GLP1-RAs in Type 1 Diabetes: more than meets the eye?

Some people will be aware, and some not, that there is a reasonable minority of people with Type 1 Diabetes using GLP-1 Receptor Agonists (GLP1-RAs) such as WeGovy and Mounjaro (which is a dual incretin also containing Gastro Inhibitory Polypeptide, GIP), especially in the USA.

They are used for a couple of reasons. Often as an antidote to dealing with double diabetes and to aid weight loss, which is often harder for those with type 1 given the demands of exogenous insulin, but also as a mechanism for inhibiting post prandial glucose rises.

This article will dig into the latter part of that discussion, and in order to do so, let’s look at the “double bubble” of type 1 diabetes. The missing hormones and extra enzymes that make homeostasis and living a normal life with type 1 that much harder.

The background

As many people will be aware, there are a number of hormones that people with type 1 simply don’t have, and excesses of other things. One of these is Glucagon.

Roger Unger and Glucagon

Diabettech has written about the problems of glucagon in the past, focusing on the work of Roger Unger, a renowned physician who focused on the role of unopposed glucagon in type 1. In fact, back in 2015, we were asking the question “Why isn’t glucagon suppression part of type 1 management” in response to Roger’s work.

His key postulation was that Type 1 Diabetes is as much a condition of excess glucagon as it is of lack of insulin, indeed, if the excess glucagon can be controlled, then insulin requirements become much lower. He successfully demonstrated this with mice (lucky mice), but I don’t believe there were ever human trials of his theories.

Levicure

Subsequently, Levicure, an Israeli start up looking to reverse type 1 using readily available therapies has built an amazing model of the mechanism of action of their solution:

It’s a little complicated, but it focuses on three points. 

• Inhibiting the immune attack on beta cells without aggressively suppressing the entire immune system.
• Stopping the metabolic self-damage of beta cells and promoting their regeneration
• Increasing insulin secretion while decreasing glucagon secretion

It uses three readily available compounds to do this. DPP-4 inhibitors (Sitagliptin), Proton Pump Inhibitors, and GABA (Gamma-Aminobutyric Acid).

It turns out that most people with Type 1 have excess levels of the enzyme DPP4. One of the jobs of DPP4 is to cleave the GLP1 incretin, which reduces the amount in circulation. GLP1 is important because it triggers the cAMP messenger, which in turn activates Protein Kinase A. This is a key trigger of insulin secretion, but also glucagon inhibition. In the Levicure model, they also use GABA to inhibit glucagon release.

There are multiple studies (examples here and here) where GLP1-RAs have been shown to reduce glucagon production.

The upshot is that by either increasing availability of GLP1 or increasing the reaction to GLP1, glucagon production is inhibited.

Other Hormones

Amylin

 As we’ve mentioned already, one of the key issues in Type 1 is the lack of various hormones. A big one is Amylin, which reduces the speed at which food passes through the gut.

One of the key benefits of GLP1-RAs (indeed, one of the concerns with GLP1-RAs), is that they reduce that rate. In the absence of Amylin, this slowing down of food passage will reduce the rate of absorption of nutrients as the food passes through the intestines, and effectively reduce post prandial highs as a function of this activity.

Ghrelin

Another malfunctioning hormone in T1D is what’s normally known as the “Hunger” hormone. Ghrelin regulates appetite. More Ghrelin = greater hunger. Within type 1 we have unregulated Ghrelin production. Ghrelin is especially good at encouraging the consumption of sweetened foods, and may play a part in “Hypo Hunger”.

One of the key actions of GLP-1RAs is to block Ghrelin receptors in the brain, reducing the feeling of needing to eat.

GLP1-RAs and Type 1 diabetes

So far then, we’ve determined that GLP1 restricts glucagon production, slows down gastric transit and suppresses appetite. How does this help with Type 1 diabetes?

Reducing glucagon production

One of the challenges with unregulated glucagon production is that the body does so in response to almost any stimuli. It’s a natural reaction to receiving certain proteins that require insulin to extract the Amino Acids, for example, or in response to certain proteins in various foods.

If we can reduce glucagon production, we potentially reduce the amount of insulin required in general, as there’s a significant reduction in glucose production from the liver and therefore using exogenous insulin is better directed when it needs to be. 

Slowing gastric transit

This is pretty straightforward. Slower movement through the gastric tract reduces the rate of absorption of foods and therefore the rate at which we might expect glucose levels to rise in response. In theory, post prandial glucose levels will be lower, but might be more challenging to manage, as rises may take longer than the faster acting insulins that we now use. Automated Insulin Delivery systems may need functionality to manage this type of variation. 

Blocking Ghrelin effects

While this seems a little less important, it may help play a part in reducing the risks of “Double Diabetes”, simply by reducing food intake. If you you stop eating earlier because you’re not hungry, then it may also help to reduce post prandial glucose levels, especially with the reduction in digestion speed. 

Final Thoughts

This all suggests that increasing the availability of GLP1 within the body should have positive benefits for those with type 1.

Do GLP1-RAs present an opportunity for those of us with type 1 to increase our time in range, and perhaps time in tight range? Potentially, yes.

Do they enable the use of AID systems in a fully closed loop model, where there is no requirement to bolus for meals? Again, potentially, yes. Anecdotes in the Open Source world would suggest so.

In the next part of this series, we’ll take a look at the pharmacokinetics of GLP1-RAs and how they affect the dosing regime and the mechanisms by which the incretins work. It’s perhaps a little more complex than we’d expect.