Sunday, January 30, 2011

Glucagon / Leptin type-1 "Cure" in the News

This posting discusses research which has mostly been done on mice.  Please remember that anything that cures type-1 diabetes in mice is always years away from general availability in people.  I'm posting about this because it is making a big splash in the news, so I expect to get questions about this from friends and relations. I've already gotten questions from BBs.  Here is an example of one the better news articles:
http://www.sciencedaily.com/releases/2011/01/110126161835.htm

This research is quite different from other research aimed at curing type-1.

Drs. Unger and Lee Publish a Mouse Study Explaining Why Leptin Might Cure Type-1 Diabetes (or make it asymptomatic)

History

Several months ago, these researchers published a paper showing that giving Leptin to NOD mice was in some ways better than giving them Insulin.  Mice given Leptin had much better BG control than mice given Insulin, and that many mice given Leptin did not need to take Insulin at all.
Abstract: http://www.pnas.org/content/107/11/4813.abstract
Previous blog: http://cureresearch4type1diabetes.blogspot.com/2008/09/discussion-of-recent-press-reports-of.html
Related research: http://www.pnas.org/content/107/40/17391

Just recently, these researchers also started a clinical trial of Leptin, to see if people would have the same benefit seen in NOD mice, which I've covered a little bit.  But I did not cover it aggressively, because it was not clear if it was a cure for type-1 diabetes, or just a better treatment:
http://cureresearch4type1diabetes.blogspot.com/2010/12/possible-cures-for-type-1-in-news-late.html
http://www.clinicaltrials.gov/ct2/show/NCT01268644

Now, they have published another mouse study, which describes why they think Leptin helps type-1 mice so much.   And it is clear that they think they are on to a cure mechanism for type-1 diabetes.
Abstract: http://diabetes.diabetesjournals.org/content/60/2/391
Extract of commentary: http://diabetes.diabetesjournals.org/content/60/2/377.extract

What The Current Paper Means

This paper suggests a much different mechanism for type-1 diabetes than previously believed.
First, it suggests that mice can utilize the carbs in food without producing their own insulin.  That even animals with no beta-cells to produce insulin and no injected insulin, will still live long, happy lives if they are injected with Leptin.  Insulin is not the "key that lets sugars into cells" that we have been told that it is.
Second, The high blood glucose levels that are seen in type-1 diabetics who do not take insulin are actually caused by glucagon.  And these researchers believe that glucagon (in type-1 diabetics) is incorrectly over generated by the body, triggered by a lack of insulin.

Obviously, this suggests that type-1 diabetes can be treated by preventing (or lowering) the generation of glucagon.  In fact, from a functional point of view, it may be that preventing (or restricting) the body from making glucagon results in a "cure" where the person does not need to measure carbs, inject insulin, or suffer the long term side effects of type-1 diabetes.  This could "kick off" a long discussion of what is a cure, what is not a cure, and so on.  Different people have fundamentally different definitions of a cure, and this can lead to huge arguments.  My definition of a cure (which is on my blog) is "functional".  Others think you must stop the autoimmune attack for a real cure. I don't think it is a worthwhile argument to have now, but do remember: even in the absolute best case, this research is aimed at a functional cure.

Leptin is an example of a treatment which is known to restrict glucagon generation, but there may be others.  Some research showing Leptin's impact on glucagon:
http://www.ionchannels.org/showabstract.php?pmid=19401420

As this research progresses, it will be interesting to see if Leptin used in this way effects the use of emergency glucagon injections.  My guess is that it would not, there would be so much glucagon in the injection that a Leptin dose earlier in the day would make little to no impact.  But testing would be needed to make sure of this.

Some General Discussion

One comment I got about this research is this: "They cured mice.  So what.  Happens all the time, why care about these guys."  And that's true.  When someone announces a mouse cure, they are usually 2 years away from the start of a human trial, and often never get even that far.  But these researchers are in a different situation. They are NOT announcing a mouse cure.  They announced the mouse cure a year ago.  They have already started the human trial (3 out of 15 people already have started the treatment).  What they are announcing now is research into the mechanism that is curing these mice.

But notice how many times I used the word "mouse" in the previous paragraph.  One thing to keep in the front of your mind throughout this discussion, is that people are not mice, and mice are not people.  We know that type-1 diabetes is not the same in mice as in people.  We get mice cures at a rate of several per year.  We get people cures at a rate of zero so far.  Over 100 mouse cures have NOT worked in people.  One of my serious worries about this research is that it won't work on people at all.  That it is based on something in mice that is not there in people.  The only way to allay that fear is human trials, and that is why I'm excited that these guys have already started such a trial.

Also, it is important to remember that there were two studies, with two types of mice.  The first study, which used Leptin to cure type-1 diabetes used NOD mice.  The mice in the second ("mechanism") study were not NOD mice, and did not have autoimmunity. They were given a drug that killed their beta-cells, which induces diabetes, but not the autoimmunity part. In theory, for this research, that should not matter, but I'm always nervous about researching type-1 diabetes in mice that don't have autoimmunity.

One obvious issue is that this theory assumes that insulin is NOT actually needed to get the energy from carbs.  It assumes that if glucagon is removed, a type-1 diabetic will still be able to use all the energy in the carbs eaten.  However, this goes against mainstream medical theory that has lasted for decades.  It seems a little unlikely that no one has noticed -- even after decades of research -- that type-1 diabetics can process carbs without insulin.

Another issue is that some people have had their entire pancreases removed, and those people would not generate any insulin or glucagon.  However, they do have the classic symptoms of type-1 diabetes.  That doesn't fit in with this theory.  (Thanks to CWD's LantusFiend for pointing this out.)

I sometimes get asked "do you think it will work" (about a lot of research, not just this research).  I know that question is in the back of many people's minds.  But the question is meaningless.  It doesn't matter if I think it will work, for me or anyone else.  It only matters if it actually works, and that means data from clinical trials.  Not opinions.

How do we get from here to a cure?

I don't think we can replicate the recently announced mouse experiments in people.  These experiments used specially bred "glucagon knockout" mice.   These are mice which are a specific genetic defect that turns off their glucagon system.  I don't think there are people like that walking around.  Even if there were, we would need to find people who didn't have a glucagon system and did have type-1 diabetes.  And even if such people existed, according to these researchers, their type-1 diabetes might be asymptomatic.  They wouldn't even know they had it!  So they couldn't be recruited for a study.

So back in reality, the only way to test this in people is to find a safe way to turn down the glucagon system of someone who already has type-1 diabetes.  If this theory is right, their type-1 diabetes would become asymptomatic (or maybe they would require far less insulin than they do now).  But turning off a major hormone is not something done lightly.  Hormones are very important, and a little tricky: we often don't know all the functions that one hormone has.  Researchers are often surprised that a hormone that they thought just did X, also does Y, or stops Z from happening.  So shutting it down to help with X might cause problems in Y or Z.

So, with all that as background, these researchers know that Leptin lowers glucagon generation, so giving Leptin to type-1 diabetics is an obvious clinical trial to run, and they have already started such a trial.  However, there may be other ways to limit, control, or stop glucagon generation, and it might be interesting to run other clinical trials that use other method to turn down a type-1 diabetic's glucagon system (carefully).

An obvious question is: how safe is Leptin?  The current phase-I study in type-1 diabetics is not the first trial for Leptin.  It has already completed some phase-I studies in people who have type-2 diabetes and in people who are over weight.  However, the real question is, how safe is it when used on type-1 diabetics in the dose needed for them to get the good effects we want?  And also, do any safety issues surface in the larger phase-II and phase-III studies (for any indication)?  And those issues can only be resolved by going through the clinical trial process.

Finally, Amylin is a commercial company that is researching Leptin, and they are a collaborator in the clinical trial.  Amylin is a big name in the treatment of type-2 diabetes, but as far as I know, they do not have a drug aimed at type-1 (so no "conflict of revenue").  They are interested in Leptin as a combination weight loss treatment.  But obviously, good results in treating type-1 could open up a whole new market for them.

One Last Point

If these guys are right about glucagon and Leptin in people, and their study uses the right dose, then they are going to find out quickly.  Their current study is NOT blinded, and they believe the effect is not honeymoon dependent.  So even though their experiment is supposed to last until early-2013 (and may last longer), the researchers involved (and the patients involved) may know sooner.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. 
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

3 comments:

ls said...

Hi, Josh! There is a reason why the pancreas removal people are not the same as the test mice. The pancreas removal folks do not make glucagon. The mice made glucagon, but their cells were engineered to not respond to it.

Thanks so much for posting this! I cannot even understand the skepticism by other T1s. This new mechanism may change everything we knew and may gt us on the right path to a cure.

Anonymous said...

Unfortunately, the authors of this study rather irresponsibly remarked at the end that it might show the route to a cure for humans, and the news media picked up on that, thus intensifying the confusion. The simple fact is that type 1 diabetic humans lose weight without injected insulin, while the mice in this experiment could maintain normoglycemia and normal weight with mere glucagon receptor suppression but without exogenous insulin. From millions of type 1 human diabetics who all lost weight before starting on insulin injections, we know that these mice results are totally irrelevent to human diabetes.

lukesdday said...

Thanks for unpacking speculation around this study and providing more context/info! This study raises a lot of questions, but even diabetes media outlets have just been passing along the same synopsis of the study without additional comment. Really useful post.