164: Can Your Body Make More GLP-1 Naturally?

Here's something that should change how you think about GLP-1 medications. In some people, the GLP-1 response to carbohydrate is blunted, sometimes almost entirely absent. The one macronutrient that drives insulin the hardest is the same one that has stopped telling them to stop eating it. And we have a good idea why. The cells that make GLP-1 carry insulin receptors, and when insulin stays high long enough, those cells go insulin resistant and quit responding. So the drug is supplying a signal your own gut stopped making. And that is exactly why it works best as a window rather than a destination. While the pull of sugar and refined flour is quieter, that is your chance to rebuild meals around protein and whole foods, to lift something heavy, and to make a new pattern become automatic. Habits built in that window lower your insulin. And lower insulin is what lets the L cell start making GLP-1 again. So with your clinician, the dose is able to come down because you are no longer leaning on the drug to do what your own physiology can now do on its own. This is lecture 164 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Millions of people are, are now taking a GLP-1 medication, and nearly all of the conversation around these drugs concerns how much weight comes off and how long someone has to keep paying for the prescription. I want to spend time in this mini lecture to discuss what these drugs are complementing and why some people may not be making enough in the first place, and how a person can use the time they're on the medication to To get to where they no longer need it. Let's get started. GLP-1, as you may remember from previous mini lectures, is a hormone made by the L cells in your small intestine. When a meal comes through the small intestine and these nutrients get to those cells in your, in your gut, they stimulate the cell. That's part of the stimulus that tells the cell to release GLP-1. And of course, among the myriad effects of GLP-1 is that it slows the rate at which the stomach empties, and thus it reduces the amount of nutrients that are then moving from the gut into the blood. This is GLP-1's strongest effect: the delayed stomach emptying. When obese men in a particular trial were given GLP-1 at physiological concentrations, the rate at which nutrients entered. The circulation in the blood dropped, and the insulin response to the meal also fell. A healthy GLP-1 response lowers the amount of insulin a meal demands. This is why GLP-1 is often considered, among those of us that know, as being insulin-sparing. That's an important distinction. Most people, when they talk about the actions of GLP-1, talk about it as being an insulin secretagogue, or something that's stimulating insulin. That is something it can do. But when you actually look at a full in vivo physiological response, the GLP-1 actually ends up being insulin sparing. Now, let's consider what happens in a person whose response with GLP-1 fails right when they need it most. One of my favorite studies on this topic that I like to cite is work from 1996. I've talked about this abundantly in the past. Researchers gave 6 women with obesity and 6 lean women of the same age an oral carbohydrate load on one occasion and an oral fat load on another. So a high-carb meal versus a high-fat meal. And then they looked at the gut hormone response over 3 hours. In the women with obesity, the GLP-1 response to the carbohydrate was markedly blunted. In fact, It essentially didn't respond at all, particularly when they compared that to their GLP-1 response in the lean women. So the lean women ate the high carbohydrate meal and had a significant GLP-1 response. The obese women ate the same meal and they had essentially no change from baseline. The macronutrient that raises insulin the most is therefore the same one that has stopped generating a satiety signal in the people probably eating the most of it. Flour, sugar, and other processed carbohydrates drive insulin higher and hold it up longer than anything else a person can eat. And then the person who needs the most help, the, the people who need the strongest signal telling them to stop, are the people who aren't getting it. That signal is maybe a quiet whisper, or it's completely silent. Now, the physiology with GLP-1 medication starts to be very relevant here because this now can supply— the GLP-1 agonist that's injected can supply from the outside a response that, especially to carbohydrates, that is missing in part from the inside. Based on that study that I shared with you, so these women who were not making a GLP-1 response to the most craveable carbohydrates now they can with the use of the GLP-1 drug. So let's talk now. Let's transition to talk about why the L cell isn't cooperating here. The obvious question is why the L cell stops responding to carbohydrate, and I think the answer. And the evidence takes us back to insulin. L cells express insulin receptors, and insulin itself is part of what stimulates them to release GLP-1. So earlier I had mentioned that the canonical thinking is that GLP-1 is simply released in response to nutrients that are consumed. Yes, that's certainly a big stimulus, but a part of that stimulus is insulin. When investigators examined this in L-cell models, including L-cells from mice, L-cells from rats, L-cells from humans, insulin drove GLP-1 secretion through the same signaling machinery that insulin uses in other tissues like muscle and fat. But they then made those cells become insulin resistant by exposing them to high insulin. for a prolonged period. Now, this is of course important because that's exactly what chronic hyperinsulinemia looks like, but at the level of the cell. And when they did this, when they made these cells insulin resistant because of too much insulin, the signaling response collapsed. GLP-1 secretion in response to insulin and to other stimuli just plummeted. In a mouse model then, like a, a whole animal now? With chronic hyperinsulinemia and insulin resistance, glucose that was given to the animals by mouth, so an oral glucose load, failed to produce the normal GLP-1 response. So we can effectively recreate the scenario in which some people don't have an adequate GLP-1 response by simply making the gut, those L cells, become insulin resistant. Now, more on this A separate series of experiments in different publications found that when they exposed these L cells to palmitate— that is the most dominant circulating saturated fat within the blood— they found that that also disrupted insulin signaling in the L cell, and it once again eliminated the rise in GLP-1 release that insulin should normally be producing. Now, I've talked in the past about palmitate. And lest you think that would be a reason for you to eat less, less saturated fat, no. Let me remind you that studies in humans have shown that the circulating amount of palmitate, or this dominant saturated fat, is actually more largely driven by the consumption of refined carbohydrates and the insulin response, because most of that saturated fat in the blood is actually coming from what the liver is producing. Rather than the saturated fats that a person may be just eating. Now, what's the relevance then? As just a brief tangent, it's probably the palmitate-induced ceramides. And as the ceramides are accumulating in those L cells, they are directly disrupting the insulin signal. And with a disrupted insulin signal comes a disrupted or dysfunctional GLP-1 response. So this is an interesting spin, isn't it, on insulin resistance? In the past, when I talk about insulin resistance, I'm usually focusing on things like the brain or the muscle or the liver or even the fat tissue. But we see the same thing happening here with the L cells, those, those endocrine cells in the gut whose job it is to release GLP-1 after a meal. But notice what set this in motion. Chronically elevated insulin makes the L cell insulin resistant. The L cell releases less GLP-1. Less GLP-1 means the stomach empties faster. A faster emptying stomach is going to deliver glucose to the blood more quickly. The resulting glucose spike demands more insulin, and the elevated insulin further suppresses the L cell. Can you see this vicious circle here now? What we know here is that insulin resistance can suppress endogenous GLP-1. So the body's production of its own GLP-1, and we have a very coherent cellular mechanism explaining why the carbohydrate-specific blunting shows up in the people with the highest insulin levels. Back to that 1996 study, the obese women were the ones who would have had the highest insulin resistance. They would have had the highest insulin levels. They certainly would have had the highest insulin response. To that high carbohydrate meal, all of which could act in turn to blunt an adequate GLP-1 response. Now, if there's any hope here, and I think there is some, it's that this pathway can run in reverse. If chronic hyperinsulinemia is what silences the L cell, then lowering insulin and restoring insulin sensitivity should over time allow that cell to do its own work again. Again, the person who lowers their insulin load is working toward making more of their own GLP-1. And that brings me to how I think these medications should be used, and it's not how they're usually described or prescribed. I'm not a fan of using GLP-1 drugs just as a weight loss drug. Now, of course, weight loss happens. Weight comes off because intake You know, overall consumption falls, but I submit it should be a reduction in a specific type of consumption. I'm interested in how these drugs change our cravings for and consumption of carbohydrate-rich, highly processed foods. And as those cravings are better controlled, yes, weight loss happens, but ideally new habits are being built. And a person who needs to build their own habit— this— so the person needs to build their own habits while they're on the drug. The trial data on cravings supports treating this as a window, the use of the drug, rather than a permanent state. In the 2-year semaglutide trial, they measured eating behavior and they looked at the cravings for sweet and refined carbohydrates. They did this at the beginning of the study, They did it again at 20 weeks, and then at 52 weeks, and at 104 weeks. Cravings for sweet foods improved against placebo at 6 months, and it was still improved at a year. However, by 2 years, the cravings had returned right back to where they started. So the siren call of refined carbohydrates comes back while the person is still on the drug, even still escalating the dose, and they're still paying heavily for it financially. So we have roughly what looks like a year during which the cravings for carbohydrates is more easily controlled thanks to the use of the drug. And what happens inside that period, I think, determines whether the person has changed anything. Someone who spends that time eating smaller portions of the same food that they used to eat has just bought some time and nothing else. Someone who spends that time rebuilding habits and learning to make different meals and develop different times of eating and habits around different eating— they're focusing more on protein and fats and whole foods while controlling their consumption of refined carbs— that's a person who's, yes, lowered their insulin and lost weight, but they've done so by building habits that ideally linger longer than the drug. Now, dosing is where clinical practice and metabolic reasoning tend to part company. And this is my opinion, of course, rather than evidence from a specific trial. So this is just insight, as usual, from your friendly neighborhood scientist. The prescribed use of the GLP-1 drugs escalates toward high maintenance doses because the registration trials were designed to produce the largest possible weight loss. So the studies that were used to justify the use of the drug— high doses also produce more nausea, they have more overall food aversion, and more of that kind of flat, apathetic state in which nothing sounds appetizing. Now, some people mistake that for success, but someone who can barely eat and doesn't care to do anything and get off the couch is not building a new way of eating or living. What I would rather see is a dose low enough to take the edge off carbohydrate craving while leaving a person able to still have some hunger, some appetite, some interests in life so they can sit down at a meal and choose to eat something differently. So the goal, I think, should be a calmer and more controlled relationship towards the most tempting foods in which someone chooses smarter protein and fat options while noticing that things like bread and sugar have less temptation than they used to. But during all of this time, they're simply focused on developing new habits. Discipline like this that can be repeated and developed through repeated practice under conditions that overall make the practice possible is the best use case. Now, there is a practical argument here as well. Side effects climb with the dose, and people stop taking these drugs because they feel unwell. So any plan that requires feeling sick indefinitely is going to fail outside of— out of the trial, outside of a very specific study window. Now, one last thought on this before I talk a little bit about lean mass and the concerns there that I think are misplaced. One other way to express kind of all of what I'm getting around here is that the dose should be low enough that a person is able to control their cravings for carbohydrates, but they still have to think about it. It's a little difficult for me to describe. There's a little nuance there, but you should still feel some hint of those temptations where the muscle in your brain, that, that discipline, the mental discipline you have to manifest and exert in order to overcome that temptation should still have to be worked. I hope I'm articulating that in a way that makes some kind of sense. So you should be using the drug, in my view, at a low enough dose. That you still feel the temptation towards that craving. You can you can recognize it that that old enemy that has plagued you for so long, and yet there's enough of you, not just the drug. There's enough of your own will and discipline and agency that you can say, "I'm not going to do that." I think that is an important thought that you are developing. The mental muscle that helps you, that you're getting it stronger so that as the— when the day comes that you're starting to wean off the drug, you have that mental muscle in place that as it can flex and work, it's strong enough now to help you continue to say no to that temptation. Okay, now a little bit about muscle because it's certainly the concern that is raised the most often. In some of the trials that have been published, about a quarter to a third of the weight that has been lost on people with these drugs, it shows up as lean tissue or lean mass or fat-free mass on a body scan. But lean mass is everything that's simply not adipose tissue. That means it includes water, it includes glycogen, just the storage form of— stored form of glucose. It even includes a little bit of connective tissue, some other internal organ mass, and, and the fat, even the fat-free portion of adipose tissue itself. That last component is kind of interesting, and it matters more than people realize because fat tissue is a living tissue with its own blood supply, its own protein pool, its own water and fluids, as modest as that may be. And the nonfat part of it Can account for something like 15 to 20% of the adipose tissue mass. So losing 12 kilograms of adipose tissue actually also brings with it the loss of roughly 2 kilograms of material that would be scored or marked as lean mass, and none of that would have been muscle right there. That accounting alone can explain some of the number that people find so alarming, but even more interesting. A lot of that so-called lean mass loss is, um, may actually be fat, but not fat from your fat tissue, but fat from other tissues like your liver or your kidneys. A liver shedding fat and glycogen, which it does as a person is just eating less, especially fewer carbs, and losing weight. The, the liver's becoming smaller. because of the reduction in fat and glycogen, which is a perfectly fine outcome. In fact, the loss of the liver fat is a desirable outcome. But the scan is going to detect this as fat-free mass because it's not the adipose tissue. It's not your conventional fat tissue. This is fat stored in other tissues, including even muscle. The muscle can be too fat in people who are overweight or obese. And as the muscle fat is reducing, that can be marked as a reduction in Lean mass. Importantly, trial after trial that has actually looked at muscle function shows some pretty positive results. In particular, one 12-month study following 106 patients with severe obesity on a GLP-1 drug, they found that grip strength rose by 4.5 kilograms, and the share of patients meeting criteria for sarcopenic obesity— so too much fat too little muscle fell from 49% to 33%. So people got stronger while the lean mass line, perhaps on the report, went down. Where the concern does have a little bit of substance is in older adults and in anyone dropping weight very rapidly at the high doses while they're barely eating any protein and they're barely getting off the couch. That's just, I think, one more argument for the lower dose. Where you still have some interest in getting up and going to the gym, you still have some interest in eating, and that just when you are eating, you're eating protein-rich foods filled with healthy fats. Okay, now to the evidence everyone points at when they argue these drugs must be permanent. Adults in an extension group of a GLP-1 trial, so a subset of the trial, these are people who agreed to be followed for a year after treatment ended. They lost a mean of just over 17% of body weight across 68 weeks on the weekly drug. That's pretty significant. They then stopped both the drug and the structured lifestyle support and regained roughly 12 percentage points over the following year. So net loss from baseline at week 120 in this study was about 6%. So approximately two-thirds of what had been lost came back. Not surprising, improvements in things like blood pressure, blood lipids, inflammatory markers, A1C drifted back toward baseline for most measures, with blood pressure returning completely while still some other benefits across lipids and inflammation lingered after a year. A second withdrawal study found the same pattern but from a slightly different angle. After a 20-week run-in, on the drug, people randomized to continue held where they were or extended their loss, while those switched to placebo regained weight over the following 48 weeks despite ongoing lifestyle counseling. So these results get summarized as proof that obesity requires lifelong medications. There's a better interpretation that I think fits the physiology better. If pharmacological appetite suppression Was the only thing that changed, then removing it returns the previous eating pattern, and the previous eating pattern returns the previous weight. What those trials demonstrate is that leaving the drug without having changed—I would say carbohydrate-driven eating—is a poor plan, which is a different statement from saying the drug can never be left. So a deliberate exit off the drug starts with defining success before the first injection. If success is the lowest weight at the highest tolerated dose, a person has optimized for a number that will disappear when the drug does. If success is a stable pattern of eating that a person can maintain without a prescription, Then the drug has a finish line, and everything done during the months on it points toward that line. The second piece is being deliberate during the craving window. While sweet and highly processed food has less pull, that is the moment to remove the things that were hardest to give up— all of those refined starches and sugars, those, those processed packaged snacks. Meals should be built around protein and whole fats. And remember that 1996 paper, fat consumption actually generated a modest but still roughly normal L-cell response, the GLP-1 response. It was specifically the carbohydrate response that failed. So the foods you're moving toward are the ones your own gut can still respond to. The 3rd component is the one this whole lecture, I hope, has been building toward. Lowering refined carbohydrate, improving things like sleeping habits, resistance training, all reduce the chronic insulin load. And reducing that insulin load is the route to improving your own GLP-1. Less insulin resistance at the L cell means a better chance that meal-stimulated GLP-1 recovers on its own. The drug acts as a cover for a weak signal while a person removes the dietary pattern that potentially weakened it. In the first place. Now, another principle here: the reduction in dose as a person wants to start weaning themselves off a GLP-1— it needs to be planned with a clinician rather than executed by abruptly stopping at the peak dose during a difficult week. Come down gradually. You're paying attention to your cravings, you're paying attention to your meal patterns and how food is How your interaction and relationship with food is changing, or how you're behaving around your food. Again, I'm not your clinician. Work with your clinician to find a good way to reduce the dose. A GLP-1 medication is a tool for carbohydrate craving control. It is leaned on for a specific period of time, and the destination, the outcome, the end goal is a gut that is capable of making more of its own GLP-1 because the L cell is no longer restrained. with insulin resistance, and you have new habits in place that can help keep it that way. Class dismissed. Until next time, more knowledge, better health.