Autism and diabetes…not ready for prime time

21 Oct

A recent news story on autism discussed: Common Link Suggested Between Autism and Diabetes: Study Implicates Hyperinsulinemia in Increased Incidence of Autism. I figured I’d take a day or two to read up on this and try to write about it. I didn’t figure on Emily Willingham. If you aren’t following her articles and you are into autism and science, you might want to consider doing so now. She’s already covered the story and in much better detail and expertise than I ever could in: Autism and type 2 diabetes linked because “both are increasing”?

Which tells you a lot right there. This is another “there is a temporal correlation, maybe there’s a link” type of story. The journal article is an opinion piece, not a research study. The Opinion Article, Insulin signaling and autism, is by Michael Stern of Rice University and appears in Frontiers In Cellular Endocrinology. In it he makes it clear it is a hypothesis. Unfortunately, Rice University has promoted this far beyond it’s current importance. A press release, including a YouTube video are out.

As Ms. Willingham points out, the language of the press release could be much better. Starting with the title:

Research proposes common link between autism, diabetes
Study implicates hyperinsulinemia in increased incidence of autism

This isn’t a study. It is an opinion piece. It’s great to have new ideas thrown out. I’ve seen many come and go in just the past few years. But let’s consider the opinions calmly and on their merits.

The YouTube video, in my opinion, goes further into overplaying this story:

Well, I think the key point of the hypothesis is that both autism and type 2 diabetes or obesity have the same common underlying cause, which is hyperinsulinemia.

It then goes on into the discussion of the proposed link. It goes on long enough, in my opinion, that the key word, “Hypothesis”, is pretty much forgotten (I had to go back and listen again to hear it).

Stories on this hypothesis carry titles like
Research proposes common link between autism, diabetes
Common link between autism, diabetes identified
and
Potential Link Found Between Type 2 Diabetes and Autism

So far this hasn’t really taken off. It would be good to put the idea in front of some researchers who could actually address it. I don’t think that press releases are the way to do that.

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28 Responses to “Autism and diabetes…not ready for prime time”

  1. Anne October 21, 2011 at 10:00 #

    What I managed to pick up even from the press release is that this guy isn’t up to speed on autism research. Change kids’ diet and see if they’re less autistic? Autism isn’t just another “chemical imbalance,” it’s an atypical pattern of connectivity in the brain. Even if this pattern were triggered by hyperinsulinemia, how would normalizing insulin levels rewire the brain to the typical patterns?

    As far as changing diets improving autistic symptoms goes, of course chronic tummyaches are going to make kids miserable enough to act “more autistic” than they would otherwise.

  2. daedalus2u October 21, 2011 at 14:09 #

    The link to Emily Willingham’s piece is broken.

    This is a really unfortunate idea. I hope none of the quacks start to give insulin to children with autism (unless the child is diagnosed with diabetes by a competent doctor). This guy doesn’t seem to know much about autism (or insulin physiology). He also doesn’t seem to appreciate what the quacks might do with this. We could have people dead or brain damaged from insulin shock because of this.

    Anne, the problems of atypical connectivity are (mostly) functional connectivity. This is the connectivity that happens in sub-second time intervals and keeps the brain functioning “in sync”.

    This functional connectivity is what is observed on fMRI BOLD, and is reduced in people with autism. There are reported instances where there is acute and temporary resolution of autism symptoms, as during fever.

    http://daedalus2u.blogspot.com/2008/01/resolution-of-asd-symptoms-with-fever.html

    This acute resolution could not be due to the formation of new actual connections (because it is too fast and is transient), it has to be due to a modulation of functional connectivity. What is measured in BOLD is where the level of nitric oxide is high enough to activate soluble guanylyl cyclase and cause vasodilation. My hypothesis is that the high NO levels that occur during fever augment the basal NO level and are responsible for the increased functional connectivity.

  3. navi October 21, 2011 at 14:40 #

    Heh. Diabetes is impossible for my son. He can’t process sugars…. good, considering it runs in his dad’s family.

  4. daedalus2u October 22, 2011 at 01:24 #

    I just remembered one of the papers I was thinking about in the context of this.

    http://www.ncbi.nlm.nih.gov/pubmed/14615391

  5. Anne October 22, 2011 at 10:17 #

    Daedalus,

    I think we may be talking about different types of structural anomalies. I’m talking about differences in volumes of various anatomical structures in the brain. Are you saying these are irrelevant?

    http://journals.lww.com/pedresearch/Fulltext/2011/05020/Structural_MRI_in_Autism_Spectrum_Disorder.10.aspx

    http://www.ajnr.org/content/32/9/1607.short

    and many more behind paywalls.

  6. daedalus2u October 22, 2011 at 17:34 #

    Anne, I am not talking about structural abnormalities, but rather differences in functional connectivity.

    Each neuron makes about 10,000 connections to other neurons. All of those connections cannot be active simultaneously. Those connections would be what I would call structural or physical connections. Which ones are actually active is what represents the functional connectivity.

    Changes in mental activity that occur rapidly (seconds) cannot be due to changes in physical connectivity (because the physical connections can’t change that rapidly), they can only be due to changes in functional connectivity.

    In the Rett Syndrome mouse model, when MeCP2 gene is reactivated in mice exhibiting RS symptoms, the RS symptoms go away very rapidly, including the characteristic paw-mouth motions called stereotypies. These changes occur so rapidly that they can’t be due to large-scale rewiring of the physical connections in the brain, the changes must be due to changes in functional connectivity.

    Similarly, in some children with autism, when they have an acute fever, some of their autism symptoms get dramatically better. When the fever abates, their autism symptoms return. These changes can’t be due to large-scale rewiring of physical connections in the brain, the changes must be due to changes in functional connectivity.

    There is coupling between physical connectivity and functional connectivity, and in both directions. The process of neurodevelopment is mediated in part by that coupling, by which the operation of the brain (i.e. its functional connectivity) differentially modulates its physical connectivity. The physical connections in the brain are not static, but they are not as dynamic as the functional connectivity is.

    My hypothesis is that if the functional connectivity can be restored to a more neurotypical state, that the brain will self-modify to produce a more neurotypical physical connectivity. The loss of autism symptoms during fever is very likely due to increased functional connectivity due to higher NO levels during fever. Fever is not the appropriate way to do that, but there are other techniques.

  7. Anne October 23, 2011 at 01:39 #

    Ok, I guess there are processes going on that I wasn’t aware of.

    I’m still bothered by the whole cure mentality and the possibility that treatment could make things worse, which nobody seems to mention.

  8. daedalus2u October 23, 2011 at 03:08 #

    The whole cure mentality really bothers me too. What the curebies want (their autistic child to disappear and an NT child of identical physical appearance to appear in their place) isn’t going to be possible, ever.

    What is possible is increasing the functional connectivity of an individual with an ASD such that they can develop in a more NT neurodevelopmental trajectory from that time forward. That is something that people with ASDs will like, it is something that people who care about and who care for people with ASDs will like, it won’t be good enough for the curebies.

    That is the type of thing that the reputable autism funding agencies are trying to find, but they don’t know how to find it. That is why they are mostly funding genetic stuff because the genetic stuff just has to be important someway, somehow, somewhen. The genetics of autism is showing itself to be extremely complicated, so complicated that (to me), it shows that autism is fundamentally not genetic.

    None of the reputable autism research groups are pushing any treatments, and won’t until they have been tested properly. The reputable groups do appreciate there is a possibility of harm, it is the irresponsible quacks who don’t.

    • Sullivan October 24, 2011 at 04:51 #

      Thanks, Emily,

      I think I have the link fixed now.

  9. Anne October 23, 2011 at 19:33 #

    Which people with ASDs want to take a drug that will “put them on a more NT developmental trajectory”? If the sensory impairments and communication deficits are already established, how is it likely that changing later stages is going to help? And how do you predict who will benefit if we can’t use biomarkers? Not all autistics improve during fevers; some function lower than usual. So whatever signaling pathway is goofed up isn’t consistent. Plus, the parents will be the ones choosing, and they have conflicts of interest.

  10. daedalus2u October 23, 2011 at 21:54 #

    Anne, those are all very good questions which I think I have answers for, but which I don’t have data to demonstrate that my answers are correct. I am pretty sure, but don’t have the research data to demonstrate it.

    Yes, fever does not always improve function. Fever is not a good way to correct the dysfunction that is present, even though it sometimes does. That fever sometimes does produce those changes is very strong evidence that in the people that fever helps, the dysfunction is not structural; that is it is not due to actual physical neuronal connectivity, it is due to functional connectivity.

    There are other ways, and I think I have a way that will work better than fever. It isn’t a panacea, it won’t “cure” anyone, but I think it will produce changes in function that people will think is beneficial. There should be no adverse effects even in people who don’t “need” it.

    My blog on fever therapy discusses the physiology behind what I am talking about.

  11. Anne October 24, 2011 at 06:07 #

    Daedalus,

    I didn’t mean to imply that fever was the recommended treatment, just that there’s evidence the mechanism you observed is not universal.

    Thanks to getting up too early for a conference the past few days, I don’t have the brainpower to grok what I read on your blog.

  12. daedalus2u October 24, 2011 at 12:56 #

    Anne, I put the comment about fever not being a good way to do it to try and deter the quacks from trying fever. Quacks don’t know what they are doing, and as the saying goes, “fools rush in where angels fear to tread”.

    The mechanism is universal, it is just that fever does not always trigger it, normal compensatory pathways usually work to prevent things like fever from affecting it. Those same compensatory pathways make it really hard to influence in non-physiologic ways.

  13. Victoria Gillen October 24, 2011 at 14:19 #

    Caveat: I have not read the study. That being said, AEDs and psychotropis both cause tremendous weight gain… add to that behaviour plans often use food for tangible reinforcers. High incidence of Type 2 diabetes is no surprise…

  14. RAJ October 24, 2011 at 19:28 #

    Diabetes and auto-immune disease has been linked to autism risk in many studies. I fail to see Sullivan’s complaint. In Toronto’s Hospital foe Sick Children their study found that the prevelance of diabetes type 1 in autistic people was greater than population norms.

    In DiGeorge, Velo-Cardio-Facial syndrome (22q11.2) ASD is present in 25% of cases. 73% of cases have an immune deficiency or autoimmune deficiency including Graves Disease and Rheumatoid arthritis. Auto-immune disease in the mothers are associated with risk for premature and low birth weight deliveries which are independantly associated with autism risk.

    The 22q11.2 deletion syndrome is as common as Fragile X (1in 4,000) and is not inherited either with 90% of cases having a de novo mutation in contrast to being an inherited event.

    Klinefelter Syndrome is a genetic disorder associated with ASD risk that occurs only in males. Kliefelter syndrome also is not inherited with all cases being caused by a do novo mutation. Klinefelter syndrome is also associated with the auto immune disease systemic lupus erythematosus. Klinfelter disease is the most common genetic disorder associated with autism risk ocurring in 1 in 500 males.

    http://ghr.nlm.nih.gov/condition/22q112-deletion-syndrome

    http://ghr.nlm.nih.gov/condition/klinefelter-syndrome

    http://care.diabetesjournals.org/content/28/4/925.full?ijkey=523a0544d80989f6e6e8333b7870c5ee99a23aca&keytype2=tf_ipsecsha

    • Sullivan October 24, 2011 at 19:48 #

      The author of the opinion piece stated in an interview that he wrote it because there wasn’t anything out there already.

      Aside from that, perhaps a closer read of the article would give you an idea of my point, RAJ. Then you could at least “fail to see” the correct point.

  15. Emily Willingham October 24, 2011 at 23:35 #

    And I guess it might also reveal that the type of diabetes in question is Type II. That’s just not the same animal as type I.

    Klinefelter? XXY? Interesting. Or it would be if your link mentioned autism in connection with it. But wouldn’t that be counter to the hypothesized androgenization mechanism of autism?

    I find on PubMed research primarily all from the same group alleging a higher rate of autism traits in KS men. I’m curious about how much they think just being KS and the social inputs resulting from that might influence a person’s social interactions.

    Bishop’s group has an interesting paper on sex chromosome trisomies in general and ASD/social impairments that’s also open access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107947/?tool=pubmed

  16. RAJ October 25, 2011 at 02:38 #

    The author who claimed he had never seen anything out there is simply wrong.

    One of the most replicated finding in autism studies is the association with gestational diabetes with autism risk:

    http://www.ncbi.nlm.nih.gov/pubmed/21972225

    http://www.ncbi.nlm.nih.gov/pubmed/19567888

    As far Klinefelter Syndrome and autism is concerned there are numberous articles demonstrating a high prevelance of autism in Klinefelter boys who were diagnosed with autsm using gold standard diagnostic tools (ADI-R).

    http://pediatrics.aappublications.org/content/123/5/e865.long

  17. Anne October 25, 2011 at 07:24 #

    Raj,

    Your diabetes goalposts are shifting around a bit. Gestational diabetes (temporary, in the mother) =/ Diabetes Type 1 (loss of insulin production) =/ Diabetes Type 2 (development of insulin resistance) Gestational diabetes could cause all sorts of things, but it’s still something different than the paper under discussion covers.

    Could you also explain how KS relates to the original paper about a link between Type 2 Diabetes and autism? Sorry if I’m overlooking some obvious link you explained.

  18. RAJ October 25, 2011 at 12:52 #

    Anne:
    Diabetes is a spectrum disorder. There is actually a journal called ‘Diabetes Spectrum Disorder”. Gestational Diabetes is associated with autism risk and mothers with a history of gestational diabetes have a seven fold increase risk of being diagnosed with diabetes type 2. About 10% of mothers diagnosd with gestational diabetes are found to have diabetes type 2 that was undiagnosed prior to the pregnancy. Children born with a history of gestational diabetes are also at risk for obesity and diabetes type 2. People with diabetes type 2 can go undiagnosed for decades. A diagnosis is based on blood sugar levels. Medication and or dietary changes can reduce blood sugar levels. A person diagnosed with diabetes type 2 whose blood sugar levels are reduced by treatment may no longer meet criteria for diabetes type 2.

    http://ndep.nih.gov/media/fs_post-gdm.pdf

    Diabetes type 1 is at the severe end of the spectrum and results from autoimmune destruction of insulin-producing beta cells of the pancreas. Lifetime insulin therapy is required.

    The association between autism risk and autoimmune disease has been well established. In Klinefelter syndrome the men are at increased risk for systemic lupus erythematosus (SLE). In DiGeorge-Velo-cardio-facial Syndrome (22q11.2 deletion syndrome) 77% of individuals have an immune deficiency or autoimmune disease including Graves Disease, systemic lupus erythematosus, diabetes type 1 and rheumatoid arthritis among others. Mothers with autoimmune disease or imune deficiencies are at greater risk for prenatal infection and low birth weight and preterm deliver both of which are also independantly associated with autism risk.

    Sullivan’s claim that ‘Diabetes is not ready for prime time’ is a huge stretch based on one speculative paper. One could find a paper that failed to replicate a previous genetic study and make the same claim ‘Genetics are not ready for prime time’.

    http://www.ncbi.nlm.nih.gov/books/NBK1523/

    In my view ‘autism’ is a complex multifactorial disorder with many layers of complexity. Genetic variances of small effect are not specific to ‘autism’. Environmental pathogens of small effect are also not specific to ‘autism’. Pre, peri and neonatal complications are also not specific to autism. Factors of small effect whether they genetic, epigenetic, environmental or associated with unfavorable events in the pe, pei or neonatal period all contribute to autism risk individually and in aggregate add to overall autism risk.

    Sullivan’s complaint about the hypothetical paper in question is a complaint I share as well, but to extrapolate that to claim ‘Diabetes is not ready for prime time; is disengenous. People who claim there is a single underlying cause explaining all cases whether it is ‘diabetes type 2 causes auitsm’ or ‘genes cause autism’, or ‘vaccinations cause autism’ or ‘high levels of fetal tetesterone causes autism’ are invoking simplistic explanations that relies on ignoring the evidence from many fields of autism research. If there were a single causal mechanism that ’causes’ autism it would have been discovered long ago.

    • Sullivan October 25, 2011 at 14:48 #

      “Sullivan’s complaint about the hypothetical paper in question is a complaint I share as well, but to extrapolate that to claim ‘Diabetes is not ready for prime time; is disengenous.”

      then

      “People who claim there is a single underlying cause explaining all cases whether it is ‘diabetes type 2 causes auitsm’ or ‘genes cause autism’, or ‘vaccinations cause autism’ or ‘high levels of fetal tetesterone causes autism’ are invoking simplistic explanations that relies on ignoring the evidence from many fields of autism research. If there were a single causal mechanism that ‘causes’ autism it would have been discovered long ago.”

      Sorry, are you trying to imply that this sentence follows from the previous one in your paragraph? It doesn’t. Very clearly it doesn’t. You’ve been reading this blog long enough to know that.

      Silly debate tricks like that are one reason why your comments tend to stifle discussion rather than encourage it.

  19. Prometheus October 31, 2011 at 18:49 #

    OK, I’m trying to get my head around RAJ’s concept of diabetes types 1 and 2 being a “spectrum disorder”. The journal he was referring to is actually titled Diabetes Spectrum (no “disorder”) and is put out by the American Diabetes Association. Even if he had gotten the title correct, journal titles are not scientific data.

    Still, I’m trying to reconcile how the acute destruction of the beta cells in the pancreas (type 1 diabetes) by viral infection, autoimmune attack or a combination of the two is on a “spectrum” with increasing insulin resistance in (almost) all body cells and a gradual decline in insulin production (type 2 diabetes). To my rather simplistic eyes, there seems to be very little common ground on which to create a “spectrum”.

    The fact that type 2 diabetes often responds to weight loss and diet change isn’t the same as saying it “goes away” or that those people are no longer at risk. Long-term follow-up seems to suggest that even after weight loss and diet modification, there is an increased risk that “ex”-type 2 diabetes patients will end up needing medical therapy for diabetes. It may be – as was shown with hypertension and salt intake – that obesity causes the type 2 diabetes to manifest earlier and addressing the obesity will allow a period of “normality” until the disease progresses further.

    The connection between gestational diabetes and autism is also rather tenuous – more work is needed to tease out the contribution of gestational diabetes to prematurity, intrauterine stress, etc. While it is an intriguing “clue”, it may turn out to be a “red herring”.

    Prometheus

  20. daedalus2u October 31, 2011 at 22:45 #

    RAJ, I claim there is an single underlying cause of autism, and I did not come at that through looking at anything simplistically or by ignoring any reliable data in the literature. That single cause is low nitric oxide during certain periods of neurodevelopment. Multiple things can cause low nitric oxide during those certain periods, but the final common causal pathway for autism is low nitric oxide.

    Diabetes type 1 and diabetes type 2 are two completely different disorders. You can have one, or the other or you can have both. Diabetes type 1 is pretty well understood and can be well treated. Diabetes type 2 is not well understood and many of the treatments for it are poor and don’t reflect the underlying disorder (which is not too much glucose in the blood). The underlying problem in diabetes type 2 is not enough glucose inside of cells.

    Hyperglycemia can cause low nitric oxide via generation of superoxide by NADPH oxidase, or via RAGE. Hypoglycemia can cause low nitric oxide via generation of superoxide following activation of andrenergic receptors. Gestational diabetes is usually too late to cause autism. That is why the odds ratio in the paper you cited is only 1.76. That is, if the incidence of autism without gestational diabetes is 1 in 100, the increased odds with gestational diabetes make it 1.76 in 100.

    The various teratogens that cause autism are nitric oxide synthase inhibitors. That includes thalidomide, valproate and phenyltoin. They cause autism in the first trimester.

    Diabetes type 2 is characterized by increased levels of asymmetric dimethylarginine (ADMA) as is gestational diabetes. That is an endogenous nitric oxide synthase inhibitor. That is probably the mechanism for increased autism due to diabetes type 2 and gestational diabetes.

    http://www.ncbi.nlm.nih.gov/pubmed/20960114

  21. sharon October 31, 2011 at 23:30 #

    @daedalus2u, when you refer to a single cause of Autism, do you include all spectrum diagnosis such as Aspergers in that? Or are you referring to classic Autism?

  22. daedalus2u November 1, 2011 at 04:21 #

    I include all. That includes the autism associated with copy number variants. Those CNVs produce metabolic stress that perturbs the basal NO level and that perturbed basal NO level results in autism-like symptoms. There are degrees, depending on the NO level when the neuroanatomy developed. At any stage (even adult) if the basal NO level is increased there is movement on the spectrum toward a more NT phenotype.

    I really see the ASD spectrum as the fundamental cognitive trade-offs that humans have evolved. The two fundamentally human traits, language with grammar and syntax, and tool making and tool using both require a large brain with lots of plasticity over the lifespan. The two computational tasks are to some extent incompatible, so to optimize a brain for one is to de-optimize it for another. Because the maternal pelvis is limited in size, the infant brain is limited in size at birth, so there isn’t neural substrate to do both.

    A big brain with lots of cognitive capacity is extremely useful, but different cognitive tasks take different neuroanatomy to accomplish. To see well you need a big visual cortex. To hear well you need a large aural neuroanatomy. To be agile and coordinated you need a large motor area. Because humans can communicate, a tribe that has a diversity of cognitive abilities can share those abilities and can out compete the tribe where everyone is the same. Because humans evolved mostly in tribes of highly related individuals the needed neurodiversity couldn’t be coded for by genes because the people in the tribe shared many of their genes. The neurodiversity had to derive from some other source of variation, it must have derived from the environment, and it had to be the environment in utero.

    I think that the tribes where in utero neurodevelopment was variable simply due to noise, the Brownian motion of molecules jiggling the DNA and transcription factors and what ever else was going on, had greater neurodiversity and so had a spectrum of cognitive abilities. I think that selected for DNA where neurodevelopment was extremely sensitive to first trimester stuff.

  23. sharon November 1, 2011 at 05:20 #

    How do you account for Aspergers being of seemingly high heritability. Possibly moreso than any other ASD?

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