COMMENTARY

Hypoglycaemia Take Homes from EASD

Prof Simon Heller

Disclosures

September 20, 2019

This transcript has been edited for clarity.

My name is Simon Heller. I'm professor of clinical diabetes at the University of Sheffield. And it was my privilege to be one of the co-chairs at the session where oral presentations describing hypoglycaemia research were presented here at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting.

It proved an excellent session. Presentations were of high quality and there was good discussion.

I want to highlight a few of those presentations, which I think suggested advances in the field and increased our understanding of hypoglycaemia.

CGM & Hypoglycaemia

The first presentation that I want to highlight was one from the University of Edinburgh where they did a retrospective study looking at hypoglycaemia rates measured by continuous glucose monitoring (CGM) in patients with type 1 diabetes [1]. They related this to the secretion of C-peptide, which of course, reflects ongoing activity in the beta cells and endogenous insulin secretion.

What they found is that even if you just produced a small amount of C-peptide, what are called micro-secreters, then the incidence of hypoglycaemia as measured by continuous glucose monitoring was significantly less. They didn't study enough patients and have sufficient data to look at a direct relationship, but certainly they showed that in a category with even more C-peptide secretion. hypoglycaemia was less.

I think this is really important for two reasons.

First, it suggests that if we can maintain some degree of beta cell function in patients with type 1 diabetes, and this might be achieved by tight control of blood glucose, particularly at diagnosis, then we can perhaps protect patients with type 1 diabetes from the highest risk of hypoglycaemia. This is probably because of continued endogenous release of insulin, which in turn, preserves the glucagon response to hypoglycaemia, a response, which we know diminishes early after the diagnosis.

I think this is potentially a very important finding, which of course needs confirmation in further studies.

Hospital Admissions, Hypoglycaemia, and Death

Another really interesting study, again in type 1 diabetes, was conducted by investigators from Graz in Austria, and also in Swansea, Wales.

In Wales, they have a big database, which allows them to do large epidemiological surveys and what they what they looked at in this retrospective survey was the relationship between patients hospitalised with severe hypoglycaemia and subsequent mortality [2].

What they showed is that the greater the number of admissions with severe hypoglycaemia, the greater the risk of death.

Now, we know from studies in type 2 diabetes, that there is a strong association between severe hypoglycaemia and cardiac mortality. But what we don't know is whether this is causal, or possibly just a risk marker. And by that, I mean, it may be that patients who experienced more severe hypoglycaemic episodes, are just frailer, have co-morbidities, which means that they are more likely to die, but this isn't necessarily causal.

I think the importance of a study in type 1 diabetes, of course patients are much younger, indeed, the mean age of this group was 31 years, and it seems highly unlikely that many of these patients would have co-morbidities which would mean that they were frail, although it is true that chronic kidney disease was one of the factors implicated. 

Nevertheless, I think, although more work needs to be done and they are intending to look at post mortem examinations when performed, it's certainly going to increase our understanding of this important relationship. Although I think we would agree that, whether it's causal or not, severe hypoglycaemia should be reduced, if at all possible.

'Dead In Bed'

Another interesting study was from our own group, where we were looking at the potential mechanisms of 'dead in bed syndrome', a rare tragic complication of type 1 diabetes [3]. It's thought to be due to cardiac arrhythmias. A post-doctoral researcher in our group has done modelling using a model sino-atrial cell, which affects the heart rate, because it's the pacemaker for the heart.

Using modelling and adjusting the conditions of hypoglycaemia, lowering the glucose, lowering the potassium, and changing the effect of the autonomic nervous system, he was able to show that under certain conditions, in this computational model, the heart rate went very slow. Indeed, in some of these simulations, there was sinus arrest.

Now, of course, this doesn't prove anything. But it does suggest mechanisms which might explain why sudden cardiac death due to arrhythmias might occur in hypoglycaemia, and, again, needs further work to confirm these findings.

Dishabituation

The final study, and perhaps the most interesting of all, was one which looked at the effect of what's called dishabituation on responses to hypoglycaemia [4]. The rationale behind this study was that perhaps reduced awareness of hypoglycaemia, which affects both type 2 and a quarter of type 1 patients, and makes them more vulnerable to severe episode of hypoglycaemia because they can't recognise when their glucose is low, might be due to adaptation because of repeated episodes of hypoglycaemia. The investigators from the University of Dundee reasoned that if they could cause dishabituation (they were going to induce hypoglycaemia by high intensity exercise) could they reverse this?

They took patients with reduced awareness of hypoglycaemia, and they did intermittent, acute high intensity exercise on a bike. The patients did this on a number of occasions, and then their responses to hypoglycaemia were tested. 

Really interestingly, they could improve the catecholamine response to hypoglycaemia, which again, we know is an important defence to hypoglycaemia in patients with diabetes, which becomes impaired in reduced awareness. 

Again, this is a proof of concept trial. It needs to be proved in a much larger study, but it does offer hope that we might have a specific treatment for patients who have reduced awareness of hypoglycaemia. 

So in summary, I think these are really interesting studies. They raise the possibility of new treatments for hypoglycaemia. And hopefully, we'll see more from these the laboratories.

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