Tuesday, July 29, 2008

More on Islet Regeneration

A decade ago, there was a lot of excitement about INGAP (which stands for Islet Neogenesis Associated Protein), but for a variety of different reasons, much of that excitement disappeared to the point where many new patients or parents of children with type 1 diabetes really know little about this promising potential treatment, even though many diabetes veterans view all regeneration efforts -- including Denise Faustman's -- as having a number of similarities.

Back in March, I wrote that INGAP seems seems to have something like "nine lives" based on the number of times it has died and come back to life (this may also explain the decline in enthusiasm for this treatment). At that time, INGAP had resurrected itself yet again, thanks largely to a generous donation from Canadians John and Pattie Cleghorn (Pattie herself has a diabetes, as does their young grandson). My previous posts (see here and here for those) provide much more detailed history on INGAP if you wish to review it. INGAP was discovered by colleagues Dr. Aaron I. Vinik (the Strelitz Diabetes Research Institute of Eastern Virginia Medical School's Research Director) and Dr. Lawrence Rosenberg who now works at McGill University in Montréal, (Québec) Canada.

The INGAP treatment itself is now being developed by Kinexum Metabolics but has traded places repeatedly over the past decade -- from Procter & Gamble Pharmaceuticals to GMP Companies. At the ADA 68th Annual Scientific Sessions in San Francisco a few months ago, there was news that plans were underway to conduct human clinical trials using a new "drug combination" to reverse type 1 diabetes. One of those "drugs" was INGAP, the other was Lisofylline (LSF), which is an immunomodulator and anti-inflammatory small molecule that is believed to have the effect of calming the body's errant immune system which causes type 1 diabetes to occur. See Abstract No. 1620-P, "Unique Drug Combination for Reversal of Type 1 Diabetes" for more on that potential treatment.

Previously, clinical trials with INGAP itself were undertaken, with the idea that if it could be used to replenish insulin producing beta cells, then perhaps ongoing treatment with INGAP could result in sustained insulin independence. Back in 1997, I commented to someone that I thought the approach was akin to pouring water into a bucket with holes it -- the trick is to make sure that water is flowing faster into the bucket than it is flowing out, but instead of water, we're talking about beta cell regeneration. Unfortunately, the trials showed that recurrent autoimmunity was a continued problem in patients with type 1 diabetes, thus it was back to the drawing board. (Sometimes one has to wonder about researchers and trials vs. common sense, but this applies to so many areas of diabetes research, not just this one -- alas, I digress). The clinical trials already undertaken with INGAP have proven that it is possible to regrow new functional insulin-producing cells in diabetic patients.

From a historical perspective, up until 2004, when UCLA's Dr. Peter Butler (and colleagues from the Mayo Clinic) showed Evidence of Sustained Islet Turnover even in longstanding type 1 diabetes patients, the prevailing assumption was that there is a finite pool of beta cells and once they're gone, you'll need insulin for life. However, since then, researchers at Joslin have since confirmed Dr. Butler's findings, which has given the idea of beta cell regeneration much more credibility as a viable means for a cure.

As I noted in my interview with Diabetes Research Institute Immunologist Dr. Norma Kenyon, her thoughts were that INGAP might work best in patients with some remaining beta cell functionality (I'll spare you a diatribe about why I think biosynthetic "human" insulin and insulin receptor ligands better known as insulin analogues are responsible for complete beta cell destruction, whereas many who began on animal-sourced insulin still have detectable endogenous beta cell functionality) provided the right immune system treatment is applied, too!

In any event, most of the preliminary research seems to have been undertaken at Eastern Virginia Medical School, but thanks to the donation from Canadians John and Pattie Cleghorn, more progress has occurred at McGill University Health Centre in Montréal as of late.

The most recent edition of "Diabetes In Control" features a story on a submission to the July 2008 issue of the journal Laboratory Investigation entitled "Cellular origins of adult human islet in vitro dedifferentiation" authored by Stephen C. Hanley, Amélie Pilotte, Bernard Massie and of course, Lawrence Rosenberg. The full article is available online (for a fee, naturally) but the abstract can be viewed for free at http://www.nature.com/labinvest/journal/v88/n7/abs/labinvest200841a.html.

In essence, Dr. Rosenberg and colleagues have uncovered what they believe is a key mechanism behind regenerative therapies for diabetes. Through a process they call "dedifferentiation", they were able to re-trace the steps that "stem-like" progenitor cells go through before becoming islands of (Islets containing) alpha, beta and delta cells scattered throughout the pancreas.

The Montréal-based researchers have shown in vitro that insulin-producing beta-cells can return to a more primitive developmental state called stem-like cells. This process is known as dedifferentiation and the researchers say that it highlights the plasticity of this cell type. This same result has also been validated for the three additional types of cells (including glucagon-producing alpha cells, and the seldom-acknowledged delta cells which produces the hormone somatostatin) which -- along with beta-cells -- collectively make up the islets of Langerhans. Together, these islet cells produce insulin and other hormones in the pancreas. While it is often overlooked, one reason people with type 1 diabetes suffer much more from hypoglycemia than their type 2 counterparts (according to the medical literature, people with type 1 experience a 25-fold greater incidence than insulin-requiring patients with type 2 diabetes), and especially issues such hypoglycemia unawareness is because the other cells found in the Islets of Langerhans are also destroyed. Their counterregulatory response to insulin-induced hypoglycemia is totally destroyed. But medicine has remained largely fixated on beta cells, rather than the bigger picture, much to the dismay of patients who suffer from hypoglycemia unawareness and are routinely "blamed" for their failure to recognize hypo symptoms which are not even there for them to recognize!

Dr. Rosenberg said "The potential for dedifferentiation of all the different cells that make up the islets of Langerhans is a totally new finding. At this stage, we can't confirm whether the cells' ability to turn into stem-like cells occur naturally in a healthy pancreas, but the results are very encouraging for the development of regenerative therapies to fight diabetes."

The cell's in-vitro plasticity also opens up totally new avenues of investigation into the underlying causes of diabetes, and will validate the development of innovative treatments, including INGAP.

Commenting on INGAP, Dr. Rosenberg said "We know that the peptide works, but we are still lacking certain theoretical bases to explain its mechanism. This finding will allow us to move ahead on firmer ground."


Anonymous said...


Type 1 or Type 2 diabetes is a long-term, chronic problem, as you already know. Short-term studies with animals, with healthy (non-diabetic) people, with a cherry-picked group of T1 or T2 diabetics or any research done today by corporate America and their medical cronies should be looked at with no more significance than is paid to their advertising campaigns. Add to that the backing these “researcher” get from government, charities, and paid-for media, and you get INGAP-type research. Is this rather like Alaska’s famous ‘Bridge to Nowhere’?

I would like to see a moratorium placed on diabetic drugs. Bring back CHOICE until we figure out whether biomedical “drugs” are really what they are purported to be. I would suggest that the FDA require any biomedical product be tested on a representative, healthy population of non-diabetics for a period of at least 5 years before being released for use on a chronically-ill population. I really would like to know if hypoglycemia unawareness, beta cell regeneration (requiring C-peptide testing), insulin antibody response and a variety of things we have all discussed show up in this healthy population, comprised exclusively of executives, stockholders and peddlers of the products we now call “new age insulins.” My second choice for a test population would be a group made up exclusively of medical professionals and anyone who PRESCRIBES these products; who is better able to handle whatever ‘comes down the road’ regarding unexpected effects of drugs they prescribe.


Anonymous said...

Is any of this actually going to be used, or will it be dumped back into the laps of researchers who are and forever will be 'working on the problem'? The only ones I see winning here are the researchers, who keep drawing a paycheck. INGAP has been around for a long time and if there was even a tenth of the interest in making it work that there was for somethign like Cyalis or Viagra, we'd have something other than subcutaneous insulin therapy right now. but as we all know, sick children can't pay as much money to a pharmaceutical company as middle-aged impotent men can *rolls eyes* Will there ever be any incentive to cure us, rather than just forcing us into lives of perpetual financial slavery to our medications? Or will we keep being beseiged by endless papers detailing the ins and outs of islet regeneration in perpetuity, where there is never enough money, time or incentive to actually take potential therapies for this nightmare disease to the next step - human testing? So what if INGAP has mole lives than your average feline - INGAP will never make it to the stage where we can use it as a treatment. it will just keep getting bought by newer players who want of the diabusiness gravy train. There is always 'MORE RESEARCH REQUIRED'. And sadly, there always will be.

Anonymous said...

I don't know who the second "anonymous" commenter is--but obviously someone who understands very well the treadmill that IS diabetes research. Welcome to the choir.


Anonymous said...

It's kind of funny, they know what diabetes is, they know which cells are involved, the know where this "shoot out" is taking place in the body, they know what effects it and what doesn't, but they claim that it's still a mystery how diabetes really works. I find myself feeling stupid sitting here taking insulin, and thinking c'mon guys you can do it! Just look a bit closer, somethings wrong here and always has been. You're right, it's about the money, not the quality of life, it is about the "ongoing research" show me a biologist, or cell researcher that has type one, and ask him if he believes his community about what dead end streets they have taken us down. Like I said in the beginning, they have researched everything around diabetes, but they refuse to look right there in the center and see what is going on. They pretend that they are working hard, well, I say quite wasting my time, and do some d**n real science research and find out whats going on. Everything else medically around us has advanced 2 fold, but not the problem. Hell, they are driving down into nano tech now, and are probably have many cool things going on in that sector, wonder if any of those nano guys will think of us.