Article citing new "cure" with suppression of glucagon - lots of questions

General
1

Hi everyone,

A friend of mine posted the following article on facebook: http://www.sciencedaily.com/releases/2011/01/110126161835.htm

The article states that a team of scientists found that when glucagon is suppressed, BG control is achieved in mice without the use of insulin.  This article really confused me and has made me realize that I was thinking about the function of glucagon incorrectly.  I have a bunch of questions and I'm going to throw them out there in hopes that someone can shed some light on this topic.

Firstly, glucagon is produced in the pancreas, right?  I always thought that when autoimmune disease destroyed the islet cells, glucagon function was also impaired, which is why type 1 diabetics get low blood sugar (since glucagon prevents low blood sugar in non-D people, correct?)  After reading this article, my theory obviously didn't make sense, so I tried to do some research on glucagon function in type 1 diabetes but haven't had much luck.  What I've been able to gather is that the pancreas continues to produce glucagon even after islet cell destruction.  Glucagon is produced only in the absence of insulin, so when type 1 diabetics are not injecting insulin, their blood sugar gets extremely high because glucagon production increases (this explains why my blood sugar gets insane whenever i forget to re-attach my pump, or if I'm having a site problem.)  If glucagon production impairment is not the reason that type 1 diabetics get low blood sugar, does that mean that we only get low because of insulin overdose?  If we produce glucagon, why doesn't it prevent our lows?  Also, if glucagon is produced only in the absence of insulin, why doesn't basal or long acting insulin inhibit the production of glucagon? (If it did, there wouldn't be blood sugar without food, right?) 

So, if what I've said above is correct, that means that type 1 diabetics need to inject large doses of insulin in order to balance out the overproduction of glucagon that is occurring because of their inability to produce insulin? (I just confused myself...no wonder my blood sugar is so hard to control lol)  If this is true, I can understand why suppressing glucagon would eliminate the need for basal or long acting insulin, but I guess my big question is: how would suppressing glucagon eliminate the need for insulin to cover carbohydrates consumed as food?

Sorry if what I wrote was hard to follow (or really dumb), but I'm trying to wrap my head around the concept and my thoughts are more than a little scattered!

Thanks in advance!

Molly

2

My understanding was that the healthy pancreas doesn't normally release insulin at such extreme levels that it couldn't be kept in check by releasing its natural store of glucagon.  And, actually, what the article says about the dosage of insulin by injection being much higher than what the body would need if it were produced internally because we need enough insulin for it to actually reach the cells that need it kind of makes sense.  But I do believe that if someone without diabetes were injected with enough insulin, they would experience hypoglycemia, the same as us.  (I remember reading that, during the One Flew Over the Cuckoo's Nest era of mental health "care," in addition to the other barbaric things they tried out on mental patients, they were sometimes actually injected with insulin in order to induce hypoglycemia, to the point of unconsciousness/seizure, as a form of shock therapy.)

However, I did always think that glucagon was as important as insulin in metabolic function...if there were no glucagon in one's body, how would any glucose be released into the blood stream?  Obviously, we need some.  And, surely, if carbs (or anything that ultimately turned into glucose) were not being digested (it wouldn't be, would it, if there were still no insulin?), wouldn't the starvation-like effects of diabetes still play out, even if the unused glucose didn't spill over into the bloodstream?  As well as ketoacidosis, etc.?  Where would the glucose go, for that matter, if it weren't being broken down and it didn't end up in the blood?  This article is very confusing...

3

Hi Molly, I have often wondered the same thing, do we still produce glucagon? I guess the answer is yes - Insulin is produced by the beta cells and glucagon by the alpha cells in the islets of langerhans - I guess the immune attack just kills the beta cells. That means that we do get low because the insulin dose is excessive (for example, in healthy humans insulin release goes down to 10% of basal once aerobic exercise commences), so not only would this counter the glucagon response, it would also decrease glucagon release. The reason basal or long acting insulin doesn't completely inhibit the production of glucagon is because they are in balance. One will likely never be completely shut off, so although insulin reduces glucagon production, it wont inhibit it completely. The reason inhibiting glucagon may reduce the need to ingest insulin to cover carbs is because there are glucose transporters at our cells that sit there without insulin present (basal glucose transporters). Insulin just brings a lot more of these to the cells surface to take in more carbs. I'm not sure how inhibiting glucagon, however, was sufficient to completely prevent a rise in blood glucose levels. Maybe glucagon also inhibits these basal transporters. Another thing to consider is the need for glucagon - I don't think it's efficable just to shut it down - how would we get the extra glucose we need to perform any kind of physical activity? I guess it waits to be seen - very cool article though 

Dylan  

4

Oh, OOPS!  I just posted about this study, too!  Wild!

5

[quote user="John"]But I do believe that if someone without diabetes were injected with enough insulin, they would experience hypoglycemia, the same as us.  (I remember reading that, during the One Flew Over the Cuckoo's Nest era of mental health "care," in addition to the other barbaric things they tried out on mental patients, they were sometimes actually injected with insulin in order to induce hypoglycemia, to the point of unconsciousness/seizure, as a form of shock therapy.)[/quote]

You're totally right on this, it was a pretty common practice.  I first ran across a reference to it in Sylvia Plath's The Bell Jar, actually.

[quote user="John"]wouldn't the starvation-like effects of diabetes still play out, even if the unused glucose didn't spill over into the bloodstream?[/quote]

This was my first thought when I read about the study!  Isn't that why so many type 1s lose weight right before diagnosis.?

6

Yes, I agree with John and Elizabeth - the body still needs insulin to deal with the carbs we eat. Hmmm?

7

[quote user="John"]

However, I did always think that glucagon was as important as insulin in metabolic function...if there were no glucagon in one's body, how would any glucose be released into the blood stream?

[/quote]

Do you mean glucose released by the liver?  I wonder this as well, because don't we rely on those glucose (from a survival standpoint, for example, if we were starving) for basic bodily functions that use energy like breathing.  And also, our brain cells function solely on glucose, so how could we survive without that basal stream of glucose from the liver?

[quote user="John"]

  Obviously, we need some.  And, surely, if carbs (or anything that ultimately turned into glucose) were not being digested (it wouldn't be, would it, if there were still no insulin?), wouldn't the starvation-like effects of diabetes still play out, even if the unused glucose didn't spill over into the bloodstream?  As well as ketoacidosis, etc.?  Where would the glucose go, for that matter, if it weren't being broken down and it didn't end up in the blood?  This article is very confusing...

[/quote]

Good point about the starvation effects of diabetes!  I hadn't even thought of that.  We'd all suddenly be experiencing constant ketosis, and while I'd love the rapid weight loss, I can't imagine my kidneys would appreciate that. ;)  And I agree with you, this article definitely is confusing!

Molly

8

[quote user="Dylan"]

Hi Molly, I have often wondered the same thing, do we still produce glucagon? I guess the answer is yes - Insulin is produced by the beta cells and glucagon by the alpha cells in the islets of langerhans - I guess the immune attack just kills the beta cells. That means that we do get low because the insulin dose is excessive (for example, in healthy humans insulin release goes down to 10% of basal once aerobic exercise commences), so not only would this counter the glucagon response, it would also decrease glucagon release.

 

[/quote]

Ahh okay, that makes sense!

[quote user="Dylan"]

The reason basal or long acting insulin doesn't completely inhibit the production of glucagon is because they are in balance. One will likely never be completely shut off, so although insulin reduces glucagon production, it wont inhibit it completely. The reason inhibiting glucagon may reduce the need to ingest insulin to cover carbs is because there are glucose transporters at our cells that sit there without insulin present (basal glucose transporters). Insulin just brings a lot more of these to the cells surface to take in more carbs. I'm not sure how inhibiting glucagon, however, was sufficient to completely prevent a rise in blood glucose levels. Maybe glucagon also inhibits these basal transporters. Another thing to consider is the need for glucagon - I don't think it's efficable just to shut it down - how would we get the extra glucose we need to perform any kind of physical activity? I guess it waits to be seen - very cool article though 

[/quote]

I didn't know about basal glucose transporters!  Very interesting.  It would make sense that glucagon would inhibit basal transporters though.  If glucagon is produced in a non-diabetic person when insulin is not present (and insulin is not produced unless there is excess glucose in the blood), it seems that glucagon's purpose is to provide glucose to cells when dietary glucose is not available.  If dietary glucose is not available, and insulin is not present, why would it make sense biologically for basal glucose transporters to continue to function at the same rate?  If anything, it would make sense for some function of basal glucose transporters to be inhibited to prevent low blood glucose.

Also, I agree that completely shutting off glucagon doesn't seem right.  How would we get enough glucose to execute basic metabolic functions?  Fat and muscle would begin to break down.  Anyway, thanks for your response!

Molly

9

[quote user="Elizabeth"]

Oh, OOPS!  I just posted about this study, too!  Wild!

[/quote]

 

Great minds think alike! ;)

10

[quote user="Dylan"]

Hi Molly, I have often wondered the same thing, do we still produce glucagon? I guess the answer is yes - Insulin is produced by the beta cells and glucagon by the alpha cells in the islets of langerhans - I guess the immune attack just kills the beta cells. That means that we do get low because the insulin dose is excessive (for example, in healthy humans insulin release goes down to 10% of basal once aerobic exercise commences), so not only would this counter the glucagon response, it would also decrease glucagon release. The reason basal or long acting insulin doesn't completely inhibit the production of glucagon is because they are in balance. One will likely never be completely shut off, so although insulin reduces glucagon production, it wont inhibit it completely. The reason inhibiting glucagon may reduce the need to ingest insulin to cover carbs is because there are glucose transporters at our cells that sit there without insulin present (basal glucose transporters). Insulin just brings a lot more of these to the cells surface to take in more carbs. I'm not sure how inhibiting glucagon, however, was sufficient to completely prevent a rise in blood glucose levels. Maybe glucagon also inhibits these basal transporters. Another thing to consider is the need for glucagon - I don't think it's efficable just to shut it down - how would we get the extra glucose we need to perform any kind of physical activity? I guess it waits to be seen - very cool article though 

Dylan  

[/quote]

This is all really interesting...and I didn't know 99% of it.  Thanks for the explanation.

Now that I think about it, I'm pretty sure I've read that the glucagon that is in fact still being produced by the diabetic pancreas is responsible for some of the indirect annoyances of diabetes (or should that be effects of insulin management?).  Isn't glucagon part of the process that sometimes results in a huge spike in blood sugar shortly after hypoglycemia, or am I thinking of something else?  Synthesizing what I've read about glucagon in this thread with what I'm remembering, I think what happens is that when the blood sugar goes low enough, for long enough, then the release of glucagon is triggered to raise the blood sugar.  But i think it doesn't happen soon enough to be effective in treating the hypoglycemia, because the pancreas is not equipped to respond to a fairly crude dose (of synthetic insulin) that has not been regulated at all by one's own endocrine system, so later on, you end up dealing with the glucagon-related glucose on top of the fast-acting sugar you've (hopefully) taken to treat the hypoglycemia.

In that instance, at least, the fact that the pancreas is producing glucagon but not insulin is useless - and, in fact counterproductive.  Have I got that right?  If so, while I'm still having trouble wrapping my mind around glucagon suppression being a substitute for insulin, maybe diabetes management would be easier in some ways without the glucagon?

And, now that I think about it, is glucagon what makes our blood sugar run consistently high when we are sick?  I know it's been explained to me that something triggers the body to release more glucose because the cells need it to fight off infection, but of course if you're sticking to your regular insulin regimen then the glucose just becomes sugar in the blood.  Is that glucagon that causes the blood sugar to rise during sickness, as well?  And, what would happen in those situations if there were no glucagon...would we be chronically hypoglycemic when we're sick, because the cells use up all the glucose they can access?

And, just to further complicate everything, even if cutting off glucagon would be at all effective in treating diabetes, how would it be accomplished, at least in a human as opposed to a mouse?  Glucagon originates in the pancreas, right, which I believe is very hard to access surgically (isn't that why the prognosis with pancreatic cancer is so bad?).

11

[quote user="John"]

Synthesizing what I've read about glucagon in this thread with what I'm remembering, I think what happens is that when the blood sugar goes low enough, for long enough, then the release of glucagon is triggered to raise the blood sugar.  But i think it doesn't happen soon enough to be effective in treating the hypoglycemia, because the pancreas is not equipped to respond to a fairly crude dose (of synthetic insulin) that has not been regulated at all by one's own endocrine system, so later on, you end up dealing with the glucagon-related glucose on top of the fast-acting sugar you've (hopefully) taken to treat the hypoglycemia.

In that instance, at least, the fact that the pancreas is producing glucagon but not insulin is useless - and, in fact counterproductive.  Have I got that right?  If so, while I'm still having trouble wrapping my mind around glucagon suppression being a substitute for insulin, maybe diabetes management would be easier in some ways without the glucagon?

[/quote]

This explains why my blood sugar always bounces back really high after an exceptionally low blood sugar (less than 40, usually).  What a pain!  It would be nice if our glucagon response could effectively help us avoid lows, rather than ruining the rest of my day after an extreme low with uncontrollable highs.  I think you're right...in some ways, it does seem that blood sugar management could be easier without glucagon.

[quote user="John"]

And, now that I think about it, is glucagon what makes our blood sugar run consistently high when we are sick?  I know it's been explained to me that something triggers the body to release more glucose because the cells need it to fight off infection, but of course if you're sticking to your regular insulin regimen then the glucose just becomes sugar in the blood.  Is that glucagon that causes the blood sugar to rise during sickness, as well?  And, what would happen in those situations if there were no glucagon...would we be chronically hypoglycemic when we're sick, because the cells use up all the glucose they can access?

[/quote]

In regard to cells needing more glucose to fight off infection, I learned that high blood sugar actually makes it harder for the immune system to fight infection because blood glucose bonds with sites on the immune system cells that regularly bond with and immobilize bacteria (or other intruders).  So when our blood sugar is high, it makes it harder to fight infection because glucose is interfering with immune system cell function.  Maybe in a healthy individual, a small amount of increased glucagon function does help the body fight infection, because I'm sure the mobilization of the immune system requires more energy (glucose) than usual. Maybe glucagon production also increases during times of illness in anticipation of a deficit in dietary carbohydrate (reduced appetite or inability to acquire food during illness?)  This is another reason that glucagon makes it harder to manage BG levels!

[quote user="John"]

And, just to further complicate everything, even if cutting off glucagon would be at all effective in treating diabetes, how would it be accomplished, at least in a human as opposed to a mouse?  Glucagon originates in the pancreas, right, which I believe is very hard to access surgically (isn't that why the prognosis with pancreatic cancer is so bad?).

[/quote]

I also wondered this.  Don't some oral medications used for the management of Type 2 Diabetes reduce the amount of glucose released from the liver?  These drugs must be affecting the release of glucagon.
12

This study is blowing my mind.

It's kind of annoying to read though b/c it completely ignores what we're supposed to do for food.

It also only looks at insulin's effects on blood sugar even though it's important for other metabolic processes too.  Insulin is crucial in regulating blood potassium levels, which rise if insulin is absent, which could lead to array of problems that can become emergencies really quick.

John/Molly, the post-low highs you see are called the Somogyi effect.  Ex: if you're sleeping and you go low and don't treat then body dumps glucagon which bumps you up and might end you up with a high b.g in the morning.  Check it out:

13

This article made me realize I didn't know a lot of things and I looked up everything a pancreas does and can't believe all the functions it does do. I thought that with diabetes my pancreas didn't work but now I realize that it's just the insulin part that doesn't. This article does leave you with more questions then answers though. It's a good starting point at least.

14

[quote user="Ideen"]

This study is blowing my mind.

It's kind of annoying to read though b/c it completely ignores what we're supposed to do for food.

It also only looks at insulin's effects on blood sugar even though it's important for other metabolic processes too.  Insulin is crucial in regulating blood potassium levels, which rise if insulin is absent, which could lead to array of problems that can become emergencies really quick.

[/quote]

It is blowing my mind too. OK - so I get that the alpha cells of pancreas produce glucagon - the hormone that directs the liver to dump glucose stores. If in the normal body, insulin and glucagon production are balanced - then the liver is only dumping enough glucose to meet the bodies demands.

This summary article does address food - as it mentions the glucose challenge test (that icky orange drink). And says that the mice without glucagon and insulin handle it fine - but it doesn't explain the how. To me, this was the most interesting and confusing part of the summary - I will need to find the actual journal article and read it to see if it explains further.

15

This editorial extract helps a little more... I'm still trying to figure out if I can get the full text of the original scientific article and the full text of the editorial for free. (Sorry folks, I don't have $45 to spend on the articles today.)

http://diabetes.diabetesjournals.org/content/60/2/377.extract

 

16

I have free access to this journal through my college's library.  However, I'm having a hard time locating the article (I think because it is so new.)  I will keep trying and maybe I'll call the library and see if they can help.  If I find it I'll post it here!

 

Molly

17

Molly -

LOL - I posted about this in the technology group a few days back...  I thought the article/study itself made a lot of sense when paired with the description of insulin function here: http://joe.endocrinology-journals.org/cgi/reprint/170/1/13

I agree with everyone that these two hormones are required for enough other processes and functions that removing the second to make up for the lack of the first is likely to have deleterious effects.  Great post - and interesting new things to consider as we are moving forward :)

Cheers!

A-D

 

18

[quote user="Molly"]

I have free access to this journal through my college's library.  However, I'm having a hard time locating the article (I think because it is so new.)  I will keep trying and maybe I'll call the library and see if they can help.  If I find it I'll post it here!

 

Molly

[/quote]

That would be awesome.  One of the few things I miss about being a student for much of my adult life - and about the only thing I miss about working for a university - is the library access.

19

[quote user="Ideen"]

This study is blowing my mind.

It's kind of annoying to read though b/c it completely ignores what we're supposed to do for food.

It also only looks at insulin's effects on blood sugar even though it's important for other metabolic processes too.  Insulin is crucial in regulating blood potassium levels, which rise if insulin is absent, which could lead to array of problems that can become emergencies really quick.

John/Molly, the post-low highs you see are called the Somogyi effect.  Ex: if you're sleeping and you go low and don't treat then body dumps glucagon which bumps you up and might end you up with a high b.g in the morning.  Check it out:

[/quote]

Thanks, Ideen.  That is so interesting.  I had wondered after I posted if glucagon ever serves to effectively treat mild hypoglycemia before we even realize it, and in that way, being without glucagon would make diabetes harder, but it looks like anytime that might happen, the result would be disastrously high blood sugar some time later.  So, I'm still curious if glucagon, to whatever extent it's present for us T1s, is ever useful...

20

John,

among other processes, i believe glucagon is responsible for kicking off some of the cycles that let us digest fatty acids (someone can correct me if I'm misinterpreting this) -

So at least for that - it is useful :)

Cheers!

A-D