Glucagon response in T1D

So when you’re diagnosed with Type 1 diabetes, doctors, dieticians and CDEs will bombard you with lots of information about T1D. At least that’s my experience. They’ll talk about how the body normally maintains glucose homeostasis, they’ll explain hyperglycemia, hypoglycemia, glucagon production by alpha cells, insulin and the destruction of beta cells. But… nobody ever explained what happened to the glucagon response in T1D. Why are my alpha cells not able to prevent hypoglycemia? Is this actually known?


The alpha cells are not completely functional, they are somewhat “sleeping”, just unaware. Alpha cells are still present in normal numbers, but their function is impaired. After a length of time in T1D’s there is a loss of communication between the alpha cells and the beta cells.

I think it is true that not all T1D’s experience this, but most do after a number of years.


I think you should, if you have time, watch Dr. Najeeb’s USMLE lectures on the arrangement of alpha, beta, delta cells in the pancreas.
What became clear to me is that alpha cells are not organized around the blood vessels that contain blood sugar; they are clustered around the insulin-producing beta cells. So instead of responding to blood sugar levels directly, they use insulin levels as a proxy for blood sugar. In T1Ds, where insulin levels in the blood are controlled by our injections/random guesses, that means the main signal these alpha cells are using is dysfunctional. That’s why having even a few functioning insulin producing beta cells may protect against hypoglycemia (I presume); they’re at least a legitimate signal that is well correlated to BG levels, so they can somewhat modulate glucagon response in a more normal manner.

ETA: This is part 1 of 4, but I watched all four parts really quickly in one sitting. Thought it was super interesting. The guy has a cheesy style that is weirdly very effective.


It is amazing how much I remember months after watching it - the Alphas (males), the Betas (beautiful… women) and the deltas (dogs)… :laughing:

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I don’t think any of this is a very good answer to the OP’s question!

I asked myself the same question a few months ago. I did a bunch of reading. But I was not able to get a good answer to my own satisfaction.

I am sure that I was not thorough enough in my research. But I also think there is not a good response to this question within the existing state-of-the-art understanding of diabetes. I could be wrong though.

I was under the impression we do have functional alpha cells. I can clearly see small bounces on the cgm when it drifts down to 60. If it is nose diving then it is gonna crash - I don’t think the alpha cells are super alpha cells. But a gentle drift it seems is at least some times is handled.

I believe that is correct. But the several studies I read (very incomplete research) indicated that either they are not signalling correctly, or their signals are not being properly read by the liver.

Either way, the system is not working, because hypoglycemia is a major cause of D death.

I don’t know that your statement is correct.

I don’t know that we know that:

From this source:

The majority of IDD (group A) reached a slightly lower steady-state glucose level and exhibited similar glucagon and GH responses while the epinephrine response was augmented.


These [group B] subjects had no glucagon and epinephrine responses while their GH and cortisol responses were normal.

This article shows two instances where (a) a group of PWDs has a normal glucagon response but (b) another group does not, meaning that one one case the alpha cells seem to properly generate glucagon (therefore they receive the signals they need and function properly) but in another they do not, either because they do not function properly, or because they are not getting a chemical signal that tells them to function in a specific way.

This article demonstrates similar glucagon and epinephrine levels between PWDs with and without counterregulatory response to hypoglycemia:

peak values for glucose production, glucagon, epinephrine, norepinephrine, cortisol and growth hormone were similar in the diabetics with and without clinical hypoglycemia

Therefore, in this experiment, the alpha cells function properly in all cases, but in one group you still see hypoglycemia, meaning that another part of the body must be reading their signals wrong.

I agree with that:

glucagon-producing alpha cells in the pancreas remain relatively protected from the toxic environment created by metabolic stress, while insulin-producing beta cells are not protected and die by apoptosis.

[ Btw, I found an interesting nugget in this paper – alpha cells may be able to turn into beta cells:

There is an emerging role for alpha cells in transdifferentiation into beta cells ]

I am not sure that it is true/always true: see above. It could also be that they function properly but don’t get the right chemical signal, or that they function properly but that their signals are not read properly by the liver, or? No proof.

I was not able to find sources that identify this communication between alpha and beta cells to be either (a) a part of the counterregulatory response to hypoglycemia, or (b) impaired in the case of PWDs. But this may be due to faulty research.

So the only thing I can say is that I don’t think your statement is supported, in its gist, by the mainstream understanding of hypoglycemic response in PWDs – but I also don’t think anyone understands that response either.

In the end, I think that the reason why (some) PWDs are unable to respond to hypoglycemia is still a mystery to science at this time: Defective counterregulation and hypoglycemia unawareness in diabetes: Mechanisms and emerging treatments - PMC

This article reviews recent advances in how the brain senses and responds to hypoglycemia.

In response to hypoglycemia, patients with Type 1 diabetes and advanced Type 2 diabetes are not able to suppress circulating (exogenous) insulin levels or increase glucagon secretion. Thus, patients with diabetes rely extensively on the sympathoadrenal system as their primary counterregulatory defense against hypoglycemia. Adrenergic activation leads to the release of norepinephrine at nerve terminals located throughout the periphery. Adrenergic stimulation of the adrenal glands stimulates epinephrine release. Activation of the adrenergic system combats falling glucose levels by increasing glucose production, reducing peripheral glucose utilization, and eliciting symptoms of hypoglycemia.

But, as we actually saw in other studies above, (a) glucagon generation sometimes seems unimpaired, and (b) even with normal epinephrine release, groups of PWDs were unable to avoid hypoglycemia. Clearly, people argue about it, and there is no good understanding of the phenomenon.

[And, btw, I found another nugget in this last article:

The mechanisms by which low glucose levels lead to sudden death has not been entirely worked out, but appears to be related to intensive sympathetic activation leading to fatal cardiac arrhythmias ]


I think I can simplify…

For reasons that nobody understands, with type 1 diabetes your beta cells which produce insulin to prevent hyperglycemia definitely don’t work well.

Also for reasons nobody understands your alpha cells which produce glucagon to prevent hypoglycemia probably don’t work well for all practical purposes…

Deeper understanding not entirely necessary. Do what it takes to keep your blood sugar normal if you have type 1 diabetes. This will involve corrections to adjust it upwards and downwards because your body’s mechanisms to do so either doesn’t work at all, or really sucks at its job.


I don’t think anyone knows why and how glucagon response becomes blunted in long-term type 1. In type 2, the opposite seems to occur: the glucagon response isn’t turned off by insulin so you keep pouring out glucose from the liver even after eating carbs. Robert Unger has been studying glucagon for decades, and his articles are a good place to start.


I had heard similar to TiaG that it was the insulin level that was key factor in glucagon release. Hope to watch the video she posted later.

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@Gretchen - Thanks for the additional info!!! So that sounds like a pretty big difference between T1 and T2 which would explain why some of the articles I read seemed to conflict. As well, the distinction of “long-term” T1 for the “blunting”.

I really think I see an alpha cell/glucagon response in my T1 with a slow cgm drop when she hits about 60 and the diagnosis was about 7 or 8 years so perhaps this is still early enough that the alpha cell response is still there but conceivable this would change as the years progress?

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@Thomas. Because it’s not certain what causes the alpha cell decline, it’s difficult to know what to do to prevent it, but keeping BGs as close to normal range as possible certainly wouldn’t hurt.


@Gretchen, welcome to the forum, so glad to see you join us!

If you wish you can introduce yourself in the introduction thread!