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 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 idea was if they do it fast enough, then they can keep all of the water being added from pouring out. 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....

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."

Views: 63

Tags: 2008, Canada, INGAP, Lawrence Rosenberg

Comment by Jan on August 2, 2008 at 1:59pm
Question regarding your comment:
"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!"
My question is: For children diagnosed in this decade, all of whom were only offered biosynthetic human insulin and for whom, presumably, total beta cell destruction has occurred, can INGAP with LSF work? Do these children have any hope that the cells in the islets of Langerhans will have the capacity to dedifferentiate? There will be a lot of therapies for the recently diagnosed and perhaps newly dx'd children will eventually have the option of getting insulin with C-Peptides, but what about most Type 1 children?
Comment by Scott Strumello on August 2, 2008 at 2:26pm
Hi Jan,

We don't know the answer to your question. Theoretically, INGAP should regenerate beta cells for anyone with diabetes, and the trials have proven that it works. Dr. Kenyon's comment was based on her feeling as an immunologist that beta cells tend to replicate themselves, meaning that existing beta cells tend to spin off new beta cells. But most of her experience has been in the islet transplant environment rather than regeneration.

Theoretically, however, the treatment with LSF and INGAP should work in anyone with diabetes as long as the substance which modulates the autoimmune response works effectively, then once that is resolved, INGAP can regenerate islets without further immune system interruption. The trials should answer this question definitively, however! Stay tuned (it will be a few years!)

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