Friday, May 09, 2008

Another Argument for the Conservation of Insulin

New research continues to demonstrate that our creator, science or evolution (depending on your perspective, naturally) knew what it was doing when it came to insulin. The hormone works almost the same way in all animal life, and differs very little between species. In fact, very recently, scientists at The Salk Institute in San Diego have managed to prove that the humble fruitfly also relies on the same insulin-regulated molecular pathway to maintain its energy balance. The journal Cell Metabolism recently documented this discovery:

Biao Wang, Jason Goode, Jennifer Best, Jodi Meltzer, Pablo E. Schilman, Jian Chen, Dan Garza, John B. Thomas, and Marc Montminy; "The Insulin-Regulated CREB Coactivator TORC Promotes Stress Resistance in Drosophila"; Cell Metabolism, Vol 7, 434-444, 07 May 2008.

Although fruitflies lack a pancreas, researchers have discovered that they do have specialized cells in their brains that produce hormones remarkably similar to insulin and glucagon which mimic the functions of their human counterparts.

This is not the only study to find metabolic similarities between humans and bug-like creatures; previous research has also found that the insulin signalling pathway is also fully conserved between humans and nematode worms, too (see here and here for more details on that). This means that in some form or another, insulin exists in virtually all forms animal life, and it works just about the same in creatures ranging from the fruitfly and nematode worms, to more complex animals including fish, and the most complex of them all: mammals like us.

Marc Montminy, Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology, who teamed up with fly expert John Thomas, Ph.D., a professor in the Molecular Neurobiology Laboratory for the current study, said it best: "Basic biological processes are remarkably well conserved through evolution."

In the fruitfly, the researchers found that after eating, the cells release insulin into the circulatory system, which signals the "fat body," the flies' energy-storing organ, to store away fat and sugar. In humans, these functions are handled by multiple organs, including most notably the liver which stores sugar, as well as in certain fat cells. But clearly, the basic mechanism and the key to that mechanism -- insulin -- is the same in both cases.

(see also for more)

This should be raising questions on the value of insulin analogs. Its fairly well-established that insulin analogs, an entirely man-made creation which exists nowhere in nature, has some benefit of more rapid absorption, distribution, metabolism, and excretion (ADME) characteristics, but the true value has really been in fattening the bottom lines of manufacturers, as the clinical evidence has not been as favorable in terms of improved glycemic control. But the fact is that regulators have said the only criteria they wish to use to evaluate diabetes medicines is lower HbA1c's. In fact, I reported before, that most diabetes clinical trials ignore everything BUT blood sugar control, as if everything else is irrelevant -- too bad that wasn't the case!

But the U.S. Food and Drug Administration continues to argue that glycemic control, as measured by HbA1c (or possibly fructosamine) is an effective "surrogate" for improved patient outcomes, when in fact, the actual results of using HbA1c have been, well ... mixed. In many cases, drugs have lowered blood sugar only to create other problems, including among other things, increased cardiovascular risk. In other cases, the drugs/insulin increases the rate of noncompliance because the side effects are worse than the disease they are supposed to be treating. In the most recent "Draft Guidance" the Agency published for diabetes medicines and biopharmaceuticals, the FDA repeatedly mentioned using HbA1c as a "surrogate" for patient health, as if nothing else matters. In my formally submitted comments on this guidance, I wrote that the FDA can no longer afford to rely solely on HbA1c to evaluate new medicines to treat (not cure) diabetes, and that the agency needs to consider the bigger picture. Whether my comments are seriously considered remains to be seen.

The FDA's definition has evolved away from strictly "insulin" to what they now call "insulin receptor binding agonist", and the agency has stated that anything which binds to the insulin receptor and enables glucose to enter the cells is perfectly acceptable for the treatment of type 1 diabetes. Although they still must prove efficacy and safety, new treatments need not be insulin as such. Insulin analogs are one such example, but its hard to say what tomorrow will bring.

But we should question whether using HbA1c is the best measure of efficacy. After all, shouldn't side-effects also be considered? What about other benefits, including reduced hypoglycemia, weight-loss or maintenance, improved cardiovascular health, or beta cell regeneration? Although the deadline for submissions on the FDA's guidance has passed (I notified everyone about it in March). A growing chorus of doctors have already moved in this direction, but the simple fact is that we need our regulators to get with the program if we expect to see any changes to the status quo.


Scott K. Johnson said...

Very interesting find about the fruitfly... I never, ever, would have guessed.

Thanks too for again pointing out the shortcomings of looking at just a single thing in a whirwind of things surrounding diabetes management.

Anonymous said...

Re: Draft Guidance & public comments.

Scott--I know several individuals who offered suggestions/comments regarding this draft guidance. You might think that the FDA would appreciate hearing from individuals (patients) who might offer guidance that is patient-oriented, not profit-oriented. NOT.

After the comment period closed, I checked the site, and can find not a single "individual" comment. Apparently, if your submission is not made on pharmaceutical-corporate letterhead, it is disregarded? I e-mailed FDA (on the Monday following the closing date) to ask about where/when my 'public' comment could be viewed. I'm still waiting for a response.


Anne said...

Scott, this is sort of unrelated but have you ever heard of people developing problems absorbing Humalog properly? I seem to have a 1-3 hour delay and a huge tail which is wreaking havoc. I have gone off the pump and tried 4 vials (from different lots) so guess it's just me. Is there a big difference between people's experience with Humalog vs. Novolog vs. Apridra? I realize they are all different molecules but have heard that they are also all about the same. I would even consider going back to humulin but am pretty sure I would enjoy that for about 1 day.

I've checked most of the obvious explanations I think...


BetterCell said...

I wonder then if the humble Drosophila ever develops T1DM or IRD.
If so, then the ADA can add them to the "Walk For A Cure."

Anonymous said...


The basis for every ‘CON’ is to play on the weaknesses of a victim. If you can define those weaknesses (especially in terms of numbers), then it is easy to control the victim. Insurance companies and doctors who can control diabetics, using bG’s and HbA1c’s, are certainly not much better than con artists.

As you so aptly expressed, and stated in your comments to the FDA, the HbA1c is by no means the total picture. Research has already shown that “improving” that number quickly can have disastrous consequences for those with impending complications. In terms of safety, improving bG and HbA1c tolerances usually leads to increased episodes of hypoglycemia, and increasing occurrences of hypoglycemia unawareness. DRIVERS BEWARE!

The real question may be WHY (when insulin is such a standard biochemical hormone in the animal world) do we not know more about this hormone’s interplay with the other biologic processes, co-produced by the pancreatic system. In fact, those animals which don’t have a pancreatic system, but DO produce insulin could be looked at more closely in terms of the other co-factors like C-peptide and proinsulin, which play a role in metabolic health (in terms of complications). In fact, if you read through a paper by Tattersall (from 1983), you will find that improving bG did not necessarily improve HbA1c’s, nor did it improve antibody response, C-peptide levels or proinsulin production. Mind you, this was back in 1983, and their ultimate conclusion was “match the insulin to the patient’s needs, and check antibody response.” The pharmaceutical industry’s answer is to give us MORE analogs, causing more significant antibody response in some diabetics.


You might want to check your antibody response—if your doctor knows what he’s looking for.


Scott said...

Thanks everyone for your responses! Anne, as a follow-up to your inquiry, you should know that the FDA requires the mean and/or median time-activity curves to be disclosed in the package inserts, but they don't usually provide the standard deviation, which might suggest how far from those figures the sample in the trial ranged. That little disclosure flaw has produced several variations which the FDA claims are all essentially the same, but may respond very differently in different people!

You may wish to ask your doctor for a sample of Novolog/Novorapid and/or Apidra to try as an aternative ... see if the activity profile differs.

To follow-uo Brent's point, antibody responses can develop over time, and some people (myself included) have found that switching from one brand to another does resolve those issues -- at least temporarily. There's no easy answer, but its definitely something worth looking into!