← The Metabolic Classroom with Dr. Ben Bikman
The Metabolic Classroom with Dr. Ben Bikman
How Glucose Overload Breaks Your Metabolism (And How to Fix It)
00:27:37
More Knowledge, Better Health
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- [00:02]
A
My perfect day has sand, salt water and friends, but my moderate to severe plaque psoriasis can take me out of the moment. Now I'm all in with clearer skin thanks to Skyrizi Risankizumab RZA, a prescription only 150mg injection for adults who are candidates for systemic or phototherapy. With Skyrizi. Most people saw 90% clearer skin and many were even 100% plaque free at four months. Skyrizi is just four doses a year after two starter doses.
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Don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.
- [00:41]
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Thanks to Skyrizi, there's nothing on my skin and that means everything.
- [00:46]
B
Nothing is everything.
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- [02:09]
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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.
- [18:31]
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My perfect day has sand, salt water and friends, but my moderate to severe plaque psoriasis can take me out of the moment. Now I'm all in with clearer skin thanks to skyrizi risen Kizumab RZA, a prescription only 150mg injection for adults who are candidates for systemic or phototherapy with Skyrizi. Most people saw 90% clearer skin and many were even 100% plaque free. At four months, Skyrizi is just four doses a year.
- [18:57]
B
After two starter doses, don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.
- [19:11]
A
Thanks to Skyrizi, there's nothing on my skin and that means everything.
- [19:15]
C
Nothing is everything.
- [19:19]
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- [20:54]
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Studies from 2014 showed that low carb diets can significantly improve that ratio in both liver and muscle in just a few weeks. And given what we discussed about hyperglycemia and that pseudo hypoxia, you can see why controlling blood glucose is so important. When you keep glucose levels in a healthy range, through controlling your carbohydrate consumption, you prevent that vicious cycle of the reductive stress, the mitochondrial dysfunction, and more. Now, I mentioned sedentary living being a problem, and of course that means exercise and physical activity is a solution. Indeed, it is one of the most powerful ways to improve NAD levels. When you exercise, your muscles demand energy, which drives the conversion. You're using up the NADH and restoring it or recycling it back to nad. Additionally, exercise stimulates the production of new NAD through enhanced biosynthetic pathways. Regular exercise increases NAD levels and improves metabolic and mitochondrial function through multiple mechanisms. Third, if eating too much is part of the problem, then eating less frequently will be part of the solution. And indeed, time restricted eating or intermittent fasting is very effective when when you fast, you stop the constant influx of glucose, allowing your cells to clear out accumulated NADH and restore the NAD levels. Additionally, fasting activates sirtuins which consume the NAD but also stimulate its production through feedback mechanisms. So time restricted eating is a very good way to improve the ratio and improve thus metabolic health. Fourth, adequate sleep sleep deprivation has been shown to reduce NAD levels and impair the NAD to NADH ratio. Circadian rhythm disruption impairs NAD biosynthesis so you're making less when you're sleeping less. And then of course I noted the problem with alcohol. Well, let's say that's a fifth one. Given alcohol's significant indeed rapid effects at reducing NAD levels, reducing or even eliminating alcohol altogether can be a powerful way for improving metabolic health. Now those are lifestyle changes, but I know what you're thinking, which is, well, what about supplements? This is an area that has received considerable attention in recent years and there has been significant marketing hype around compounds like nicotinamide riboside or nr, and nicotinamide mononucleotide nmn. So let's just take a moment to discuss that evidence to see really what they're doing. First, the biological rationale is sound. It's part of what makes these supplements so appealing. Both NR and NMN are precursors that can be converted to NAD in the body through specific enzymatic pathways. In theory, providing these precursors could boost NAD levels, particularly in people whose levels have declined due to aging or metabolic dysfunction. And indeed, the preclinical evidence in animals is quite compelling. Studies in mice have consistently shown that NR and NMN supplementation can increase NAD levels, improve mitochondrial function, enhance insulin sensitivity, and even extend lifespan. In some models, NMN administration improves glucose tolerance as well in diabetic mice. But here's where we need to be careful the human data is far more limited and considerably less impressive. Let's start with what we do know. Several human trials have confirmed that oral NR supplementation can increase NAD levels in blood cells. 1000mg per day of NR for 6 weeks increased NAD levels in peripheral blood mononuclear cells by about 60%. Now that sounds promising. However, whether those increased NAD levels in blood cells translate to meaningful increases in the tissues that matter for metabolic health, like muscle and liver and fat, or even the brain when it comes to aging, that remains totally unclear. Unfortunately, most human studies have not measured tissue NAD levels directly because that would require invasive biopsies. Now you could get biopsies from things like the muscle and fat and even the liver. Good luck getting a brain biopsy. More importantly, though, the question we really need to answer is do these supplements produce clinically meaningful improvements in metabolic outcomes? And here's where the evidence becomes even more murky. A 2018 trial examined NR supplementation in obese, insulin resistant men. The results were disappointing. Despite successfully raising blood NAD levels, there were no significant improvements in any of these metabolic outcomes compared to placebo. The researchers concluded that simply raising NAD levels was not sufficient to improve metabolic function in this population. A paper published the next year tested NR supplementation in healthy older adults. While the supplement was well tolerated and did increase supplements some markers of NAD metabolism, once again, it didn't significantly improve any metabolic outcomes or overall physical performance. Now, that's not to say there hasn't been any positive findings. A 2021 paper found that NMN supplementation improved muscle insulin sensitivity in pre diabetic women, though notably the effect was only seen in women and the magnitude of improvement was Very, very modest. Another trial found that NR supplementation improved some markers of metabolic health in people with mild cognitive impairment. So what explains the disconnect between the impressive animal data and the underwhelming human results? There are, I think, a few possibilities that come to mind as I scrutinize the data. First, bioavailability may be an issue when you take oral NR or nmn. These compounds must get through, must be intact through the digestive system. They got to get absorbed into the bloodstream and then they got to be taken up by the tissues and then converted to nad. Each of these steps is a pretty significant bottleneck. Studies can suggest, and indeed do, that much of the oral dose may be broken down before it ever reaches any of the target tissues. Second, the dosing used in the human studies may simply be insufficient. Many of the animal studies use doses that, when adjusted for body weight, would be equivalent to several grams per day in humans. But most human trials have used less than a gram, so that could be due to constraints due to cost or concerns with side effects. Third, and I think this is critical, raising NAD levels may not be sufficient if the underlying problem is is chronic NADH accumulation. Remember our discussion with the pseudo hypoxia and even the reductive stress? If you're constantly flooding your cells with glucose that generates massive amounts of nadh, simply adding some NAD precursors may be like trying to bail out a boat that has a gaping hole in the bottom. You're just simply not addressing the fundamental problem. And this brings me to an important point about the supplement industry. NAD boosters have become extremely popular and they're being marketed aggressively with claims that often, I think, pretty well exceed the actual evidence that supports it now. Nevertheless, companies are selling these products for hundreds of dollars per month, based largely on mouse studies and some of the mechanistic reasoning. As tempting as it may be, My.
- [28:44]
A
Perfect day has sand, salt water and friends, but my moderate to severe plaque psoriasis can take me out of the moment. Now I'm all in with clearer skin thanks to Skyrizi Risankizumab RZA, a prescription only 150mg injection for adults who are candidates for systemic or phototherapy. With Skyrizi, Most people saw 90% clearer skin and many were even 100% plaque free. At four months, Skyrizi is just four doses a year. After two starter doses.
- [29:11]
B
Don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.
- [29:23]
A
Thanks to Skyrizi, there's nothing on my skin and that means everything.
- [29:28]
B
Nothing is everything.
- [29:31]
A
Ask your doctor about Skyrizi, the number one dermatologist prescribed biologic in psoriasis. Visit skyrizi.com or call 1-866-Skyrizi to learn more.
- [29:42]
B
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- [29:45]
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Can I make my site firmer? Can we sleep cooler?
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- [30:15]
C
The reality is that we don't yet have strong evidence that NAD precursor supplementation produces any clinically meaningful improvements, let alone in metabolic health outcomes in humans. A person eating a high carb diet, remaining sedentary and sleeping poorly isn't going to supplement their way to metabolic health with NR or nmn. That said, there may be specific populations who could benefit people with genetic conditions affecting NAD metabolism in individuals with severe age related NAD depletion, or even maybe those who have already optimized their diet and lifestyle but still show some evidence of insufficiency of nad. They all may benefit to some degree, but even then it's all There's a lot of speculation there and they would be the exception, not the rule. The most prudent approach at this point is to focus on the interventions that we know work control carbohydrate carbohydrate intake to prevent chronic hyperglycemia and NAD accumulation, exercising regularly to drive NAD plus recycling, incorporate some time restricted eating, optimizing your sleep, and minimize alcohol consumption. All of these can address both sides of that NAD to NADH equation. They reduce NADH production while simultaneously supporting NAD regeneration. If someone has implemented all of these lifestyle strategies and then wants to experiment with NAD precursors, then I think it's perfectly reasonable to try. The supplements appear to be very safe, at least in the short term, so there's little concern there. But expectations should be tempered and even quite realistic. People should understand that they're paying a premium price for something that has very limited human evidence. The relationship between nad, NADH and metabolic complications, including insulin resistance, nonetheless does illustrate how important these molecules are in optimal cellular metabolic health. These are molecules that matter more than just describing them in a biochemistry textbook. They they really are fundamental to how the cell knows its own energetic status and what it ought to do in response to that. A healthy NAD NADH ratio is both a marker and, I would say, a mediator of metabolic health. When the ratio is optimized through the strategies I've mentioned like diet, exercise, fasting, lifestyle, then every metabolic outcome, those related to the ratio get better and metabolic complications are going to plummet. The science is clear that the ratio matters. What's less clear is what we can do about it with regards to supplements. But those lifestyle strategies, I think stand supreme. Be physically active, control your carbs, incorporate some periods of fasting, prioritize sleep, and these fundamental strategies are going to work at more of a deeper molecular level to restore metabolic health by restoring the ratio. Thanks for joining me for this mini lecture on all these bizarre and deep metabolic topics. Until next time, thanks for joining me in the metabolic classroom. More knowledge, Better Health.
- [33:45]
A
My perfect day has sand, salt water and friends, but my moderate to severe plaque psoriasis can take me out of the moment. Now I'm all in with clearer skin thanks to Skyrizi Risankizumab RZA a prescription only 150mg injection for adults who are candidates for systemic or phototherapy with Skyrizi. Most people saw 90% clearer skin and many were even 100% plaque free at four months. Skyrizi is just four doses a year after two starter doses.
- [34:12]
B
Don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.
- [34:24]
A
Thanks to Skyrizi, there's nothing on my skin and that means everything.
- [34:29]
B
Nothing is everything.
- [34:32]
A
Ask your doctor about Skyrizi, the number one dermatologist prescribed biologic in psoriasis. Visit skyrizi.com or call 1-866-Skyrizi to learn more.
- [34:43]
B
Why choose a Sleep number Smart bed Can I make my site softer?
- [34:46]
A
Can I make my site firmer? Can we sleep cooler?
- [34:50]
B
Sleep number does that cools up to eight times faster and lets you choose your ideal comfort on either side your sleep number setting. Enjoy personalized comfort for better sleep night after night. And now during our President's day sale, take 50% off our limited edition bed shop now for a limited time only at a sleep number store or sleepnumber.com.
- [35:13]
A
Hey listeners.
- [35:14]
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Hey.
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He needed to get the word out.
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Sounds like a smart move. Russell.
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How's business looking now? Sweat is pouring and so are the installs. Spread the word about your business with.
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