Dr. Lewis,
I am wondering if it would benefit type1 and type 2 diabetics to have a test for AAt levels? And would taking the drug AAT benefit the person, even if they are not having islet cell transplantation?
Also, would someone having islet cell transplantation require anti rejection drugs if the AAT works?
Ann, that's an important note you make and a great chance for me to deliver some rarely known facts. Alpha-1-antitrypsin is normally found in our serum. In fact it is the third most abundant protein circulating in our blood, after albumin and antibodies. We measure the levels by standard binding assays, and hospitals do this checkup in various situations. So the test is readily available. The problem is -- why would a person go and ask for AAT levels?? That is precisely why the deficiency in this protein is strikingly under-diagnosed. More than 50% of individuals have some degree of deficiency, from 15% reduction in levels to 90% reduction. The extreme cases are more easily diagnosed, as they are typically identified at birth/infancy and are accompanied by liver problems (becasue the liver produces the protein wrongly, and is 'hi-jacked' by the misfolded form). But the intermediate cases of decifiency are usually not detected, perhaps the reason some variablilty exists in the way each of us tackles infections.
But the case for diabetes is unique: In multiple studies, the levels generated by diabetics are normal. Yet, in the rare instances where activity of AAT was also examined, aside from its levels, it was shown that diabetics have in inactive form of AAT. We don't know why, we suspect random glycations along the protein, as happens with other serum proteins (you all know HbA1C).
So -- what to do. It's always good to establish your AAT levels. Ask to be tested and at least rule out frank deficiency. If you do have low levels, you're eligible for replacement therapy, which is an injection of AAT (purified from pooled human plasma) once a week. But if your levels are normal, you still have to figure out whether your AAT is active or inactive. At this point I cannot provide an easy solution, as much as I'd like to. The activity-assay is not a routine assay but rather a research/experimental assay that's integrated into labs that happen to work on AAT. My only recommendation is, in the case of normal AAT levels, you may seek such research groups and hope for compliance. There is no clear policy for replacement therapy for 'inactive' AAT, just low levels, but at least you (a) know, and (b) have something to present when you ask for fresh AAT injections. Since the spontanous glycations take more than a week, the repeated administration of 'good' AAT may be beneficial. We hope that clinical trials will provide this information later on.
Ann,
You asked whether immunosuppression would still be required in the case that (hopefully) AAT would be sufficient in preventing islet transplant rejection. Of course, I'd like to say that these drugs will become obsolete, but that's still something to be determined... In animal studies that's the case: AAT works alone, in humans we still don't know.
But here is a point worth mentioning. The side-effects of these drugs may, at least in part, be blunted by AAT. That's good. So, the combination of AAT together with common drugs may be more tolerable. We're testing now whether it can actually remove the diabetogenic effects of some common immunosuppressants. Just consider this awful statistics: about 1 in 5 kidney transplant recipients will leave the hospital with drug-induced diabetes. We want to avoid that by perhaps including AAT in their protocols.
A slightly more scientific issue would be the action of immunosuppression on T cells. This may be a hard point to grasp... but I'll try: the classical immunosuppressives will halt a T cell in its tracks. This is supposed to be good for the graft, and unfortunately also good for any infection that takes the chance on the patient. At the same time, there are what we call T regulatory cells. These used to be called a while ago 'T suppressors'. These are good for grafts, and they inhibit the aggressive T cells from attacking the foreign organ. In fact, since they have the ability to recognize and target, they may actually promote graft-specific protection. Now go back to the typical immunosupppression: it blocked all T cells from funcitoning. Thus, T regulatory cells are also defeated.
The findings we obtained, partly in Colorado (UCHSC) and partly in Israel (BGU), prove that AAT does not tackle T cells. It 'pulls the rug under their feet' by significantly blunting inflammation, but it does not 'kill' their function overall. Thus, T cells proliferate and secrete their products in the presence of AAT, and in fact, T regulatory cells suddenyl start to appear!
One of my concerns is that some immunosuppressants might actually interfere with AAT. If the trial will have standard immunosuppression maintained, and the patient checks a box saying 'I agree to also have AAT added to the existing protocol' -- I'm thinking we might be compromising the full potential of AAT. I'm sure there'll be benefits, since islets will survive better, but I'm talking about the long-term memory regulation of the immune system, which has to be, so to speak, actively 're-educated', and not passively shut-down and blacked-out until the drugs are withdrawn. This is all still a matter of ongoing studies in our lab, just keeping you in the loop!
I have had three kidney transplants and am currently dealing with Type 2, so both these topics are of interest to me. Regarding the salsalate, I'm wondering if you are aware that there is an OTC white willow bark extract with concentrated salicin (a precursor for salicylic acid conversion, I believe). Salicin does not cause gastric irritation like aspirin does. I wonder whether this is another alternative for daily supplementation by Type 2 diabetics.
Also, I developed steroid-induced diabetes after my first transplant (in 1983) and my third (in 2004), but was able to get off the insulin after a couple of months each time. Then in 2007 I was diagnosed with Type 2 but have kept my HbA1c around 6.6 without medication. I recently went on a low carb diet (~15% carbs) and have lost 15 lbs. in the last two months, so now my BMI is 23. I am aiming to get my A1c level <6. Having been on immunosuppressants for most of the past 27 years, I am hoping Dr. Lewis' research on AAT therapy is ultimately successful! I do take a number of anti-oxidants in the form of nutritional supplements and also a proteolytic enzyme (serrapeptase) and an herbal anti-inflammatory (curcumin) for spinal stenosis. Perhaps these will serve as effective anti-inflammatories to protect my vulnerable islet cells.
Steve, Your comment regarding your taking curcumin for spinal stenosis intrigues me. I have been battling this illness for a few years with no satisfactory results. Please tell me more about your use of curcumin. Has it been successful? I hesitate to have more spinal cortisone injections because it raises blood sugar very high I'm told.
Steve and Lynne, I just wanted to refer you to some colleagues of mine (two floors above me actually at BGU) who study Curcumin's effects quite intensely for many years now. I hope you can find some useful information through them! 
lyossi@bgu.ac.il
Steve,
Wow! What a life story you have! I'm impressed! Your choice of safe alternatives is great. It's only a matter of time before 'intelligent drugs' will be able to mimic what some of these natural regimens have to offer. I mean, just take aspirin as an example.
As for type 2 diabetes and chages along your time-line, I find it interesting and a good entry point to impart some more ideas: the state of insulin resistance is made up of many factors, linked by some 'equation' that we have yet to identify. Your description of being hyperglycemic, then normal, then up again, really shows you how the outcome of this 'equation' relies on so many and variable factors. Weight loss was one good parameter (good job on that by the way!). Some drugs were probably harmful, then perhaps you may have increased exercise volume and helped a bit. Blood glucose chages accordingly.
This I use to exemplify that a great deal of the condition is in your hands! It's a point that surfaced earlier in this blog -- the genetic factors are hard to tackle -- but all the rest of the factors have great value in flattening your glucose. List them, do them [in moderation] and you will probably do yourself better than any high-end research would achieve. At least you'll be in the best possible condition in order to assist in any drug that is offered in the future.
Lynn,
I tried to post a reply to you on Thursday but I'm having trouble posting onto this site. I use an herbal formula that contains a highly-available form of curcumin that also contains a high-quality boswellia extract, l+d-phenylalanine, & nattokinase. (I don't know if I can mention brand names on this site.) I use ~1500mg of this complex twice a day. In addition I've been using 80,000 (activity) units of serrapeptase twice a day. The serrapeptase needs be taken at least 1/2 half before and 2 hours after eating, or else it will act as a digestive enzyme instead of systemically as an anti-inflammatory & fibrinolytic. I take them before bed and first thing in the morning since that is the easiest time to stay away from food, and also because my symptoms are the worst first thing in the morning.
I recently read about and became interested in your research at UCHSC. I am a Colorado resident diagnosed last year with type 2. I wonder if you are accepting people into your study, and how to apply, if you are?
Dear Colorado blogger,
You asked about joining a type 2 diabetes study with alpha-1-antitrypsin. Unfortunately we're still not recruiting. The studies on the line are first of all for type 1 patients: one is for recently diagnosed and the other, pending technical issues, for islet transplant recipients. A study for type 2 diabetes is still being designed and the location is still not determined. But it's coming up and I'm sure to prompt the blog when I have more specific info!
Thanks Dr. Eli these are the fact that most of don't know about Diabetes.
Dear blog followers,
Just to let you know that our lab got accepted for six (!) oral presentations in an upcoming international conference in Immunology, held in Athens, Greece. We'll be presenting studies that have to do with the effect of AAT on islet grafts, as well as on grafts from two species, on beta cell viability, on lymphocytic B cells (in light of the recent success of anti-B-cell therapy), on dendritic cells and in special mice that express human AAT in their lungs. I'm proud both of our lab and also for my BGU university, what presence!! Well, if you're planning to include Athens in your trip plans between July 22nd and July 26th, you'll welcome to come and hear us live! 
The next round of such presentations will be in October, Chicago.
Lewis
Dearest blog followers,
I'm glad to share with you this barely one day-old press release! Our clinical trials are to begin in less than a month!! 
You're welcome to press here
Optimistic,
Eli
Anne, That's great. Oh it just keeps getting better. We just got invited to present a 1 hr feature talk about our talk in an Immunology conference! This is huge exposre. JDRF and BGU way up in the recognition slide! And the blog will be mentioned to whomever wishes to keep a close look at the advance of our clinical trial.
Take care,
Eli
If you all want to read an interview I held after the JDRF-AABGU capitol event you're welcome to it! The topics overlab our blog here. BTW, I myself read some other intervews by Pamela Chaiet, worth following her work!
Eli
That's a valid point you make. But I think the difference can only be really appreciated by a diabetic individual, not a researcher. You're standing in your kitchen before dinner and glucose readout is 100 mg/dl. You go out of your house and it's 100 mg/dl. you get ready for bed, and you know you wake up with just the right amount of 'sweetness' that is physiologically appropriate, no sweat, no fear of hypo, just a normal night with it's normal day to follow. At some point, when you're asked whether you're a diabetic, you have to think twice before answering. All this is not possible with insulin at any given format, only real islets can do it. I agree though, this description requires the addition of pills and monitoring to see that the immune system is functioning well under these conditions. It's the choice between hyperglycmic long-term complications, which do exist even in the model patient, and normal glucose with tight immune control. Not an easy choice. I wonder if there's an islet graft recipient forum?
Eli
Dr. Lewis:
Yea there is a islet recipient forum on Facebook. Search for "islet transplant group" or something like that. Aside from the dizziness, nausea, weakness, weight loss, hand tremor, low neutrophil count, and canker sores, I suppose one could consider an islet cell transplant with the use of immunosuppression. But I don't know; seems kind of iffy to me.
Dr Lewis
I read that a newly diagnosed Type1 child had this treatment and insulin requirement was gone and this continued. Is this true?
Many thanks
Dear Father of T1D,
This is true. Since it's the family's priavte matter, I cannot disclose any info. But the truth of the matter is that a father that had his kid just diagnosed for T1D (this was more than a year ago) decided to consult with all us researchers around the US and Israel, and he came to his own conclusion that he's not going to wait for a clinical trial. He arranged for his kid to be injecte with AAT and since then, insulin requirement has been extremely low, the kid's diet is basically normal, antibodies are very low (almost absent) and c-peptide is high upon challenge. The drug exists, it's simply prescribed for deficiancies in AAT (incl. in youngsters), so safety is as established as can be. If it works terrific, if not, nothing was lost but the sum of money it cost to administer it. Those were his considerations and he made his independent choice.
Eli
As a type 1 diabetic for over 10 years with HbA1C levels around 6.5, I am always interested in the new and exciting research out there. I was wondering if you have seen anything in your research that might suggest that AAT supplementation (if there is a deficiency) would help in someone who is a long-term type 1 diabetic (like me), without any transplants. I understand that your research up to this point has been primarily on animals, but with the few cases where early supplementation has been implemented (where the islet cells have not been completely destroyed) is there any reason to believe that this may help all levels of type 1 and type 2 diabetics?
You know what? That's a great question. It really fits the 'advanced' category of questions!! I write this because it reflects that you agree that AAT protects islet7s, in the face of transplant stress as well as autoimmune stress. At this point we start to look farther; this is yet unpublished stuff -- we show that AAT also protects against free fatty acid stress (the hallmark of type 2 diabetes islet injury), as well as immunosuppression-induced damage (which is the reason it's so tappered down for islet transplantation to begin with). We also have evidence that it may be involved in islet expansion. This is where you come in as an individual with diabetes: what can we do to help with the residual islet mass left? Well for one, the attack is dynamic. Waves of insults are encountered, and every obstacle in their way is beneficial. Second, expansion of islets is a highly favorable issue. Once we are sure that expansion is also an attribute of AAT we will surely feel more comfortable including individuals with diabetes at a later stage. Menawhile, I must say this: what do you have to lose!? Check your levels, then beg for an activity assay (that will uncover the loss of AAT's activity within its normal concentrations) and then try to be eligible for replacement therapy, like thousands of others with the genetic deficiancy. See, you probably have a functional-deficiency in AAT (due to it being over-glycated), so why not ask for new fresh protein to do the islet protective work?! And if it didn't, then all you did was boost a normal material that the body makes anyway.
Eli
Just a small good read to remind us where we stand today and how motivated our research is.
http://www.nytimes.com/2010/07/20/health/20essay.html?_r=1
Are all the people with diabeters you've tested do they have AAT deficiency or not active or what %? Thankyou.
Peter,
These are two items that you mention that are in many ways separate and deserve specific attention:
AAT levels: Whether someone has a genetic deficiency in AAT is easy to detect. Hospitals measure AAT in the blood and you know your levels two days later, just ask your physician. There is no report of overt deficiancy as being greater in individuals with diabetes. Yet, the frequency exists, it may well be the case in many readers here (extreme deficiency is about 1 in 3,000, other grades of deficiency are undetected and less accounted for, we believe them to be very frequent, as high as 1 in 10 or 15). We've been conducting a small project to do with diabetes during pregnancy and were surprised to find that 2 out of 13 women were severly deficient, they were unaware of this before we asked to look at their levels. Bottom line, individuals with diabetes would benefit from knowing whether they're AAT-deficient. In such a case, they're eligible for 'augmentation therapy', getting new AAT every week.
AAT activity: This is a more striking story when it comes to diabetes. AAT can circulate but be inactive. In fact, it appears that glucose can do this to AAT, just like it hits hemoglobin HbA (and then you measure HbA1C levels to see how bad HbA was hit over time). As far as literature goes, this is overwhelmingly established with AAT: adolescent kids, gestational diabetics, adult diabetics and so on, almost all have a functional deficiency in AAT. These studies date back to as early as 1967 and I easily collected a dozen such reports from studies around the globe. Levels are fine, just function is lost. See, AAT lives for about a week (every protein has some turnover). This is a period of time that is sufficient to glycate the protein when glucose is high. Shorter-lived proteins don't experience this, longer-lived proteins do. It also depends of glucose levels, the higher the worse-hit the protein. Testing for functionality of AAT is not routine, but rather is a test various research labs do depending on their field of research. At this point, you might ask what is the advantage of injecting new AAT? The answer is -- since it lives for 1 week, the newly-injected material evades this phenomenon before the subsequent new AAT is administered one week later, and the patient enjoys 'good' AAT throughout this course of treatment. Plus, most of the glycation occurs inside the liver, where AAT is manufactured AND glucose is at its highest levels.
Hope this helps!
Eli
Reading with much interest about the AAT trials about to start at various locations in the US, is there anything similar taking place in Europe?
Dr Lewis - disappointing that there are currently no trials in Europe where my family is currently based. Our son is 9 and was diagnosed in August as T1 (ironically while we were visiting the USA during the summer). Is there some information on the logistics / practicalities of what would be involved in participating in the AAT trial and in any subsequent monitoring? It would not be easy for us being based in Europe, but we would not want our son to miss out on this unique window of opportunity while he is in this early stage of T1.
Dear AmericanOverseas,
I'm sorry to hear about your son, and you are right about seeking somewhere to try do something extra while the disease is young. The point where glucose rises is when a lot of the pancreatic islets have been shut down (not lost, so much as paralyzed from infalmmation). But not all islets, and the ones remaining are not necessarily gone. You called it a window, in medicine this phenomenon is called penumbra. I think in latin has to do with a shadowy area. It's found in stroke victims for example, where a region around the directly inflicted area is not alive nor dead, but rather strikken with injury and with hope for some heroic intervention; these are cells that can be rescued. Of course, this is time dependent. The approach we support involves the major tissue-recovery molecule, which our liver generates systemically everytime we're sick. It protects lung walls from being lost to enzymes, and necrotic tissue from being abolished by extreme conditions. Since our bodies make it, I feel at ease recommending you find a way to add to its levels. Note my reply to Peter above (chat no. 13), you can find out whether your kid is eligible for augmentation therapy regardless of the trial by a series of tests. If on the other hand he exhibits normal AAT and normal-functioning AAT, then it's only this particular trial I can offer at this point. Look, any physician who's convinced enough that this is safe and worthy, will probably go that extra step to help you. We've had one case already when the father took it on himself, after consulting myself and a dozen more researchers, plus his medical staff, and he's an MD himself. It's not whether the material is safe for use, it's simply whether it's indicated or not. Deficiency -- indicated. Diabetes -- well, not yet. I hope soon it will be indicated for diabetes as well, and we can all enjoy the fruits of my team's reseacrh!
Good luck and take care,
Eli
Any updates Dr Lewis??
I understand the AAT trial is underway. Best of luck. Most researchers believe the primary culprit in developing Type 1 is the autoimmune attack causing beta cells to die. You and a growing number of others believe it is the inflammation itself which kills off the beta cells, so if you stop the inflammation, you stop the process. It would seem to me that you both might be right and each one is not mutually exclusive of the other. Has there been any thought to joining forces and coming up with a "combination therapy" which consists of both elements, say an ATG (I know you know what this is, but for others its an immunosuppressant drug which is FDA approved for certain uses, and in clinical trials now for Type 1 diabetes) and AAT regimen?
John, you’re ten steps ahead of us!! We do think AAT alone is just the beginning, it may require some help. When we examined islet grafting between animals and also diabetes in the NOD mouse, it was sufficient by itself to reverse disease and prevent rejection. But we humans are more complex, and the disease, well, we know what happens in the NOD but not so much in the human type 1 diabetes condition… In fact, a year ago an article criticized this mouse, saying we have to stop trying to fit the disease to the mouse, and start finding a new way to study diabetes! Where do your ATGs come in? In xenografting. This is yet unpublished but too exiting to keep below the surface; when we perform xenografting of islets from one species to the other (representing in humans the not-so-futuristic use of pig islets), we find that AAT alone doesn’t work, and ATG alone do not work, but the two put together produce astounding outcomes! We’ve presented this in two conferences already and are on our way towards near publication. The idea is that the immune attack involved in the xenoresponse is overwhelming. Every bit of molecule in the incoming creature is foreign to the immune system, and will not go away until the host rids of them with every possible tool it has. Using a pre-approved remedy, ATG, and our pre-approved AAT, we feel safe to suggest this as a real option for individuals with diabetes. ATG is a short course of antibodies generated in horses against human thymocytes. Once introduced into the transplant candidate, they rapidly deplete T cells which recover within two weeks in a spontaneous manner. This provides a time-gap where the graft can establish its roots in the host with the aide of AAT. Again, we’re optimistic! Good job on your choice of combination!!
Eli
The only update I can release is that recruitment is ongoing and some have begun infusions. The criteria are strict, starting with age >16 years old and including requirement of some c-peptide above zero after challenge. Barbara Davis Center in Colorado is working hard on each individual who comes in, and within a few days he/she know if they fit the criteria. As for outcomes... too early to tell!
Best,
Eli
My 11 year old daughter was just diagnosed with Type 1 Diabetes on Tuesday. Her diagnosis came early (and as a complete surprise) via a blood test for a family stomach bug we could not shake. How can I determine if AAT therapy could be an option for her? Would it only be available via trial? We are obviously overwhelmed with all of the information we are taking in at this point and came across the amazing work you are doing during our research. We don't want to miss out on an opportunity for early intervention if this therapy might work for her.
Dr. Lewis, I forgot to attach my e-mail. I would be so grateful if you could email me to discuss options for my daughter - mjasman@rcn.com. Thank you.
Sorry for this delay, I've been busy slash taken ill. Look at these trials. You're right to move fast. Good luck! Eli
http://clinicaltrials.gov/ct2/show/NCT01319331?term=diabetes+antitrypsin&rank=3
http://clinicaltrials.gov/ct2/show/NCT01183455?term=diabetes+antitrypsin&rank=2
http://clinicaltrials.gov/ct2/show/NCT01183468?term=diabetes+antitrypsin&rank=1
http://clinicaltrials.gov/ct2/show/NCT01304537?term=diabetes+antitrypsin&rank=4
Thank you for your reply. We have explored all of the trials you recommended and they are not an option for our daughter. The ones in the US are not recruiting and the one in Israel cannot consider patients who live outside of Israel. Are there any other options for our daughter? Are there any doctors who can prescribe AAT off label? We could come to Israel if that would be the way to get it. We would appreciate any advice you could give us.
Matt
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When I was in a clinical study of the anti-inflammatory drug salsalate, my completely absent phase 1 insulin release was restored to about half normal. This is consistent with the inflammatory hypothesis.
That's a great point you raise. First of all, I'm glad you have some improvement in insulin release!
Aspirin was reported to be beneficial for diabetes a while ago (in fact, a surprising number of years back, the earliest report in 1950 [!!!] when infalmmation was considered totally distinct from T cell antigen specific responses). The problem was that the doses required would add the side-effects of aspirin overdose. Finally, the derivative, salsalate, holds great promise. And shows that even though this is an autoimmune condition where T cell ablation would due the job (and provide proof for T cell involvement), there is ample room for tampering with the amplitude of inflammation and achieve measurable positive outcomes.
I think they noticed as far back as 1876, or something like that, that people who used aspirin had less diabetes. But, as you note, the problem was the side effects from high-dose aspirin.
Even the salsalate gave me unbearable tinnitus, but I was the first one in the study, and after that they reduced the dosage. But for that reason I stopped taking it when the study was over and declined to try a second round on the lower dosage.
So, alas, I'm afraid my insulin resistance is still with me.