Insulin and glucagon: Roger Unger

@LucySW It's an interesting discussion, but however you look at it, there's a very clear relationship between Insulin and Glucagon. The loss of insulin that is driven by the destruction of the Beta cells throws that relationship out of kilter.

One of the interesting aspects of the bodily system is that Pancreatic insulin is released into the hepatic portal vein and it's first impact is felt on the liver, which is where a significant amount of the glucose processing takes place. What it also does is reduce gluconeogenesis. The muscles then get insulin post the liver. In the way that insulin is injected, the muscles get the insulin first, followed by the liver, leaving a much longer gap for GNG to take place. This is where Afrezza is proving interesting as it is more or less straight into the blood and therefore hits liver and muscles at the same time, restricting the GNG process (and seemingly countering initial glucagon releases).

My take, based on the evidence of me and my Libre, plus eating quite a bit of protein, is that he's talking along the correct lines, but I don't think it's loss of control of glucagon, I think it's much simpler than that. I think the body reacts to foods as though it has both Glucagon and Insulin, and therefore releases glucagon as though it had insulin to counter where necessary. We know, of course, that it doesn't.

It's an interesting article @LucySW and given my experiences of the last few months, I fully understand where they are coming from. I think too much of clinical management of diabetes doesn't holistically manage the broken closed loop system that insulin and glucagon participate in.

There is a paper from 2000, where the writer calls the 20 years from 1960 to 1980,the 'black age' of endocrinology

The effects of this ‘black age’ are still with us because these incorrect hypotheses have, with the passage of time, been turned into dogma and become cast into ‘tablets of stone’ in undergraduate textbooks. They are also carried forward into postgraduate teaching. For example, even in well respected texts it is still common to find statements such as ‘The basic action of insulin is to facilitate glucose entry into cells, primarily skeletal muscle and hepatocytes.

Click to expand...

He asked this question of groups of students (undergrad and postgrad on anaesthetics courses) fro several years

is the fasting hyperglycaemia of diabetes due to overproduction of glucose by the liver or underutilization of glucose by peripheral tissues?

Click to expand...

and the vast majority said it was (wrongly) the latter.
He goes on to demonstrate that this glucose is from the liver ,there is a very strong relationship between fasting glucose and production of glucose from the liver. This is true in T2 and in insulin withheld type 1s.(brave souls that they were)
As muscle cells can use glucose without insulin that doesn't cause nearly as large a problem as that caused by the failure of the insulin brakes on the liver.
http://bja.oxfordjournals.org/content/85/1/69.full

(by the way Unger is very well known for his work on lipotoxicity and the metabolic syndrome I wouldn't dare put the name of , or conclusion, of this well cited paper on this forum
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880185/

phoenix said:

I wouldn't dare put the name of , or conclusion, of this well cited paper on this forum

Click to expand...

Lol.... I can see why... Especially not with that very large experiment...

LucySW said:

But is this claim well known? I've never seen any reference to it. Why isn't there research on safe glucagon suppressants?

Click to expand...

The gist of his argument is that dogma is such that glucagon has not been considered as important in the diabetic equation, so there is little research. It has long been considered a two factor problem. Insulin and glucose.

What I found interesting was the statement that amylin has been found to be a glucagon suppressant, and guess where that comes from? Yup, those long dead little beta cells.

Given what I've been experiencing on low carb but quite a bit of protein, this discussion makes a lot of sense to me.

A few years ago I remember reading of quite a few people with T1 in the US taking Symlin . I haven't noticed any recently (but then I don't look at their forums very much
http://jdrf.org/press-releases/jdrf...wo-hormones-for-treatment-of-type-1-diabetes/

prospect of using leptin to surpress glucagon
http://deepblue.lib.umich.edu/bitstream/handle/2027.42/90267/j.1399-5448.2011.00797.x.pdf?sequence=1

This topic has inspired me to update my blog: http://www.crick-tech-munch.blogspot.co.uk/2015/05/multi-factor-treatment-of-type-1.html

Thanks Lucy!

For the science afficionados - you might find George Henderson's latest blogpost (How a high fat ketogenic diet prevents diabetic ketoacidosis – somatostatin) of interest - all this type 1 stuff goes right over my head:

http://hopefulgeranium.blogspot.com.au/2015/05/how-high-fat-ketogenic-diet-prevents.html

The Newburgh and Marsh paper mentioned by George Henderson is available on the internet.
https://archive.org/stream/archivesofintern26ameruoft#page/557/mode/1up p647ff


The initial treatment was a very low cal high fat diet. This first diet seems to last for between a couple of weeks to a month. It was low cal but nowhere near as low as Allen's starvation treatment. The patient was then put on a slightly higher calorie diet. This was certainly an the advantage since it meant that patients were able to have a more normal level of activity on discharge.

Allen was opposed to the extra fat. He describes two deaths which he says was due to this 'Other clinical experience convinces me firmly that the attempt to give a high caloric diet or to build up the body weight too high with fat or any other food is injurious and leads to a fatal result in every genuinely severe case of diabetes'

Newburg and Marsh describe the histories of just 5 of the 73 patients. They seem to be people that we might call LADA rather than classic T1. One at least is more like a T2 . I would suspect that all had some residual insulin; which when glucose levels were lowered would put a brake on ketone production . One child is mentioned as being specially treated in the Paediatric dept ( the therapeutic result was 'not entirely' satisfactory because the child departed from the diet)

When they were glucose and acidosis free they were let out of hospital (the one glucose level I could find on a chart was a final level of 0,176g/l which is almost 10mmol/l so not that low)
The authors say
" While our experience with the high fat diet has been brief in relation to the chronicity of the disease and we are not in a position to discuss the eventual results our diet, we are, nevertheless, greatly impressed by the excellent condition of our patients months after leaving the clinic."
There are only 3 subjects described in follow up. They were OK but the max period being a 40 year old after 9 months.

And that lack of follow up means we don't really know if this diet or any diet would eliminate DKA if insulin levels fell; certainly it's rival diet, the starvation diet had a very poor longer term success rate. In Allen's case series of 76 patients seen between 1914 and 1916, 43% were dead by late1917 and most didn't survive for many years, even the oldest had only an average of about 7 years [ nor referenced ;memory from another paper]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062586/?report=reader#B4

example diets from paper


Re Somatostatin,
It is is used quite frequently in lab experiments as it inhibits both insulin and glucagon,. In the body it can be stimulated by low PH (ie acidity; maybe other things,don't know but this one is relevant ) . .
It is released from several places including the delta cells in the Islets and they think that delta cells are intact in T1 ( a least they think they can regenerate them into B cells; in diabetic mice ) It certainly seems to be involved in being part of that that on/off switch which prevents DKA in non type ones
.https://kclpure.kcl.ac.uk/portal/en/publications/a-role-for-islet-somatostatin-in-mediating-sympathetic-regulation-of-glucagon-secretion(760dd5c5-697c-48e0-88e0-64114d23a275).html

Even if they are intact, I would have thought that they aren't working effectively, or perhaps not getting the right signals , else we wouldn't be prone to DKA.
George Henderson's example used injected somatostatin .
Release of too much doesn't seem to be a good thing for all systems. It also inhibits the release of pancreatic enzymes.(so too much and you can't break down those fats an proteins) Elsewhere in the body it also reduces the release of TSH so not so good if you also have hypothyroid. Too much somatostatin can of course lead to diabetes (because it inhibits insulin)
http://www.yourhormones.info/Hormones/Somatostatin.aspx
Interestingly, octreotide (a somatostatin mimic) has been trialled for use in retinopathy; with mixed success.

As Indy, said all this T1 stuff goes over my head!
As I'm weird and my balance between, glucose, glucagon and over production of insulin.
The science is too much!
Can someone put this thread into layman's language. I am very interested in how it effects me.
I'm also on sitagliptin, which helps me greatly, it is a diabetic med, and what it does is create more insulin but inhibits the glucagon, this helps the reduction of glucose in the blood. It is a dpp4 inhibitor.
So is this why the balance between liver and pancreas is so important?

Nosher, its a bit like a see saw. If working properly when glucose levels fall so does insulin, glucagon levels rise , glucose is released so that the levels in the blood are returned to the proper place.
see this:
http://health.howstuffworks.com/diseases-conditions/diabetes/diabetes1.htm

It's more complicated than that though because there are a lot of pathways involved and something going wrong in one place sets the whole thing out of balance.

Siptagliptin acts to increase incretin hormones that are found in the gut .

These incretins normally start to work during a meal .They send 'messages' to the pancreas to increase insulin release and to decrease glucagon because food is on the way . You don't want any extra glucose from the liver anymore but you will need more insulin .
In normal working systems up to 70% of the postprandial insulin response is caused by the actions of these hormones . ( but if you inject glucose they don't work )
One of these incretin hormones is called GLP-1
Normally GLP-1 is broken down very quickly by an enzyme called DPP-4. So the signal stops.
DPP4 inhibitors are drugs that inhibit the release of the enzyme so the GLP-1 isn't broken up so quickly. The GLP-1 stays in the system longer and the pancreas is signalled to make more insulin and also less glucagon. The diagram on the wiki page might help.http://en.wikipedia.org/wiki/Dipept...media/File:Incretins_and_DPP_4_inhibitors.svg

This paper (and it is very sciency) http://care.diabetesjournals.org/content/34/Supplement_2/S251.full#ref-4
says that the loss of what they call the incretin effect is a specific and early characteristic of T2 (where that leaves you.??)
It also says that the incretin effect is lost in other types of diabetes ( including diabetes caused by pancreatitis, T1, LADA and MODY) This has the effect of glucagon levels being too high

phoenix said:

Nosher, its a bit like a see saw. If working properly when glucose levels fall so does insulin, glucagon levels rise , glucose is released so that the levels in the blood are returned to the proper place.
see this:
http://health.howstuffworks.com/diseases-conditions/diabetes/diabetes1.htm

It's more complicated than that though because there are a lot of pathways involved and something going wrong in one place sets the whole thing out of balance.

Siptagliptin acts to increase incretin hormones that are found in the gut .

These incretins normally start to work during a meal .They send 'messages' to the pancreas to increase insulin release and to decrease glucagon because food is on the way . You don't want any extra glucose from the liver anymore but you will need more insulin .
In normal working systems up to 70% of the postprandial insulin response is caused by the actions of these hormones . ( but if you inject glucose they don't work )
One of these incretin hormones is called GLP-1
Normally GLP-1 is broken down very quickly by an enzyme called DPP-4. So the signal stops.
DPP4 inhibitors are drugs that inhibit the release of the enzyme so the GLP-1 isn't broken up so quickly. The GLP-1 stays in the system longer and the pancreas is signalled to make more insulin and also less glucagon. The diagram on the wiki page might help.http://en.wikipedia.org/wiki/Dipept...media/File:Incretins_and_DPP_4_inhibitors.svg

This paper (and it is very sciency) http://care.diabetesjournals.org/content/34/Supplement_2/S251.full#ref-4
says that the loss of what they call the incretin effect is a specific and early characteristic of T2 (where that leaves you.??)
It also says that the incretin effect is lost in other types of diabetes ( including diabetes caused by pancreatitis, T1, LADA and MODY) This has the effect of glucagon levels being too high

Click to expand...

Thanks @phoenix , that's really good reading that (phew!)
My glucagon level is too high without my meds, I have been told that! Also my response to my first mouthful plays an important part in my 'balance' of hormones produced.
Normal and diabetic patients, get a slight dip in their spike after eating. I don't! Mine carries on regardless until I spike and I spike higher because of the high levels of glucagon, glucose and glycogen, so I need more insulin to counter that effect.
So the more insulin I produce the result is that, after 3-4 hours after eating, I have residual insulin in my blood, so I continue on the downward arc towards Hypoglycaemia.
I think my see-saw is out of balance and my metabolism is totally different to normal.
I am going to read more on the incretin effect and RH.
It's so easy to understand! (Not!)
Thanks again.

LucySW said:

Has anyone watched this video by Roger Unger at Univ of Texas? I was led to it by procrastinating and reading Malcolm Kendrick's blog (which I find excellent), in particular some blogposts on rethinking diabetes here.

Unger is presenting research that seems to demonstrate that the centre of Type 1 is not the body's loss of insulin, but its loss of control over glucagon. ie, that while current principles of control by insulin are not wrong, current thinking about how Type 1 works is wrong.

Enjoy.

Click to expand...

Thank you for posting this. I had never heard of Unger. I thought I had it all understood. Now I realize I understand nothing. That's good. I need to learn more.

I googled Unger and read intensively. It seems what he and UT are discovering dovetails with what Prof. Taylor uncovered about T2 diabetes and visceral fat.

I found this news item but it's behind a pay wall so here it is in full:

MIND BLOWERS: DR. ROGER UNGER
McMullan, Dawn. D - Dallas/Fort Worth

38.11

(Oct 2011): 69.

Abstract (summary)
TranslateAbstract

Since Frederick Banting discovered insulin as a treatment for Type 1 and Type 2 diabetes in 1922 (before that, it had a 100 percent fatality rate), not much has changed.
*****
Everyone in Roger Unger's father's family had been a doctor. It only made sense that he'd go premed when he started at Yale. He can't remember considering any other option.

Unger grew up in Westchester County, outside of New York City. His father, Lester J. Unger, was a well-known doctor who invented the first direct blood transfusion instrument. While in private practice after medical school, the younger Unger had a friend who changed the course of his career - and, potentially, the lives of many living with Type 1 diabetes.

His patient, a star tennis player in the '50s, was having a difficult time managing his diabetes during the latter sets of long matches. Unger traveled with him to a major competition, trying his theory that glucagon injections could keep blood sugar levels stable. "At that time, glucagon was considered a contaminant of the insulin extraction procedure, and I felt that was very unlikely," he says. "I felt it was a true hormone, and I wanted to prove it."

He has been working on, in, and around that concept ever since.

Since Frederick Banting discovered insulin as a treatment for Type 1 and Type 2 diabetes in 1922 (before that, it had a 100 percent fatality rate), not much has changed. It was such a miracle that nobody wanted to mess with it. Consider this: we discovered insulin five years before Charles Lindbergh crossed the Atlantic. And we're still treating diabetes the exact same way.

During his studies, Banting extracted glucagon, which has the opposite effect of insulin. Unger's work in the '60s and '70s showed that a lack of insulin was accompanied by an excess of glucagon. If you suppress the glucagon, you don't need insulin, Unger says.

"The treatment from the time of Banting until today is to replace the insulin and ignore the glucagon," Unger says. "The problem with that strategy is if you give enough insulin to suppress the glucagon, you are giving too much to the rest of the body. Now what we've done is suppress the glucagon and then give low levels of insulin instead of the seesaw, roller-coaster, up-and-down glucose levels that are characteristic of every Type 1 diabetes patient. We get perfectly normal glucose levels, just like a nondiabetic."

He is now in the middle of a two-year study that is translating his work with animals to humans. If successful, there will be a large-scale national study, and, eventually, he'll take what he's learned to Type 2 diabetes research. If it doesn't work, he jokes that he'll join the witness protection program.

"I don't want to jinx it, but all I can say is we are very hopeful," he says. "Otherwise, we wouldn't be wasting our time. I'm hopeful that all of this work is going to make a big difference for diabetes patients Until I know whether it will, there's sort of a chronic suspense. If it's no **** good, what did I do all of these years?"

*****
I don't know what happened to the large-scale national study.