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Hey everyone, it's Mikki here. You're listening to Mini mikkipedia. And today I wanna tackle one of the most polarizing debates in nutrition science. Is fat gain driven by calorie excess or is it driven by insulin resistance? And before we dive in, I do wanna say that this debate has been raging in academic journals, on social media, and in clinical practice for years. And I really wanna look at what the actual mechanisms are, what the research might show,

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and where both sides get things right or wrong. So it's pretty detailed, but I hope that at the end of this, you come away with more of an idea of my perspective and not just me, but where many people's perspectives are on this topic and why it isn't an either or. However, if you spend any time online, you'll hear two very confident positions. One camp says calories are all that matter. It's energy balance, it's thermodynamics, end of story.

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The other camp says, no, insulin drives fat storage and hunger. People overeat because insulin is dysregulated, not the other way around. The carbohydrate insulin model explains obesity better than the energy balance model. And here's what I want to make clear from the start. I think both camps are pointing to real physiology. Not just I think, they are. The problem is that neither tells the whole story on its own. So today, I'm going to walk you through

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what the carbohydrate insulin model of obesity actually proposes, the cellular and molecular mechanisms of insulin resistance, what happens during refeeding after energy restriction using classic studies like the Minnesota starvation experiment, and ultimately how we can integrate both perspectives into something more useful. Before I kick on into the carbohydrate insulin model of obesity, just to be clear, and I'm sure you know, is that the

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Energy balance equation of weight loss is that if you burn more calories than you consume, you will lose weight. End of story. Calories at the end of the day are king. So the carbohydrate insulin model, however, is a framework that challenges this conventional thinking about obesity. The carbohydrate insulin model, or CIM, was most comprehensively articulated in a paper 2021 by the American

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in American Journal of Clinical Nutrition by David Ludwig, Gary Torbs, and colleagues from Harvard, Duke, and other institutes. The CIM proposes a reversal of causal direction from what we typically think. The traditional energy balance model says people who eat too much and move too little create a positive energy balance which results in fat gain. The CIM flips this around and says hormonal responses to high glycemic load carbohydrates, dry fat deposition in adipose tissue, oh

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and this drives positive energy balance through increased hunger and decreased energy expenditure. In other words, overeating becomes a consequence of fat accumulation, not the primary cause. So here's the proposed sequence of events. When we consume rapidly digestible, high-glycemic load carbohydrates, like refined starches, added sugars, refined processed carbohydrate foods, several things happen.

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First, we get a rapid spike in blood glucose. This triggers a substantial insulin response from the pancreas. Elevated insulin does several things simultaneously. It promotes glucose uptake into muscle and liver for glycogen storage. It activates de novo lipogenesis, which is the synthesis of new fatty acids from glucose. And it suppresses lipolysis, the breakdown of stored triglycerides in adipose tissue. Now here's the critical part according to the CIM.

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When insulin is chronically elevated, especially in the context of insulin resistance, which we'll get to in a minute, fat becomes trapped in adipose tissue. Lipolysis is suppressed, meaning stored energy can't be easily accessed. This creates what Ludwig and colleagues call a pull on circulating nutrients into fat cells. Energy that could be used by lean tissues like muscle gets preferentially partitioned into that adipose tissue storage, i.e. you store fat.

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There are two things that happen as a consequence. First, circulating fuel availability drops. Even though you have plenty of stored energy in your fat tissue, your muscle and other tissues can't access it efficiently. This creates a metabolic signal of energy deficiency. Second, this energy deficiency drives compensatory responses, increase hunger through effects on hypothalamic circuits, and reduce energy expenditure through metabolic adaptation.

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Even though you've got all the stored energy, your body can't access it. So it thinks it's in an energy deficit and it's going to do things to seek out more calories and conserve more energy. So according to the CIM, you're not getting fat because you're eating too much. You're eating too much because the hormonal environment is driving fat storage and creating a state of relative energy deprivation in your lean tissues. So how is this distinct from the energy balance model?

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What is important to note is, and Ludwig and colleagues are very clear about this, the CIM doesn't violate thermodynamics. Energy balance still must be positive for fat gain to occur. The difference is the direction of causation. The CIM says the hormonal changes come first, driving the energy imbalance rather than energy imbalance being the primary driver. So there is solid mechanistic support for several components of the CIM.

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Animal studies clearly show that diet composition affects body composition independent of calories. You can feed animals isocheloric diets with different macronutrient compositions and see different fat accumulation. Insulin does suppress lipolysis. This is not controversial. When insulin is elevated, hormone-sensitive lipase and adipose triglyceride lipase activity decreases, and this reduces fat mobilization.

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and the breakdown in use of fat as a fuel. In insulin resistant states where with chronic hyperinsulinemia or high insulin, there is impaired access to stored fat. We see this clinically. And there's evidence that low glycemic load diets and low carbohydrate diets can produce greater weight loss than low fat diets in some studies. And typically what you see, and there was a trial

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cannot recall the author, but it was the A to Z trial of diets. And it found that those who were insulin resistant, fed better on a low carbohydrate diet for fat loss. Whereas people who were insulin sensitive could choose to lose weight on either a high carb or a low carb diet. It didn't make a difference for them. However, and this is important, several predictions of the strong version of the CIM don't hold up well.

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If insulin alone drove fat gain regardless of energy balance, we should see fat gain at calorie maintenance when insulin is high. We don't see this consistently in controlled studies. High carbohydrate populations like traditional Asian cultures consuming white rice should show higher obesity rates according to the model. They don't. Note, I'm talking about traditional people who are eating traditional diets, not those who have been westernized.

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Overfeeding studies comparing high fat versus high carbohydrate diets show that fat overfeeding actually produces similar or greater fat gain than carbohydrate overfeeding despite lower insulin secretion. And I know people who have gotten fat on a keto diet actually. We will see when we're talking about the refeeding studies, the pattern of weight regain after dieting doesn't match what you'd predict if insulin were driving everything.

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So the CIN points to real mechanisms that matter, but it doesn't appear to be the complete explanation for obesity. So now let's talk about insulin resistance itself, because this is central to understanding how insulin dysfunction contributes to weight problems. At a clinical level, insulin resistance means you need higher than normal insulin concentrations to maintain normal blood glucose levels. At a cellular level, it's defined as insufficient strength of insulin signaling from the insulin receptor

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through to the final substrates of insulin action in target tissues, primarily skeletal muscle, liver, and adipose tissue. So let me walk you through normal insulin signaling first so you understand where things go wrong. When insulin binds to the insulin receptor on a cell surface, the receptor undergoes autophosphorylation. It phosphorylates itself on tyrosine residuals. This activated receptor then

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phosphorylates insulin receptor substrate proteins, particularly IRS-1 and IRS-2. Stay with me. These IRS proteins activate phosphatidyl-inositol-3 kinase, or PI3K. PI3K activates AKT, also called protein kinase B, and this is really the master regulator here. In muscle cells, AKT promotes translocation of glute 4,

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transporters to the cell membrane, allowing glucose uptake. It also activates glycogen synthase, promoting glycogen storage. In the liver, AKT suppresses gluconeogenesis by phosphorylating and inactivating FOXO-1, which is a transcription factor that drives production of gluconeogenic enzymes. And AKT also activates lipogenesis through a couple of different proteins. In adipose tissue, AKT promotes glucose uptake.

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Lipogenesis and crucially suppresses lipolysis by inhibiting hormone sensitive lipase. So that's the normal pathway. Insulin does a number of things. You can see why dysregulated insulin can have such consequences. The most well-supported mechanism for insulin resistance involves accumulation of lipid metabolites in muscle and liver. When you have chronic positive energy balance, i.e. eat too many calories,

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particularly with a high fat intake, or when adipose tissue becomes dysfunctional and releases excess fatty acids, these fatty acids enter muscle and liver cells. Inside cells, these fatty acids are converted into bioactive lipid metabolites. So these metabolites, the diacylglycerols, DAGs, activate novel protein kinase C isoforms. And there are two different types, theta and epsilon, in the muscle and the liver.

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These activated PKCs phosphorylate the insulin receptor in IRS proteins, which I mentioned earlier, on serine and threonine residues rather than tyrosine. So this action blocks insulin signaling. So it's like putting this molecular break on the pathway. So when the IRS-1 is serine phosphorylated, it can't be properly activated by the insulin receptor, so downstream signaling is impaired.

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This also happens through a couple of other different mechanisms with a couple of other different proteins. The end result though, in muscle, impaired glute four translocation, reduced glucose uptake and reduced glycogen synthesis. In the liver, impaired suppression of gluconeogenesis. So you get excess hepatic or liver glucose production even when insulin is elevated. And paradoxically,

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Because some of these pathways remain active, you can get continued fat synthesis or the creation of fatty acids. There are actually other factors which contribute. There's mitochondrial dysfunction, which can lead to incomplete fatty acid oxidation, creating more lipid intermediates that interfere with the signaling. There is inflammation, particularly in the adipose tissue, which leads to the release of these pro-inflammatory cytokines like TNF-alpha, IL-6.

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which promotes insulin resistance through other pathways such as NF-kB. And there's emerging evidence for roles in autophagy dysfunction, oxidative stress, and even gut microbiota in modulating insulin sensitivity. There's a lot going on guys, and what you end up with is a vicious cycle. Insulin resistance leads to compensatory hyperinsulinemia as the pancreas tries to overcome the resistance. So that means that

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that you get even more insulin in your system. This promotes further fat storage, particularly in the ectopic depots like the liver and the muscle. And this will worsen insulin resistance. Insulin resistance impairs adipose tissue function, leading to more fatty acid release. These fatty acids worsen insulin resistance in muscle and liver. And round and round it goes. So what's the connection between appetite and energy regulation then? The CIM,

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proposes that chronic hyperinsulinemia and insulin resistance don't just affect glucose metabolism, they affect appetite regulation. Insulin normally acts on the hypothalamus to suppress appetite, but in insulin resistance states, you can develop central insulin resistance, through the insulin signaling in the brain becomes impaired. At the same time, there's impaired leptin signaling, which often occurs alongside this insulin resistance.

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Leptin is produced by our fat cells and it normally signals satiety. But leptin resistance means the brain doesn't see the body's fat stores properly. You do also see alterations in ghrelin, our hunger hormone, with some evidence that ghrelin levels are dysregulated in insulin resistant states. The overall effect is disrupted appetite control, increased hunger despite adequate or excess energy stores, reduced satiety signaling and altered food reward processing.

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So the likes of Ben Bickman, who I love by the way, and others such as David Ludwig, are absolutely right that insulin resistance creates this metabolic environment that promotes overeating. That mechanism is real. But how much does this mechanism contribute to obesity at a population level compared to other factors? And can we intervene on it effectively? So the Minnesota starvation experiment is one that people often refer to when they're looking at

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testing whether insulin alone drives fat regain or whether energy balance matters more. So this is a study conducted by Ansel Keys. Yes, he is the same Ansel Keys that proposed that saturated fat causes heart disease. But this was done in 1944 and 1945 during World War II. So Keys recruited 36 conscientious objectors, healthy young men for a grueling year-long experiment.

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The goal was to understand the physiology of starvation and the best methods for refeeding, which would be needed for millions of starving civilians in war-torn Europe. The experiment had three phases. They had 12 weeks of normal eating at about 3,200 calories per day to establish baseline. They had 24 weeks of semi-starvation at about 1,800 calories per day with a diet mimicking what was available in Europe. Potatoes, swede or rutabagas, turnips, bread, macaroni.

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and they had 12 weeks of controlled refeeding, with some men continuing for an additional eight weeks of unrestricted eating. So during that 24-week starvation phase, the men lost an average of 25 % of their body weight. But the changes went far beyond just weight loss. Basal metabolic rate dropped by about 40%. Heart rate fell from 55 beats per minute to around 35. Body temperature decreased. They became extremely cold and tolerant. Psychologically, the effects were dramatic.

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The men became obsessed with food. They collected recipes. They hoarded cookbooks. Some men even changed their career plans. Several who had never been interested in food ended up becoming chefs after the study. They experienced severe depression, irritability, difficulty concentrating, and loss of libido. The psychological impact was profound. So interestingly, while weight fell 25%, the proportion of body fat fell almost 70%, and muscle mass decreased about 40%.

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So they lost both fat and significant amounts of lean tissue. Now, with the refeeding, Kees divided the men into four groups during the controlled feeding phase. Each group received different calorie levels, 400, 800, 1200, or 1600 calories above their starvation intake, which if you remember is 1800 calories a day. The men assigned to the lower calorie groups, those getting only four or 800 calories, showed almost no improvement. They remained depressed.

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hungry and weak. Even though insulin would have risen with increased food intake, this modest increase wasn't enough to support recovery. And, for what it's worth, this is one of the arguments against reverse dieting. Keyes eventually concluded the recovery from starvation required about 4,000 calories per day, substantially more than they'd ever eaten before starvation. This is a really important point. Pre-starvation intake levels weren't sufficient for recovery.

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During refeeding, metabolism speed back up, but only in the groups receiving the highest calories. Those with the greatest caloric intake saw the largest rise in basal metabolic rate. So what about the pattern of weight regain then? And this is what's fascinating about body composition during recovery. By the eighth month of rehabilitation, the men who had fully recovered were back to about 100 % of their original body weight, but they had approximately 140 % of their original body fat.

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So in other words, they regained weight in a different composition than they lost it. They lost fat and muscle. They regained mostly fat initially, and it took much longer for muscle mass to recover. And I've spoken about that in other podcasts, just on normal dieting, actually, and maintaining weight loss. This fat overshoot phenomenon has been observed in multiple studies since. After significant weight loss, the body appears to prioritize fat repletion over muscle repletion during early refeeding. And what about insulin?

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So if insulin alone was driving fat storage, as the strong version of the CIEM suggests, then during refeeding, any increase in calories should immediately produce fat gain because insulin rises when you eat, especially carbohydrates. That's not what happens. In fact, modern controlled refeeding studies show that during early refeeding after energy restriction, insulin does rise sharply, but the priority is restoration of glycogen stores, which is muscle carbohydrate.

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and lean tissue, i.e. organs, etc. Not immediate fat gain. Muscle glycogen can be severely depleted after prolonged dieting. And studies using muscle biopsies show that glycogen-depleted muscles have dramatically enhanced insulin sensitivity. When you refeed, glucose is preferentially taken up by muscle for glycogen repletion, which makes perfect sense evolutionarily. Glycogen is immediately usable energy. You need it for survival.

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for hunting, for escaping predators, for basic function. Fat storage can wait. A 2015 study published in the AJCN replicates aspects of the Minnesota experiment. 32 non-obese men underwent sequential overfeeding, one week at 50 % above energy needs, caloric restriction, three weeks at 50 % below energy needs, and then refeeding, two weeks at 50 % above energy needs. Now note this study is quite a bit shorter.

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probably because they had ethics boards that they had to go through to get the studies to be signed off. During the restriction phase, these men lost six kilograms. Fat mass and fat-free mass both decreased. Basal metabolic rate dropped 266 calories a day. Insulin dropped by 54%. Leptin by 44. T3 thyroid hormone dropped 39. These are all expected adaptations to dieting. They're quite significant because the

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caloric restriction was quite severe. During refeeding, they regained three and a half kilograms over two weeks. Now, if insulin were the primary driver, we'd expect fat to be regained immediately and preferentially because insulin rises with refeeding. But here's what the researchers found using detailed body composition analysis. Glycogen stores were depleted first, as noted earlier. Water weight increases, glycogen was stored, with glycogen pools water with it.

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lean tissue began to recover, fat mass did increase but only when energy intake exceeded what was needed for glycogen repletion and lean tissue restoration. Critically, insulin sensitivity improved during refeeding, even though insulin levels rose. This was the opposite of what you'd predict if high insulin inherently caused insulin resistance and fat gain. Look, multiple studies have shown weight loss via caloric restriction improves insulin sensitivity.

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The Journal of Clinical Endocrinology and Metabolism found that just seven days of caloric restriction produced substantial improvements in insulin sensitivity, even before significant weight loss occurred. Research in women who successfully maintain weight loss for extended periods showed they had better insulin sensitivity than BMI-matched controls, who had never lost weight, independent of diet composition and physical activity levels. And the mechanism appears to be the reduction in ectopic fat in liver and muscle, so fat in the liver and muscle.

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you lose fat from these tissues, lipid metabolites like diacylglycerols, which I mentioned earlier, decrease. Insulin signaling improves and sensitivity is restored. However, insulin sensitivity does worsen again if weight is regained rapidly or if it's accompanied with loss of lean muscle tissue that wasn't recovered, continued high stress and poor sleep, sedentary behavior,

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or a return to highly processed high-glycemic low diets. In this context, you can reenter this vicious cycle of insulin resistance, hyperinsulinemia, and impaired fat mobilization. But the key point is this. The initial response to refeeding after restriction is improved insulin sensitivity and preferential restoration of glycogen and lean tissue, not immediate fat gain driven by insulin. This pattern suggests that while insulin is important for nutrient partitioning,

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Energy balance is still the primary determinant of whether net fat gain occurs. So where does this leave us? How do we make sense of all of this? I think the most physiologically accurate way to frame it is that calories set the boundary conditions. They determine the direction. You cannot gain fat without an energy surplus. You cannot lose fat without an energy deficit. That, I do feel, is non-negotiable. And not just I feel. Studies show it's non-negotiable.

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The Minnesota study makes this crystal clear. Even with high insulin from refeeding, men in the lower calorie groups didn't recover. They needed a substantial caloric surplus above baseline to restore body composition. The refeeding studies show that insulin rising during refeeding doesn't cause immediate fat gain. Fat gain occurs when energy intake exceeds what is needed for that glycogen repletion and lean tissue restoration.

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But insulin sensitivity determines the difficulty of maintaining energy balance. And this is where the CIM does make an important contribution. Insulin resistance, especially with chronic hyperinsulinemia, makes it much harder to maintain energy balance because it increases hunger through the impaired hypothalamic insulin and signaling. You feel hungry even when you have adequate stored energy. It reduces satiety, signaling.

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You don't feel satisfied after eating. Meals don't suppress appetite as effectively as they should. It impairs access to stored fat. Even in a calorie deficit, if lipolysis is suppressed by high chronically high insulin levels, your body struggles to mobilize fat for fuel. This makes a deficit feel more extreme because you don't have that stored fuel to tap into for energy. It can reduce energy expenditure through metabolic adaptation.

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and it affects food reward processing in the brain, potentially increasing preference for high calorie, high carbohydrate foods. So insulin resistance doesn't cause fat gain independent of calories, but it shapes the physiological and psychological context in which eating behavior occurs. So it narrows your margin for error. When you improve insulin sensitivity through weight loss, through exercise, through dietary changes, through reducing ectopic fat, several things happen.

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Appetite becomes better calibrated. Hunger and satiety signals work more effectively. You can access stored fat more efficiently. The same calorie deficit feels less harsh because your body can tap into fat stores. Nutrient partitioning improves. More of what you eat goes to muscle glycogen and protein synthesis rather than fat storage. Metabolic flexibility increases. You can switch between fuel sources of fat and carbohydrate more easily.

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And all of this makes maintaining a calorie deficit more sustainable or maintaining weight loss more achievable. And the integrated model, looking at CIM and energy balance, helps explain why different dietary interventions work for different people. As I said, low carb diets can be very effective for people with severe insulin resistance and high per-insulinemia or higher chronically high insulin levels.

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By reducing insulin secretion and improving insulin sensitivity, these diets make it easier to maintain a deficit in excess fat stores. But for someone with good insulin sensitivity, a low carb diet offers no metabolic advantage for fat loss at the same calorie intake. Low glycemic load diets may be helpful by reducing that postprandial or post-meal insulin spike and improving satiety, making calorie control easier. And you know how I feel about protein. High protein diets work partly by increasing satiety.

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and partly by preserving lean mass, both of which make energy balance easier to maintain. In exercise vada panacea, this improves insulin sensitivity directly by increasing muscle glucose uptake, reducing that intramuscular lipid in a non-athlete individual, and improves mitochondrial function. It also preserves or builds muscle mass, which is critical for long-term metabolic health. So the practical takeaway then?

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For someone struggling with weight, the question isn't, should I focus on calories or should I focus on insulin? The question is, what's my current metabolic state and what strategy will best address it? If you have signs of insulin resistance, elevated fasting insulin, high triglycerides, low HDL, fatty liver, PCOS, difficulty losing weight despite reasonable calorie deficits, then addressing insulin resistance could be part of the strategy.

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That might mean a lower carb diet focusing predominantly on vegetables with a little bit, maybe, of fruit and starch. Definitely more protein, resistance training to build muscle, strategies to reduce liver fat, adequate sleep, and stress management. But those strategies still need to create an energy deficit for fat loss to occur. They just make that deficit more sustainable and more effective. And then if you have good insulin sensitivity, to be fair, most of the strategies I mentioned are strategies for you as well.

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But the focus can be more on overall energy balance, satiety and behavioral strategies. So here's where we land. The debate between calories versus insulin, I do think is a false dichotomy. It's not an either or proposition. Energy balance is the ultimate constraint, just cannot violate thermodynamics. But insulin resistance is a real biological force that shapes hunger, energy expenditure, nutrient partitioning and the subjective experience of maintaining energy balance.

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The refeeding studies show us that even with rising insulin, the body will prioritize restoration of glycogen and lean tissue before fat storage. They show us that insulin sensitivity often improves after weight loss. They show us that insulin is more complex than just insulin. They show us that the story is more than insulin makes you fat. But they also show us that after starvation or severe restriction, recovering metabolic health requires substantial energy intake, often more

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than before restriction. And they show us that the body defends against energy deficits through powerful compensatory mechanisms. So, practical application. If you want to lose fat, you need a calorie deficit, but you want to create that deficit in a way that preserves your insulin sensitivity, maintains muscle mass, and keeps hunger manageable. If you have insulin resistance, addressing that through diet quality, exercise, sleep, and stress management, then that diet quality is about a lower-carb diet.

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This will make everything easier. And if you've lost weight, understand that maintaining that loss requires sustained attention to both energy balance and metabolic health. Can't just go back to old patterns and expect to maintain a lower weight. So I do think that the CIM carbohydrate insulin model and energy balance model are pointing to true things, but the synthesis is more useful than either extreme. So thanks for sticking with me on this much more detailed episode than usual.

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but I hope it gives you a little bit more nuanced understanding of how these systems actually work. Questions, hit me up. I'm in my DMs over on Instagram @mikkiwilliden, also there on threads and X, Facebook @mikkiwillidenNutrition, or head to my website, mikkiwilliden.com, book a one-on-one call with me. All right, team, have a great week. See you later.