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Welcome to the Metabolic Classroom Podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. 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 Metabolic scientist and professor of cell biology Today's mini lecture focuses on one of the most fundamental aspects of cellular metabolism, the relationship between nad, NAD and insulin resistance. NAD and NADH are critical players in every single cell of your body. NAD stands for nicotinamide adenine dinucleotide, and when it picks up hydrogen atoms during metabolism, it becomes nadh. Think of NAD as a rechargeable battery in your cells. It accepts electrons during one process and donates them during another. This constant cycling is essential not only for energy production, which of course, as a metabolic scientist, I focus on the most, but also things like DNA repair, cell signaling, and more. Here's what makes this particularly relevant to metabolic health. The ratio between NAD and NADH appears to be a critical determinant of such things as insulin sensitivity. When this ratio shifts in the wrong direction. Specifically, when NADH accumulates and NAD drops, insulin resistance can follow. In today's mini lecture, we're going to explore exactly how this happens, why it matters, and what you can do do about it. But let's of course start with the fundamentals. Nad, as I noted, exists in two forms in your cells. The oxidized form, which is identified or indicated as nad, and the reduced form, nadh. You can think of NAD as something like an empty shopping cart, but when it's nadh, that cart has been filled with hydrogen atoms and electrons. These molecules are involved in hundreds of metabolic reactions, but their primary role is in cellular respiration, the process by which your cells get energy from the food you eat. When you consume things like carbohydrates and fats, they're broken down through various pathways. And during this breakdown, NAD picks up electrons and hydrogens, like I noted earlier, and becomes nadh. This NADH then carries those electrons to the mitochondria, the power plant or the powerhouse of the cell. That's where they're used to generate ATP, which is the energy that every cell in the body can use. In the process, NADH gives up its electrons and returns to being nad, which means it's ready to go. Pick up more this cycling is constant NAD and essential. In fact, your body recycles the entire NAD pool hundreds of times per day. But the critical point, and this is where insulin resistance can come into play, is that the ratio between NAD and NADH matters tremendously. When you have a high NAD to nadh ratio, it generally indicates a healthy metabolic state. The cells are efficiently processing nutrients, the the mitochondria are functioning well and energy production is humming along nicely. But when the ratio Drops. When NADH accumulates and NAD is depleted, then metabolic problems can emerge. Research demonstrates that the NAD to NADH ratio acts as a metabolic sensor, and it influences everything from glucose metabolism to fat oxidation to mitochondrial function in any number of ways. And critical again for the discussion today is I want you to appreciate that there's evidence to suggest it also affects insulin signaling. So how exactly does it do this? How does the NAD to NADH ratio influence insulin signaling? There are several mechanisms that are interconnected here, but they all revolve around a simple principle. When cells are overloaded with nutrients, particularly glucose, and you could even say fats, to a degree, the NAD to NADH ratio shifts in a way that promotes insulin resistance. Now, let's walk through how that might happen. The idea goes that when you consume excess calories, and I would say especially from refined carbohydrates, and we're going to touch on that more in a bit, your cells are floated, flooded. They're loaded with glucose. This glucose enters the glycolytic pathway, or the glucose burning pathway, where it's, of course, broken down to produce energy. During the process, NAD is converted to nadh. Under normal circumstances, that NADH would quickly be recycled back to NAD in the mitochondria. But here's the problem. When there's too much glucose coming in too fast, the mitochondria become overwhelmed. They can't process all that NADH quickly enough. It's like a traffic jam on the highway. Cars keep entering, but they can't get through fast enough, and everything gets backed up. This backup of NADH has several consequences. First, it directly inhibits key metabolic enzymes. When the ratio drops, it impairs the activity of sirtuins, a family of proteins that are absolutely critical for metabolic health, mitochondrial function, and other things. Sirtuins, particularly Sirt1, require NAD to function. They're like quality control managers in the cell. And they are, of course, in this role, overseeing everything from things like DNA repair to the synthesis of new mitochondria to metabolism of fat and more. When NAD levels drop because it's all tied up as nadh, then the sirtuin activity plummets and the metabolic dysfunction will follow. In other words, those things that SIRT1 is doing, they can't do it as well. Second, a low NAD to NADH ratio promotes the accumulation of problematic lipid metabolites. A 2011 paper showed that when that ratio is low, it favors the production of diacylglycerols and then my favorite fat ceramides, and ceramides in particular, is a lipotoxic molecule that we've discussed many, many times previously on this podcast. These lipids can directly interfere with insulin signaling, blocking the ability of insulin to stimulate glucose uptake and do any other number of its actions in cells. Third, and this is particularly elegant, we may say the NAD to NADH ratio influences a pathway called the hexosamine biosynthetic pathway. When NADH is elevated, it pushes more glucose derived metabolites into this pathway, which produces molecules that can modify proteins in other ways that can further impair insulin signaling. A 2002 paper showed that when this pathway is hyperactivated, it is a driver of insulin resistance in both muscle and fat tissue. Then, finally, a chronically low ratio impairs mitochondrial function itself. The mitochondria become less efficient at burning fuel, they produce more reactive oxygen species, and they signal to the rest of the cell that something is not working correctly. This mitochondrial dysfunction is both a cause and a consequence of insulin resistance, which can then, of course, create a vicious cycle. Now, let's look at glucose again and use this as an example to explore one of the more insidious aspects of how this ratio can influence metabolism within a cell. This is a phenomenon that researchers studying diabetic complications discovered in the late 90s. And it is very important to understanding another reason or mechanism whereby chronically high blood glucose is so damaging. When blood glucose is chronically elevated, like in pre diabetes and certainly type 2 diabetes, something unique is happening within the cell. The volume of glucose flooding into the cells overwhelms the normal ability of the cell to metabolize it. And this creates what researchers call pseudo hypoxia, or a reductive stress. Now, let me explain what that means. Hypoxia is when cells don't have enough oxygen. You'd think that would be the opposite of what happens when you have plenty of glucose and oxygen available. But what's fascinating about this is how it's a bit counterintuitive. When glucose levels are too high, they behave metabolically as if they're starved of oxygen, even when the oxygen is abundant. This happens because the massive flux of glucose through glycolysis generates ADH at a rate that completely overwhelms the mitochondria's ability to process it. The NADH to NAD ratio. I've just flipped that. But in this case, the ratio flip goes so high that it mimics what would happen if the cells couldn't get oxygen to the mitochondria. The cells enter a state of reductive stress, they're too reduced, too loaded with electrons that have nowhere to go. But hyperglycemia creates a second problem through the polyol pathway. Under normal glucose conditions, the pathways that this particular pathway is quite quiet. But when glucose is chronically elevated, a significant portion of that excess glucose is getting shunted into this alternative pathway. This does so through the actions of an enzyme called aldose reductase, which converts glucose to sorbitol. And this process consumes nadph, which is a cousin of NADH that is critical for the antioxidant defense of the cell. So you're depleting your antioxidant reserves. Then another enzyme converts the sorbitol to fructose. And this step generates even more nadh. So the polyol pathway creates a double metabolic hit. It depletes the antioxidant capac capacity while simultaneously adding to the NADH burden. Some studies in the 2000s showed that this pathway is a major contributor to diabetic complications, particularly in areas like the eyes and nerves and kidneys. Now here, where it gets even cooler, when NADH accumulates to these high levels, it starts inhibiting a critical enzyme in glycolysis gap, DH glyceraldehyde 3 phosphate dehydrogenase. This enzyme normally helps keep glycolysis moving quite smoothly. But when it's inhibited by too much nadh, the glucose metabolites back up and higher up in the pathway. And this is just another instance of where the damage can be so present. These backed up metabolites don't just sit there. They get diverted into other pathways that cause other complications. One is that more of the glucose gets pushed into the polyol pathway, generating fructose, like I just mentioned. Second, the glucose metabolites can activate protein kinase C, which can damage blood vessels when it's excessively turned on. And third, they flow into the hexosamine pathway, which can create insulin resistance. And fourth, they lead to the formation of advanced glycation and end products, the ages, which can damage proteins and fats and DNA everywhere throughout the body. Some landmark data published in 2000 demonstrated something pretty fascinating. All four of these damaging pathways could be traced back to a single unifying mechanism, the mitochondrial overproduction of superoxide radicals. Driven by this altered nadh, NAD ratio. When the mitochondria are overwhelmed by nadh, they can't process it efficiently and electrons leak out of the respiratory system, forming these damaging reactive oxygen species. Tragically, all of this creates a bit of a self perpetuating cycle. High glucose alters the NAD to NADH ratio. That ratio then causes mitochondrial dysfunction and oxidative stress. This mitochondrial damage can of course, compromise insulin resistance, which leads to higher blood glucose. And the higher blood glucose just feeds the cycle further. Now, this is not the same as a simple caloric excess when you overeat, but your blood glucose remains controlled, which is what happens on a, I would say a well formulated, low carbohydrate diet. The NAD NAD ratio can recover between meals if only your cells can get a break. But with chronic hyperglycemia, remember, the glucose is elevated even during the fasted state. The reductive stress is constant. The pseudo hypoxia never resolves. We're going to come back to that, the importance of controlling blood glucose. So now that you hopefully understand a little more of why the NAD to NADH ratio matters and the unique damage that is caused by hyperglycemia, let's examine what can drive it down in the first place. And I've touched on this a little bit. I'm just going to state it a bit differently. The culprit really is that metabolic overload, particularly from chronic or excessive carbohydrate consumption. When you eat that high carb diet, especially with refined starches and sugars, you're constantly flooding the cell with glucose. Each glucose molecule that enters glycolysis generates nadh. And if you're constantly relying on glycolysis, you're constantly generating NADH faster than the mitochondria can handle it or recycle it back into nad. High carbohydrate feeding in both animals and humans leads to a dramatic reduction in the NAD to NADH ratio in the liver and muscle tissue. Another factor that goes beyond diet is just simply aging. As we get older, NAD levels naturally start to decline. Multiple studies, including some big ones in 2016 in the Journal Cell Metabolism, have shown that NAD levels can drop by 50% or more between young adulthood and old age. This decline contributes to age related metabolic dysfunction and the compromising of many other processes in the cell, some of which we've mentioned here. Now, beyond age is alcohol, where alcohol consumption can also significantly affect NAD levels. When alcohol is metabolized in the liver, it consumes NAD and produces nadh, dramatically shifting and rapidly shifting that ratio. Chronic alcohol consumption can deplete hepatic nad, and this is a significant contributor to fatty liver disease and likely further contributing to insulin resistance in the liver. And finally, sedentary behavior plays a role. Exercise is one of the most powerful stimulators of nad. Production and utilization. When we're physically inactive, we don't create the metabolic demand that drives NAD recycling and regeneration. So with these ideas in mind, what might we be able to do with it? How can we improve that NAD NADH ratio and improve metabolic and mitochondrial health? The good news is that we do in fact have several evidence based strategies. First and most importantly, I would say it's dietary carbohydrate restriction by reducing carbohydrate intake, particularly refined carbohydrates. Remember my mantra, if the carbs come in a bag or a box with a barcode, they are carbs to avoid. In that case, when you're eating them you reduce or when you're avoiding them, you can reduce the flood of glucose entering into glycolysis into every cell. This immediately reduces the NADH production and helps restore a more optimal NAD to NADH product ratio.