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Type 2 Diabetes May Be a Protein Misfolding Disease

Here’s a paper that will not calm anyone down about the possibility of prion-like diseases. Those, as many will know, are spread by misfolded proteins that, on contact, template others to follow their example. I last wrote about this field a couple of years ago, when examples appeared of transmissable amyloid pathology in humans, spread by surgical instruments. This latest work (commentary here at Science) is also amyloid-related, specifically IAPP (islet amyloid polypeptide). That forms a protein aggregate that’s commonly found in the pancreatic tissue of patients with type 2 diabetes, and as is usual in these things, no one’s ever been sure if diabetes gives you amyloid (the majority view over time) or if amyloid gives you diabetes (a hypothesis that’s apparently been gaining ground – here’s a review from the same group).

Alarmingly, this paper has evidence for the latter case. If you take mice that are transgenic for the human form of IAPP, and inject them with pancreatic homogenate containing the IAPP aggregate, they rapidly start showing deposits of the same protein precipitate themselves. And then they start developing symptoms strongly reminiscent of diabetes: elevated glucose levels, impaired glucose tolerance, changes in beta-cell mass, and so on. The same thing happens with injections of purified synthetic IAPP, so it’s not some other factor in the pancreatic mixture. Otherwise, there were no abnormalities in either gross organ pathology or histopathology. Injecting other amyloidogenic proteins (such as tau) had no effect.

So how does this fit in with the widely accepted view that insulin resistance is a key factor in type 2 diabetes? The authors think it’s all part of the same picture – insulin resistance might come on first (through mechanisms that are very much open to argument), but the forced overproduction of insulin that it brings on also produced more IAPP, giving the aggregation a chance to really kick in and cause still more damage.

The big question is whether this mechanism is actually operating out here in the real world. It would seem difficult to transmit pancreatic proteins from one person to another, wouldn’t it? On the other hand, it’s hard to know just how much of the protein aggregate one needs to be exposed to for trouble to start. I would tend to be skeptical of this as a means for type 2 diabetes to actually spread in the population, since it would seem that environmental and genetic factors are enough to explain things, patient by patient. I mean, you look at the figures for obesity over the last few decades, and it’s hard to make the case for diabetes being this mysterious scourge that came out of nowhere. But I can’t rule this idea out completely, and I definitely think it needs more investigation. At the very least, it could be telling us how diabetic pathology might spread inside any given individual, once it gets going.

40 comments on “Type 2 Diabetes May Be a Protein Misfolding Disease”

  1. SP says:

    But if you watch one of those animations of the spread of diabetes and obesity rates over the last 30 years, it does look like the same kind of map you’d see for the spread of an infectious disease, on a much slower time scale.

    1. Anon says:

      It’s also probably the same map as the availability of the “stuft crust pizza” and “super sized meals.”

    2. Vader says:

      Is it possible that insulin resistance encourages obesity?

  2. I would urge caution regarding the science coming out of this lab. Specifically, there have been numerous documented instances of data problems (western blot splicing, image duplication, etc.) from Claudio Soto, and colleague Claudio Hetz. Here are a couple of examples…

    As is typical in such cases, emails from me to the University informing them of these problems have been summarily ignored. So far, only these 2 papers have been corrected (with the usual apologies for mistakes and no effect on the conclusions). Here is a file documenting the various problems in Soto’s papers, which I blogged about in 2012 (file was updated in 2014 with new evidence)…. The vast majority of these issues have not been dealt with by the journals.

    There are also some legal issues surrounding Soto, at a previous institution, for those who care to search for case briefs.

    1. Derek Lowe says:

      That’s rather disturbing evidence – noted, and thanks.

    2. AC says:

      Thanks for pointing those problems out.

    3. Chrispy says:

      Stuff like this really steams my clams! It is hard enough to do good science without people blatantly falsifying results.

      Thank you for pointing it out and having the courage to do so under what I assume is your real name.

      It is a pity that the repercussions amount to nothing.

    4. Just desserts says:

      Speaking of fraud: “‘Pharma bro’ Martin Shkreli convicted of fraud”


  3. Barry says:

    The epidemiology of NIDDM/TypeII diabetes looks more like an industrial (behavioral) disease than like a transmissible infectious disease. But the result with purified, synthetic (misfolded? misaggregated?) IAPP remains to be explained.

  4. Lane Simonian says:

    Insulin resistance and type 2 diabetes are probably the result of the nitration of the insulin receptor substrate-1

    Nitro-oxidative stress contributes to amyloid formation and amyloid formation is one of many contributors to oxidative stress. While some of the factors leading to amyloid production (bacteria, viruses, etc.) are infectious agents, amyloid itself is not.

  5. ScientistSailor says:

    Peroxynitrites next?

  6. cynical1 says:

    Actually, although no expert in the area, I could imagine an infectious component in LADA (Latent Autoimmune Diabetes in Adults) which if memory serves represents ~10% of the Type II population. In those individuals, the “normal” risk factors for the disease do not seem to hold. I’m not suggesting that someone injected prions into their abdomen but I could imagine an infectious or transmissible environmental causative factor.

    1. loupgarous says:

      If you include “fed” in “injected prions into their abdomen”, you could be looking at the causative factor; ingested prions are probably the proximate cause of new variant Creutzfeld-Jakob Disease – the “human mad cow” outbreak in western Europe centered in Great Britain.

      Who’s to say a relatively silent prion-mediated disease in cattle or swine doesn’t get much more virulent when it’s passaged into man through ground meat (where the less-appetizing tissue such as pancreas and parts of the paunch/GI tract may go in less scrupulous meat packing plants)? It’s a possibility that ought to be explored.


    TUESDAY, AUGUST 1, 2017

    Could Insulin be contaminated with and potentially spread, Transmissible Spongiform Encephalopathy TSE Prion, what if?

    Terry S. Singeltary Sr.

    1. Some idiot says:

      With respect, this is either highly unlikely or simply incorrect. The vast majority of the insulin on the international market is from expression in cell lines in big fermentation tanks, and has been this way for many, many years. This insulin has never seen a cow in its life… No way in the world this could give rise to the effect we see in the developed nations.

    2. loupgarous says:

      Highly unlikely is right. Eli Lilly sold their plant for making insulin from livestock pancreas to Russia back in the 1990s, after they’d gone over to making insulin in recombinant E.coli culture. The only link between the human insulins and recombinant insulin analogs sold in the US today and any living creature is the nucleic acid base sequence inserted in the bacteria which now make our insulin here. You have to import pork and beef insulin from Russia or the other places it’s still made, and it’s not easy to do – much paperwork is involved.

      But it raises another question: not all beef and pork pancreas ever made it to the former insulin producers here, and in the past 20 years there’s been NO significant market for pancreas outside the meat packing industry itself. What if, all this time, pancreas in livestock’s been a vector for transmission of a prion or other infectious agent responsible for type 2 diabetes, and ALL the beef and pork pancreas in the meat industry for the last thirty years has gone, say, into ground meat?

      1. Barry says:

        anyone who has read the packaging on e.g. chorizo knows that bovine and porcine pancreas are still in the human food-stream.

        1. loupgarous says:

          Interesting epidemiological cue, then. And a good application for BIG DATA!
          Seriously, we database meat processors by how much of the bovine neuroendocrine system they sell as food, and look at figures for type 2 DM, dementia (by type eg Lewy Bodies, AD, etc), ALS, et cetera and so forth. Shouldn’t be a very hard sell to Congress, but you never know who’s owned by the meat packing industry, who periodically get meat inspection defunded. So we fund it through Homeland Security as “food security”.
          Of course we could work it backward and focus our snooping on meat processing plants that sell in places with unusually high incidence of dementias, neuroendocrine disorders (diabetes, neuroendocrine cancers/carcinoid, hyperparathyroidism), the various dementias and ALS. It’s the biggest piece first, but the insurers are already pushing for patient databases, as are the big regional health providers.
          Either way, we can either confirm, deny or get inconclusive data on whether eating neuroendocrine tissue’s a vector for amyloid-related diseases.

  8. Lane Simonian says:

    To add another wrinkle, amyloid plaques may actually protect against prion diseases by entombing copper and zinc which limits the production of hydrogen peroxide.

  9. Some idiot says:

    Derek, off-topic but blog house-keeping: both yesterday and today I noticed that a comment arrived in the comments area out of sync (I.e. I saw that there were (say) comments, but there were only 4 listed, but then later (10-20 minutes) the “missing” entry appeared amongst the earlier 4 (but not as a reply). In both cases it was the same person. No idea if it means anything, but just an observation…

    1. Some idiot says:

      Sorry, should have said “there were (say) 5 comments but only 4 listed”

      1. Lane Simonian says:

        I should let Derek reply, but I believe the issue is this. If you post a comment with links, the comment does not appear for awhile even though it is added right away to the number of comments.

        1. Some idiot says:

          Ah… thanks… that makes sense…! 🙂

  10. Kelvin Stott says:

    Like most forms of amyloid, IAPP oligomers form toxic porin-like holes in cell membranes, which are visible by EM and cause the cells to work overtime in order to maintain homeostasis. This causes oxidative stress and all sorts of other problems until the cells ultimately burn themselves out. Thus any therapeutic will need to plug or block the formation of these holes within the membranes.

    Years ago (in 2001) I founded a start-up and we developed short hydrophobic N-methylated retroinverso peptides as potent and selective membrane-permeable inhibitors of amyloid formation. They worked well in vivo, but alas our funding ran out and we couldn’t raise more. I still believe they hold great potential with all these diseases.

    1. Dionysius Rex says:

      Kelvin, what you need is retro-inverso stapled Protac peptides!

  11. steve says:

    What’s interesting is that IAPP deposits are not found in mouse or pig; for example, it doesn’t appear in standard mouse models like db/db. Derek’s supposition that insulin resistance leads to increased amyloid deposits sounds like the right direction as insulin resistance is the underlying cause of T2D in mice even though they’re resistant to IAPP aggregation.

  12. johnnyboy says:

    Meh. The model (if results can actually be trusted) is highly artificial. Amyloid is commonly found in islets of aging animals of many, if not all, species, without causing any diabetes.

  13. Thoryke says:

    I know I’ve read that some researchers suspect Type II and Alzheimer’s may be related…. would a proof of concept be a trial to see whether drugs that block or destroy amyloid have any effect on the # or ratio of misfolded proteins?

    1. Lane Simonian says:

      A different proof of concept trial is whether reducing levels of amyloid has any significant effect on either Alzheimer’s disease or type 2 diabetes. The answer for the former is increasing looking like no and the latter as far as I know has never been tested.

      With insulin resistance, more glucose ends up in the brain, This leads to higher levels of myo-inositol–a compound which is a relatively accurate biomarker for the conversion from mild cognitive impairment to Alzheimer’s disease and a precursor molecule to oxidative stress and amyloid formation.

      High levels of glucose in the brain and hyperinsulinemia both contribute to Alzheimer’s disease, but primarily by increasing oxidative stress (in part via insulin receptors and platelet derived growth factor receptors) rather than by increasing amyloid.

    2. HFM says:

      As I understand it, the hypothesis is that IDE (Insulin Degrading Enzyme) is competitively inhibited by, well, insulin, preventing it from doing its more important job of breaking down amyloid beta, IAPP, and related aggregation-prone proteins.

      It’s possible that, if too much insulin leads to IAPP plaque buildup, and the plaques are toxic to pancreatic cells, that this is a mechanism for the breakdown of insulin production that can happen in the late stages of T2 diabetes. But even if we’re granting that the world really is that simple and well understood, it doesn’t explain how T2 diabetes gets started.

      1. Derek Lowe says:

        In that case, the whole attempt to use IDE inhibitors therapeutically is doomed, then, right?

      2. Lane Simonian says:

        The assumption is that the removal of amyloid will help in the treatment of Alzheimer’s disease and type 2 diabetes and this very well may not be the case for either disease.

        In any case, there is a link between inducible nitric oxide and a decrease in insulin degrading enzyme in Alzheimer’s disease and in type 2 diabetes.

        “Nitric Oxide Decreases the Enzymatic Activity of Insulin Degrading Enzyme in APP/PS1 Mice”

        Preventing the formation of inducible nitric oxide helps protect mice at least from both an Alzheimer’s like disease and type 2 diabetes.

        “Protection from Alzheimer’s-like disease in the mouse by genetic ablation of inducible nitric oxide synthase.”

        “Inducible Nitric-oxide Synthase and NO Donor Induce Insulin Receptor Substrate-1 Degradation in Skeletal Muscle Cells*”

        The problem again is not so much amyloid per se, it is the nitro-oxidative stress that inhibits enzymes, damages receptors, causes inflammation as a result of DNA damage, and leads to the death of cells via caspase 3 activation.

        1. Lane Simonian says:

          I forgot to include a reference to a decline in insulin degrading enzyme activity in type 2 diabetes.

          “Hyperglycaemia and hyperinsulinaemia: is insulin-degrading enzyme the missing link?”

          I would think efforts to inhibit insulin degrading enzyme activity for type 2 diabetes are misplaced.

          And just to continue with the theme of why hyperglycemia and hyperinsulinemia likely contribute to Alzheimer’s disease:

          “Insulin-induced peroxynitrite production in human platelet-rich plasma”

          “Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies”

          1. Lane Simonian says:

            I keep missing points, but maybe this is the last one.

            “Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells.”

            Over the years, I have seen many proposed mechanisms for how amyloid damages cells: breaking through cell walls, strangling neurons, etc. but proof that amyloid is involved in apoptosis through any of these mechamism to the best of my knowledge has never been established. The role of certain forms of amyloid (such as excessive amounts of the amyloid precursor protein and amyloid oligomers) in producing oxidative stress appears to be the only established link between these forms of amyloid and cell death.

  14. gippgig says:

    It is interesting to note that inhibiting the unfolded protein response with a PERK inhibitor (GSK2606414) is toxic to the pancreas.
    It would be interesting to see what effect protein synthesis reactivators (not toxic to the pancreas) have here since they block harmful effects of misfolding in some other cases.

  15. JimM says:

    ALS is also associated with a misfolded protein, and there is strong suspicion that the misfolding is caused by a toxic amino acid (BMAA) produced by blue-green algae, so after reading this post, I was curious to see whether there might be any research out there showing an association between type 2 diabetes and ALS.

    And there is, but not quite as I was expecting:

    In this Danish nationwide study to investigate the association between diabetes and ALS diagnosis, our findings are in agreement with previous reports of a protective association between vascular risk factors and ALS and suggest that type 2 diabetes, but not type 1, is protective for ALS.

    There is also a surprising feature in clusters of ALS in the US, where people who live around bodies of water with periodic algae blooms show higher rates of ALS, but people who drink that very same water but don’t live right next to it seem not to, even though there are ‘significant’ levels of BMAA in the water.

    I’ve been assuming that difference could possibly be due to the fact that the liver has a chance to detoxify ingested BMAA before it gets into general circulation, whereas inhaled BMAA could go directly from the lungs to the heart and then into the bloodstream, and a small Japanese study showing that ALS sufferers and people with motor neuron disease in general are much more likely to have antibodies to Hep B than controls, is at least consistent with this idea.

    However, the Danish study not only shows a protective effect against ALS from type 2 diabetes, it suggests that type 1 diabetes actually makes development of ALS more likely:

    The Danish registry does distinguish between types, but doctors often enter the wrong code, said Kioumourtzoglou. However, she was able to use age as a proxy for diabetes type. Type 1 tends to arise in younger people than type 2 does. People diagnosed with diabetes after age 40 were protected from ALS, with a 48 percent lower risk. Conversely, those who had diabetes before 40 had a 66 percent higher risk, though this was not statistically significant because there were so few people in that group. “What we saw would indicate that type 2 diabetes is protective, and that type 1 might be a risk factor,” said Kioumourtzoglou.

    I think this is important because type 1 tends to kill the beta cells, and at a young age, leaving a life-long deficit of beta cells in the pancreas — and that points us toward a model in which the protective effect against ALS afforded by type 2 diabetes depends on an ability of pancreatic beta cells to absorb BMAA not neutralized by the liver and sequester it in deposits of misfolded protein.

    Which would make blue-green algae a prime suspect in causing type 2 diabetes and associated obesity as well as ALS.

  16. Probably a complex process of B cell overdrive from persistent hyperglycemia. See this in fat cats. The protein synthesizing and quality control machinery of the cell cannot keep up.

  17. loupgarous says:

    Ground meat probably transmits prions from neuroendocrine tissue in general. So if bovine prions cause type 2 diabetes in man, every time you go to Burger King, Mickey D’s, or cook your own burgers/favorite ground meat dish, you could be shooting craps for a case of Type 2 diabetes. Another argument in favor of cultured meat.

  18. titulo_site says:

    I had almost all these syntoms but got tested today and was not a diabetic so i am happy. :)

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