Why isn’t Glucagon suppression part of Diabetes treatment?

But why? Well I have been convinced that T1D is not just an underproduction of insulin. It appears to be a glut of glucagon without regulation as well. Why have I arrived at this conclusion? Because things happen that don’t make a vast amount of sense without it. 

Let’s take eggs. Eggs, for many T1s, require almost as much insulin as carbohydrate. Yet eggs contain no noticeable carbs. What they do have is loads of protein and fats, and considering that eggs are food sources for chicks to grow up, probably very easily assimilable access to amino acids. When we eat eggs, we see blood glucose levels rise in a relatively short period, yet there’s no discernible reason for this if we look at traditional methods of accounting for carb raises. 

In 1967, it was identified that Leucine causes an increased insulin reaction by Fajans, Floyd, Knopf and Conn and associated with hypoglycaemic symptoms, but also, at normal physiologically available levels, a glucagon reaction. Eggs are high in Leucine and T1Ds are low in  insulin, so will only get a glucagon reaction.

Further, Glucagon has been linked to issues with glycaemic control in studies dating back to 1975 and 1978, notably by Roger Unger. This doesn’t appear to have been given a huge amount of attention within the diabetic community.

In the ADA journal in 2010, we also find this study which closes with the statement:

“In summary, interfering with glucagon action (by decreasing its secretion or inhibiting its action) in the diabetic state is beneficial across species.”

Following this up in 2012, Unger et al published the following article, detailing much of the evidence that Glucagon plays a much more important role in Diabetes than is ever acknowledged.

In January 2015, a further study was published that looked at what happens when Glucagon is inhibited. It was another one from Roger Unger. And it’s very interesting. Essentially, it shows that when a glucagon response is eliminated in mice and rats, hyperglycaemia essentially goes away. There is much less of an issue with elevated blood glucose levels.

Given the other point about Glucagon is that it gets secreted in response to glucose levels increasing, and we can see that in a T1D, it’s a real nuisance of a hormone.

Now I suspect that all good Diabetologists will point to the idea that Glucagon is a key protective mechanism in the metabolism of Type 1 diabetics. It is the last line of response for overnight hypos. And yet, in 1984, a paper was published that established that in T1Ds of more than 10 years duration, the glucagon reaction to hypoglycaemia was generally severely compromised. Admittedly, scale of the study at 18 patients is very low, however, it is also a complication that adds to the risks of lack of hypo awareness as one gets older. Further papers suggest that a loss of intraislet signals between alpha and beta cells may be the cause, as the production of insulin drops to practically zero in long term T1s, although the signalling mechanism of this aspect is still relatively unknown. There also seems to be evidence that this lack of response can occur earlier than after ten years. I’m sure there is more to be done on this topic.

Looking back at all these papers and tests that have been done, there seems to be a clear mechanism for reducing Hyperglycaemia by reducing the ability of the body to produce Glucagon. There also seems to be quite a bit of evidence that the backstop of glucagon as a safety net for hypos is a rather vague assertion once T1D has been in place for a long period.

This may also raise questions about severe hypoglycaemia and why it happens. If intraislet pathways exist that cause glucagon to stop a very bad hypo in a long term T1D due to reactions to insulin, it means that some long term T1s that still produce insulin (as per Jonathan Valabhji’s  research) are potentially far less susceptible to severe hypos than those who don’t and this perhaps should inform treatment.

Could glucagon suppression therefore eliminate or severely reduce hyperglycaemic episodes in those who struggle to control their diabetes? Novo Nordisk certainly thought so with their unsuccessful clinical trials of GLP-1 agonist Victoza. Sadly, the study didn’t note whether hyperglycaemic episodes were severely reduced, only that the reduction in Hba1C wasn’t significant enough. These two outcomes are significantly different enough in my mind to require a different review of the data.

Other suppressants include Amylin, also produced by beta cells, and lacking in T1s. There is a synthetic version available, Symlin, but only in the US. The dosing guidance is here. It is not licensed in Europe.

Questions have also been asked as to whether Afrezza inhibits glucagon response due to it entering the blood so quickly.

All in all, there have been enough studies with varying numbers of participants (the only double blind RCT type efforts seem to have been related to Symlin) that suggest that Glucagon is a bad guy in the ongoing management of diabetes, and that this is not new news, yet there has been little developed therapy for this aspect of diabetes. Early in the research related to diabetes, the action of Glucagon was recognised, but ignored to to a belief it was linked to adrenalin. The evidence now paints a rather different picture.

I, for one, would be willing to try out Symlin off license in the UK. Stopping accelerated highs seems like a no brainer. It has received FDA sign off and as a result, must be considered to be safe but European licensing seems a long way off.

Summing up his 2012 paper, Unger states:

“Failure to translate decades of favorable preclinical evidence to the management of human diabetes must reflect insulinocentric skepticism concerning the pathophysiologic importance of diabetic hyperglucagonemia.”

Is this another aspect of Diabetes Therapy that we need to shout more loudly about?