Monday, July 14, 2008

New Research Clarifies Distinction Between Different Types of Diabetes

In recent years, there has been some speculation within the medical profession that type 1 and type 2 diabetes share more similarities than differences despite their distinct etiological differences. Some authors even argued that type 1 and type 2 diabetes are actually the same disorder of insulin resistance, set against different genetic backgrounds (unfortunately for them, their so-called "Accelerator Hypothesis" had numerous shortcomings, particularly the fact that relatively few of the children in their own research sample were overweight, the insulin requirements of lean patients were statistically much lower than those who were overweight, as well as many other shortcomings). While higher body mass may lead to increased insulin requirements which accelerate beta cell death, it fails to explain why lean children suffer from beta cell failure at all, making the hypothesis provocative, but severely flawed.

Adding fuel to the fire, JDRF's former CEO Arnold W. Donald ruffled more than a few feathers when he stated something along those lines in an interview (see page 9) with Kelly Close back in November 2006:

"While I have some empathy for those who feel a need to drive type 1 as an agenda item because I'm at JDRF, I think that sometimes we get caught up on the distinction that, number one, medically is not as clean as we may have thought it was in the past. And, number two, in terms of addressing the human impact, it may be more academic. So, my attitude is, look, type 1 is an autoimmune disease, and based on that, it requires certain types of research that may be unique. But the learnings from the research in both areas can lend a huge amount of benefit to the other, and so where I'm at is we need to eliminate diabetes. That's the deal."

The Internet was flaring shortly after that interview was published with less-than-flattering remarks about the suitability of Mr. Donald to lead the organization. (Incidentally, as I reported, Mr. Donald stepped down unexpectedly as CEO on February 29, 2008 -- it was a leap year, remember -- citing urgent "family matters" as the reason for his decision. To the best of my knowledge, JDRF has yet to name a replacement CEO.).

The irony, however, is that research had grown increasingly fuzzy on the distinctions between type 1 and type 2 diabetes (although some argue that's by design, not due to compelling evidence), so Mr. Donald's remarks weren't really too far off-base even if they weren't especially PC. Notably, the SEARCH for diabetes in Youth study found that many kids diagnosed with type 2 diabetes actually tested positive for insulin and islet cell antibodies, and what's more, some adults with type 2 also test positive for insulin antibodies (although some suggest that this is due to biosynthetic human insulin and its analogues not having a perfect three-dimensional structure, as manufacturers only know if the molecular weight is the same -- regardless, it may not necessarily be attributed to the insulin molecule itself, just imperfectly-formed insulin molecules).

Regardless of your personal feelings on this issue, new research from Australia appears to have definitively answered the question that the two main types of diabetes are very clearly unrelated from an etiology standpoint. Until now, it was simply assumed that the processes leading to beta cell death were similar in both diseases (if not exactly the same).

As you may know, type 2 diabetes mellitus is a metabolic disorder defined largely by insulin resistance, meaning the cells in the body no longer respond properly to insulin. The confusion arises largely because in type 2 diabetes, the insulin-secreting beta cells in the pancreas sometimes also die, albeit at different rates from type 1. (By comparison, type 1 diabetes is not due to insulin resistance but an autoimmune process more similar to multiple sclerosis or Crohn's disease.) The cause of beta cell failure was the argument used by the medical profession that the diseases are more similar than different.

Scientists at the Garvan Institute of Medical Research in Sydney have now shown that the causes of cell death are very different. The Garvan Institute of Medical Research was founded in 1963 -- initially as a research department of St Vincent's Hospital in Sydney, but has since grown to become one of Australia's largest medical research institutions with approximately 400 scientists, students and support staff.

Last year (in April 2007), Garvan Associate Professor Trevor Biden and Dr. Ross Laybutt published a paper establishing the existence of ER (Endoplasmic Reticulum) stress in people with Type 2 diabetes. The ER is the part of a cell where simple strings of amino acids are structured into three-dimensional proteins which then go on to perform specific tasks in the body. Insulin is one such protein. When the correct re-structuring of proteins is disrupted, beta cells suffer ER stress, and eventually die. In other words, in type 2 diabetes, beta cell death is not caused by white blood cells targeting the cells (under the mistaken assumption they are an infection or virus) as it is with type 1 diabetes, but because some of the insulin molecules produced by the body are slightly deformed due to some type of disruption in the body's natural insulin production process.

The new study, undertaken by PhD student Mia Akerfeldt, expands the knowledge about ER stress in Type 2 diabetes, while completely ruling out its relevance in Type 1 diabetes. The paper is now online in the journal Diabetes.

Mia Akerfeldt is hopeful that the findings will translate quickly into treatments for type 2 diabetes and help stop eventual beta cell loss in that disease. "Garvan was first to show that ER stress was present in people with Type 2 diabetes, and that reducing it could slow down beta cell death," she said. "We've not only shown the same thing again, we've identified a potentially useful therapeutic agent."

Project leader Ross Laybutt echoes Akerfeldt's optimism. "One interesting aspect of the new study is that we used a "chemical chaperone", an agent that helps the secretory protein, in this case insulin, to form properly. This compound relieved cell death and ER stress in laboratory experiments."

"The compound, known as PBA, is already FDA approved for use in another clinical application. That suggests it could be fast-tracked for use in humans to prevent or delay beta cell dysfunction."

"A study conducted in the U.S. demonstrated that this compound cures [type 2] diabetes in animals. The next step would be to conduct clinical trials on people."

What does this mean for type 1 diabetes? Initially, not much, but it does clarify the distinction and likely eliminates the growing movement to try and lump the two diseases together as far as research, not to mention drug development (no doubt, the pharmaceutical industry will not be pleased with this finding). But it does strengthen the argument for continued Federal funding for the special type 1 diabetes research program which was recently extended for 2 years by a veto-proof majority in Congress. If anything, the research has solidified the distinction between the two forms of diabetes and helped establish the need for unique research for each individual disease sharing the poorly-distinguished disease name "diabetes".

See also http://www.garvan.org.au/news-events/news/potential-to-prevent-loss-of-insulin-in-type-2-diabetes.html.

7 comments:

Bennet said...

Thanks.

Very good job of covering the research papers and putting it into actual, understandable English.

Anonymous said...

This research coming out of Australia at first glance appears to be a significant finding regarding the etiology of T1 and T2 diabetes. The significance of the catch-all term “malformed insulin,” used to distinguish apparent difference, becomes the Catch-22. Researchers for a long time have known symptomology for these TWO diseases is characteristically near enough the “same” to allow the two diseases to be lumped together. The problem I see occurring with the approach out of Australia is the fact that no one can really IDENTIFY a perfect insulin molecule. Until we have the technology to differentiate the “perfect” from the “near perfect” in a 3-dimensional manner, like we can fingerprints in a 2-dimensional manner, all we can do is GUESS at the probability of WHY. We have heard in the past that T1 diabetes may be the result of malformed insulin, which in turn causes the autoimmune response. So what’s new about the T2 proposal? Could it be that we know so little about the insulin receptors in the body that perhaps T1 is an insulin-production problem while T2 is an insulin-receiver problem?

Just the other day, I went into my local hardware store to have several keys made for my car. Of the three “identical” keys produced from my master—two allowed me to start my car—one didn’t. Of course, since all master keys are made with encoded electronic alarm controls, etc., none of the copies would engage/operate the ‘electronic’ gadgetry. Additionally, the two that did work also set off the car’s alarm system. Suppose that the ‘perfect’ molecule of insulin has all the right stuff, but one amino acid located in the ‘right spot’ is slightly skewed, left or right, from its two-dimensional plane. How does the insulin receptor “see” this molecule if it happens to be located at the point of reception? Unfortunately, diabetics’ heightened immune systems seem to detect DEFAULT much better than most of our scientists understand.

This whole study does make one question—at least a little—the veracity of pursuing MORE analog insulins to further confuse the body.

--Brent

David Edelman said...

Thanks for posting this, Scott, and taking the time to explain it so thoroughly.

I recently did an interview with Dr. Michael Weiss, a researcher at Case Western Reserve University. His research is focused on understanding beta cell exhaustion in type 2 diabetics as well. He reached the same conclusion. Our interview covers how the misfolding occurs and how the process might one day be stopped in easy-to-understand terms.

Listen to the podcast: Understanding Beta Cell Exhaustion in Type 2 Diabetics.

Scott said...

Thanks Brent and David,

You both raise interesting points, and that is that we know there are problems with the insulin structure created in people with type 2 diabetes, and perhaps in some with type 1 also. I suspect that the "folding" process Dr. Weiss described can have a mishap at any number of points in its creation, but at least with endogenous insulin production there is a possibility to produce some perfect molecules and some which aren't -- the one's which aren't perfect cause the beta cells which product them to be the target of inflammation which kills them.

The issue of biosynthetic insulin is even more troubling because these products have never been tested (indeed, no such tests existed until recently) to determine if the insulin molecules coming out of Lilly's or Novo's synthetic factories (or anyone else's for that matter) are "perfect" either, but there is a clue that they aren't, largely due to the insulin antibodies present in so many people with type 1 and type 2 diabetes. Its possible that there are some good molecules and some junk regardless of how its made, but the relative and lack of regulatory oversight on biosynthetic insulin is an issue that deserves more attention!

tmana said...

This is very interesting research, and does appear to be an explanation of a/the pathway of insulin resistance.

David Edelman said...

Scott, I never thought of it that way. That is very interesting indeed. I we can get some evidence on the topic, this may be an issue worthy of advocacy. If synthetic insulin can be damaging over the long-run, then it's worth fighting for better insulin production.

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