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a better help ad hold on one second. I just need to. What if you had a room where no one interrupts? No notifications, no expectations, just space to talk with BetterHelp Therapy happens in a space that's yours. Visit betterhelp.com randompodcast for 10% off your first month of online therapy. Welcome to the Metabolic Classroom Podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. I don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical and engaging. Welcome back to the Metabolic Classroom. I'm Ben Bickman, 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 is a puzzle that deserves some attention in this simplistic paradigm. In type 1 diabetes in 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 three things working together. And we're going to talk about each of these. And 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 three 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 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 symmetrical 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 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. 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 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 in your. 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 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 by. Most studies in pre diabetes 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 map in mind, let's now navigate the three metabolic forces that are driving the nerve to failure. Okay, the first pillar, hyperglycemia. Let's start with the obvious one. Chronic hyperglycemia damages nerves. To understand why, you need to understand one fact about how peripheral neurons in their support cells handle sugar. Peripheral neurons 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 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 myo inositol, 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 a 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. And 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 bur through NADPH in order to dispose of the glucose, it can't keep the glutathione in its, 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 nerves 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 it's 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 can 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, this glucose adduct. And then we have this, what's called advanced glycation end products or age. Ages do two bad things. They not only distort the structure and function of the proteins that they're attached to, 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 seven 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 a 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 one year lifestyle intervention based on the Diabetes Prevention Program. Skin biopsies showed measurable cutaneous re innervation on follow up. That's really important. So restoring insulin sensitivity in patients who didn't even meet diabetes criteria were able to regroup. They regrew 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 IGF1 receptor.