Why Controlling Glucose is so Tricky

Hint: Even the natural human body struggles with it in strange and unexpected ways.

Whenever I hear other T1Ds say how they are looking forward to the day when automated, closed-loop insulin delivery systems can eliminate the daily burden of managing their diabetes, I always reply, “...and if that day were to come, what would you do? How would you live with T1D?”

I’ve heard a variety of answers from “I’d eat to my heart's content!”, all the way to, “I just want to live a normal life.” 

Such a simple wish. Nothing extravagant. No wealth or fame. No huge plans to conquer the world. Just a desire to ease the burden.

It’s no wonder that T1Ds place such hope in new, promising technologies, whether it’s the elusive cure (which is only 5-10 years away!) or an artificial pancreas, or a closed-loop automated insulin pump. And it’s this latter case that has most people’s attention, given that many are on the market, and claims are that they will be able to be “fully automated” soon, where such devices will take over the day-to-day management of controlling diabetes, allowing them to live a normal life.

That expectation, unfortunately, is a bit ambitious. For context, even those who get full pancreatic islet transplants, where they are able to have fully-functional beta-cell capacity to create their own insulin, still have an exceedingly difficult time maintaining glycemic control. According to the 2023 literature review article from the NIH titled, “Pancreatic islet transplantation in type 1 diabetes: Current state and future perspectives,” only 73.7% of islet transplant patients were able to achieve A1c levels <7% after the first year, as shown by the chart below from the paper.

These sobering statistics should make it abundantly clear that the ideal case of full replacement of beta cells is not itself a panacea. As this article takes great efforts to clarify, even the natural human body has a very hard time maintaining glucose levels.

How much glucose is in our blood, and why does it vary?

Let’s start with a perspective that may be shockingly simple: The average person has between four and five liters of blood, so a “normal” blood glucose level of 100 mg/dL means that a typical person has about one teaspoon of sugar throughout their entire bloodstream. That’s a whopping 4.2g of glucose. Here’s a visual representation, brought to you by AI. 

The average human has 4-5 liters of blood. A teaspoon of sugar is 100 mg/dL of glucose.

As you can see, 4.2g of glucose is proportionally tiny to the total volume. If you were to add another 2.1g of glucose–a half a teaspoon of sugar–then that would equate to 140 mg/dL. But as any diabetic can tell you, eating a half teaspoon of sugar isn’t going to raise glucose levels that high. How much you’d have to eat would vary a lot, from time of day, whether you had insulin onboard already, if you were exercising, if you were sick, and so many other things. Everyone is different in this way, which is part of the whole point here. There’s a lot going on in a body in how it shuttles glucose around, so when such tiny amounts can potentially make a huge difference, it hints as to why keeping glucose levels stable is incredibly difficult.

When you think of insulin, you’re assuming that it takes glucose out of your bloodstream and puts it into cells that use it for energy. Yes, that’s true, but this oversimplified view masks the more important and essential aspects to managing glucose levels. For one, insulin isn’t the only way glucose is cleared; it can happen via many different pathways. Moreover, insulin isn’t even involved in some cases.

For example, research shows that your brain represents only 5% of total body mass, yet holds 20% of the body’s total glucose volume at any given time. It also burns through it at an impressive rate of ~78.4 mg of glucose per minute. That’s about 1g of glucose every 12 minutes. And yet, insulin is not involved in the brain’s metabolization of glucose. Think about that for a minute. (Whoops, there’s another chunk of glucose you just consumed.) 

The brain is not unique here; many organs get glucose without insulin mediation (or sometimes, in conjunction with it). From this fact alone, glucose levels are affected by the brain and other organs that don’t rely on insulin to mediate delivery. What insulin and other hormones do is interact with cells that active various kinds of glucose transporters. Insulin, for example, activates glucose transporter #4 (GLUT4), causing it to rise to the surface of the cell, allowing glucose to passively enter from the bloodstream. Different body parts and tissues use different types of glucose transporters, which are activated by other hormones besides insulin. You can get a full rundown in this paper published in BioPhysical Reviews called, “Glucose transporters: physiological and pathological roles.” 

In case you’re wondering, the brain mainly uses glucose transporter 3 and 6 (GLUT3 and GLUT6), although GLUT4 is sometimes considered a “facilitator” in this and other regions. 

See how complicated this is getting? Regulating glucose involves a lot of things going on at once, and each one of them is volatile and inconsistent. Disrupt any one of these processes–say, insulin availability—it triggers a cascade of responses attempts to restabilize glucose levels. And that chain reaction is highly unpredictable and volatile too, even for the natural human body.

That’s just insulin—I’m only just getting started! In the article, “The Six Dysfunctional Hormones of Type 1 Diabetes,” the author reminds us of other essential hormones that fall out of balance, all of which reside inside the islets in the pancreas, alongside the beta cells that the immune system has attacked:

• Glucagon, produced by the alpha cells helps with the production of glucose by the liver to help avert hypoglycemia, among other things.

• Amylin, also produced by beta cells, works with both insulin and glucagon in cell receptors to aid in glucose stabilization.

• Somatostatin, produced by delta cells, inhibits the secretion of both glucagon and insulin to maintain glucose homeostasis.

• Pancreatic polypeptide, produced by the gamma cells, is an important regulator of glycogen storage in the liver, and enhances insulin sensitivity.

• Ghrelin, produced by epsilon cells, stimulates appetite and growth hormone release from the pituitary gland.

Each of these cells are integral to the larger constellation of signaling hormones that are essential to glucose regulation. One can’t just expect to regulate glucose by dosing insulin in response to blood glucose levels the way we expect a future automated insulin pump to work. And those are just the hormones inside the pancreas. Once you get into other areas of the body, the entire system gets even more complex.

This diaTribe article enumerates 22 factors that affect glucose levels that can affect even more hormone imbalances. Examples include things like medication, sickness, infections, poor sleep, or even the simple task of being a kid. (If you have a teenager, or have seen one on TV, you may have observed what happens when hormone activity goes awry. Now imagine their glucose levels.)

One thing that may sound too dumb to ask, but I’ll do it anyway: Why is it necessary to keep glucose levels low and stable? The short answer is, excess glucose can be exceedingly toxic, raising a paradox between choosing between two evils: too much insulin can be just as bad as too much glucose.

For instance, when blood glucose levels increase to 140-160 mg/dL (A1c of 6.5% and higher), proteins get too sticky (glycosylation), which obscures the narrowest part of the vascular system, beginning with the tiniest capillaries. Sticky proteins make it hard to deliver oxygen to tissues, leading to things like retinopathy (which leads to blindness), nerve damage, and other problems. This is why infections take a long time to heal.

As time passes, increased glucose levels affect progressively larger organs, such as the liver, kidneys, heart and vascular system. So abrasive is glucose to the lining of veins, it rapidly increases the risk of atherosclerotic cardiovascular disease (ASCVD), which happens to be the leading cause of death in America. Highly elevated glucose levels just accelerates the process. For T1Ds, it can reduce life expectancy by ten or more years, depending on years of exposure and levels of elevation, according to this 2016 article in the journal, Circulation, “The Prediction of Atherosclerotic Cardiovascular Disease in Type 1 Diabetes Mellitus.”

The toxic effects from glucose on the body explain why diabetes is defined as having a 90-day average glucose level at or above 140 mg/dL, because that’s when damage begins. When you think of it in these terms, a simple teaspoon of sugar in the bloodstream is healthy, but add another half-teaspoon, and things go awry.

By the way, when you think of the “normal” glucose range is 70-180 mg/dL, that’s because these are the levels found among the general population of non-diabetic individuals. Now that you know that 140 is where things go awry, why would a non-diabetic regulatory system allow levels to get to 180? And why is that “normal?”

The short answer is, it doesn’t want to! The metabolic system tries very hard to keep glucose levels lower, but again, our lifestyle choices overwhelm what the body is able to do.

Glucose levels under 140 is necessary to experience fewer complications and live longer lives. But few people can do that, and neither can the natural human body. The only way to achieve those levels is to work at it. (More on that later.)

With this context, let’s look at CGM patterns for non-diabetic adults, and get a closer look at what the body is trying to do to keep glucose levels stable.

Non-diabetic glucose patterns are problematic

One of the benefits of CGMs is the ability for researchers to get an accurate picture of the glucose patterns in otherwise healthy, non-diabetic individuals under various controlled and real-world conditions. Here’s a hint: It ain’t pretty.

This 2015 study from Stanford University involved healthy, non-diabetic subjects being given exactly the same food and activities at the same time each day for two weeks. And yet, researchers found large variations in blood sugar levels, as shown by the following chart of three individuals involved in the study. 

Three separate non-diabetic individuals who were given the same food at the same time each day

The study has been replicated over the years since, involving thousands of similarly healthy individuals, all with similar outcomes. The lesson we learn is that, even when under the most restricted control, glucose levels swing in volatile and unexpected ways among otherwise healthy non-diabetic individuals.

Naturally, one would expect that diet can adjust for such volatility, but, once again, it’s not that simple. It’s not just about glucose control or carbohydrate intake, but the availability of sufficient balance of carbohydrates, protein and vitamins. Each of these also has an effect on glycemic control, not just one. For example, consider this 4-day glucose patterns of a healthy non-diabetic on a ketogenic diet.

A healthy non-diabetic on a Ketogenic diet

Glucose variability (GV) is a direct byproduct of the metabolic system attempting to keep glucose stable against the turmoil of counter-regulatory hormones triggered by changes in diet, the environment, pathogens, and even just emotions. That very turmoil is itself unhealthy. In the study titled, “Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients,” the authors write, “… oscillating glucose can have more deleterious effects than constant high glucose on endothelial function and oxidative stress, two key players in favoring cardiovascular complications in diabetes.”

Since that study showed effects on non-diabetic subjects as well, all the more reason why T1Ds should be even more conscientious about their glucose variability.

Believe it or not, this is a good thing, because it also illustrates the metabolic system’s adaptability. As food types and sources change, the metabolic system adjusts itself to react accordingly. If it didn’t, we wouldn’t survive periods of famine, extreme heat or cold, running after (or away from) wild animals, or even the process of procreating. (Keep those hormones in check, dear reader.) But the whole thing is also a double-edged sword, too, and insulin is the culprit.

Why too much insulin is bad

Since we’re talking about insulin, let’s talk about why too much of it can also be bad, even for non-diabetics. While it’s essential for clearing glucose from the bloodstream, insulin is also the primary shuttle for excess glucose to be stored as fat. Yes, that ugly stuff.

There are many different types of fat, but the one we’re concerned about is visceral fat. This is not what you see around your torso or under the skin, nor is it in the foods you eat. It’s the type that surrounds internal organs, including the stomach, liver, kidneys, heart, muscles and intestines, and it’s made entirely because of insulin’s interaction with the GLUT4 transporter. As insulin clears out excess glucose from the bloodstream, it progressively builds more and more visceral fat, which leads to inflammation, and ultimately, a degradation of performance of all these organs. 

In the body’s attempt to keep the amount of visceral fat from accumulating, the fat becomes a primary source of insulin resistance, which again, is another wonder of the metabolic system’s adaptability, but also presents a flaw. The resistance keeps more fat from being made, but it also keeps that glucose in the bloodstream, which is also bad. It’s a no-win situation.

Ideally, the person would reduce caloric intake, but many people find that difficult, so as more carbs enter the bloodstream, the body makes more insulin (or the T1D injects it) which makes more fat, increasing insulin resistance, which then requires even more insulin to keep blood glucose levels down. As the feedback loop accelerates, we get to obesity.

This might make it abundantly clear now: If the natural body were so good at managing glucose levels, there wouldn’t be 40 million type 2 diabetics in America, with another 98 million undiagnosed.  Insofar as T2D is concerned, this feedback loop happens without any symptoms at all, because while that fat accumulates, blood glucose levels remain low and stable. Of course, because the non-diabetic body makes its own insulin, and so long as it can, then fat just accumulates by removing excess glucose.

The sad part is, T1Ds are following suit: As I’ve written before, T1Ds’ singular aim of lowering their A1c levels has resulted in their taking too much insulin, raising the rate of obesity and along with it, many of the same metabolic disorders as T2Ds. According to the Lancet article, “Obesity in people living with type 1 diabetes,” only 3.4% of T1Ds were obese in 1986, compared to 37% in 2023.

It’s easier to see insulin resistance in T1Ds because you can see how much insulin they take, and the rate of increase. Any T1D who’s overweight must have some degree of insulin resistance, and that’s very hard to reverse.

To foreshadow one of the main drawbacks of automated insulin pumps is that they cannot assess—or make a judgment about—insulin resistance. They can only look at blood glucose levels (via a CGM), and will do as told: Keep those levels lower by administering insulin, even if it generates more fat. And since pumps cannot detect any of the other hormonal activity going on, it’s going to err on the side of giving more insulin than less. Of course, the user can override that and keep target glucose levels higher, but then you’re going to have the problem with excess glucose: toxicity.

This is, once again, why the user must be engaged in their personal health. The best way to clear glucose from the bloodstream is physical exercise. It not only activates GLUT4 transporters on its own (with increased exertion), thereby reducing insulin requirements, but exercise also assists in converting visceral fat back into glucose so it can be used for energy. Exercise also builds new muscle fibers and mitochondria, which improves the volume and efficiency of glucose clearance from the bloodstream. Exercise can also reduce appetite (depending on aerobic fitness), making it easier to eat less, further reducing glucose, while improving cardiac performance, relieving stress on the liver and kidneys, improving sleep, emotions, and sexual health. (We’re adults here, right?)

Of course, we know that exercise isn’t that easy for anyone, much less T1Ds. Hypoglycemia (and the fear of it) keeps many from even starting exercise. It’s a complicated process, because insulin reduction rates vary, so one has to go about it intelligently. And automated pumps perform particularly badly with exercise, because they are not “adaptable” the way your body is; your past glucose patterns will definitely not apply to future outcomes. It just has to be done manually.

The best way to get started is remarkably simple: walk for 15+ minutes after meals. A tiny effort goes a long way. Most people who do this find their insulin requirements drop steadily. If they ramp up to faster walking or even light jogging, weight is reduced and glucose volatility drops too. From there, you might find that managing T1D isn’t actually “hard" (as it pertains to tasks). It’s just a matter of bothering to do it. You can read more about my journey in my article, “Why I Haven’t Died Yet: My Fifty Years with Diabetes.”