Role of glucagon in diabetes - article only available until 5 March 11

[Copepod]

http://www.newscientist.com/article/mg20928013.600-diabetics-is-it-time-to-bin-the-insulin.html

Proposes "neutralising" glucagon as a way of maintaining normal blood glucose levels without insulin.

Requires registration (free) and will only be available until 5 March 11.

 

[Robster65]

That is a fascinating article. Thanks copepod.🙂

Raises the question of how the glucose fuels the muscles.

Rob

 

[HelenM]

Raises the question of how the glucose fuels the muscles

A few weeks ago I came across 2 papers. They are by the same authors and say much the same thing, but reading both helped me understand the points being made.(I think!)
They suggest that most people, including most doctors have a complete misunderstanding of the role of insulin and hyperglycaemia.
When I first read them I noted that they hadn't been cited by other authors much and wondered whether they were just 'mavericks'.
Then, when I read the work on the glucagon it seemed to confirm what I'd understood from the papers
Here are 3 quotes from the papers

The ?black ages? of endocrinology followed early in vitro experiments in the 1950s that showed insulin to be capable of stimulating glucose uptake into bits of rat muscle and fat. Before long the biochemists had extrapolated from these experiments to conclude (wrongly) that the hyperglycaemia of diabetes was due to a ?damming back? of glucose in the blood stream as a result of a failure of glucose to enter cells as a direct consequence of insulin
deficiency. The concept of glucose uptake into muscle being ?insulin dependent? was born, and has been prevalent in textbooks and teaching up to the present day, even though it was shown to be rubbish 25 years ago.

As hepatic glucose output is ?switched off? by the chalonic(inhibitory) action of insulin, glucose concentration falls and glucose uptake actually decreases. Contrary to most textbooks and previous teaching, glucose uptake is therefore actually increased in uncontrolled diabetes and decreased by insulin administration!

even in the fasting state or in a state of absolute insulin deficiency, there are sufficient glucose transporters already in place in the cell membrane to allow glucose uptake to exceed that of a normal individual when the gradient of glucose concentration across the cell membrane is sufficiently high.
This ?mass action? effect accounts for the observations which show unequivocally that tissue glucose uptake can exceed normal even in the face of severe insulin deficiency such as occurs in uncontrolled diabetes mellitus'

It seems to be that GLUT 4, glucose transporters, which enable glucose to get into muscle and skeletal cells are capable of being stimulated by both insulin and muscle contraction. It seems that there is a pool of these transporters, some stimulated by insulin and some by muscle contraction and that either can be used to transport sufficient glucose into the cells .
( I'd thought that it was only whilst we were 'exercising' that glucose could get into the cells without insulin)
The authors also seem to suggest that insulin acts in the main by inhibiting the uncontrolled release of glucose from the liver.... obviously surpressing the glucagon directly would have the same effect.

(To be honest, it's at the edge of my understanding as I don't have a background in biochemistry and had to do some reading around to try to understand how GLUT works so might have got it completely wrong.)

http://bja.oxfordjournals.org/content/85/1/69.full

http://joe.endocrinology-journals.org/cgi/reprint/170/1/13

 

[Robster65]

I think I may need some more lessons to get a proper grip of it all

As I understood it, and from what you said, MISunderstood it along with most of the textbooks, the insulin enables the glucose to pass through the muscle cell walls but the eyes and nerve cells don't need insulin, hence their damage from high BG with or without insulin present.

But muscles can burn their store of glycogen for a short burst and can fuel themselves anaerobically for further short bursts until lactic acid buildup becomes a problem.

FOr aerobic fuelling, doesn't insulin need to be present ?

Rob

 

[Andy HB]

I bought the New Scientist today which I think had this article in it (I don't know because I don't want to register for the online version!).

If anyone is interested, I can post the salient points here.

Andy 🙂

 

[Robster65]

I bought the New Scientist today which I think had this article in it (I don't know because I don't want to register for the online version!).

If anyone is interested, I can post the salient points here.

Andy 🙂

If you could explain it in layman's terms Andy, that would be appreciated. I registered online and read the article but foudn some of it a bit confusing.🙂

Cheers

Rob

 

[Andy HB]

If you could explain it in layman's terms Andy, that would be appreciated. I registered online and read the article but foudn some of it a bit confusing.🙂

Cheers

Rob

I'll do my best, but can only really pull out the main points of the article.

It seems that recent experiments in mice at University of Texas Southwestern Medical Center in Dallas may give the hope that regular insulin shots and regular glucose monitoring may be consigned to medical history books.

Insulin clears surplus glucose from the blood wheras glucagon does the opposite ordering the liver to release stores of glucose or to make more if none is available.

The research used engineered mice lacking glucagon receptors so they couldn't respond to the hormone. When tested, the mice had normal levels of blood glucose.

Then, the team destroyed the pancreatic beta cells in the mice (the swine!). Again, when tested, the mice had normal levels of blood glucose.

Other diabetes reasearchers are encouraged but cautious about the developments. They wonder whether the results are just relevant to rodents and may not be applicable to people. They also wonder where the surplus glucose goes in the mice lacking both insulin and glucagon [receptors]. This is something the guys at Dallas are looking at using labelled glucose. They believe that it is still stored in the liver, but this then raises the further question as to what happens when it is "full up".

Finally, another researcher made the point that the mice didn't have any glucagon activity from birth. He asked the question as to whether the effect would be different if the hormone was subsequently blocked in humans or animals.

There was more stuff about GLP-1, but that's getting too technical for me!