Wednesday, July 16, 2008

Innocent Until Proven Guilty

The other day, I did a post about some new research that clarified the distinction between type 1 diabetes and type 2 diabetes. One of the key findings was that in type 2 diabetes, beta cell destruction is caused (in part, anyway) because of some insulin molecules produced by the body being slightly deformed due to some type of disruption in the body's natural insulin production process. In other words, the body recognizes that at least some the insulin molecules are imperfect, and responds by sending out the immune system to destroy the "offending" beta cells responsible. If you think about insulin's role as a "key" which allows glucose to enter the cells, then you quickly understand that a key which is slightly off simply doesn't fit into the lock (in this case, the cell receptor) and open the cell door! Of course, its a bit more complicated than this explanation, but the important thing is that imperfect insulin molecules trigger a response which ultimately leads to beta cell destruction. Diabetes Daily's David Edelman did a fantastic podcast on that subject, and the doctor he interviews explains just what goes wrong in the case of imperfect insulin production and the impact on type 2 diabetes.

However, you should realize that no one's body makes 100% perfect insulin molecules all the time and that doesn't necessarily trigger an immune response; but when the process is disrupted and a consistently malformed molecules are then produced, then immune system sends out its armies to stop the offending beta cells. The issue is when those "offenders" constitute a large number of the insulin-producing beta cells, then type 2 diabetes occurs. Note that this really has nothing to do with body mass, rather it is a cellular problem.

What happens, exactly? Well, here's the scientific part (skip the next paragraph if you don't want the technical details):

Insulin is a small protein molecule and is produced as part of a larger protein to ensure it folds properly. In the protein assembly of insulin, the messenger RNA transcript is translated into an inactive protein called pre-proinsulin. Pre-proinsulin contains an amino-terminal signal sequence (in other words, a string of amino acids which provide "operating instructions") that is required in order for the precursor hormone to pass through the membrane of the endoplasmic reticulum (ER) for post-translational processing. The so-called post-translational processing then clips away those portions not needed for the bioactive insulin hormone. Upon entering the ER, the pre-proinsulin signal sequence, now largely useless, is then removed to form proinsulin. Once the post-translational formation of the three vital disulfide bonds occurs, specific peptidases then cleave proinsulin. The final product of the biosynthesis is active insulin. Finally, insulin is then packaged and stored in secretory granules, which accumulate in the cytoplasm, until the insulin is needed and its release is triggered. If you're up for it, more details can be found here!

Okay, I realize this is pretty meaty stuff, but I include it here mainly because I wanted to demonstrate that the production of insulin is far more complicated than just mixing a few chemicals in the right proportion (the way most drugs are made) and then viola: insulin is formed.

But the genuises in the biotechnology industries, which by the way did not exist until the late 1970's, figured all that out, right? Well, the fine folks at Salon.com (a site which, by the way, has produced numerous acclaimed authors) summarized it pretty well by saying with biotech products, the regulatory attitude seems to be "innocent until proven guilty." In other words, unless someone has somehow been able to accumulate enough data to prove some kind of harm, the assumption is that everything is just fine. In an interview with author Denise Caruso, the author claims it's actually a little worse than that.

I won't go into too much more than to say that people with diabetes are the guinea pigs in this experiment, and that since 2005, biosynthetic insulin has been the only choice offered to patients in the U.S. Ironically, there were reportedly 300,000 patients still using Iletin II when Lilly pulled the plug on it -- hardly an insignificant market. But many would probably not have switched, and with good reason, had they not been forced to do so. Many patients switched to synthetic but still complain about unstable blood glucose levels, inconsistent insulin-to-carb ratios needed, loss of hypoglycemia symptoms, weight gain, and a whole host of other issues. In fact, an entire book was written about this topic, and its a short (72 pages, in paperback) but a compelling read. Others refused and import natural insulins at their own expense from the U.K., Poland or Argentina.

The real question is if biosynthetic insulin and insulin analogues were so terrific and so superior to the old stuff, why did the manufacturers have to discontinue the old product in order to force those 300,000 patients to switch?

I don't purport to have the answers, but all I can say is that 300,000 people weren't wrong nor should we automatically assume they were unsophisticated patients who grew up in the dark ages of diabetes care. In fact, this month's JDRF Frontline newsletter (see page 4) reports that George King, M.D., Senior Vice President and Director of Research at the Joslin Center in Boston found in their Medalist Study that many individuals with established type 1 diabetes (even those who have lived with it for 50 years or more) are still producing some of their own insulin. The Joslin Study also found that even after 50 years, about 30% of the patients they studied did not experience any of the common complications such as eye, kidney, or nerve disease. Clearly, these people were doing something right, therefore their claims should not be casually dismissed.

But I am particularly concerned by issues I have already raised, notably the move for manufacturers to outsource manufacturing of insulin to third-parties because its cheaper (and therefore more profitable) for them. While they can ensure the master cell banks are their own, that doesn't really mean all that much because there's much more to ensuring a product than the master cell bank. For example, we know Lilly uses E.coli bacteria in producing its biosynthetic insulin. This is a strain of the bacteria which is found in feces (eeeew!), although as the CDC reports, there are other varieties of E.coli and while some are harmless, others pose a health hazard. (Novo uses a form of yeast in its manufacture, but I'm not sure about Sanofi Aventis).

But getting back to the theme I raised at the beginning, how can we be sure that biosynthetic insulin crystals are perfectly formed? For example, we KNOW that phenol (a widely-used preservative used in biosynthetic insulin) in quantities in excess of 0.2% can cause the insulin crystals crack. Should we trust third-party manufacturers to be as dedicated to quality control? No need to worry because Federal regulators at the FDA and the USDA are looking out for us? No, wait, I guess the Salon.com interview with Denise Caruso suggested that may not be an assumption we should be making. We also know that time of storage of insulin preparations at various temperatures will reduce biological potency of insulin, thus the need for the preservative content. Allie Beatty discussed the issue of various preservatives in her blog posting back in March. But precision and careful quality control in manufacturing is key.

Aren't you glad that on Nov. 21, 1997, Congress enacted the Food and Drug Administration Modernization Act (FDAMA) which amended the Federal Food, Drug, and Cosmetic Act relating to the regulation of food, drugs, devices, and biological products, which effectively repealed all of the statutory provisions under which the FDA certified drugs containing insulin? After all, knowing that because insulin is grandfathered as a small-molecule, chemical drug which does NOT need to adhere to the legal quality control procedures for biotech drugs mandated in Public Health Service Act should have all of us asking what is being done to ensure consistency in the drug's potency and efficacy.

So why am I the only one asking these questions?

7 comments:

Scott K. Johnson said...

Wow Scott. It is more scary than I think I am willing to acknowledge.

I also sometimes feel very insignificant and unsure how to approach such a big issue in a way that will make a difference.

What should we do? How best do we attack this issue?

P.S. - I know I've said it before, but I really, really appreciate your ability to break these things down into understandable lingo.

Scott said...

Scott, My biggest concern is that we just do not know -- they might be fine, or maybe not. But the consequence of not knowing is the problem. There are new methods to examine the 3-D structure of insulin crystals. Also, the European Medicines Evaluation Agency (EMEA, similar to the FDA) mandates batch testing of biosynthetic insulin and analogues made in Europe, so Novo and Sanofi Aventis insulin is likely to be monitored (at least until Novo starts making it in North Carolina).

One option might be a citizen petition to the FDA requesting that biosynthetic insulin be reclassified as a biotechnology medicine (which it is). This might delay generics, but since no one is launching generics yet anyway, the risk of that appears very low.

BetterCell said...

You are not the only one "asking these questions" about Insulin.
As you already know Scott, it is cheaper and quicker to manufacture Insulin Analogues on a Global Market economy than to stay with Bovine/porcine Derivative Insulin.
In addition, since moslems are not immune from Diabetes, there prohibition against Porcine derivatives serves to enhance an already lucrative Market.
As we both know, the cost of Insulin has gone up considerably in price compared to the time when it was Bovine/Porcine Derived. Not only was it more affordable, but it provided the necessary benefits of C-peptide which protected people w/T1DM against the ravages of Kidney, Heart and Eye Complications (and more) which remain and are associated with the Disease of Diabetes, DESPITE good HgBA1C NUMBERS!!!!!!
IT IS ALL ABOUT MONEY.

The Patients Voice said...

Hi

We have just launched a test version of a new site which you might find of interest

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Thanks

Belinda

David Edelman said...

Hi Scott, I've responded on Diabetes Daily. Great, great post!

MelissaBL said...

This was fascinating! Thanks for the post.

Anonymous said...

I have watched the so called development of the GM insulin's since they 1st came in. All I can say is thank goodness I live in the UK and have access to bovine insulin. I have been type 1 for 43 years and would not use the synthetic muck for all the tea in China. I have no complication either.
I have loved reading your blog many thanks for all your useful info.