148: Why Neuropathy Isn’t Just About Blood Sugar

Neuropathy isn't just a blood sugar problem. We have been oversimplifying it. High blood sugar does indeed damage nerves. So lower it and the problem is solved, right? Well, not exactly. In type 2 diabetes, you can in fact still lower blood sugar and still damage the nerve and have that nerve damage progress. So what's really going on? Your nerves are actually being hit from 3 directions. First, yes, it's high glucose. Too much sugar in the blood can damage the nerve. But second, insulin resistance. Your nerves need insulin to repair, and without it working well, they start to fail. Third, blood sugar swings— the constant spikes and crashes of blood glucose. They all may have the same average blood sugar but very different outcomes. So if you're feeling the tingling and the numbness or the burning, it's likely not just one issue. It could be all three at the same time. That's why focusing on blood sugar alone isn't enough. This is lecture 148 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, biomedical scientist and professor of cell biology. Today we are going to talk about one of the most common, but I think also one of the most misunderstood, complications of metabolic disease, and that is peripheral neuropathy. You've probably heard the standard story The diabetes is a disease of high glucose, high blood sugar after all, and that high blood sugar damages the nerves. Therefore, neuropathy is simply a hyperglycemia problem, end of story. You just lower the glucose and you just save the nerve. But there's a puzzle that deserves some attention in this simplistic paradigm. In type 1 diabetes, intensive glycemic control does in fact help prevent neuropathy. In fact, it does so spectacularly well. In type 2 diabetes, the same intervention doesn't really move the needle, the same approach, but you have very different outcomes. Well, why is that? The answer is the animating question in today's episode. It's the metabolism of neuropathy in that it's not just about glucose. It's really about 3 things working together. And we're going to talk about each of these. Yes, high blood glucose is a problem. So hyperglycemia is one of these drivers, but so too is insulin resistance. And lastly, so too is glycemic variability. Once we appreciate each of these, we then really understand why the nerve dies. So let's build this from the ground up. What neuropathy is, then how each of these three forces, the high glucose, the compromised insulin signaling, and the bouncing around glucose independently and even synergistically injure the peripheral nerves. Let's start with just defining it. Peripheral neuropathy is damage to the nerves that are outside of the brain and the spinal cord. The peripheral nervous system has 3 main fiber types. First, we have the motor nerves, which are coming from that central nervous system, the brain and spinal cord, that drive our muscle action. We have the sensory nerves that bring information in from the skin and the joints and the, the viscera, all of the organs within our abdominal cavity. And then we have the autonomic nerves that regulate some of the involuntary functions from like heart rate, heart contractility, gut motility, and even things like sweating. Any of these can be affected with peripheral neuropathy. The most common form in metabolic diseases is distal symmetric polyneuropathy. That's a lot of words there. It's formally described as a length-dependent Symmetric neuropathy. So the symmetric term is apparent. The length-dependent is a very important phase here. It means the longest nerves tend to go first, which is why patients describe symptoms beginning in the toes and feet, then ascending the legs, and then eventually appearing in the fingertips as well. The symptoms in these locations are very, um, expected things like numbness or tingling or burning pain, or even a loss of the ability to sense things like vibration in the feet. In this case, on a skin biopsy, you see fewer of the tiny nerve endings that normally feed into the skin. So these nerve endings start to retract and then die. On a nerve conduction test, the signal travels too slowly as well. These are two related conditions that I think are worth knowing. Um, another version of this is cardiovascular autonomic neuropathy, when you have damage to the nerves that regulate the heart and blood pressure. The other is small fiber neuropathy, which hits the, which hits the smallest nerve fibers first and is now considered one of the earliest signs of the disease. All right, so that gives you a general overview of what the disease is, but how common is it? Well, it is remarkably common, which is one of the reasons why I'm devoting time and you're perhaps devoting time listening to it. In adults with diabetes, the lifetime prevalence of diabetic peripheral neuropathy exceeds 50%. It's the leading cause of foot ulceration and non-traumatic lower limb lower limb amputation. That's really an important thing here. So when someone has to get a lower limb amputated, this is the main driver. And this is important. It doesn't wait for diabetes to be diagnosed. Most studies in prediabetes report a prevalence of peripheral neuropathy of 10% or higher, with several reports putting small fiber involvement at 30 to 70%. That's a pretty big range, but that upper level is pretty high. Neuropathy is showing up in metabolically dysfunctional people before they meet the glycemic cutoffs for diabetes. That alone tells you the story is not just about glucose. So with that, uh, map in mind, let's now navigate the 3 metabolic forces that are driving the nerve to failure. Okay. The first pillar, hyperglycemia. Uh, let's start with the obvious one, but chronic hyperglycemia damages nerves. To understand why you need to understand one fact about how peripheral neurons and their support cells handle sugar. Peripheral neurons and the— and a cell type called Schwann cells, named after the person who discovered it, those are glial support cells that wrap and nourish the peripheral axons. So these long nerves, they take up glucose without needing insulin's permission. That's important. So these are insulin-independent glucose transporters, but Interestingly, these transporters are always open. So when blood glucose is high, the inside of the nerve is flooded with sugar. The nerve has no way to regulate or slow that influx. And once glucose is elevated inside the nerve cell, then some things start happening. The first of those couple things is the sorbitol pathway. When glucose accumulates inside the cell and isn't burned for energy or stored for later energy, then the— there's an enzyme called aldose reductase, which converts it to sorbitol. You might have heard of sorbitol. It's actually a sugar alcohol. This is normally a very minor pathway, but in the hyperglycemic, or I should say glucose-loaded nerve, it becomes a major one and it damages the nerve through several mechanisms all at the same time. One idea here within this other sub-idea is that sorbitol does not easily cross cell membranes. So as it is accumulating within the cell, it's pulling water in with it. That is something called called an osmotic pressure. So where you have more sorbitol accumulating in the nerve, it's starting to pull water from outside the nerve, which can cause the nerve to start to swell. Now the nerve doesn't want to do that. So to compensate, while the sorbitol is accumulating, the nerve cell will expel or export other small molecules that are actually really necessary. One of them is myoinositol, which is critical for the function of the sodium potassium pump. That's a way of maintaining the electrical signal on the nerve. So as sorbitol is building up, myoinositol, among other small molecules, is being pumped out. And then the nerve's ability to conduct the signal starts to slow down. Now that high glucose in the nerve also has a second hit, which is when that enzyme, the aldose reductase, when it's using— when converting the glucose into sorbitol, it starts to consume NADPH. NADPH is what the cell relies on to keep its antioxidant systems running. When you think about major intracellular antioxidant molecules, the main one being glutathione, it gets oxidized when it neutralizes a free radical, and NADPH is what regenerates that glutathione back into its active and ready form. So when the nerve is burning through NADPH in order to dispose of the glucose, it can't keep the glutathione in it's in its reduced or active state, then the antioxidant system starts to run on empty, and then we have more free radicals accumulating. So the nerve's defenses are being spent reducing the sugar instead of being available to defend against some of the oxidative damage. Okay, now we're still talking about hyperglycemia. So the first one was the sorbitol and its two distinct problems. Then the second one is glycation. When glucose is floating around in a high concentration, it isn't just sitting there. It start to chemically stick to proteins and lipids. This is something that can happen without an enzyme. There's no regulatory step. It's just a slow chemical reaction between the glucose and the other molecule, like a protein or a fat. The longer lived that other molecule, then the more glycation it accumulates. And the peripheral nerve is full of long-lived proteins. These are long-lived cells. Like think of the myelin sheath, that fatty covering, the axonal cytoskeleton, all the small little proteins within that nerve, the basement membrane of the tiny blood vessels that are feeding the nerve. All of these are very loaded in very susceptible proteins. Over months and years, these proteins can become coated with these, this glucose adduct. And then we have this, what's called advanced glycation end products, or AGEs, AGES do two bad things. They not only distort the structure and function of the proteins that they're attached to, um, but then they also bind to a receptor called RAGE, the receptor for advanced glycation end products. And that binding triggers an inflammatory cascade in the cells that have that RAGE, that receptor. Inflammation in the support tissue surrounding the nerve is one consequence here. We have inflammation in the vasculature the, the blood vessels feeding the nerve. That age-rage axis is now considered one of the central drivers of diabetic complications across many tissues, but it does have a particular impact on peripheral nerves. Okay, so high glucose is the first pillar. The second pillar is my old friend insulin resistance. Most of the time when we talk about neuropathy, we talk about the glucose, but hyperglycemia is usually the consequence of a deeper problem in type 2 diabetes, which is insulin resistance. And insulin resistance, it turns out, damages nerves through mechanisms that are partially independent of that glucose. A large prospective study of over 1,000 patients with type 1 diabetes— they were followed for over 7 years, and then the study asked which factors apart from glycemic control predicted incident neuropathy. The answer: The incidence of neuropathy was associated with potentially modifiable cardiovascular risk factors, including typical ones like raised triglycerides or elevated BMI or smoking and hypertension. Importantly, these are markers of insulin resistance and metabolic syndrome. Glucose was not the only thing that predicted that nerve damage. The picture actually gets a little clearer in type 2 diabetes and obesity. A substantial body of human evidence has been built around this idea. Major reviews have made the explicit argument that the metabolic syndrome beyond glucose is a major driver of neuropathy. A cross-sectional study of an obese population found that polyneuropathy was associated with metabolic syndrome components independent of glycemic status. A subsequent analysis concluded that diabetes and obesity are the main metabolic drivers of peripheral neuropathy, with the recommendation that interventions targeting these factors are really essential. Perhaps the cleanest demonstration is the lifestyle intervention work. Patients with neuropathy associated with impaired glucose tolerance or prediabetes were enrolled in a 1-year lifestyle intervention based on the Diabetes Prevention Program. Skin biopsies showed measurable cutaneous reinnervation on follow-up. That's really important. So restoring insulin sensitivity in patients who didn't even meet diabetes criteria were able to regrow— they grew the nerve fibers. That's a pretty remarkable human result, and it's hard to explain with just a glucose-only model. So what is insulin actually doing at the nerve? This is where I want to be careful, because we should distinguish physiological insulin signaling at the nerve from the super physiological levels of insulin that we start— or just the higher physiological levels and the chronic levels of insulin that we see with insulin resistance. Under normal or helpful conditions, insulin is a trophic factor for peripheral neurons and Schwann cells. The Schwann cell, that's the glial cell that wraps around the, the peripheral nerves. It makes the myelin sheath and it provides metabolic support to the axon. Well, it expresses both the insulin receptor and its close sibling, the IGF-1 receptor. These receptors, when they are activated, in turn activate the, the Schwann cell to drive the helpful production of the beneficial lipids or the fats that, that the cell needs. And the lipids are needed. They are exactly what the myelin is made of. When Schwann cells lose that insulin signaling, they lose the substrate, they lose the signal to maintain that myelin. We know this experimentally in a clean genetic experiment. Both the insulin receptor and the IGF-1 receptor were deleted specifically in mouse Schwann cells. The result was reduced expression of fatty acid and cholesterol synthesis, and the mice developed a sensory neuropathy phenotype. And this included a reduction in myelin and altered nerve function. So this is, I think, the cleanest mechanistic demonstration that the loss of insulin signaling in the support cell of the peripheral nerve is by itself sufficient to produce neuropathy. So that's important, right? In these animals, glucose levels were totally normal. And if you compromise the insulin signal, you compromise the nerve function. Now, in a person with insulin resistance, the same thing is happening through a different route. The Schwann cell, like the muscle cell or the fat cell or the liver cell, becomes insulin resistant. So it's resistant to insulin's signal. And, and this is happening in the setting of elevated insulin and the the lipotoxicity that can come from that, where the elevated insulin is driving the accumulation of harmful lipids rather than the beneficial lipids that these nerves need. So this is the second pillar in the metabolically dysfunctional state. The nerve is not just getting hit by too much glucose. In fact, it might not be getting hit by too much glucose at all, or intermittently, but it's also being deprived of the insulin signal that it needs to repair or remyelinate to maintain its trophic or growth relationship between Schwann cells and the nerve. Okay. Now let's get to the third pillar here, which is glycemic variability. That's the, the newest pillar, but it's the one we couldn't really study until continuous glucose monitoring made it possible to see what blood sugar actually does over a day. Average glucose summarized in the A1C number. It's useful in a way, but it's a one-dimensional summary of what I think is a very dynamic signal. 2 people can have an identical A1C of 7%, but can have very different glucose profiles. One may be staying in a very narrow band between, say, 100 and 130 or 140 milligrams per deciliter, but the other person may be oscillating wildly between 60 milligrams per deciliter up to 200-something multiple times a day. They have the same average, they may have the same A1C, but wildly different glycemic profiles. Experiences. The hypothesis is that glucose variability, or the magnitude of those swings, is itself a driver of nerve damage beyond just mean glucose. The mechanistic rationale is that intermittent hyperglycemia appears to provoke more endothelial reactive oxygen species generation than sustained hyperglycemia at the same average. Each upward excursion is a fresh hit on the NADPH superoxide axis that we discussed earlier. The nerve doesn't get— it doesn't have time to acclimate, and the result is just a repeated insult from this. The human evidence has accumulated pretty meaningfully over the past 10 years or so, again, as we have been able to use continuous glucose monitoring. One particular study had patients with type 2 diabetes, several hundred of them, who had fairly well-controlled diabetes where the A1C was consistently below 7, but they were evaluated with a CGM. The mean amplitude of glycemic excursions, abbreviated as MAGE, M-A-G-E, was an independent predictor of diabetic peripheral neuropathy. Again, this is in people with the same A1C. The patients with bigger swings had worse neuropathy. That's a direct, in this case, a human sign that the variability matters above and beyond mean glucose. A separate nerve conduction study found similar results. The higher the MAGE— that glycemic variability— was associated with reduced compound nerve action potential amplitude. So, so the degree to which the nerve could send its signal. And other work has shown that long-term variability in HbA1c itself which is going to be a longer-term fluctuation, is associated with diabetic peripheral neuropathy in type 2 diabetes. And then even more recently, there was another multi-year longitudinal study reported that fasting plasma glucose variability predicted incident painful diabetic peripheral neuropathy. So the implication is, I think, pretty clear, also pretty remarkable. Time in range and time in tight range may matter as much as average glucose for protecting the peripheral nerve. A patient who spends most of the day between 70 and the low hundreds with infrequent excursions is in a fundamentally different metabolic environment from one who oscillates wildly, even if their A1C is identical. And the nerve appears to know or feel that difference. I think this is the practical takeaway from CGM-based metrics. A1C is a useful summary, but time in range and magnitude of excursions are where the action, I think, really is when you want to consider nerve protection. So to start to sum it up, the metabolism of neuropathy is not a one-input problem. It's really three inputs happening at the same time: hyperglycemia, insulin resistance, and glycemic variability. In type 1 diabetes, two of the three pillars are reasonably addressed with the good effective use of exogenous insulin. The average glucose, and with current technology, you're minimizing the variability as well. And there's no, or rarely, underlying insulin resistance in type 1 diabetes. Now, it can happen, as a, as a tangent, and there's evidence to show that the more a type 1 diabetic has to treat with insulin, the more they are becoming insulin resistant. So intensive glycemic control reaps most of the benefit there. In type 2 diabetes, you can lower A1C and still leave insulin resistance and variability largely untouched. So intensive glycemic control reaps a fraction of the benefit in this case that you would see in type 1. And in prediabetes and metabolic syndrome, where average glucose is barely elevated but insulin resistance and postprandial excursions are more profound, you can have small fiber neuropathy again, even with normal A1C. Let's close. So when a patient asks why their feet are burning or their fingers are tingling, the answer is not just, well, your sugar's too high. The answer should be something like, well, your nerve is being attacked on three fronts simultaneously. Yes, hyperglycemia is one, but the loss of insulin signaling, particularly at the Schwann cell, is another, and the volatility of your glucose is a third. The therapeutic implication, I think, is pretty straightforward. You cannot out A1C your way out of metabolic neuropathy. You have to address the insulin resistance. You need to flatten the glycemic variability. You have to do the things that improve all three pillars, ideally at once, which, as it happens, are the same things that improve every other manifestation of metabolic dysfunction. Control your carbohydrates. Adopt some fasting protocols to help your blood glucose really stabilize and enhance your insulin sensitivity. Exercise, especially some resistance exercise to help your muscles, and try to engage in better sleep habits. That is, in my view, the solution in understanding and resolving the metabolism of neuropathy. Thanks for joining me in the Metabolic Classroom. Until next time, more knowledge, better health.