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What is causing the increase of type-1 diabetes? (part 1)

Discussion in 'Research' started by joshualevy, May 19, 2013.

  1. joshualevy

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    I'm not completely happy with this posting, but I've been working on it for many weeks, and at this point I think it is better to publish what I have, than to continue to struggle with it. Maybe in the future, will post an improved version.

    This posting is a little different from my usual fare. Instead of discussing specific research results, I'm going to discuss, in more general terms, a subject that has come up repeatedly:

    What is causing the increase of type-1 diabetes?

    Every six months or so we get a study, government report, or newspaper article claiming that there must be something in the environment which is causing the number of type-1 diabetics to go up, way up. These articles usually follow the same path:

    1. Description of type-1 diabetes as having a genetic and environmental cause [d0].
    2. The number of type-1 diabetics is going up (way up!)
    3. The number of younger type-1 diabetics is going up even more than older ones.
    4. So there must be an environmental cause (usually a toxic chemical) which is growing, and causing the numbers of type-1 diabetics to grow.
    They often contain a quote like this one:
    Despite a strong genetic component to the susceptibility of T1DM, this marked increase in incidence in different populations within a short period of time cannot be explained by increased transmission of T1DM susceptibility genes. So what is the cause? [r1]
    Or like this one:
    Essentially all researchers agree that changes of this magnitude cannot be explained by genetics alone. [r6]
    (The d-numbered footnotes refer to extra discussion and r-numbered footnotes refer to references, both are at the bottom of the posting.) Before you get too worried about such news reports, it's best to think about what should be happening. The simple answer is: of course the rates of type-1 diabetes are going up, and we should all expect that. Why? Type-1 diabetes has a large genetic component. Before 1920, most people who were diagnosed with type-1 diabetes died before they had children. Now, those people are living longer, happier, richer lives, with children and grandchildren of their own. So the genetic component of type-1 is becoming more common, and of course the rate of type-1 diabetes is going up [d1]. We certainly would not expect it to be going down or staying the same.

    So the the correct response when someone says the rate of type-1 diabetes is going up (way up!) is to yawn, and say "Of course, I would not expect anything else" and "Isn't it great that what was previously a fatal disease is not any more". However there are still some issues which need some more discussion:

    1. Referring to age at diagnosis: why is the rate of very young type-1 diabetics going up more than the rate of older diabetics?
    2. Is there something in the environment which is contributing to the increase of people with type-1 diabetes, and especially a toxic chemical of some kind? Even if some of the growth rate is caused by genetics, maybe some of it is not?
    3. Are sentences like "the increase is too high to be explained by genetics alone" (or similar) supported by the data we have, or are they fear-mongering?
    Why are more children getting diagnosed at a younger age?

    I'm not going to review it in detail, but I think there is pretty strong evidence that more children are getting diagnosed with type-1 diabetes at a younger age than previously. For example [r1,r2] both show this. The percentage diagnosed between ages 0 and 5 is going up faster than the more traditional diagnosis between 10 and 20 years old.

    The first thing to realize here, is that you would expect this behavior based on the genetics and impact of type-1 diabetes. Type-1 is not (usually) caused by a single gene. It is caused by complex groups of genes which, acting together, make it more likely that you will get type-1, and other groups of genes that make it less likely. It is likely [need to specific references here] that there are gene groups that tend to cause type-1 in younger kids, and other gene groups that tend to cause type-1 in older kids. Prior to the 1920s, everyone who had type-1 diabetes died very close to diagnosis. So if you had the genes for the age 0-5 type, you had zero chance of having children. But if you had the genes for a 10-20 year old diagnosis, then maybe you would have children (especially in earlier times, with younger parents). Obviously, this would be a very small number of births, but it would be higher than zero. So the genetic "filtering" that type-1 death caused, was stronger for those "younger" genetic variants. Therefore when the genetic "filtering" is removed, we should expect type-1 diabetes to rise more quickly in younger kids than older kids. And that is exactly what is seen.

    Summary: faster growth in type-1 diabetes diagnosis in younger kids is something that we should be expecting based on the known genetics and lethality of the disease.

    Is there something in the environment causing more type-1 diabetes?
    Maybe a toxic chemical?

    Obviously, there are a huge number of chemicals out there, and any one of them might increase the incidence of type-1 diabetes. Even if we proved 1000 (or 10,000) chemicals do not cause type-1 diabetes, it might always be caused by one we have not tested. So the possibility of chemicals causing type-1 diabetes will always be with us. But I think there are two important points that should be made here:

    First, it is easy to show that a chemical causes type-1 diabetes.

    We have an animal model of type-1 diabetes. It's called the NOD mouse, and has been in widespread use for decades [d3]. The number of these mice who will naturally come down with type-1 diabetes, and when it happens, is well known. And some of these mice won't come down with the disease, even if most do. Therefore, any chemical you want to test, you can just give it to these mice, and see if the rate of type-1 diabetes goes up, or if the mice get it more quickly, than the untreated mice. [d4]

    This is the kind of mouse-based research that is done all the time, and it isn't even that expensive. Running a test on 300 mice is vastly cheaper and faster than running a test on even 1 person.

    So if anyone really believed that they know which chemical or drug caused type-1 diabetes. They could become famous quickly, easily, and inexpensively by testing their theory in mice. The fact that no one has done this suggests to me that none of the common chemicals sometimes suggested as a cause of type-1 diabetes, really do cause it [d5].

    Now, some people will make excuses. They are likely to say "we can't test chemical X because no one will fund it", but that is untrue for a number of reasons. Most obviously: non-profits, environmental groups, and government agencies often fund safety research. But also, companies that produce competitors to a chemical have a strong economic motivation to fund research that the other chemical is unsafe, since that would lead to higher sales of their (competing) chemical. Finally, remember that fame is an important motivator (in addition to money), and providing strong evidence that a common chemical is unsafe is a sure path to fame in the university, non-profit, and government worlds.

    Here are examples of experiments of that kind (could show chemical danger in NOD mice) but did not find any problems:

    Trichloroethylene (TCE): http://www.ncbi.nlm.nih.gov/pubmed/18958647 [d6]
    Mercury: http://www.ncbi.nlm.nih.gov/pubmed/11529910 [d7]
    Bisphenol A (BPA) is a more complex case, which I may cover in a future posting (time permitting).

    Second, not a lot of chemicals fit the dosing/timeline profile.

    The second problem with blaming a toxic chemical, is that the chemical needs to have a use profile that matches type-1's growth profile, in those countries where we have good data on type-1's growth profile.

    For example, it couldn't be DDT. Because in the USA, DDT use skyrocketed right after World War II, and then dropped to nearly zero in the 1970s. But the rate of type-1 diabetes continues to grow at a pretty constant rate. There was no big increase right after WWII and no dropping off in the 1970s. Similar arguments can be made against lead, PCBs, BPAs, and many other toxins [d9].

    But it turns out that type-1 diabetes growth appears to be pretty constant. More kids are diagnosed each year, but the increase is linear, and there are no big troughs or hills. (Although [r6] shows some small bumps up and down.) Indeed, if you look at the whole time period from 1920 to 2012, the growth is pretty constant the whole time (as much as we have data for). [Need to add specific references for this.] I think that suggests that there is no chemical environmental cause, because the environmental chemicals common to the 1920s are not common now, and visa-versa. I just don't see a good candidate. However, since testing the chemical is cheap and easy (see previous discussion), the moment someone does identify a chemical who's use has been steadily growing for the last 90 years, without any large troughs or hills, that chemical could be quickly tested. And if it happened to match the small ups and downs in the [r6] data in the same countries where that data was gathered, that would be even stronger evidence.

    Based on all this, if there is an environmental factor, a toxic chemical is not my leading contender. I think something like the "hygiene hypothesis" is more likely, or maybe something in the diet, or something related to affluence [d8].

    The increase is too high to be explained by genetics alone.

    Think about this claim for a minute. This sentence is based on three pieces of data:

    • We know how much type-1 diagnosis is increasing.
    • We know how much it should be increasing, based on genetics.
    • Therefore, we can see that there is a gap, which must be filled with an environmental cause of growth.
    Of these three statements, only the first is true. See [r1,r2, r6] and other studies. Even there, our knowledge is imperfect, but we do have some data about the overall change in the rate of type-1 diagnosis. But for the next two, we have nothing; absolutely nothing. Not all the genes that lead to type-1 diabetes have been identified. Not all the genes that protect against type-1 have been identified. How these genes interact to cause or avoid type-1 diabetes is not known. In short, we have no idea, what the levels of type-1 diabetes "should" be, based on genetic susceptibilities. Obviously, since we don't know 2, we can't know 3. In my opinion, people who say "there must be an environmental cause for the increase in type-1" are fear mongering, or looking for more research funding.

    Remember: I agree that there is an environmental cause of type-1 diabetes, but I'm also saying that there is no evidence that it is growing. Put another way (with double negatives): I'm not saying that there is no environmental component that causes type-1 diabetes. We know there is [d0]. Rather, I'm saying that there is no evidence that this environmental component is causing the increase in type-1 cases. It is not growing or causing more cases of type-1 diabetes.

    Summary: There is evidence that an environmental component exists, but there is no evidence that the environmental component is causing growth in type-1 diagnosis.



    continued in next posting...
     
  2. joshualevy

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    What is causing the increase of type-1 diabetes? (part 2)

    ...continued from previous posting

    Looking at Genes Specifically


    As far as I know, no researcher is looking at the overall genetics of type-1 diabetes to see if the overall genetic change is causing the overall type-1 diagnosis change. However, there are a couple of studies that look at a single gene specifically [r7]. These studies both looked at a gene highly associated with type-1 diabetes [d10] and they both found that specific gene had become less common in the population. Not more common, as would be expected. One study looked at the period from the 1960s to the 2000s, and the other compared the 1980s to the 2000s (roughly).

    Proponents of an environmental cause to increases in type-1 diagnosis can point to these studies as support for the idea that the growth is not caused by genetics. However, these studies provide only the tiniest support. Neither of these studies actually looked at the total genetic change affecting type-1 diabetes. Indeed, they couldn't do that, because we don't yet know all the genes that affect type-1 diabetes. It's like trying to guess if the value of pocket change is going up or down, based on the number of nickels in people's pockets, when you don't even know all the kinds of coins in circulation.

    So while these two studies are scientifically interesting, and should form the basis of more research, they are nowhere near the level of knowledge we need to say that the current growth in type-1 diabetes diagnosis is caused by an environmental factor.

    Discussion


    [d0] We know that the cause of type-1 diabetes has a genetic component, because it is more common in people with relatives who also have type-1 diabetes. In particular, the closer a relative who has type-1 diabetes, the more likely a person is to have it. This is a classic sign of a genetic component. However, we know that there is an environmental component as well, because of "twin studies". For a purely genetic condition, there should be no cases of identical twins, one with type-1 diabetes and one without. However, there are. In fact, in less than half of identical twin pairs do both twins have type-1 diabetes. It is more common that only one does [r3]. This difference in disease between identical twins is a classic sign of an environmental component. So it is clear that type-1 diabetes is caused by a combination of both genetics and environmental causes.

    [d1] No matter how I phrase it, some people read those last two sentences, and think I'm "blaming" parents for their children's type-1 diabetes. I'm not, and that's a silly idea in any case. I'm discussing genetics. It has nothing to do with blame. No one decides what DNA to pass to their children. And it is completely unreasonable to think "well something might go wrong with my kid, so I won't have any." If people thought like that, no one would ever have children, because something can always go wrong.

    [d3] Technically, we have at least three animals models for autoimmunity-based diabetes. Another is the BB ("Biobreeding") rat [r4], and the third is an animal that given a small dose of a beta cell toxin. The beta cell die off somehow triggers autoimmunity. This last technique is quite different that given the animal a large dose of a beta cell toxin (which is more common). Giving a large dose kills the beta cells, but does not trigger autoimmunity. It can be used to test insulin replacement, but not autoimmune effects.

    [d4] I know a lot of people are frustrated with NOD mice, because cures that work in those mice have failed when used on people. However, in this case, we are using NOD mice to show danger, rather than improvement. The "standard of proof" is much lower to show danger, as compared to showing safety and effectiveness. To show safety and effectiveness most people would require several tests in animals followed by several tests in people. On the other hand, to show danger, even one or two tests in animals would be enough to convince most people that a chemical was unsafe. The big frustration of NOD mice (that cures don't work when tried in people) doesn't affect this kind of danger testing, because if the chemical is found unsafe in mice, it's done: no tests in people are needed.

    [d5] Basically, the first time I hear someone say that chemical X might cause type-1 diabetes, I look at a calendar. I then wait a few years. If no one has published results for the obvious test in NOD mice, then I'm pretty sure chemical X does not cause type-1 diabetes. I then wait a few more years. By that point, if no one has published results, then I think it's settled that chemical X does not cause type-1. A logician will continue to chant "absence of evidence is not evidence of absence," but in the real world, it is.

    [d6] A quote from their abstract:
    To test whether TCE [Trichloroethylene, a chlorinated hydrocarbon] can exert similar deleterious effects on organ-specific autoimmune diseases, non obese diabetic (NOD) mice were given 5 mg/ml TCE via the drinking water for 12 weeks. ... Contrary to what has been found in systemic models of autoimmunity, TCE did not accelerate the diabetes of NOD mice and may have a protective effect.
    [d7] A quote from their abstract:
    We found that three weeks of treatment with mercury was also able to significantly suppress the development of insulitis and postpone the onset of diabetes in these mice. Thus, mercury-induced immune activation can counter-regulate the Th1 cell-mediated autoimmune responses and confer a partial protection against autoimmune diabetes in NOD mice.
    (Although I don't think people will line up for a clinical study injecting mercury or TCE to delay onset of type-1 diabetes. :)

    [d8] I am not saying that I think the "hygiene hypothesis" is correct. I am saying something much weaker: that the evidence we have for the "hygiene hypothesis" is stronger than the evidence we have for any single, specific chemical causing type-1 diabetes.

    [d9] This line of reasoning also tends to exclude breast feeding as an environmental protective against type-1 diabetes. Breast feeding rates were high in the 1920s, dropped to their lowest in the 1960s, rose in the 1970-1990s, and have been drifting higher since then [r5]. None of that is reflected in type-1 diabetes rates. If breast feeding protected against type-1, then the type-1 rate would be dropping slightly right now, not rising. Also, it would have been much higher in the 1960s, than in the 1980s, but the reverse is actually seen.


    [d10] I'm not a geneticist. Both studies dealt with something called "HLA class II". One study looked at a gene called "HLA-DR, DQ" , while the other looked at a genotype called "HLA-DR3/4-DQB1*0302". I'm not sure if they were both looking at the same gene, or slightly different genes. But in either case, they are clearly only looking at a tiny part of the genetics that lead to type-1 diabetes, which is my main point.

    References

    [r1] Incidence of childhood type 1 diabetes: a worrying trend by Ronald C. W. Ma and Juliana C. N. Chan
    October 2009
    http://www.nature.com/nrendo/journal/v5/n10/full/nrendo.2009.180.html

    [r2] Type 1 Diabetes in Urban Children Skyrockets, Increasing by 70%
    Jan 22, 2013
    http://www.newswise.com/articles/ty...kets-increasing-by-70-in-children-under-age-5
    http://vitals.nbcnews.com/_news/2013/02/01/16811346-type-1-diabetes-rising-in-kids-study-shows

    [r3] http://www.ncbi.nlm.nih.gov/pubmed/22569240
    This Italian twins study found:
    Genetic contribution to type 1 diabetes susceptibility was 40%, and the shared and individual-specific environmental components were 51% and 9%, respectively. [I removed the confidance intervals from this sentence, but they are in the original abstract if you want them.]
    [r4] Wikipedia on BB rat: http://en.wikipedia.org/wiki/Biobreeding_rat

    [r5]
    From 200-2008: http://kellymom.com/wp-content/uploads/US_BF_rates.png
    From 1850-2000: http://www.historyandpolicy.org/papers/policy-paper-89.html (see Figure 3)

    [r6]
    http://www.diabetesandenvironment.org/home/incidence/historical

    [r7]
    http://www.ncbi.nlm.nih.gov/pubmed/18356404
    http://www.ncbi.nlm.nih.gov/pubmed/21307077
     
  3. swellman

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    Thank you.
     
  4. TheFormerLantusFiend

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    From what I've read, only 25% of type 1 diabetics have a first or second degree relative with type 1 diabetes. Since the introduction of insulin came a mere 81 years ago (ie, not a whole lot of generations), the increased longevity of diabetics cannot explain much more than this portion.
    If a genetic shift is responsible for the increased number of type 1 diabetics, and if the increase is as large as some of those studies claim (which, I, for one, do not believe) then the genetic shift was not caused by the introduction of insulin. The vast majority of type 1 diabetics today (as in all previous generations) have no ancestors who had type 1 diabetes. Although 25% have a first or second degree relative with diabetes, less than 25% have a parent or grandparent (a large portion of this quarter has a sibling or an aunt or uncle). Since the evidence is furthermore that type 1 diabetics have a smaller number of children than nondiabetic adults, the impact of our survival on genetic changes is even smaller than you might estimate.
    I think it's slightly more reasonable to claim that increased fertility in people with other autoimmune conditions has an impact. The most likely candidate there is Hashimoto's, which is considerably more common in the mothers of children with type 1 diabetes, and which, untreated, causes infertility.

    However, I think data suggesting that there is a linear increase in type 1 diabetes is suspect and I have read many studies with conflicting data. For instance, there has been a study published on the incidence of childhood onset diabetes in my own area (Chicago) which found no increase of type 1 diabetes over the period of 1980-2000. Other studies in different areas have found different trends.
     
  5. Angela

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    Worried Parent

    Thanks for this post...
    It is worrying to all parents with children that have diabetes that the other children will develop this disease as well. Our daughter was diagnosed at the age of 4, I now have an 18month old and another on the way.. I hope we do find a cure soon.
     
  6. Michelle'sMom

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    A question related to your bolded comment above:
    How does the rise in Type 1 relate to the rise in incidence of all autoimmune disorders? Do you know if the rates are similar?

    Just over the last year or so, I've read of studies blaming everything from GMO foods to heavy salt intake.
     
  7. Lenoremm

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    Thank you for this Joshua. Some people have observed ?clusters? or pockets of type 1. Sorry if this is slightly ot but I think it relates to or influences the belief that there are environmental factors contributing to the increase in diagnosis.
     
  8. TheFormerLantusFiend

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    I don't know. The data probably exists only for a few European countries. As you are probably aware, it's much harder to get data on this topic in the United States than it is for those countries with socialized medicine.
     
  9. swellman

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    I would love to see a graph of incidence vs population growth.

    Edit: and I would love to see a topo graph of population density overlaid with T1D Dx.

    Edit 2: Why can't I find a density map of T1D Dx?
     
  10. Michelle'sMom

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    Sad that the US doesn't track this info. The T1D Exchange is a start, but my dd goes to one of the busiest clinics in our state, & it isn't participating. I did sign up several years ago with the AARDA, long before my dd's T1 dx. They've at least been trying to track autoimmune disorders, although I'm not sure it's as widely known as it should be.

    I appreciate your time & effort for giving us these updates.
     
  11. sgh

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    won't be able to address everything but...

    OK, so thanks for this, Joshua. I feel like I'm one of the few people in the world who has been pushing for studies on toxic chemicals and type 1, so I'm mostly surprised when you say that usually the increase is blamed on toxic chemicals? Where are you seeing that besides from me? I'd like to know these people, since I can't find many! I'm a mom, and don't have the ability to do the studies myself. I've been trying to get scientists to do the studies, and there isn't funding or for whatever reason, they aren't doing them.

    It would be easy, theoretically, to measure chemical levels in the participants of the TEDDY study or any other human type 1 study, and those researchers are talking about doing that, but there are difficulties. One, it's incredibly expensive to test for chemicals. Two, if you store blood in plastic vials, then the blood becomes contaminated from the plastic it is stored in. No researcher stores blood in glass, unless they knew ahead of time they were going to test for chemicals. Which they didn't, since everyone has been trying to look for viruses, cow's milk, gluten, now vitamin D levels-- everything except chemicals. Animal studies have not been done either, I don't know why. Maybe since animal studies are not as convincing? I don't know. There are plenty of animal studies on diabetes and chemicals and they are alarming, but since animals don't get type 1 or type 2, they are thought to be type 2, not type 1. But no one looks to see if the type of diabetes resembles type 1 at all. You cite a couple that were done on type 1 specifically, and here are some others just published-- BPA (www.ncbi.nlm.nih.gov/pubmed/23496298) and flame retardants (http://www.ncbi.nlm.nih.gov/pubmed/23640034). I am hoping that these will trigger some more studies, and maybe allow the human researchers to get funding. But I know a few scientists who have tried to get funding for chemical studies and have not been able to, because there is no research on this to justify the funding. So it's a vicious circle. But I don't think that we can dismiss the possibility just because studies haven't been done yet-- I've talked to tons of researchers, and some have told me that "no one" thought type 1 was linked to chemicals. It was not part of the mindset in the past. I've been trying to change that mindset, but it's hard to do with little to no evidence!

    We've also learned a lot more about chemicals recently that can help explain some of the patters you cite. First, a fetus in the womb is now exposed to many hundreds of chemicals even before birth-- more than ever before-- and most of these chemicals are untested for health effects (the effects they do test for do not include type 1 diabetes or even anything close to it). We have absolutely no idea of the effects of all these chemicals in combination. Back in the '60s, levels of lead and DDT and PCBs were higher than now, but we've now added hundreds more chemicals to worry about. And we are finding that the ones like DDT and PCBs can have even worse effects at low levels than at high levels-- and they are still in all of our bodies-- they are very persistent. So that can help explain why type 1 levels didn't go down after the '60s.

    Now, for genetics, I agree that people like me with type 1 are now reproducing and even our children are getting type 1, like mine, but that does not explain the increase. I've found documented increases (published in peer reviewed scientific journals) in type 1 in children from 58 countries and counting, worldwide. That's hard to explain with diet or anything besides chemicals, really. What other influence is that worldwide? Note that they already account for population growth, so that isn't a cause. The genetic risk of type 1 was higher in the middle ages than it is low (they dug up bones and analyzed them). I can't find the papers right now but will look later. A number of studies have found that the genetic risk of type 1 was higher in the past than now. That people are getting the disease who have a lower genetic risk than those who got it before. There is general agreement among scientists that the environment is playing a role. It's not just genetics OR the environment though-- the environment can affect genes (epigenetics) and these effects can be passed down from one generation to the next sometimes, on the genes, so that could be involved as well. Those epigenetic changes can be caused by chemicals, diet, stress, etc. All these factors are probably playing a role, and it's likely that different factors play a role in different people, based on their genes, diet, etc.

    While some do, chemicals don't generally work like people think they do-- it's not that if you are exposed to say asbestos, you will likely get lung cancer or whatever. That if you are exposed to chemical X, you will likely get type 1, and that we just have to figure out what chemical X is. It's more probably that numerous chemicals can affect numerous (hormonal) processes in the body, at very low levels, and in combination with other environmental factors and genetics, and affect your risk of whatever diseases, including type 1. Like, estrogen and testosterone probably play a role in type 1 development, so therefore, chemicals that can mimic or block those chemicals could too. We already know that many chemicals can affect beta cells in the lab (in animals and cell cultures), as well as affect autoimmunity in people and the lab-- why *wouldn't* they play a role in type 1 in some people? We have to look at the timing of exposure, the dose, the gender, the genetic risk (like you say, all the genes that are involved), the combination of chemicals, stress levels, the hormonal state of the person-- all of these interact to determine the health effects of chemicals. Obviously a couple of studies are not going to able to fully explain what is going on-- we'll probably need decades of animal and human studies to figure it out. They've been studying viruses for a hundred years or more, and there's still controversy over whether a virus can trigger type 1! I can count the human studies of chemicals and type 1 on one of my hands. With maybe only 2 fingers. (e.g., http://www.ncbi.nlm.nih.gov/pubmed/16629713 from 2006-- why hasn't anyone followed up?? I have no idea). All the animal studies ever done on chemicals and type 1 I can count on the other hand.

    I will reread your message and see if there's anything else-- :)

    Also, for those interested, I've summarized studies on chemicals and diabetes at www.diabetesandenvironment.org. There are a lot of studies coming out on type 2, but not many on type 1 yet. I hope to change that!

    thanks

    Sarah
     
  12. sgh

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    some genetic studies

    I guess I think your main point, that it is "easy" to see if chemicals cause diabetes in animals, is not accurate. It's actually very difficult to do that-- for reasons of funding, dose, timing, type of animal, etc. The chemical companies take advantage of this actually-- they can easily design studies that do not find harm, by tweaking little things that no one but the experts would notice-- that raise people's doubts about the original studies that may have found harm. And to do the studies, you'd need to have a lab set up to do it, which almost no one does, as well as the interest in doing it, which almost no one has. Most type 1 researchers know very little about chemicals, have never looked at them, and would not know how to do the research. This is not something that you learn about in med school or any other school, unless you happened to take a toxicology course.

    I'm happy to discuss this more-- I'm thrilled when I find someone who actually might be interested in this topic! It's rare, let me tell you :)

    Here are some more studies on genetic time trends over time, aside from the couple you already mentioned:

    Spoletini M, Zampetti S, Campagna G, Marandola L, Capizzi M, Buzzetti R. 2013. Temporal Trends of HLA, CTLA-4 and PTPN22 Genotype Frequencies among Type 1 Diabetes in Continental Italy. PLoS.One. 8(4):e61331.

    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061331

    Witas HW, Jedrychowska-Danska K, Zawicki P. 2010. Changes in frequency of IDDM-associated HLA DQB, CTLA4 and INS alleles. Int.J.Immunogenet.

    http://www.ncbi.nlm.nih.gov/pubmed/20345871

    Hermann R, Knip M, Veijola R, Simell O, Laine AP, Akerblom HK, Groop PH, Forsblom C, Pettersson-Fernholm K, Ilonen J. 2003. Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes--indication of an increased environmental pressure? Diabetologia 46(3):420-425.

    http://www.ncbi.nlm.nih.gov/pubmed/12687342
     
  13. Michelle'sMom

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    So, following the toxic chemical idea....identical twins, raised in the same environment yet only one develops T1D. That rules out purely a genetic cause, so does it not also rule out toxic chemicals?
     
  14. sgh

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    scientists' view

    I just want to also point out that I've asked dozens of scientists about this topic-- chemicals and diabetes. I've found that most of those who research chemicals (i.e., the toxicologists), think it's entirely plausible that chemicals could influence type 1 diabetes development. I've found that some of those who research type 1 do also, and a few don't. Many of them say, well, they are interested, but that's not what their lab is working on. It's a lot of effort, time, money, etc, to change what a lab is working on. And then they ask me, well, what is chemical X? Which one do you think it is? What should I look at?

    Honestly, I can't answer that question. I'd guess that it could be a lot of different ones, probably endocrine disruptors, but not one or two in particular. It could be combinations of chemicals. It could be different chemicals in different people. There are all sorts of possibilities. I don't know which is most likely. Maybe it's arsenic (known to lower insulin secretion), maybe it's mercury (known to trigger autoimmunity), maybe it's PCBs (known to affect beta cells)... there are immune system disruptors, beta cell disruptors, and thousands upon thousands of chemicals out there, dozens already known to have effects that *could* influence type 1. One thing that some scientists would like to do is screen the tens of thousands of chemicals out there for their ability to potentially influence type 1 development, and they are having a difficult time even doing this-- to just narrow down the list enough to know what to look for. It's a question of time, funding, and expertise.

    Re the last question of twins-- fetuses even in the same womb can be exposed to different chemicals, and certainly after birth, so it wouldn't rule anything out. Also, type 1 diabetes has been around for thousands of years, and chemicals are almost certainly not the only environmental factor that plays a role. I'd never say that. I suspect viruses play a role and are a likely very important player in type 1 (even though it's not proven yet!), probably cow's milk and gluten in some people, probably vitamin D deficiency in some people, etc etc. I got type 1 that was apparently triggered by being pregnant, and clearly that doesn't cause most people to get type 1! Go figure. I know someone who got type 1 after a car accident. Who knows what happens in individuals. We are just trying to help explain overall population-wide trends really. And we need to keep in mind that while we can rule out some things in some people (my son didn't get type 1 from being pregnant...), that doesn't rule it out for everyone. :)
     
  15. joshualevy

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    No, because two different people are often exposed to different chemicals, even if they grow up together. Maybe one develops a taste for raw milk but the other doesn't, and the raw milk contains something that triggers type-1. That sort of thing. Or one likes to play soccer, and the bugs on the soccer field spread the thing that causes type-1.

    Joshua Levy
     
  16. joshualevy

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    My posting on possible environmental causes of type-1 diabetes generated more interest than I expected. I have already been asked the following questions, which I hope to answer in a future post. I've put them in order of importance, so I'll answer as many as I have time for, from the top, down. Please reply privately, or post a comment on the blog, if there are other questions you'd like me to address, or if you think one of these questions is particularly important. And thanks to everyone who sent in questions; they really help me know what kind of topics people care about.

    1. No one in my family has type-1 diabetes, and that's true for most type-1 diabetics. Doesn't that point to an environmental cause [for the increase]? Put another way: Why there is in increase in which families had no history of diabetes? Maybe it is the environment?
    2. Several people were diagnosed with type-1 in my tiny (pop 5000) town, right after my child was. Doesn't that point to an environmental causes which is possibly contagious? Put another way: doesn't the existence of clusters mean there is an environmental cause for the increase in type-1 diabetes?
    3. How does the role of virus fit into this, if at all? I've always heard that in many people a viral infection seems to be the final trigger for T1D.
    4. Can we learn something from the fact that he increase in T1D incidence has reached a plateau in Norway?
    5. Is it possible in part that the rates are increasing because more and more adults (over 21) are being properly diagnosed with LADA, a variant of Type 1, whereas before, they were being lumped into the T2 group?
    6. Is there evidence that wheat causes type-1 diabetes?
    7. Is there evidence that sunlight protects against type-1 diabetes?
    8. Is there evidence that GMO foods or heavy salt intake causes type-1 diabetes?
    9. Are Jews more likely to get type-1 diabetes?
    10. How does the rise in Type 1 relate to the rise in incidence of all autoimmune disorders? Do you know if the rates are similar?
    11. Does that genetic argument also explain the growth of Autism?
    12. Do vaccines cause type-1 diabetes, and especially the increase of type-1 diabetes?


    Plus, I need to reply to sgh's posts, which bring up several interesting points, also.

    Obviously, this will take a while.

    Joshua
     
  17. sgh

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    more qs

    Addressing further what I said about low doses having significant effects, here's a review with over 800 references citing what I am talking about: http://edrv.endojournals.org/content/33/3/378.long. A seminal paper.

    Basically, chemicals that act like hormones have dose response curves that rise at low levels and then fall at high levels, due to the way hormones act. At very high levels of exposures, cells just die and most things would be toxic at some level. But at lower levels, there can be variations in the effect. It's called non-monotonic or non-linear dose response curves. A real life example is birth control pills-- the chemicals in the pills are at much lower levels now than they used to be, since we know they are just as effective if not more so at lower levels than at high levels. "Low doses" refer to things like part per million or billion or trillion depending on the situation, which sound really small, but can still be hormonally active, since natural hormones act at very low levels in the body. Here's an example of a human study of pollutants and type 2 diabetes that found non-linear results: (http://www.ncbi.nlm.nih.gov/pubmed/20444671). (Most studies finding non linear trends are in animals).

    Regarding animals getting type 1, see Edwin Gale's article on congenital rubella (http://www.ncbi.nlm.nih.gov/pubmed/18641967): "There is indeed an extensive literature to prove that viruses produce diabetes in experimental animals, but no one has ever shown how this relates?other than by analogy?to type 1 diabetes, a condition found only in humans." Technically he's correct since the terms type 1 and 2 are referring to humans. But yes, NOD mice are an animal model of type 1, it just isn't *exactly* the same disease. But close enough for most purposes. I've seen other researchers call what NOD mice get type 1, so there's disagreement here. And like Dr. Gale, I think most scientists think human data is stronger than animal data, especially in prospective studies that follow people over time. But generally you'd need both animal and human studies to show probable causation. But seldom can the science we have "prove" causation, for any condition and potential cause.

    Re genetics, I can't see at all how changes in DNA can even remotely cause a 3% per year increase in incidence in anything-- DNA doesn't change that fast. Every single paper I've ever read on type 1 increasing incidence says it's at least in part environmental and can't be explained only by genetics-- that's hundreds of papers. I've never seen anyone argue that genetics alone can explain an increase of this magnitude (the increase is even higher in young children). Again, I'll cite Dr. Gale (http://www.ncbi.nlm.nih.gov/pubmed/12453886): "The changing demography of childhood diabetes has major implications for our understanding of the disease. A rapid change in incidence within a genetically stable population implies that nongenetic factors are active and that the influence of genes is relative to population, time, and place. It suggests that something has changed in the environment our children encounter or in the way they are
    reared. Understanding this historical change would open the way to rational forms of intervention, which could be introduced at the stage of development when they are most likely to prove effective. Seen from this perspective,
    the central task of diabetes prevention is to understand a historical trend, and to put it in reverse."
    Note that we *can* take action about this trend if we focus on environmental causes, but we can't change our DNA, so why bother focusing on it?

    Another point about chemicals-- since chemicals don't have to be tested for safety in this country (or many others), often the substitutes are just as bad as the originals. So if one is banned somewhere, it's hard to know what is being used instead, and usually takes a few years for someone to start looking into its effects. BPA substitutes are showing similar effects as BPA does, for example.

    I probably shouldn't have said there's "no" evidence linking type 1 and chemicals, there are just very few studies. But there are a few. And there are also *plenty* of studies showing that chemicals DO have effects that are *probably* relevant for type 1 diabetes. Like, we know that arsenic can reduce insulin secretion from beta cells-- seen in animal studies (http://www.ncbi.nlm.nih.gov/pubmed/23261974) and human studies (http://www.ncbi.nlm.nih.gov/pubmed/23349674). Arsenic can also disrupt the immune system (http://www.ncbi.nlm.nih.gov/pubmed/20940111). Now, when I put those together, I see type 1 diabetes. But has anyone ever analyzed arsenic and type 1 together? No. (But one of the authors of one of those studies is planning to do some studies, so we shall see. It just hasn't happened yet.)

    Numerous other chemicals are also already known to affect beta cells. Here's a review of them: http://www.ncbi.nlm.nih.gov/pubmed/21442161. (The authors argue that these have implications for type 2 diabetes but don't mention type 1. I emailed them and they agreed type 1 could be involved also. It's just not a research area now). And we know that there are numerous chemicals that can disrupt the immune system, and some that can cause autoimmunity. Again, not good. Would anyone want their fetus exposed to these things? Not me, thanks.

    The whole idea of chemicals linked to diabetes is pretty new in scientific terms; the study that first generated a lot of interest was done in 2006, and that was on type 2 (well, technically it didn't distinguish, so could have included type 1 as well, we don't know) (http://www.ncbi.nlm.nih.gov/pubmed/16801591). It generated an explosion of research. What we need is an instigating study that generates interest and funding, then we will see the research follow.

    The NIEHS, a branch of NIH, recently reviewed the evidence linking diabetes and chemicals and you can read the conclusions here: (http://www.ncbi.nlm.nih.gov/pubmed/22296744). They concluded, "Overall, the review of the existing literature identified linkages between several of the environmental exposures and type 2 diabetes. ... Research on environmental chemical exposures and type 1 diabetes was very limited. This lack of research was considered a critical data gap." These folks-- who are toxicologists-- are now trying to fill that gap-- and they would never say that the absence of evidence is evidence of absence.

    thanks for the discussion!
     
  18. Michelle'sMom

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    I would think it could be quite a project :cwds:, especially when there are so many T1s who, like my dd, have no other known T1s in the family, but have multiple other autoimmunes ( I have 2)....MS, Lupus, RA, Alopecia Areata, Uveitis, Hashimoto's, psoriasis....& throw in multiple cases of asthma & fibromyalgia (thought to be connected to autoimmunity). Add to that the fact that many of our CWDs had no viral symptoms in the year or more preceding dx.

    The recent articles I've seen suggesting a connection between autoimmunity & autism are very interesting.
     
  19. My_Dana

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    This is great info and very interesting, Sarah!
    Thanks!
     
  20. karri

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    Wow, thanks for posting things.
    Noticed that it has been reported that rubella infections causes diabetes in both hamsters (Rubella virus-induced diabetes in the hamster) and rabbits (Rubella infection and diabetes mellitus)
     

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