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the sheet blog
diaTribe Report: Targeting a Cure for Type 1 Diabetes

July 31st, 2011

“Targeting a Cure for Type 1 Diabetes” has been published on diaTribe by Kelly Close’s Close Concerns diabetes research organization.  It is detailed, well considered, and makes room for personal opinions, observations and predictions.  I recommend you download and read it, here.  Our work on the Islet Sheet is described in page 67 in the islet transplantation chapter.

Report coverA friend who has studied the report and writes about diabetes sent me a note:

Reading the book gave me a good overview of the pros and cons of each major type of research. BTW, would you agree with their breakdown?

  • Drugs that aim to control the immune malfunction that attacks islets/beta cells
  • Transplantation in its various forms
  • Drugs that aim to regenerate or sustain beta cells
  • The closed-loop artificial pancreas (still external insulin)
  • Anyway, what I’d really like to know is why you have chosen to dedicate yourself to option 2 (both as someone with diabetes and as a solution seeker) — and by extension, why Hanuman Medical Foundation has chosen to support this work rather than some other kind of diabetes research. Could you write a few paragraphs making that case in your own way?

    I think their breakdown is useful, my only complaint being that “Drugs that aim to regenerate or sustain beta cells” will probably require “Drugs that aim to control the immune malfunction that attacks islets/beta cells” to work.  That is, we know all people with autoimmune (type 1) diabetes have permanent auto-immunity that quickly kills native, transplanted and regenerated islets alike; therefore some form of immune suppression will be required for regeneration to be useful.

    The ultimate cure for autoimmune diabetes will be immune suppression that is safe enough for me to use in conjunction with islet regeneration drugs.  (These are my personal opinions, therefore what I am willing to do to myself.) This would restore normal islet function and cure the metabolic disease, and would have a much smaller side effect profile than current immune suppression.  Regeneration will require technology to simultaneously do two very difficult things, regenerate islets and selectively suppress the immune system without side effects.  It’s a great idea but it is something like 50 years away.

    Which brings me to my personal answer to the question you pose: I believe implantation of Islet Sheets is as close as we will get to a cure in my lifetime. I reached this conclusion thirty years ago, published here.

    Why don’t I have more hope for the artificial pancreas?  Because I am the artificial pancreas, I am the cyborg envisioned. I just checked my Dexcom CGM and my blood glucose is 118.  So far today my OmniPod pump as administered 25.2U, 60% bolus, at my direction.  Nine-tenths of my blood sugars are between 80 and 220.  I have had no hypoglycemia in weeks.  The artificial pancreas works for me.

    So you ask, why can’t it work for everyone?  The answer is my mind which I have trained for decades to use these devices.  Every decision on insulin administration uses knowledge of the previous 24 hours and plans for the next 12 added to the experience of thirty years.  Patience is essential; a serious high needs to be brought down slowly so it stays down.  You must be constantly suspicious of both your devices.  If BG goes up unexpectedly I immediately question insulin delivery has failed (both times it happened because the cannula came out).  The BG readings from the Dexcom are 85% reliable, which means some days I don’t trust it, and finger-stick BG’s confirm it is wrong, so I might do a manual BG every two hours (reverting to to pre-CGM management!)

    And I know my body.  Last night I stayed home and watched a movie.  I ordered pizza and ate too much.  So by 2AM I was up to 240; I took some extra insulin, but my BG  did not come down much.  So at breakfast when the OmniPod controller calcuated my breakfast insulin, I knew (because I had taken insulin without BG response) that I would need less insulin than the calculation.  I subtracted 1 U, and I was right, because I stabilized mid-morning at 120.  I have scores of such rules.  A moderate swim means I drop basal in half for 1 hour.  My basal is optimized for 1-2 glasses of wine with dinner; if I don’t drink the basal should be lowered by a a third for 4 hours at bedtime.

    My point is these two devices give me the power to experiment on myself and know in detail the effect of differing insulin regimes on my body.  I keep getting better.  I backslide, forgive myself, and get better again.  I am an ongoing experiment, and there can never be an algorithm that does what my mind does. I can never finally figure out everything there is to know in self management. It is endless work with no time off. So thank God for CGM and programmable pumps.  They make management better, but not easier.  And the artificial pancreas will never be a cure because no computer program can know what I know and think as I think.

    When I considered the same possibilities/hopes for curing diabetes as the diaTribe report thirty years ago, the closest to a cure was autologous islet transplantation.  Immunology does not figure into this procedure because the patient does not have autoimmune diabetes and the implants are their own islets isolated from their own pancreas.  Remarkably, even in 1980, long before the Edmonton protocol, when enough islets were recovered from the pancreas the diabetes is cured through autologous islet transplantation.  How hard would it be to solve the immune barrier in human-to-human transplants?

    Predicting when islet transplantation would be available to everyone with autoimmune diabetes was the question of how difficult it would be to prevent rejection of allograft islets, that is islets from a human donor.  It seemed possible thirty years ago that pharmaceutical immune suppression would become safe and effective.  It has not; it is improved, but is not yet safe enough to routine use.  The other approach, encapsulation, appeared to be the technology that I myself could foster and promote.  So I have. The reasons the journey to the clinic will have taken over thirty years rather than ten (as I predicted) is another story for another day.

    So to answer your question, Diana, when I considered the matter thirty years ago the Islet Sheet looked to be the most promising new therapeutic technology that would work in my lifetime.  Thirty years later much has happened, clinical and scientific knoledge have expanded greatly, but — nothing has happened to change my mind. I believe implantation of Islet Sheets is as close as we will get to a cure in my lifetime. I shall continue to foster and promote the Islet Sheet until the end.

    Diabetes in the Press.
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    One Response to “diaTribe Report: Targeting a Cure for Type 1 Diabetes”

    1. J.P. Marat says:

      There are two ways to interpret the significance of long-term, extremely slow progress in any field of medicine: Either that is a sign that we have to persist patiently on that path until we attain perfection, or that we have good evidence that we are on a path to nowhere. The notion, frequently discussed in diabetology, that somehow, someday, immunosuppressive drugs will become sufficiently non-toxic that the continuing autoimmunity of type 1 diabetes can be suppressed without causing more harm than good, thus opening the way for a still speculative restoration of adequate and lasting beta cell function, seems to belong to the ‘path to nowhere’ category. The reason is that the very goal of immunosuppression is to disable one of the most vital processes of the human body, the neuro-biochemical complex which maintains the boundary between self and other, so that significantly suppressing it has to damage the essence of what we are. The slow progress from immunosuppression by radiation and bone marrow destruction in the 1950s, to prednisone and azathioprine in the 1960s, to the calcineurin inhibitors after 1978, and finally on to the anti-CD antibodies of today has demonstrated that every intervention will either have side-effects which are much worse than uncontrolled diabetes itself, or will be ineffective. For whole-organ transplants the evidence is clear that even during the most intense immunosuppression in the immediate post-transplant period or when addressing acute rejection episodes, there is no improvement in the diabetic status of patients with type 1 diabetes. In fact, because of their toxicity, the present immunosuppressive drugs worsen blood sugar control and pancreatic beta cell health.

      Researchers who describe their vision of safe immunosuppression combined with ‘something’ which will stimulate long-dormant beta cells into renewed activity are really just naming the elements of what could be a cure rather than specifying any method to accomplish it, since there is as yet no safe immunosuppression which can stop the autoimmunity and no effective stimulus to achieve sufficient beta cell revival. The recent announcement by Dr. Anne Clark of Oxford University that pancreatic beta cell regeneration does not naturally occur in humans after age 20 further discourages any hope that this speculative cure can ever be realized.

      Now I have begun to wonder whether the remaining light on the horizon, xenograft islet encapsulation, might not also belong to the category of roads to nowhere, given that many years of tinkering with the technology have only shown incremental improvements in function. Perhaps the very mechanism which makes it possible to shield the islets from attack by the host immune system also necessarily deprives them of sufficient nutrition to be able to do anything more for patients than help them diminish hypoglycemia unawareness, which seems to be the fall-back position to which LCT has now retreated, or to allow them the supreme pleasure of drawing down a little less insulin into the syringe five times a day. From P. De Vos, et al, “Why Do Microencapsulated Islet Grafts Fail?” Diabetes, 48, 1381 (1999), to Y. Souza, et al, “Islet Transplantation in Rodents: Do Encapsulated Islets Really Work?” Arquivos de Gastroenterologia, 48 (2) 146 (2011), it seems that isolated islets just can’t do the job, unless they are replaced so often that the financial costs and surgical damage to the abdomen will quickly make the procedure impractical.

      With respect to the artificial pancreas, now the object of continuous tinkering for nearly half a century with no clinically suitable version yet available, I agree with your views about the impossibility of any algorithm being built into such a contraption which would allow it to keep up with the constant and irregular fluctuations of insulin requirements. Japanese scientists have been producing articles for years now demonstrating that insulin needs in the diabetic can only be modelled by the sophisticated mathematics of chaos theory, and no machine can operate reliably on that basis. The suppressed premise of all scientific inference is that the future will be like the past, and that is exactly what is not true in type 1 diabetes blood sugar management. I notice that my own blood sugars typically vary according to the classic theory of errors, with a set insulin dose at a fixed time with a constant blood sugar base for a standard meal generating a blood sugar centered around 100 mg/% 40% of the time but with values distributed around it as low as 40 mg/% or as high as 160 mg/%. I say that the values ‘typically’ vary around this point under this suffocatingly restrictive ritualization of my life, since about once every three or four days the blood sugar varies outside that range, reaching either 30 mg/% (near unconsciousness) or 420 mg/%. Since the meal and its outcome in this example are separated by a night’s sleep, I suspect that nightmares and their associated adrenal spike might account for the 420 mg/%, but how I can plan at my dinner time injection whether I am going to have a nightmare later that evening still eludes me. What does not elude me, as it does many diabetics, is that the whole warping of human spontaneity and freedom required by the strict blood sugar control regimen is indeed a never-ending nightmare, whose negative psychological and social effects would be weighed against their benefits by a truly rational diabetes medicine, which we unfortunately still lack.

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