A1c and T1D Complications: What It Reveals, What It Hides, and How the Damage Actually Happens

The ubiquitous HbA1c test is an easy but highly fraught metric for tracking diabetes management, risks and outcomes.

We all know the drill. Before your next appointment you get an A1c test showing your average glucose over the last ninety days. Your doctor looks at it and says some version of: “Let’s see how we can get that lower.”

Naturally, as we all know, elevated glucose levels, which A1c tests can estimate, are associated with all sorts of complications, especially long-term ones like kidney failure, heart disease, retinopathy, and more.

OK, you ask. To what?

As it happens, it’s not that simple.

The ADA’s target is 7%, so that’s the ideal level, right?

Again, it’s not that simple. That number was derived from data that was, at the time, incomplete. Yes, aggressive dosing strategies did reduce some complications, but it also was found to introduce others. And those were worse.

Ok, so it’s a trade-off?

Sing along with me now: It’s not that simple. There doesn’t have to be a trade-off. One can and should reduce glucose levels, but the methods for doing so can — and more often than not do — make matters worse.

What most caregivers recommend these days include using an automated insulin delivery (AID) system, adjusting the basal rates and insulin-carb ratios to try to keep glucose excursions at bay, and/or try a low-carb diet.

Yes, that’s what you hear, and as it happens, all those lead to worse outcomes, according to decades of medical literature.

The problem with this story lies in a very fundamental principle of physiology that science has known for decades, but has not translated to T1D management. Yes, there is an association between elevated A1c levels and some complications, but the processes that actually cause harm do not lie with glucose alone—it lies long downstream of glucose in the body. Furthermore, while that association shows up in population-wide data, the rate of individual variability is so high as to make the connection nearly useless, largely because people have more control over those downstream effects than they realize.

The T1D management guidelines we live by are aimed primarily at driving A1c levels lower — more insulin, tighter automation, carbohydrate restriction — can lead to conditions that ultimately drive the real cause of complications: oxidative stress. Yes, glucose is a fuel source for it, but the process that causes harm lies downstream of glucose. And the A1c test doesn’t measure it.

If all this sounds confusing, it won’t be by the time we start getting into it. Yes, oxidative stress will be as familiar as your own A1c value, which you will similarly realize is as useful to as the speedometer on your car. Yes, you need it to know how fast you’re going, but it doesn’t measure the health of your engine and all the other essential fluids that make your car go.

The good news is that you have far more control over those downstream processes than you do over reducing glucose levels. It’s not that you should ignore glucose levels at all. Far from it. But you need to do so with techniques that don’t cause the underlying harm. In other words, modern T1D management is so hyperfocused on A1c levels, they forgot that the methods for reducing glucose levels may win the battle, but lose the war.

In short: the best T1D management should not involve A1c levels as “targets”, because that’s what makes people unaware of the damage they’re doing to achieve it.

It may sound simplistic to hear it now, but the real goals should be physiologically balanced insulin levels, carbohydrate consumption, lean body weight, and low LDL (cholesterol) levels. These will come up again when we look at the long-haulers—those who’ve had T1D anywhere from 50-80 years. They’re not only alive, but have unexpectedly varied A1c levels, ranging from 5% to 14%. There’s no correlation at all between A1c and complications at the individual level.

If this feels like a radical paradigm shift in T1D management, rest assured that what is not new is that the physiology associated with all these processes has been known for decades and published in medical journals. By adding attention towards oxidative stress, we can both reduce the incidents of complications, while also slowing down those that are already underway.

Because of the chemical and physiological complexity, I want to lead with an analogy. Let’s start with a bicycle.

T1D and the Art of Bicycle Maintenance

Let’s say you have a brand new bicycle. You’re riding around, and it happens to start raining. That rain is like glucose. It lands on the metal and sits there a bit, but if you wipe it off, the metal is dry again. That’s the goal of keeping your A1c levels lower. Keeps the metal dry.

But you can’t get all of it because the water also seeps into the seams where it’s hard to get to. The air also has ambient moisture. And diabetes is like living near the ocean, where there’s not just a lot of air, but salty air. You can wipe down the metal, but the ambient moisture gets into those nooks and crannies that you can’t reach. And that’s where things matter., because over time, it starts to rust.

Those are three stages: water on the surface, water in the seams, rust.

That last stage is the oxidation process, because the chemicals in the metal mutate into something new and different: rust. And once in that state, it’s permanent. It’s no longer water that you can wipe away. Worse, it spreads. That chemical process turns into a feedback loop, eating all the metal next to it. That’s the insidious nature of spreading oxidation.

But it’s such a slow process that it takes decades before the bike starts falling apart. In many cases, you’ll ride your bike for decades before the seat stem breaks and you fall off. The rust destabilized the structure, but until it gives, you don’t know. And no one is measuring it, or teaching you how to avoid the rust.

The A1c test tells you how much water got into the seams, the second stage. It doesn’t tell you whether any of the harmful oxidation happened, nor does it tell you whether it will. In fact, what it measures isn’t permanent at all — water in the seams can still dry out. It’s the rust that’s permanent, and the rust is the one thing the A1c can’t see.

That may be useful in some minor ways for an individual, because it reveals how well you’re wiping the water away. But that’s just a short-term indicator, and it’s also deceptive because it turns out that the methods you’re using to try to keep the rain at bay — even avoiding being in the rain in the first place — may actually accelerate rusting. You may be pushing water into those seams by mere inattention.

You can see this rust in your connective tissue — the purest cases — like frozen shoulder, dupuytren’s contracture, trigger finger, carpal tunnel, stiff hands that won’t flatten against each other, plantar fasciitis, and achilles problems. That’s all rust. At least, the more visible part. It’s in invisible rust you can’t see that does the damage: vascularature, organs, other tissues.

Yes, those all happen to non-diabetics too. But it’s earlier, faster, and more aggressive with us because we’re living by the ocean with that constant, damp, salty air.

In our bodies, the process is called oxidative stress.

To be clear, oxidative stress is intrinsic to life. This is why people age, develop complications, and eventually, well, you know what comes next.

That oxidative stress is rooted in oxygen, but not the kind you breathe. It’s an unstable version of it, called reactive oxygen species, or ROS. They’re a normal byproduct of being alive, and that starts getting to the core of this topic. Oxidative stress is what we call it when there’s more ROS than your defenses can neutralize.

Your goal should be to neutralize the ROS, not amplify them, and the good news is that your body has ways to neutralize or clear ROS from your system. That’s what T1D management should focus on, but doesn’t. Instead, the management we’re using — more insulin, low-carb diets, pumps — either directly or indirectly add more ROS, overwhelming your defenses. Visceral fat, insulin resistance, and a whole series of downstream metabolic disorders that generate more oxidative stress are all building rust and allowing it to permeate our bodies.

You’re probably thinking, why not just take antioxidants? Vitamin C, vitamin E, the whole shelf at the pharmacy. It seems like it should work.

It doesn’t. A Cochrane review pooled 78 randomized trials covering 296,707 participants, and among the 56 trials with a low risk of bias, antioxidant supplements didn’t reduce mortality — they nudged it upward. People taking beta-carotene and vitamin E had roughly a 3-5% higher chance of dying during the study period. Vitamin C and selenium showed no effect at all, in either direction.

Those are small numbers, but notice that, among nearly 300,000 people, the best case for antioxidant supplements is that they do nothing.

The reason turns out to be that ROS aren’t only waste — they’re also a signal. When you exercise, your muscles generate a burst of them, and that burst is what tells your body to build more of its own defenses. Ristow and colleagues showed this directly: four weeks of training improved insulin sensitivity in men taking nothing, and didn’t in men taking vitamin C and E. The supplements blocked the rise in the body’s own antioxidant enzymes.

That’s the benefit of exercise: It reduces the oxidative stress that happens downstream of the A1c. Aerobic exercise in particular upregulates the body’s far more effective enzymes that stave off the rust.

What all the above have in common is insulin. After all, that’s the tool we use to manage glucose levels. Let’s take a closer look.

Insulin and the Goldilocks Effect

The first thing to know is that insulin is biphasic. That means it’s beneficial at physiologically balanced levels — too much or too little is bad. One of insulin’s many functions in the body is a vasodilator, which means it relaxes blood vessels, giving them plasticity.

A non-diabetic pancreas produces roughly 25 units a day for a physiologically weight-balanced person (not over or underweight). So 35–40 in a T1D is about 1.5× physiologic — which is what you’d expect given subcutaneous delivery, since you’re dosing to peripheral effect without the portal first-pass extraction a real pancreas gets.

One of the most important beneficiaries of insulin is the endothelium, the lining that protects your organs and arteries. It’s like the paint on the metal. Insulin stimulates nitric oxide (NO), which protects the endothelium, not just on the surface, but in the nooks and crannies — the parts you can’t wipe away.

Excess insulin becomes a vasoconstrictor, causing tissues to stiffen and weaken. It’s like the paint peeling off, exposing the metal to the elements.

When you take too little insulin, there’s not enough production of NO to achieve the vasodilation effect.

Either way, when the endothelium is affected, loss of paint allows the bad agents to enter. Hence, maintaining a healthy endothelium should be a priority, so balanced insulin levels should be prioritized. And no endo will ever explain or prescribe that.

Insulin Resistance: The Main Driver of Oxidative Stress

Another problem with excess insulin is that it’s a storage mediator, promoting fat accumulation and weight gain. But it’s not just that there’s a lot of fat. It’s that individual fat cells become engorged — a state called hypertrophied adipose tissue — and as they enlarge, they outgrow their own blood supply and go hypoxic.

Oxygen-starved tissue looks, chemically, like injured tissue. So the body responds the way it responds to injury: it recruits macrophages, the white blood cells that fight infection. They arrive and turn on the same respiratory-burst machinery they’d use against a bacterium — a deliberate burst of reactive oxygen species, or ROS, meant to destroy an invader.

The problem is there’s no invader. Nothing gets resolved, so the response never shuts off. It just runs, quietly, for years.

That’s the generalizable pattern, and it’s worth holding onto: any tissue running a chronic, low-grade immune response with nothing to resolve.

And here’s where it turns on you. The inflammatory signals those macrophages release interfere with insulin’s ability to communicate with the fat cell. Not a wall the cell puts up — the message simply stops getting through. That’s insulin resistance. The glucose stays in the bloodstream, so more insulin gets recruited to move it somewhere, anywhere that will take it.

Which promotes more storage, more hypertrophy, more hypoxia, more macrophages, more ROS. The loop feeds itself, and the oxidative stress compounds year over year. Add a damaged endothelium and you have the conditions underlying nearly every diabetic complication.

That’s the generalizable pattern: any tissue running a chronic, low-grade immune response with no infection to resolve.

And yet, your endo wants that perfect A1c number, unaware of the oxidative stress being imposed on you in order to achieve it.

With that conceptual overview, let’s look at all this from the clinical level and understand how we got here, what we can learn from it, and what we can do to fix it, beginning with the A1c test itself.

What the A1c Reveals and What it Hides

The NIH paper, HbA1c Standardisation: History, Science and Politics, explains how the A1c test was developed around 1977, but it sat for about a decade until the procedure was standardized in the mid-1980s.

The key to understanding the A1c is that it doesn’t measure your blood sugar. It measures how much of your hemoglobin — the protein inside red blood cells that carries oxygen — has glucose stuck to it. That’s called glycation, and everything that follows starts there. That’s the water in the seams. It’s not rust yet.

But note: this glycation is on hemoglobin, and hemoglobin turns over every few months. Glycated hemoglobin doesn’t harm you. What harms you is glycation on tissues that turn over slowly or not at all — collagen in your joints, your skin, your artery walls. The A1c doesn’t tell you about any of that.

Nevertheless, there’s a reasonable inference to draw: if your A1c is consistently high over time, glycation is presumably happening everywhere else too. So researchers put that assumption to the test in the first trial ever to use the A1c — the Diabetes Control and Complications Trial (DCCT), from 1983–1993.

The findings established that high glucose levels (measured by A1c tests) directly correlated to microvascular complications, such as retinopathy (leading to blindness), kidney disease, and neuropathy. As a group, people with lower A1c suffered fewer of these complications, and the group with higher A1c levels had worse outcomes. A follow-up analysis — the DCCT/EDIC — showed that aggressive insulin therapy produced a 42% reduction in cardiovascular events, 57% for major ones, and the benefit still held thirty years out.

The data was the first time a test could be used to actually set guidelines for T1D management. Since the cohort in the DCCT intensive-therapy arm achieved ~7.2%, the American Diabetes Association (ADA) recommended an A1c of 7% as the target with aggressive insulin therapy as the prescribed path. Follow-on guidelines would later expand to include the 50/50 rule for basal dosing, low-carb diets and other interventions.

But it came with costs that wouldn’t be considered seriously for decades: roughly triple the rate of severe hypoglycemia, and substantial weight gain. Participants who gained the most weight developed the lipid and blood pressure profile of those with insulin resistance syndrome, one of the largest contributors to oxidative stress.

Despite the fact that all this was eventually learned, it was too late: that the association between A1c and complications was baked into the guidelines.

So, if complications aren’t being driven by glucose alone, then what?

Advanced Glycation End-products (AGEs)

Remember the bicycle and the three stages of rust. Water, seepage, rust. Same thing with glucose.

The first stage is glycation, which happens when glucose attaches loosely to proteins. This is called the Schiff base. Then it rearranges into stable early stage complexes called Amadori products — this is HbA1c. Then, over months and years, a fraction of those mature into irreversible cross-linked Advanced Glycation End-products, or AGEs.

But that only happens where there’s oxidative stress to drive the conversion. That’s the step that turns the water lying in the seams into rust, and it’s the step that varies enormously from person to person.

The fact that there’s a fraction of a fraction from what the A1c measures isn’t as important as the fact that each fraction is highly variable and inconsistent because they only happen when exposed to particular conditions, some of which are actionable. That’s the part where inventions can and should happen.

Read that carefully: Your A1c could measure X number of glycated proteins, but your lifestyle choices and other interventions might keep many of them from becoming oxidized AGEs. Or, worse, you could engage in things that make more of those oxidized AGEs.

Accordingly, you could have two individuals with the same A1c, and yet, their management protocols with T1D could yield vastly different risk profiles.

Now look at these effects as a group: excess weight, cardiovascular disease, and eventually, kidney damage. Those aren’t three separate problems that happen to co-occur. They’re three expressions of insulin resistance and the sedentary metabolism that produces it. That means there’s potentially ONE intervention that can stave off AGE production, and we’ll see them in four separate biomarkers.

And the perfect place to look is in people who’ve had T1D for 50 to 80 years.

Long Term Correlation between A1c and Complications

The Golden Years Cohort, a group of 400 T1Ds in the UK who’ve had the disease for over 50 years, had a mean A1c of 7.6% (± 1.4). The Joslin Medalists, American T1Ds who’ve also had the disease for over 50 years — with some now passing 80 years — had an average current A1c of 7.3%. In fact, a 73-person longitudinal subgroup followed for 15 years had an A1c of 7.7%.

Across the full cohort, individual A1c values ranged from 5.0% to 14.0%.

An A1c of 14%! Imagine what your endo would tell you if they saw that.

Now let’s look at who got complications.

The paper, Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the Joslin 50-year medalist study (Sun et al., Diabetes Care 2011;34(4):968–974), examined 351 Medalists, mean age 67.5, mean duration 56.5 years, HbA1c 7.3 ± 1.0%.

After more than fifty years with T1D, here's how many of them had no sign of each complication:

• Kidney disease: 87% had none

• Cardiovascular disease: 51%

• Proliferative retinopathy: 43%

• Neuropathy: 39%

Yeah, there are complications, but what’s striking is that glycemic control didn’t predict who got the complications. The researchers also measured AGE levels directly — in blood samples from the same people, at the same time — and found that A1c predicted nothing, while AGE levels predicted a seven-fold difference in the odds of having complications.

Set that against what happens to everyone else. Among Americans 65 and older, 34% have chronic kidney disease. Among the Medalists who, after fifty years of type 1 diabetes, only 13% had nephropathy. Their kidneys were in better shape than their non-diabetic peers.

Nerves tell a more complicated story. Around 27% of adults over 70 have measurable peripheral neuropathy; among the Medalists it was about 61%. Elevated, but roughly one and a half times the background rate — not the catastrophe five decades of diabetes might predict.

We can’t compare diabetic nephropathy and chronic kidney disease to the general population because they’re diagnosed differently, and cardiovascular disease is defined so many ways the numbers stop meaning anything. But the shape is clear enough: these people did not simply survive their diabetes. Many of them aged better than the population around them.

And glycemic control didn’t explain which ones.

This brings us back to what’s under your control.

What all these people had in common was good metabolic health, normal weight, physiologically balanced insulin requirements, and crucially, low lipid levels. A1c levels is not in that list.

And of that list above, what they have in common is low insulin resistance. That’s the major driver of oxidative stress. Which is how two people with the same A1c can end up in completely different places.

We spoke about the biphasic nature of insulin — too much or too little is bad — so now let’s look at how that translates to complications.

Adiposity and Insulin Resistance

As noted earlier, insulin drives fat storage. If you’re taking too much insulin to drive down A1c, you’re likely consuming a great deal more carbs than you want to either avoid or treat hypoglycemia. That fat storage builds weight gain around the middle, particularly visceral adiposity — the fat packed around your organs, not the fat you can see or pinch. That’s what leads to insulin resistance (IR). It’s metabolically active tissue that generates a continuous oxidative and inflammatory signal. There’s your villain right there.

IR is a classic symptom of type 2 diabetes, so when it also happens to type 1s, it’s called double diabetes.

In a meta-analysis titled, “Obesity in Type 1 Diabetes: Pathophysiology, Clinical Impact, and Mechanisms,” obesity in adults with T1D rose from 3.4% at baseline (1986 to 1988, prior to the DCCT) to 22.7% in 2004 to 2007, the direct result of the aggressive insulin guidelines that resulted from the DCCT.

By March 2023, a study titled, Prevalence and Management of Obesity in U.S. Adults With Type 1 Diabetes (Johns Hopkins/CDC NHANES data) found that 62% of U.S. adults with T1D were overweight or obese.

Weight gain is a direct result of overinsulinization, and according to section 9.27 of the ADA’s 2025 guidelines, the primary cause of that is overbasalization — people setting their basal rates too high on pumps, or taking too much basal insulin. This is a long and deep subject that I cover more thoroughly in a four-part series starting with Basal Insulin and its Effect on T1D Management and Long Term Complications.

These all lead again to the goal of chasing down A1c levels.

A Second Road to the Same Place

Everything above blames insulin — too much of it drives fat storage. But there’s another factor on weight management that is an accelerant that you can have greater control over if you know about it: fructose.

Table sugar is half fructose, and so is the high-fructose corn syrup in soda and juice. Unlike glucose, fructose goes almost entirely to the liver, where it’s processed without the regulatory brake that governs glucose. What the liver mostly does with the result is make fat. Unlike glucose, which goes through a number of pathways before it becomes fat, fructose takes the shortcut.

In a ten-week trial, overweight adults drank either fructose-sweetened or glucose-sweetened beverages providing a quarter of their daily calories. Both groups gained about the same weight — but visceral fat increased only in the fructose group, along with their insulin resistance and their oxidized LDL.

Think about that for a moment: the same number of carbs, but one of those carbs is converting to fat more than the other.

Think about the proverbial juice box that many T1Ds use to treat or avert a hypo. Apple juice — the one in most boxes — is roughly 70% fructose once the sucrose splits. A 200 mL box labeled 23 grams of carb hands you about 7 grams of glucose that treats the low, and 16 grams of fructose that doesn’t.

The fructose isn’t gone, though. It goes to your liver, and about 40% of it comes back out as glucose over the next three to six hours. So the shape of the thing is: too little up front, then a slow release you never bolused for, arriving long after you stopped paying attention.

So when you give your kid (or yourself) that juice box — or most any fruit juice or a product with high fructose corn syrup — you’ll notice the box doesn’t work fast enough. You drink a second one. Maybe a third. Your glucose levels rise again, but hours later, you’re at 220 and you blame yourself for over-treating. Know that good part of was from the first box, still being converted. Depending on how many boxes you drank, you’re going to get a stack of glucose spikes along the way.

Depending on how many lows you’re treating, you’re not just absorbing a lot of carbs, you’re taking in carbs that convert to fat at a much higher rate. This is the fast-lane to insulin resistance.

None of this means treat lows less aggressively. Treat the low, always. It means glucose tabs or dextrose do the job faster, dose more predictably, and skip the liver entirely.

So that’s insulin resistance. Now let’s talk about your arteries, the source of cardiovascular disease.

Lipids and Insulin

In my article, Extending T1D Longevity: Balancing Lipids, Insulin, A1c, I cite the primary cause of death for T1Ds as being Major Adverse Cardiovascular Events — or MACE. These include heart attacks and strokes, triggered by vulnerable plaques in artery walls that have built up over time from high LDL cholesterol.

LDL is a low density lipoprotein and its job is to deliver cholesterol to cells throughout the body. Because LDL is a protein, you know what sticks to it: glucose. The more LDLs there are, and the longer they circulate, the more they oxidize. And you know what that is: AGEs.

Now put the two together: dysfunctional endothelium allows those oxidized glycated LDL particles to attach to the arteries. Cue the inflammatory immune response, and now you have the “plaque” that narrows artery walls.

You have the explosive and you have the fuse. Now you just need a spark, which can be an acute hypoglycemic event. Hypoglycemia isn’t killing T1Ds by starving the brain of glucose; autopsies don’t show that. What it does is trigger the counter-regulatory cascade — adrenaline, cortisol, a spike in blood pressure and heart rate — and that surge is what can dislodge vulnerable plaque that’s already been built up over decades from high LDL and chronic insulin exposure.

Think about how often T1Ds get acute hypos, what’s called Level 2 events. A six-trial analysis of 1,433 T1D participants found median time below 54 mg/dL to be 1.5 to 10 minutes a day. Over a year: 9 to 60 hours below 54. Other studies show similar findings.

That’s a lot of opportunities to die of a stroke or heart attack if you’re a T1D with elevated LDLs and endothelial dysfunction, not to mention oxidative stress from IR.

It’s that amplification that the medical system doesn’t treat properly.

Two people with LDLs of 80 mg/dL aren’t running the same risk if one of them has spent thirty years with elevated glucose levels.

I’m going to step out of character here in order to emphasize what I believe is the most important thing a T1D can do at their next endo appointment.

If your LDL comes in at 80 and your endo says, “that’s in the safe zone”, ask them if they’re familiar with how AGEs and endothelial dysfunction correlate to cardiovascular disease. If not, sit them down and have a hard stern talk — you know, the same kind they give you when they see your A1c elevated and they want you to raise your basal rates that led to this problem in the first place.

Ok, I’m back to my calm and collected self.

Statins are the foundation of lipid therapy, blocking cholesterol synthesis in the liver and typically reducing LDL by 30-50%. They’re well-tolerated, inexpensive ($4-20/month generic), and have decades of safety data.

There’s a lot of misinformation about statins online, and the muscle-pain question deserves a direct answer. The SAMSON trial enrolled 60 people who had already quit statins because of side effects, and gave some a placebo and others the statin. By the end, placebo didn’t show a meaningful difference. When those very participants were shown their own data at the end, half went back on a statin.

PCSK9 inhibitors (evolocumab/Repatha, alirocumab/Praluent) are the most powerful option, reducing LDL by an additional 50-60% on top of statins. The FOURIER trial followed 27,564 patients who achieved median LDL levels of 30 mg/dL, translating to a 15% reduction in major cardiovascular events and, critically, continued benefit down to LDL levels as low as 10 mg/dL with no safety concerns. The VESALIUS-CV trial in NEJM studied 12,257 randomized participants, producing a 25% reduction in major cardiovascular events and a stunning 36% reduction in myocardial infarction.

The benefit was consistent across all subgroups, including those with diabetes.

Clinical guidelines for diabetics should be far more aggressive with lipid-lowering medications than non-diabetics. When it comes to LDLs and AGEs, there is no safe level.

Some might be thinking that you can reduce LDLs using a plant-based diet. Mechanistically, yes. Saturated fat suppresses the liver’s LDL receptors so that less LDL gets cleared from the blood. Therefore, replacing animal protein with plant protein lowers LDL. Eating more beans, oats, and vegetables and less processed meat is a good idea for reasons that have nothing to do with this article.

The question is not whether diet lowers LDL. It’s whether diet lowers LDL enough given what our LDL is doing. Remember, the amplification of damage from each LDL particle means we need vast reduction, not just the modest amount that diets can provide. For extensive detail on plant-based diets and their effect on LDLs for T1Ds, see my aforementioned article, Extending T1D Longevity: Balancing Lipids, Insulin, A1c.

You might be reading this and thinking: low insulin levels, low body weight, and low glucose levels… I know the answer: low-carb diets! Surely, they’d do the trick!

Nope. But there is a fascinating nuance worth observing.

Low-Carb Diets

As it happens, low-carb diets can actually make the problem worse, but from a different physiological angle. When carbohydrate intake drops too low, the body mobilizes stored fat for energy. Whatever it can’t burn gets repackaged into VLDL particles that get shipped back out into the bloodstream. VLDL delivers its cargo, shrinks, and becomes the LDL we’ve been discussing.

You just accelerated and amplified the same LDL problem as before.

Not only do you have far more LDL to deal with, you have the insulin problem as well, but this time, in reverse. Insulin relaxes blood vessels (vasodilation) at physiologically balanced levels. But if you don’t get enough insulin, you have vasoconstriction, which leads to the same endothelial dysfunction that we saw from insulin resistance.

The protective paint falls off.

In the literature review, Low-carbohydrate diets and all-cause mortality: a systematic review and meta-analysis of observational studies, the highest-restriction quartile in these cohorts — still well above Bernstein levels (<30g/day) — had the highest risk of overall mortality (32% increase), cardiovascular disease mortality (50% increase), and cerebrovascular mortality (51% increase).

Now, this is not to suggest that low-carb diets are bad, per se. They are effective for weight loss, which is incredibly important — adiposity and insulin resistance are long-term, deleterious conditions. More importantly, diets should be temporary. There’s a distinction between using low-carb to lose weight versus keeping A1c levels low. One can save you, the other can harm you.

I mentioned that time-limited actions are a reasonable trade-off, but let’s widen the lens here. What kind of timelines are involved in all these processes?

Time Horizons

Building up AGEs in your body takes decades, not months, or even a few years. Your body can tolerate several years of elevated glucose levels, lipids, low-carb diets, and many other assaults to a point. This is not permission to do it, but it is important not to get too caught up in the risk profiles and induce psychological stress or other anxieties (which can also increase AGE production). But of course, there’s also what glucose itself can do that we need to recognize.

A1c levels above roughly 9% carries its own risks independently of AGEs: opportunistic infections, poor wound healing, selective neuropathy. Of course, duration plays a big factor in how fast and how severe each of these occur. Nevertheless, bringing glucose down is the priority, even by accepting more insulin to do it. This is often true of type 2 diabetics as well. Getting glucose levels out of the severe danger zone is a reasonable trade, but you should aim for this to be like weight-loss: a temporary measure with the goal of tapering off.

A1c between 7–8% flips the picture. Glucose is present but not overwhelming, and what separates good outcomes from bad ones is almost entirely the AGEs process: oxidative burden, insulin resistance, lipids, fitness, smoking. If you engage in these other factors, then you’ll confer both protection, and the likely byproduct of your A1c falling. But this time, in healthy ways.

It should be noted that here is where the ADA 7% target can be problematic, and it applies to both T1D and T2D patients alike: Throwing insulin at the problem to reach that target may be causing more harm than good. It’s here where other methods of lowering glucose levels is healthier, such as even the most modest amount of exercise. Metabolic health should be prioritized over insulin as a part of daily management.

A1c below 6.5%. The question stops being your number and becomes what else is going on. If you’re exercising, and your body weight and insulin levels are physiologically healthy, you’re far better off than someone with the same A1c, but has high insulin levels, is overweight, or is on carbohydrate restriction.

As a general rule, intermittent stretches of elevated A1c won’t do much harm. Two years at 8% during college, against sixty years of exposure, is a small fraction of your lifetime exposure.

And a few days here and there where your glucose spikes to 400 may have some immediate repercussions, but you’re not going to suddenly raise your risk of a heart attack or neuropathy due to a sudden growth of AGEs.

One factor that is not part of any health guideline at all, and which addresses all of these things in the healthiest and easiest way is improving your metabolic health, which you may recall was the first of the items in the list of four commonalities that the long-haulers had in common.

Metabolic Health

Metabolic health is a catch-all category that includes a number of different biomarkers that affect the body’s ability to convert fuel into energy. The full picture is beyond the scope of this article, but the lever that moves it is exercise.

Of the many different kinds of exercise, we’re primarily interested in cardiorespiratory fitness, which involves high aerobic activity, like running, cycling, rowing, and more. As stated earlier, this level of activity helps reduce the oxidative stress that contributes to the production of AGEs. That is, aerobic fitness interrupts the transition from stage 2 to stage 3 AGE production.

And again, we can see this in longitudinal data. A paper from Mandsager involved 122,007 adults between 1991 and 2015. They found that the more physically fit people were, the longer their lifespan, even in the presence of other comorbidities, such as hypertension, coronary artery disease, or even smoking and diabetes.

In fact, the positive effects from good cardiorespiratory fitness were so disproportionate after factoring in these comorbidities, they found there was no greater predictor and protector of all cause mortality than cardiorespiratory fitness.

Two people with the same A1c can have vastly different risk profiles for complications if one of them is sedentary and the other has high cardiorespiratory fitness.

The devastating part is not just that it’s another reason why A1c is a poor predictor of complications, but the hyperfocused drive towards lowering A1c puts T1Ds at risk because they don’t know how to exercise and manage glucose levels at the same time. In fact, fear of hypoglycemia (FOH) is the leading reason why most T1Ds don’t exercise, according to the literature review paper, Fear of hypoglycemia, a game changer during physical activity in T1DM. So, they choose not to exercise.

As you can see, this is not only complicated, it’s highly individualized, and often is contrary to conventional T1D management.

Note: it may not necessarily be a good idea to immediately jump off the couch and start running, especially if you’re overweight and have high LDL levels. Going from a sedentary lifestyle to full-on aerobic exercise requires managing the drawdown of weight, and incremental building muscle mass and learning proper insulin dosing.

But a very good place to start for anyone is the simplest of tasks: a 15-minute walk once or twice a day, preferably after meals. That begins two critical things: habit-building, and a tapered reduction of post-meal insulin dosing, a technique that you need to learn to master manually.

The simple act of walking can reduce risk of complications considerably. According to the paper, “Walking for Exercise,” from Harvard’s School for Public Health, this simple process can improve your lifespan by several years (not to mention quality of life).

So, why is the medical system so hyperfocused on A1c, despite all this evidence?

Actually, there’s a sad, but understandable reason: because it’s easy.

Current Guidelines

In my article, Standard of Care: Who Defines it, How, and Why it Matters, I cite a report by The American Diabetes Association that comes down to this: physicians don’t have the time, expertise, or training to teach people how to manage all the various aspects to the disease.

I can’t sugarcoat this (er, so to speak) to say there’s an easy solution. As I used to teach my students, “if it were easy, everyone would do it.” As I said at the top, there are two separate, orthogonal objectives: teaching how to manage glucose levels, which is insanely complex, and teaching metabolic health, which is also complex. And both of those are highly individualized — you cannot and should not adopt population-wide methods to individuals.

That’s puts the medical system in a bind. The ADA sets guidelines for those very physicians, and the nature of the disease is complex. But the one thing abou the A1c target is that it’s easy. It’s a simple number, it’s a target, and the complexity can be somewhat alleviated by automated insulin delivery (AID) systems — insulin pumps that do all that work.

The insidious problem with that is similarly less obvious. In my article, Medical Literature Analysis: The Performance Paradox of AID Systems, I cite medical literature that finds that, while many people who are unable or unwilling to care for themselves do very well with automated systems (compared to how they could do on their own), otherwise capable adults suffered from these problems: weight gain, loss of agency, de-skilling of self-management, limitations on efficacy, quality of life, economic impact, and the “attractive nuisance” of disengagement from self-management.

We already know the problem with weight gain. But worse, the de-skilling of self-management skills and the loss of agency handicap these people because they lost the skills to know how to wean themselves off of automation to self-manage properly again (assuming they ever knew). They’re stuck in that system.

And worse, T1Ds typically adjust their lifestyles to meet the expectations of pump algorithms. A 2022 review of AID’s psychological implications — Nefs, Frontiers in Clinical Diabetes and Healthcare 2022 — documented exactly these dynamics.

AID systems users actively restructure their lives to produce the numbers the algorithm rewarded: eating predictably, avoiding unannounced snacks, and — most consequentially — reducing or eliminating exercise that would introduce glucose variability the algorithm couldn’t handle.

Sedentary and overweight — the perfect storm.

Calgon, take me away!

GLP-1s and T1D

Lastly, people are certainly aware that GLP-1s help with insulin resistance and insulin requirements. Lots of data coming in already on how it helps lower weight, reduce insulin resistance and improve A1c. But they can also make exercise harder to manage.

These two points are essential and they go together. Yes, they reduce insulin resistance and insulin requirements, but it’s only one arm of the problem — reducing some sources of oxidative stress. You also need to address the stresses that already exist, and which continue to occur as a natural process of metabolism.

That’s where exercise is essential: it makes your body build its own antioxidant defenses, and that adaptation is the thing nothing else replicates.

But exercise also builds muscle mass, bone density, balance, aerobic capacity — the things that no drug will deliver. If GLP-1s become the next AID system, insofar as how they may be perceived as a game-changer, it may also follow the same path of creating more harm over time than intended.

I’ll write about that in ten years, when the trial data comes in. And I’ll be here to do it because... well, I exercise.

So what’s my risk?

This is the question everything above is building toward, and the answer is unsatisfying in a specific way: there isn’t one number. There is no such thing as your glycation status. AGEs build up in different tissues at different rates and times. Some are entirely protected from some, while highly vulnerable in others. But we do characterize these as being different “compartments”. There’s a retinal one, a kidney one, an arterial one, and a connective-tissue one, and they run more independently than most assume.

Remember the Joslin 50-Year Medalist Study, which examined 762 people who had lived with type 1 diabetes for fifty years or more. Among them, 49.4% had no proliferative retinopathy, 86.9% had no nephropathy, 39.4% had no neuropathy, and 51.5% had no cardiovascular disease — but only 21.2% were free of all three microvascular complications. Most people in that cohort were protected somewhere and unprotected somewhere else. The retinopathy numbers were also bimodal: about 40% had no or mild disease and about 48% had proliferative disease, with few people in between. That shape suggests retinal protection is closer to a switch than a dial.

The compartments diverge because the damage mechanisms differ. Retinal capillaries are injured by a specific vulnerability: the cells lining them take up glucose without needing insulin and, in susceptible people, can’t turn that uptake down when blood glucose rises. The coronary arteries aren’t damaged that way at all. There, glycation drives a slower structural process — modified proteins accumulate in long-lived arterial collagen and elastin, and the smooth muscle cells in the vessel wall begin behaving like bone-forming cells, which is what a calcium score is measuring. The stiff hands, frozen shoulders, and contractures that show up after decades of type 1 are the same category of process in a different tissue: crosslinks accumulating in matrix the body barely replaces. Capillary failure and matrix remodeling are different diseases wearing the same name.

This is also why two people with matching A1c charts end up in different places. The rate at which glucose becomes permanent damage depends on things that vary between individuals and that nobody measures in clinic: how efficiently you detoxify methylglyoxal, the most reactive of the glucose byproducts, using an enzyme whose activity declines with age and which needs antioxidant reserves to work; how fast the proteins in a given tissue turn over, since crosslinks only accumulate where proteins live long enough to collect them; how well your kidneys clear these compounds, which creates a loop where early kidney damage accelerates everything downstream; and how much of the load arrives preformed in food, since high-heat cooking generates these compounds directly. Exercise appears to help on several of these fronts at once. None of it is measured, and all of it varies.

That this matters is not speculative. In DCCT/EDIC, skin collagen samples taken in 1993 predicted the next decade of retinopathy and nephropathy progression — and the collagen panel predicted better than the participants’ own mean A1c during the trial (Genuth et al., Diabetes, 2005). In the cardiovascular follow-up, skin markers predicted carotid artery thickening even after adjusting for A1c during both the trial and the follow-up period (Monnier et al., Cardiovascular Diabetology, 2015). In the Medalist cohort, current and 15-year glycemic control were unrelated to who had complications, while two glycation markers carried a 7.2-fold association. A1c is a real and important number. It is not the whole exposure, and in long-duration type 1 it may not even be the best available predictor.

So you assess your risk one compartment at a time, using tests you probably already have. Your dilated eye exam is a direct optical view of small vessels — the only place in the body where capillaries can be seen without a biopsy.

Urine albumin-to-creatinine ratio and the trend in your eGFR cover the kidney.

For arteries, a coronary calcium score (CAC) gives you an actual number for that compartment; a carotid ultrasound measures a different vascular bed and shouldn’t be read as a coronary result. Arterial stiffness testing, if you can find someone who does it, is the closest thing to a direct functional readout of crosslinking. The tests that measure accumulated glycation itself — skin autofluorescence readers, collagen biopsy panels — exist but are largely research tools or European clinical devices, which is a real gap.

And a clean result tells you about the tissue it examined and nothing else. Thirty years without retinopathy is good news about your retina. It is not a certificate for your coronary arteries, and the Medalist data says plainly that it shouldn’t be read as one.

Which is why the LDL argument doesn’t depend on any of this

In my separate article about lipids and T1D, I highlight an important aspect to this that deserves restating here: our arteries are more vulnerable than a non-diabetic’s at the same lipid level. But strip the glycation story out entirely and the case for lowering LDL is unchanged, because atherosclerotic cardiovascular disease is the leading cause of death for essentially everyone, diabetes or not. Apolipoprotein-B-containing particles are causal in that process — the evidence comes from genetics, where variants in many independent genes that lower LDL lower cardiovascular risk lifelong and in proportion to the reduction, and from trials, where every 39 mg/dL of LDL reduction cut major vascular events by about 21% with no threshold in the range studied (Cholesterol Treatment Trialists’ Collaboration, The Lancet, 2010).

Glycation raises our target. It does not create the reason for the target. Those are two separate arguments and they stack.

To Be Healthy, Get Back to Basics

We covered a lot here, but the irony to this story is that what works is getting back to basics. We long-haulers couldn’t test glucose levels or use any modern technology at all. We simply adhered to the basics of good health: eat well, get good sleep, go outside and play, and keep weight down.

I’m not aiming to oversimplify to tell a story; that’s just the truth that we had at that time. Today, we have more and better technologies — both devices and drugs — but the principle of physiology haven’t changed. It’s how you use them that matters.

In my article, The Four Habits of Healthy T1Ds, the first thing I explain is that, before you can become healthy, it requires a frame-of-mind: engage with your diabetes, don’t put it in the background. You don’t need goals or targets. Targets are distracting at best and dispiriting at worst, and either way they pull attention away from the things that work:

• Familiarize yourself with your glucose patterns.

• Split your boluses, and act on what you see.

• Exercise.

• Optional but useful: log what you eat and do.

Add lipid-lowering medication, and you’ve addressed the factors that can help extend your lifespan. Best of all, they also happen to be the easiest to control.