Creating Glucose-Responsive Insulin: The Crowdsourcing Approach

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From its isolation and first use in 1922, insulin has been called one of the few miracle drugs, saving diabetics from the early death of an untreatable disease. Any diabetic nowadays, however, will tell you– insulin treatment for glucose control is a tricky business. As Dr. Bruce Buckingham said at the recent TEDxDelMar conference, insulin has “a very narrow therapeutic margin.” In other words, it’s easy to give too little– resulting in hyperglycemia– or too much– resulting in hypoglycemia. Titrating insulin dosage throughout the day is a difficult and time consuming process for diabetics, and the current system results in many dangerous excursions outside the ranges of normal blood glucose levels.
 
What can we do about this? Two prominent answers are: replace the body’s beta cells, as they are better glucose regulators than any human will ever be; or, develop an artificial pancreas that can measure glucose levels and algorithmically dose accordingly. 
 
And then there’s a third option, one that could provide an alternate route to success: make an insulin which works only when there’s glucose circulating that needs to be taken up by cells. If there’s no excess glucose, the insulin is inert, and patients don’t become hypoglycemic. If there is too much glucose in the bloodstream, the insulin would somehow be activated, lowering glucose levels and avoiding hyperglycemia.
 
Sounds cool, right? There’s only one problem: we don’t know how to make that kind of insulin yet. A number of approaches have been tried, including, for example, systems that rely on glucose and pH-sensitive hydrogels, but so far nothing has proved to be a reliable, usable way of delivering insulin only in response to glucose stimulation.
 
How hard can it be? Well, that’s where you come in. Really. The JDRF has put together an open contest, asking for written proposals for a way of developing glucose-responsive insulin. They are running the challenge through InnoCentive, a platform for crowdsourcing solutions to complex problems. The JDRF is offering up to $100,000 for the proposal or proposals they think have the most promise.  The deadline is November 9th– so get cracking!
 
To find out a little bit more about the contest, we spoke to the director of the JDRF’s Insulin Initiative, Dr. Sanjoy Dutta:

What is glucose-responsive insulin? Why would it be useful for diabetics?
Glucose-responsive insulin (GRI) is a novel form of insulin that would basically work only when the body needs it. It would deliver the precise amount of insulin in response to circulating glucose levels, to control blood glucose levels with once-daily or less frequent dosing in people who have insulin-dependent diabetes. Compared to the current administration of insulin multiple times or continuously throughout a day, glucose-responsive insulin would not need to be calibrated with carbs or blood glucose testing.
 
This type of insulin holds the potential to transform the lives of the hundreds of millions of people with diabetes who need insulin to live. It would improve glucose control, decrease or eliminate the need to test or monitor blood glucose levels, improve the quality of life for people with diabetes, and reduce their chances of both short- and long-term complications.
 
How much would glucose-responsive insulin be able to accomplish? That is, if we had glucose-responsive insulin, would we still need an artificial pancreas? Continuous glucose monitors?
A GRI, in its truest form, would be game-changing in the way insulin-dependent diabetes (both types 1 & 2) is treated. It would be an alternative for those who may not want to use devices such as pumps, glucose meters, CGMs, and even an artificial pancreas system. We envision it to be a once-a-day (or less frequent) drug, with occasional (maybe once-a-day) glucose measurement. However, it is important to understand that no drug, including a GRI, is going to work for all individuals with insulin-dependent diabetes. Therefore, there will continue to be a need to discover and develop other treatments, such as artificial pancreas systems, to benefit all individuals with type 1 diabetes.
 
Why hasn’t this been done yet? What are the challenges in creating an insulin that acts only in the presence of glucose? In other words, what makes this a hard challenge?
Designing a drug that will be device-free and deliver in response to circulating levels of glucose (or any other chemical/protein) is a very complex, hence challenging, problem. We believe it will require the concerted effort of diabetes and non-diabetes researchers, such as pharmacologists, toxicologists, biochemical engineers, and polymer scientists, just to name a few. Novel concepts and initial attempts in this field have either failed or languished due to the lack of such coordinated teams.
 
Why has JDRF decided to use the InnoCentive contest platform for this challenge? What does InnoCentive offer that is different from JDRF’s normal approach of funding individual researchers?
JDRF has opened this challenge to the public with the aim of leveraging the knowledge and skills of a new, fresh pool of talent, and to obtain different perspectives on how glucose-responsive insulin treatment could be designed.
 
This type of crowdsourcing approach usually allows for efficient and timely problem solving, and the proof is in the pudding. InnoCentive’s Challenge Driven Innovation approach has led to numerous healthcare solutions in recent months, including the identification of a biomarker for ALS and a new delivery method for folic acid to women in third world countries. In addition, our glucose-responsive insulin challenge will reach the attention of InnoCentive’s 250,000 registered Solvers. It is important that this challenge reaches the ears of potential Solvers as far and as wide as possible, and that is why JDRF is working to get the word out.
 
The prize description says that up to four ideas may be selected, with awards of up to $100,000. What will the actual value of a winning proposal be? Will there be a sliding scale of prize values, and, if so, what will the awarded amount be based on?
The submitted applications/ideas will be reviewed by a JDRF-convened panel of experts. The number and amount of prize award(s) will depend on the decision of this panel, and JDRF is open to all possibilities in that respect.
 
If a good proposal is submitted and selected, what will be the next steps? Who will lead the development, trials, and tests? How long might that take?
If we decide to award a Solver(s) for the first phase of the challenge, the “Ideation Phase,” JDRF will invite the winning Solver(s) to participate—either alone or as part of a larger team of Solvers—in the next phase of the challenge: the “Pre-Clinical Proof-of-Principle Validation Phase.” Phase two will build on successful ideas from phase one, and provide detailed research plans, including pre-clinical proof-of-concept studies in animal model(s) of T1D, timelines, and budget estimates. We are unable to predict the length of time for research at this early a stage.
 
Should phase two prove successful, JDRF would then begin a third phase, the “Clinical Proof-of-Concept Phase.” In this phase, JDRF will work to outline and then follow through with a projected path forward for the clinical development of a pharmacologically safe and effective glucose-responsive insulin.
 
Each of the steps in this challenge will only transpire according to the success of its preceding step. That is why it is critical that we receive good ideas in this first “Ideation Phase,” as it will set the scene for the entire challenge.
 
If a proposal is selected, who owns it? What role will the authors of the proposal have in the next steps of development?
Under the Challenge agreement, JDRF will obtain exclusive rights to the intellectual property of the winning solution.
 
Winning Solver(s) from the first phase will be invited to participate in the next step(s) of the challenge, either alone or as part of a larger team of Solvers.
 
In theory, if there were such a glucose-responsive insulin, how would it compare to endogenous insulin secretion? How fast would insulin have to be to be both glucose-responsive and sufficient to maintain normoglycemia?
In theory, a GRI drug should closely mimic endogenous insulin secretion, i.e., deliver the precise amount of insulin in response to the glucose levels/demands of the target organs at all times during the course of a given day. At this time, the speed of a GRI drug is not of concern since it is a “continuum” of insulin release and action based on local glucose concentrations.
 
In the current conceptions, does the insulin respond to glucose in the bloodstream, or glucose that has diffused into tissues and interstitial fluids?
Currently, insulin delivered by a pump in response to glucose levels measured by a CGM device is based on interstitial fluidic concentrations of glucose, whereas manually injected insulin is based on blood glucose levels measured by fingerstick glucometer devices.
 
When I exercise vigorously, I notice that very often my continuous glucose monitor, with the sensor inserted in my abdomen, detects a quick decrease in blood glucose. If I use a finger-stick to measure actual blood glucose concentration, I see that I am not in fact hypoglycemic. In my folk-science reasoning, I assume this is a result of differential glucose distribution during exercise, as my body moves energy sources to the muscles that need it most. How might such physiological complexities of glucose distribution affect the action of a glucose-responsive insulin? Would differential diffusion and absorption rates matter?
Again, at the present time, it is hard to address these specific metabolic conditions in the absence of a GRI drug ready for clinical evaluation. However, as discussed earlier, an ideal GRI drug would be able to deliver insulin proportional to local glucose levels/requirements, such as the skeletal muscle during exercise, or fat tissue during extended periods of fasting. Thus, differential diffusion and/or absorption rates would be accounted for in the net amount and delivery of insulin through a GRI.
 
What have researchers tried thus far to create glucose-responsive insulin? Why didn’t these attempts work?
Based on the published data base, it is our understanding that different research groups have addressed different aspects of the design, synthesis or experimental testing of potential GRI and GRI-like drugs. And there are quite a few interesting and promising concepts in the public domain. However, given the characteristic requirements of a GRI drug and complexity of diabetes, it has been difficult to successfully develop a GRI drug to date.
 
What sort of proposals is JDRF willing to entertain? Is a modified insulin molecule the most likely route? Some sort of encapsulation strategy? Would a nanotechnology-based proposal be thought reasonable as well?
At the present time, JDRF is absolutely open to and will entertain any/all novel ideas for the design of a GRI drug. We believe all of the above, plus additional approaches, are entirely feasible. The main purpose of the prize is to spur innovative thinking and generate novel ideas/concepts—and we hope some of these can be translated into bona fide GRI drugs.
 
Are there degrees of glucose-responsiveness? Would a plan for semi-responsive insulin be valuable?
Ideally, a GRI drug should be able to release/deliver insulin proportional to a wide range of ambient blood glucose concentrations, from very low blood glucose levels with minimal/no insulin release to very high blood glucose levels with large amounts of insulin release. This would enable control of blood glucose extremes, to maintain a euglycemic (normal) range and avoid hypo- and hyperglycemia.
 
Whether the solution is a GRI drug that releases insulin semi-responsive to glucose levels, or a combination of two or more such GRI drugs to cover the gamut of blood glucose values, is yet to be determined.
 
What are the potential risks? Would the constant influx of insulin made possible by such a drug be a health risk?
Safety is foremost in the design and development of any drug, and hence for GRI drugs as well. Diligent and exhaustive safety pharmacology and toxicology studies will need to be performed in both animal models and in human trials. The specific safety studies required to derisk the GRI drug will depend on the design and ingredients of the drug.
 
There should not be any constant influx/release of insulin from a GRI drug; the release should be strictly glucose-responsive. This will need to be assessed during the drug development process.
 
Are there any existing drugs that behave in a similar manner, activating only when a related, but not directly targeted, molecule is present?
Great question. To the best of our knowledge, there are devices available that deliver drugs in response to a target molecule (such as drug-eluting stents); however, we are not aware of non-device approaches to achieve this sophisticated level of drug delivery in response to a circulating signal.
 

What is your best proposal? How would you make glucose-responsive insulin?

In short, we do not have the answer! Hence the search for ideas through this prize! It would be remiss to restrict one’s thinking to approaches already considered.

 
However, prior art in this and related fields suggests that natural and/or synthetic glucose-responsive polymers can be utilized to “package” insulin such that the combination can possess the required characteristics.
 
Alternatively, one can learn from the body’s pancreatic beta cells that synthesize and secrete insulin, and mimic the machinery and/or architecture of these cells to generate glucose-responsive insulin drugs.

Karmel Allison is ASweetLife’s science editor and a regular contributor.  She writes the blog Where is My Robot Pancreas?

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Comments (20)

  1. donna schindler at

    According to the attached link, Dr. Zion of Smartcells already developed Smartinsulin, the rights of which was purchased by Merck to the tune of FIVE HUNDRED MILLION dollars in December of 2010. After which it was never heard of again, perhaps because the bulk of Merck’s massive revenues come from drugs to treat diabetes. This is all about big money, not helping the victims of this horrible disease.
    http://www.smartinsulin.com/news/news_main.html

  2. Karmel Allison
    Karmel Allison at

    Donna– Perhaps I am too naive or too much of an optimist, but please do not be so quick to write off innovation as a selfish chase for money. As Dr. Dutta points out, this is a very hard problem to solve, and there are a number of researchers and companies that have tried and failed, or that are still trying. The lack of progress is likely not a result of too little effort or nefarious motives; more likely, SmartInsulin has promising technology, but there is a big gap between a promising start and a marketable end. Don’t lose hope yet!

  3. donna schindler at

    Karmel: I believe in Todd Zion’s SmartInsulin. I guess my post was not clear. It was ready for clinical trials some time ago. It has been funded for over a decade by millions of our taxpayer dollars through the NIH for several years, and then was bought out by Merck in Dec. 2010. Since then the silence has been deafening. If you or anyone else can find out when it will begin being produced, please let me know.   Many of us have written many letters and posts and emails and we get NO response whatsoever.   It would not be a big deal, but there’s the fact that our children have a life threatening medical condition that takes constant and unrelenting diligence to keep under control and even then there may be complications.

  4. Scott S at

    To add a bit to this discussion, for Donna in particular, SmartInsulin from Merck is anything but dead.  Note that virtually ALL of the NIH-funded research to date has been preclinical, meaning it was to prove the concept works, and that involved animal testing.  But it was absolutely NOT ready for clinical trials in humans.  Todd Zion told investors that the sale of the company to Merck last December was, in part, to ensure they had the financial resources to start Phase I trials and hopefully continue to Phase III trials assuming it succeeds, although humans with diabetes are not the same as cats with diabetes, so there are no guarantees, naturally.
    When the company released its Q3 2011 earnings this morning, management noted that the combination of Merck and Schering-Plough in November 2009 created a new Company.  You may not even be aware of this, but with the Schering-Plough acquisition, Merck became the world’s largest contract manufacturer of insulin, and while you may never have considered it, almost all insulin that is used in IV bags used by hospitals is made by Merck’s Organon unit (they also are the largest supplier of insulin for animals, so its not as if the company doesn’t know what its doing, both in terms of biotechnology and distribution on a worldwide basis).  Following the Schering-Plough merger, management basically set out on it’s growth strategy into the future.  Basically 5 elements: Number 1, they want to maximize the portfolio by maximizing the growth of current products – no surprise there.  However, the second element of the company’s growth strategy is to deliver the R&D pipeline, and Merck has a long history of success in R&D. And innovation remains a core competency for Merck.  The SmartInsulin acqusition plays a key role in this, as today, aside from companion animals, Merck is a non-entity in treating type 1 diabetes.  The company aims to make that a core business.  However, to presume that it would already be on the market 

  5. Scott S at

    was a tad naive.  It takes time, but the Merck acquisition was a step in that direction.

  6. donna schindler at

    To quote you “You may not even be aware of this” “you may never have considered it” “However, to presume that it would already be on the market, was a tad naive.” I would say your comment was tad condescending. It also gave no information whatsoever about what Merck has done in the way of clinical trials in the last 10 months since it acquired SmartCells. Believe it or not, us parents of Type 1 diabetic children actually have no interest in Merck’s portfolio, or the maximizing thereof. Many of us have been writing to Merck, and to their franchise head for diabetes, Nancy Thornberry, regarding this very issue.  Do you know what response we have gotten? None. Silence. Meanwhile we live each minute of each day and night with children that we care for with a life threatening condition. And you have the audacity to babble on to me about mergers with Schering Plough and growth strategies and maximizing portfolios. I have no problem with Capitalism and I am not under the misguided impression that a multi-billion dollar corporation owes me or anyone else charity or has a soul or is any way guided by ethics. I am a realist. But if they own the rights to a better insulin that can help my child  to be safer and have a better life, then I will fight for it to be put into Clinical Trials and produced, and it will take much more than a few supercilious remarks by you or anyone else to stop me from pursuing same.  This could be a huge step up from Lantus, which is a wonderful product in my opinion.   You obviously have no knowledge of Type 1 diabetes and are only interested in this from an investor’s viewpoint. Perhaps you need to look at it from a different perspective and educate yourself a little bit on the subject you are attempting to  engage us on. You can never truly understand as much as those of us who live this condition 24 hours a day. I have no idea what your interest is in this subject anyway. You are obviously not a person with type 1 or a parent of a child with type 1. So I have no idea why you even responded to my comment. 

  7. katerinas at

    Scott thanks for the info about what Merck is doing. I think a lot of people are very dissapointed about the progress of Smartinsulin. I do not know if Merck is to blame or dr Zion who misguided us by stating that smartinsulin was ready for human trials. There was even the rumor that human trials had started in Europe. I hope what the JDRF is trying to do now will have some possitive results. I really wish I had the knowledge to help!!

  8. Randy Anderson at

    Karmel, thanks for this informative update about JDRF’s glucose-responsive insulin initiative.  I have a few ancillary comments.  First, you reference two other “prominent answers” for better treating T1DM, replacing beta cells and an artificial pancreas.  I think it is a good idea in this context to consider beta cell specific immune tolerance induction as THE most important approach to curing T1DM.  There are several biologicals that have shown therapeutic effect for stimulating beta cell growth.  However, in T1DM, all have been associated with a resurgence of autoimmune antibodies specific to peptides on or in beta cells.  Thus, a real cure for T1DM will have to accomplish immune tolerance before we can hope to successfully replenish and maintain functional beta cell mass.

  9. Randy Anderson at

    I alluded to a second point in my prior comment.  That point is that the loss of insulin from beta cells in T1DM is not the only endocrine hormone loss in T1DM.  Alpha cells are lost as well, and they produce at least one endocrine hormone important to carbohydrate metabolism, amylin.  Like insulin, amylin is very dose sensitive.  It amplifies the hypoglycemic effect of insulin by slowing gastric emptying, suppressing liver production of glucose after meals, and increasing post-meal satiety.  An artificial pancreas will better regulate insulin dosing compared to “manual” dosing, resulting in less severe hyperglycemia and hypoglycemia.  However, the best we can expect from an insulin-only artificial pancreas is still far from normal blood glucose control. 
    One additional point might be helpful to understanding the complexity of developing a glucose responsive insulin.  The kinetics of the release of active insulin will have to match the normal pancreatic release of insulin in rate, magnitude, specificity to glucose, and glucose “trigger” level.  Presumably, the molecule will need to keep insulin bound in an inactive state when blood glucose is below 100 to 120 mg/dl.    Nothing other than glucose can trigger release of the insulin, or there could be disasterous and unanticipated hypoglycemia.  The insulin release rate and magnitude will need to closely matched to the rate and magnitude of hyperglycemia.  This collection of kinetics requirements is a daunting chemistry and physiology challenge to be sure!

  10. Karmel Allison
    Karmel Allison at

    Randy– thank you for the comments. I, for one, tend to agree with you– a biological cure is the ultimate goal, and we need a better understanding of the immunology involved to do that. (Admittedly, though, I am far from a disinterested party, given that I am a bioinformaticist in an immunology lab :) ) And, as you point out, we are only beginning to understand the complexity of the cellular mechanism involved in insulin release (I think, for example, the recent research into leptin in t1d models will reveal a CNS axis that we haven’t even begun to consider).

    That said, glucose-responsive insulin would be a huge improvement in terms of treatment, and I would not be so quick to write it off as too difficult. Perfecting the kinetics, sure, but getting a better option than we have now? I’ll take it. Not to mention that anything we learn about the dynamics of insulin release along the way will be to our advantage.

    Also, for the record, the beta-cell regeneration and pig-transplant folk say that we might be able to hide or protect the beta-cells without an immune retraining. Like I said, I tend to be on your side, but I certainly don’t intend to be too stubborn to refuse a working solution if offered to me.

    I’d love to discuss more though, if you’re so inclined: karmel [at] asweetlife [dot] org

  11. Randy Anderson at

    Here, here to incremental improvements!  I’ll try any one with a positive benefit/risk profile.
    I’ll certainly be willing to use allogenic or xenogenic replacement beta cells if they work better than pumps or closed-loop pumps.  However, I think the immune system has an enormous capacity to make such interventions short-term at best.  Frequent exogenous beta cell replacements will be very expensive, I think, much moreso than pump technology, which far too few T1DMs can access currently.  So, I’m placing my first bets on the tolerance induction path. 
    Given the high concordance of autoimmune illnesses, I think the core disease behind T1DM is autoimmune susceptibility.  A T1DM cure via tolerance induction could be anywhere along a vaste immune etiologic continuum between resetting immune memory to beta cell peptide-specific regulatory T cell balance.  Some points along that continuum may have the potential for more broadly resetting this autoimmune susceptibility.  
    I like the way some at JDRF talk about three interdependent keys to a cure:  specific immune tolerance induction, beta cell regeneration, and an artificial pancreas as a necessary bridge while accomplishing the first two.  This reasoning seems focused and insightful.

  12. katerinas at

     Randy do you suggest that we give up on smartinsulin?

  13. Randy Anderson at

    Absolutely not!  A safe and effective glucose responsive insulin would be a great incremental improvement for T1DM treatment.  It is just important to appreciate the complexity of the pharmacokinetic requirements of a safe and effective glucose responsive insulin.  But, occasionally scientists get lucky.  The JDRF prize will help spawn curiosity, so that more scientists will examine the problem.  The more who look, the greater the likelihood that one will get lucky.
    The ultimate prize for us all is a curative return to normal carbohydrate metabolism.  As best I can tell, that path requires immune tolerance induction, beta cell regeneration (actually, healthy islets), and a bridging artificial pancreas to optimize the normal blood glucose needed during beta cell regrowth.

  14. katerinas at

    You don’t sound very optimistic! What do you think of the efforts so far ie dr Zions Smartinsulin? 

  15. donna schindler at

    Just a quick note – amylin is a hormone that is produced by beta cells, like insulin. It is also no longer produced in people with t1dm, but is available for injection synthetically as Symlin. Symlin has been found to reduce post prandial bg spikes, but can contribute to hypoglycemia. The alpha cells produce glucagon.

  16. Randy Anderson at

    Thanks for that key correction on alpha cells, Donna!  Your mention of glucagon also merits note in that its absence for counterbalancing insulin effects on blood glucose in T1DM leads to hypoglycemia susceptibility. Another indication of the importance of immune tolerance induction and regeneration of functional islets as the ultimate T1DM treatment.
    Katerina, sorry to take so long to reply to your comment about SmartInsulin.  I have not seen published data on its pharmacodynamic effects on blood glucose, just a few data slides from Dr. Zion’s presentations (slideshare.net).  The data appear to come from single dose administration studies in rats.  Those results look promising, but I would love to see clinical data from patients with T1DM who receive a glucose challenge after dosing and who fast for 8 hours after dosing.  I just did a clinicaltrials.gov search for Merck or Smartcell studies in T1DM and found no hits.  My guess is that Merck/Smartcell are continuing formulation work before starting clinical studies.  The time in formulation implies some ongoing challenges.
     

  17. Gary at

    To Donna,

    Scott S. is a type one and has been dealing with it a few decades like myself.  I agree its rather strange and frustrating that Merck has not started any trials yet. I believe it boils down to its just another drug in their pipeline and not a priority over anything else. We all know if Smart Insulin worked as suggested it would be a life changer for anyone with diabetes. Personally I’d way rather be rid of this nightmare altogether but that doesn’t look very realistic.. Pretty much all of potential treatments other then Smart Insulin or Dr Faustman’s BCG will be far too costly to get to the patients and even if there is a breakthrough with one of them only a few will benefit. Smart Insulin was one of the only treatments I could see getting to the entire diabetic community and quite frankly no one should be left behind. 
     

  18. Gary at

    I’d also like to add that this thing the JDRF is trying to solicit with the reward isn’t very realistic IMO. If it took Smartcells ten years to get to a point where they haven’t started a human trial any new attempts will only be ten years behind them. I guess if your a youngster and have 60-70 years to live this might be something to look forward to. People like me in my late 40’s are on borrowed time.

  19. Phil at

    Merck needs no prodding to get SmartInsulin to the market.  They will profit handsomely if it is approved and that is the best incentive anyone can have to commercialize a new drug.  If you look at their development timeline for Januvia, you will get a good sense of what to expect if things go well with SmartInsulin.

    This JDRF program has nothing to do with actually developing a GRI, but everything to do with convincing their donors that they are doing something.  It is a fool’s errand.

  20. Randy Anderson at

    Phil, I take a very different view of JDRF’s intentions.  Most of the people in decision-making roles within JDRF either have T1DM or have direct family members with T1DM.  I’ve been in drug development for 20 years, and I continue to be astounded by how much time pharma companies waste as a result of divided attention. 

    The JDRF GRI initiative has cost for JDRF only if it works to generate very promising new ideas.  Its a “long shot” initiative, but with very low risk.  It seems more like a “glass half full” proposition to me.  As a regular JDRF donor, I’d be more concerned if the organization were not taking all such chances.

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