this issue by Li et al.  suggest that PPARγ may also inhibit cholesterol accumulation in macrophages through direct regulation of ABCG1, which has been implicated in cholesterol efflux to HDL. Activation of each of the PPARs with selective agonists also inhibits the expression of inflammatory markers in the artery wall. These findings reinforce potential use of PPAR agonists as antiatherosclerotic therapies."

"The study by Li et al.  provides new insights into pathways regulating macrophage lipid accumulation and rounds out the family picture of PPARs in atherosclerosis. Both The study by Li et al. provides new insights into pathways regulating macrophage lipid accumulation and rounds out the family picture of PPARs in atherosclerosis. Both PPARα and PPARγ ligands were shown to protect against atherosclerosis in LDLR–/– mice and inhibit macrophage foam-cell formation. ligands were shown to protect against atherosclerosis in LDLR–/– mice and inhibit macrophage foam-cell formation. In contrast, the authors did not observe any effect from PPARβ activation. Given the discrepancies between PPARβ agonist effects in mice and primates, however, the possibility that PPARβ ligands may have beneficial effects on cardiovascular disease in humans is not excluded by the present study."

So it would appear that activating PPARα and PPARγ has benefit in heart disease, but likely not PPARβ.

It seems that the traditional PPARα activator drugs, the fibrates, are problematic.  PPARγ activators are widely used in diabetes therapy and there are safe choices.

In autism, a PPARγ activator has already been shown itself to be effective in initial phase 1 trials.  

Conclusions

Heart disease is well researched by clever, very well-funded, people so I am sure they will have figured out to trial PEA instead of Fibrates as a PPARα activator and of course to look at the benefits of Pioglitazone as a PPARγ activator.

Autism is not so well researched.  The PPARγ activator trial is proceeding slowly forward in Toronto.  The PPARα activator trial will commence shortly, but not with Fibrates.