What is Hypoglycemia Unawareness? (Unabridged)

What is hypoglycemia, like, actually?

Part 1: Normal Physiology

Like anything in medicine, to understand what happens when things go wrong, first we have to understand how they work when things go right.

So in a non-diabetic person, when blood glucose (BG) levels drop to about 4.4-4.7 mmol/L80-85 mg/dL, beta cells stop producing insulin. Makes sense, right? This is basically the original “suspend before low” feature. If BG keeps dropping, at about 3.6-3.9 mmol/L65-70 mg/dL two things happen:

1. Alpha cells in the pancreas start producing glucagon!
2. The sympathetic nervous system tells our adrenal glands to release epinephrine!

Both of these responses, working simultaneously and synergistically through a bunch of different metabolic pathways, work to raise blood sugar. Broadly speaking, insulin inhibits the mechanisms by which they do this, which is why the body’s first response is to stop insulin production. Glucagon also inhibits the action of any insulin still in the bloodstream, and because of this counterregulation, alpha and beta cells typically are able to work together in perfect harmony to achieve stable and tight BGs in a non-diabetic person (and correct a low without food). I think you guys can probably already tell that when you take beta cells out of the picture and start exogenously administering insulin in a non-physiologic way (as in type 1 diabetes (T1D)), this whole system gets dysregulated, but bear with me. We aren’t done talking about how it normally works yet!

So the glucagon produced from your alpha cells makes its way to the liver. The liver, under normal circumstances, stores about 100g of glucose as long chains called glycogen. Glucagon tells the liver to break down these chains and release the stored glucose into the bloodstream in a dose-dependent manner (aka not all 100g at once).

Meanwhile, our brain and nervous system is noticing what’s happening. One super important thing to know about the brain is that brain cells (neurons), despite consuming about 25 percent of our body’s glucose in a day, do not actually have the ability to store glucose. To put it a little simply, they rely on constant influx of sugar from the bloodstream to keep on firing and thinking and keeping us alive. This is actually the entire purpose of ketones—the brain uses them for fuel in low glucose states (starvation). But that’s a whole other article.

What’s important to know for low blood sugars is that when the brain senses that there maybe isn’t enough glucose in its environment, it sends messages through the sympathetic (“fight-or-flight”) branch of our autonomic nervous system to our adrenal glands, telling them to produce epinephrine (adrenaline) and cortisol.

We are all familiar with adrenaline, right? I’m writing this on a plane and during take-off we hit some truly wild turbulence. My heart was beating out of my chest, I started sweating, my hands were shaking and anxious thoughts started racing. That’s a low blood sugar!

Besides giving us all of these warning signs and symptoms telling us that something is wrong, epinephrine basically works the same way as glucagon on the liver, as well as potentiates the action of glucagon itself, raising our blood sugar.

As an aside, the hunger that we feel with a low blood sugar is not what is typically thought of as a part of the classic “fight-or-flight” response, but the research I read for this article seems to suggest that epinephrine is in fact at least partially responsible for this in the normal hypoglycemic response. Additionally, the normal hypoglycemic response does include the production of cortisol, a hormone notorious for stimulating appetite. So however it happens, the sympathetic nervous system also makes us hungry in lows, which is good because that’s how we raise our blood sugar, replenish our liver’s glycogen stores, and make sure our brain gets the glucose it needs.

Epinephrine acts instantly because it’s stored and ready, but cortisol takes a while because our adrenal glands don’t really store it and have to make it to order. Cortisol is basically your body’s go-to starvation and stress hormone, and like all steroids, will increase your blood sugar over the course of several hours. Actually, growth hormone (GH) is also released in response to our sympathetic nervous system reacting to a low blood sugar, also takes awhile to act, and also acts on the liver to promote glucose release and on peripheral tissues to promote insulin resistance.

So when blood sugar drifts down, all of these “counterregulatory” hormones serve to bring it back up through elegant and complex hormonal interaction. When blood sugar starts to rise again, similarly elegant and complex feedback mechanisms shut these hormones off, turn insulin production back on, and keep blood sugar stable and steady without the peaks or valleys those of us doing this manually are so familiar with.

Out of all of these counterregulatory hormones, epinephrine and glucagon are the main players in correcting a low. Cortisol and GH are just kind of sidekicks that get brought in as back up. It’s funny, because I remember sitting in medical school and realizing that while all of these hormones bring blood sugar up, there is only one hormone on the other side of the feedback loop that lowers blood sugar. And this makes sense, since evolutionarily speaking, not having enough glucose in your bloodstream is a much bigger problem than having too much glucose. But I couldn’t help but think how T1D would be a very different disease if there existed multiple other hormones that did the same thing as insulin, and could pick up the slack left in its absence.

Hypotheticals aside, we are going to focus on the action of glucagon and epinephrine from here on out. Besides from being the main players in normal physiology, when things get wonky in T1D, the actions of epinephrine and glucagon are also the most important to know and understand.

Part 2: Why we go low in T1D

So if we have all of these amazing counterregulatory hormone and feedback loops to keep our blood sugar stable, why do we still go low in T1D? I mean, like, my body still produces its own glucagon, like why do I have to pay a bunch of money to carry it around with me as an injectable??

The first and most important thing to understand is this: no matter how stable and in-range our blood sugars are, no matter how fancy our technology is (looking at you, closed loops), no matter how good we feel like we are at dosing and carb counting and adjusting, we administer insulin much differently, usually for the worse, than our own beta cells would.

I mean like, in a perfect system, the second you even start thinking about food, digestive hormones like GLP-1 and GIP are already perking up and starting to work to increase your insulin sensitivity, reduce glucagon production and increase insulin secretion. Insulin is then secreted in minute amounts, in direct response to the amount of glucose outside the beta cells, and this whole intricate web including hormones we haven’t even discussed yet work to keep your blood sugars steady no matter how much sugar you eat (again, this is a perfect system with no pathology).

We simply can’t replicate this with our current methods of insulin administration. But this is not to be discouraging! The more we understand about how all these hormones work together, the more we can understand about how they behave when insulin is taken out of the picture, and then put back in artificially.

So why do we go low? Because, like I mentioned above, insulin inhibits the actions and production of glucagon. When we have injected too much insulin in our system, for whatever reason, our alpha cells think that it’s because we are in a well-fed state and that their glucagon and blood sugar raising service aren’t needed.

Obviously, sometimes the amount of insulin that is in excess is just barely in excess, and suspending insulin delivery (either manually or through an automated loop) is enough to bring the insulin levels back down so that the alpha cells and glucagon can do its job. Other times, it’s not, and insulin levels remain high enough to inhibit our glucagon response and keep driving us low. This means we need to help our body along by consuming a few carbs, or in extreme scenarios, administering exogenous glucagon.

This is why any avenue through which someone decreases the amount of insulin they are taking will in turn help decrease the amount of lows, whether that’s through the adoption of a low-carb diet, anti-diabetic medication (I swear that’s actually what T2DM oral meds are called), or increasing insulin sensitivity through weight loss, diet, or exercise. When you’re dealing with less insulin, your alpha cells are less likely to be overridden and more likely to be able to help you out.

Of course, all of this is assuming that you have glycogen in your liver for glucagon to help release in the first place! Things like intense endurance exercise and prolonged fasting can temporarily reduce the amount of glycogen stored in your liver, and things like alcohol metabolism, rare genetic diseases and other toxic ingestions can reduce or inhibit your liver’s ability to break glycogen down and release it as glucose into your blood. If any of these things are true, even if your alpha cells aren’t being suppressed by excess insulin and can release enough glucagon, it still might not be able to actually do its job in the liver and release glucose, meaning that you’ll have to supplement with exogenous glucose/treat the low with carbs.

If any of you guys have ever drunk alcohol without also ingesting a lot of carbs (so in like a diet vodka soda or something similar) you’ve probably noticed middle of the night lows or next-morning lows. This is because alcohol metabolism basically uses up all the molecular supplies in your liver that would otherwise go towards glycogen breakdown and glucose release. Once the alcohol is gone and done hogging the enzymatic cofactors, glucagon can do its job properly again.

Anyway, there are a lot of reasons why all the usual biologic safety mechanisms to prevent and correct low blood sugar don’t always work in our non-physiologic, dysregulated type 1 diabetic state. It can get even more complicated once you start talking about the neural control of pancreatic hormone release and how that gets wonky in diabetic autonomic neuropathy, but I’ll stop here for now. Let’s talk about low symptoms.

Part 3: Hypoglycemia Unawareness

Like we discussed before, once your blood sugar hits 3.6-3.9 mmol/L65-70 mg/dL, your brain and sympathetic nervous system starts telling your adrenals to release epinephrine, so that it does all of its blood sugar-raising goodness, and also lets you know that something is wrong through sweating, palpitations, hunger, dizziness, anxiety and the works. These are called sympathoadrenal symptoms.

Sympathoadrenal symptoms are basically just signs of the safety mechanisms that are in place to make sure your brain has enough glucose. Therefore, they occur before your brain is actually in trouble. Neuroglycopenic (literally “low brain glucose”) symptoms (confusion, dizziness, ataxia, slurred speech, paresthesias, seizures and eventually somnolence, loss of consciousness and coma) from hypoglycemia don’t occur until your brain doesn’t have enough glucose to function properly. The threshold for this is around 2.8 mmol/L50 mg/dL.

But if there is one thing that is always true about nerves, it’s that they adapt to their surroundings. When you first put on clothes in the morning, the pressure-sensing nerves in your arms tell you that there is something touching your skin. Eventually the nerves adapt to the constant stimulus, the feeling goes away, and you forget that your skin is covered in clothing. The opposite is true, too! When you wear glasses for a long time and then finally take them off, the pressure-sensing nerves on your face and head sometimes still feel like you’re wearing glasses, or a bracelet, or a ring, or whatever.

Just like your nerves adapt to the feeling of wearing a shirt, or sitting on a chair, so too do your nerves adapt to the concentration of glucose in their environment! When your sympathetic nervous system is frequently exposed to low levels of glucose, the response to this low glucose is dampened and the low glucose threshold at which you get sympathoadrenal symptoms resets. Actually, the sympathoadrenal response has been shown to be less even after one recent episode of hypoglycemia!

This even happens in relative hypoglycemia. So like if you’re running in the 400s all the time, and then drop to 13.9 mmol/L250 mg/dL, you will probably feel shaky, sweaty, anxious, hungry—all symptoms of a low blood sugar without actually being low. You won’t get neurologic symptoms (seizure, etc.) and aren’t in any actual danger because your brain is still swimming in plenty of glucose to function, but your sympathetic nervous system is freaking out because they have reset their threshold to become accustomed to high levels of glucose, and to them, 13.9 mmol/L250 mg/dL is now low enough to be concerned about.

The reason that any of this happens is that basically your brain is constantly filtering out information that it deems is irrelevant, aka not an evolutionary threat. When something is new and unusual, it could pose a threat and your brain decides you should probably know about it. When it’s constant or consistent, it’s probably not a threat and your brain spares you the trouble of processing that information.

So if you’re going low a lot, your body doesn’t want to be impaired by those lows, and will adapt. And there are actually studies that show that during episodes of mild hypoglycemia, people with hypo unawareness return to functional neurologic baseline quicker once normal blood sugar is restored than those who do feel their lows. That is, the brain is less affected by this mild hypoglycemia! Which seems great, from a super short-term perspective.

But evolution is not a goal-oriented process, and if it were, it would know that hypo unawaress is actually a super bad idea in the long run, since it creates a vicious cycle! When you don’t respond to lows, you end up going even lower before you treat it, resetting your nerve’s response threshold and making you even less likely to feel your low the next time, increasing the risk of severe hypoglycemia and death. It would be great if our nerves didn’t adapt, but we’re stuck with the system we have, and sometimes that system leads to hypo unawareness and severe or life-threatening hypoglycemia.

The exact mechanisms by which this nerve adaptation occurs is unclear. We know a little bit of reduced hypo response is sometimes a normal finding even in non-T1Ds, especially during sleep when the sympathoadrenal response to hypos is automatically turned down a notch (again, this creates a vicious cycle in T1D and is part of why “dead in bed” syndrome exists). But the actual mechanism by which is occurs to such a great extent in T1Ds is complex, likely multifactorial, and way beyond the scope of this article.

The important thing is that we know for sure that hypo unawareness, or “Hypoglycemia Associated Autonomic Failure (HAAF)” requires these recurrent episodes of hypoglycemia to develop, which is really good news. Because even if we don’t know the exact details of how it happens, knowing why HAAF occurs helps us prevent, manage and treat it!

Just as a quick aside, there are also some medications that can exacerbate hypoglycemia unawareness. A really common one is a class of blood pressure and heart medication called beta-blockers, which blocks the same receptors that epinephrine acts on, and will reduce the development of low symptoms. There are also some case reports to suggest that SSRIs can cause hypo unawareness (basically through an atypical serotonin syndrome leading to autonomic failure) as well. Other drugs, like caffeine and some asthma/COPD medications act to stimulate the same receptors as adrenaline, and can exacerbate low symptoms, even raising blood sugar! All of these medications are still safe for T1Ds to take when indicated, but talk to your doctor to make sure that you are aware of any potential side effects or contraindications.

Part 4: So you have Hypo Unawareness/HAAF, now what?

If you are like approximately 40 percent of T1Ds, you probably have some degree impaired hypoglycemia awareness (definitions and incidence rates vary across studies, but after reading a bunch of the studies it’s my professional opinion that 40 percent is a solid number to throw around). People with hypo unawareness are at a six times greater risk of both morbidity (aka complications from severe lows like heart arrhythmias, or impaired neurologic development during childhood) and mortality from hypoglycemia than those people who can feel their lows.

Luckily, the treatment is simple: go low less often, and your nerves will adapt back to a higher low sensitivity threshold, improving your hypo awareness.

Easier said than done, though, right? Especially since nowadays the gold standard T1D treatment is intensive insulin therapy with a goal A1c of <6.5% to improve long-term outcomes for morbidity and mortality. Which is awesome! But A1cs this low are associated with a three-fold increase in the risk of hypoglycemia, which is not awesome and can lead to all sorts of morbidity and mortality of its own.

So how do we reconcile this, and balance the goal of euglycemia with the added goal of improving or maintaining our hyposensitivity and avoiding severe hypoglycemia?

The overwhelming consensus is that the best way to do this is to take advantage of continuous glucose monitoring (CGM) technology. Intuitively, it makes sense that if we can see that we are headed for a low, we can treat it earlier or avoid it altogether, helping our nerves learn a new normal and eventually reset their symptom threshold. This is even more significant and valuable during sleep, when our responses are blunted anyway and we need all the hypo identifying help we can get!

The data supports this! In one study, CGM use identified unrecognized hypoglycemia in 60 percent of patients, with almost 75 percent of those episodes happening at night! Another study showed that compared to fingersticks alone, CGM use reduced time spent in hypoglycemia from 11.4 percent to 6.8 percent, and when a hypoglycemic episode did occur, they were not nearly as severe. Finally, a 2017 study showed that in T1Ds who experienced frequent hypoglycemia, use of a CGM for up to 18 months improved awareness of hypoglycemia AND reduced the number of hypoglycemic episodes. More on this study in a minute.

The American Association of Clinical Endocrinologists (AACE), the American College of Endocrinology, and the American Diabetes Association have all released recent position statements recommending CGM use in patients with T1D who have hypoglycemia unawareness, or severe or frequent hypoglycemic episodes.

Unfortunately, CGM use is still a privilege that remains unavailable to many people. However, while it seems intuitive that CGMs help, the authors of some of these studies have remarked that it’s unclear how much of the decreased incidence (and therefore increased awareness) of lows is due to the fact that the study participants were wearing CGMs, and how much is simply due to the fact that by enrolling in these studies they were receiving a lot more intensive and frequent multidisciplinary support from physicians, diabetes educators, counselors and other clinical staff.

This is in line with what most of the people who study hypo unawareness have proposed that the answer to maintaining or improving hypoglycemia unawareness lies in just this—intensive work on the part of the patient, the doctor and the entire healthcare team to work together to come up with an individualized plan to prevent and/or reduce hypoglycemia through careful insulin management, diet, exercise, medication and monitoring, regardless of CGM use.

I’m really sorry I can’t tell you “do x thing for y amount of time and your hypo awareness will increase by z much”! I wish I could, but you and I both know that’s not how complex systems (like the ones I just spent 10 PAGES barely scratching the surface of) work.

And this complexity is what brings me to my final part, which is sort of a disclaimer for this whole article. Theoretically, avoiding hypoglycemia entirely will result in complete recovery of the counterregulatory responses (glucagon, epinephrine, cortisol, growth hormone) to the point where your body would not only be able to feel the lows, but would also be able to correct them all on its own without having to eat emergently or take glucagon, just like in a non-diabetic person. But this doesn’t seem to happen in real life, or even in studies.

In that 2017 study that I said I would come back to, they also measured endogenous glucagon and epinephrine levels in response to hypoglycemia (in addition to subjective sympathoadrenal and neuroglycopenic symptoms). What they found was that even though reduced hypoglycemic events led to significant improvements in hypo awareness, it didn’t 100 percent bring the body’s glucagon response back to that of a non-diabetic person, at least over the course of 18 months. Now this was a small study, over a relatively short period of time! It may be that the study design just didn’t have the power to detect these long-term changes in the body’s ability to correct lows itself.

But, there are several reasons why this might be the case, and in turn why, even if you avoid lows as best as you can and regain some hypo awareness, you will probably still have to correct the lows that do occur with external glucose/glucagon, especially if you have excess insulin on board:

• Even though the hypoglycemic events were reduced, they weren’t eliminated completely, and as we know even one recent hypoglycemic event is enough to cause a little HAAF during the next time. It could be that since we can’t eliminate them completely, we can’t fully regain the response either.
• We know insulin suppresses these responses, and like I said before, when we are administering exogenous insulin in a way that is inherently different than how our beta cells would, we end up further dysregulating the system and suppressing these normal counterregulatory mechanisms.
• The pancreas is actually a really complex organ, with multiple hormones and cells that all rely on each other to function. Loss of beta cell function can result in faulty signaling to alpha and other cells, and long-standing potential complications like autonomic neuropathy, inflammation and scarring and even the original autoimmunity could potentially impact our pancreas’ ability to secrete glucagon or other counterregulatory signaling factors in response to lows. This is why people in the honeymoon period typically don’t experience lows—the presence of living beta cells means that the complex signaling network of the pancreas/endocrine system is still functioning a little, and can still prevent/treat lows.

But there you have it! An overview of what hypoglycemia is, how it occurs, what hypo unawareness is and what we can do to fix it.

What’s the one big takeaway? By working carefully with your doctor to recognize and prevent hypoglycemia, it’s possible to in turn prevent and reverse hypoglycemia unawareness and all the burdens it brings. It’s possible to #livebeyond!

This piece is the unabridged version of an explanation of the occurrence of hypoglycemia unawareness. Check out the shorter version here.

WRITTEN BY Jordan Hoese, MD, MPH, POSTED 07/01/19, UPDATED 11/11/22

Jordan Hoese, MD, MPH is a family medicine resident physician in southern Oregon. She was diagnosed with type 1 diabetes at age 12, and has run seven marathons, including New York City with Beyond Type Run in 2017! She is passionate about providing comprehensive medical care in resource-limited community settings, and helping people understand and take control of their health. Her hobbies include running, travel, hiking, camping, yoga, healthy eats, coffee and hanging out at home with her boyfriend and their three cats.