Sugar Doesn't Cause Diabetes, and Ketosis Doesn't Reverse It

One of the only clinical diagnostic criteria for type II diabetes mellitus (T2DM) is a persistently elevated blood glucose (BG) level. Chasing down the cause of this BG elevation has been the subject of an enormous investigation for many decades. Many researchers disagree about the ultimate pathogenesis and pathophysiology of the disease state, and in the 21st century we have the fortune of being able to see these disagreements play out in real time online. Actual PhDs doing actual pivotal research have taken to using social media platforms like Twitter and publicly accessible academic platforms like Research Gate to debate the merits and consistency of the available data. In these places you will find an enormous breadth of opinions— some plausible, some preposterous, and some that surely reflect reality quite accurately.

Some people argue that sugar causes the disease. Others blame fat and animal products. Some even say it is merely an inescapable consequence of aging. People have many conflicting opinions about T2DM. I'm not a researcher. I'm not an expert. But for what it's worth, I'd like to share my thoughts on this subject. To do this, I want to use a bit of a different format with this post. I'm going to state my position in point form, and then I'm going to defend it by breaking each point down. So let's get to it.

1. Fatty acids cause insulin resistance, but glucose shows it to you.
2. Diabetes is a disease of excess calories.
3. Carbohydrate restriction is therapeutic, not curative.
4. Ketosis is functional diabetes, therefore also therapeutic.

Before we dive into dissecting each one of these points, we need a little crash course in cellular physiology. It won't be painful, I promise. We're just going to briefly review the Randle cycle. 

The Randle cycle is basically a series of biochemical pathways inside of your cells that signal which fuel substrates are to be burned. In one arrangement, a cell will preferentially burn glucose. In the other arrangement, a cell will preferentially burn fatty acids (FA). Under normal conditions, the arrangement is dependent on the relative proportions of each available substrate. For example, after a carbohydrate rich meal, the cycle will favour burning carbohydrates. After a fat rich meal, the cycle will favour burning FAs. Here we see a diagram of these mechanisms in action. 

On the left and right we see glucose and long-chain fatty acids (LCFA) being transported into the cytosol of an adipocyte. Here we see how the availability of either substrate dictates which substrate is to be burned as fuel. Let's start with glucose.

When glucose enters through glucose transporter type 4 (GLUT4), it is driven through an enzymatic pathway known as glycolysis and cleaved in half. This gives us two three-carbon units of pyruvate, which enter the mitochondria. Not seen here, one pyruvate goes on to participate in the Citric Acid (TCA) cycle, and the other pyruvate gets converted to a two-carbon unit called Acetyl-CoA by the pyruvate dehydrogenase complex (PDH). The extra carbon is lost as CO2. If there is too much pyruvate, this drives up Acetyl-CoA and inhibts PDH. This is a form of negative feedback. When the PDH complex is inhibited by Acetyl-CoA, excess pyruvate is shunted out of the cell as lactate.

When LCFA enter the cell, they're broken apart into two-carbon units called long chain fatty Acyl-CoA (LC-FAC) by long chain fatty Acyl-CoA synthetase (LC-FACS). These enter the mitochondria through carnitine palmitoyltransferase 1 (CPT1). From there, each LC-FAC is converted to Acetyl-CoA through beta-oxidation (β-ox). Notice how excess Acetyl-CoA does not have a negative feedback system inside the mitochondria. Instead, excess Acetyl-CoA drives up mitochondrial citrate, and thus drives up cytosolic citrate. Cytosolic citrate is the signal to inhibit GLUT4 and phosphofructokinase 1 (PFK-1). This means that if enough citrate is generated, glucose is both inhibited from entering the cell and inhibited from entering glycolysis.

Further downstream we discover that FAs do in fact have their own negative feedback system. The consequence of continuing to drive up cytosolic citrate is to eventually produce Malonyl-CoA. Which stimulates fatty acid synthase (FAS) for the purposes of storing excess fatty acids through the synthesis of new triglycerides (TG). Malonyl-CoA also inhibits CPT-1, preventing LC-FAC from being transported into the mitochondria.

There we go. We now understand the basics of the Randle cycle. Now let's talk about how this is fundamentally relevant for understanding my position on T2DM.

1. Fatty acids cause insulin resistance, but glucose shows it to you.

Let's refer back to the graphic above. We know that FAs in the cell uniquely inhibit GLUT4. It all depends on the relative proportions of FAs to glucose that are available to the cell. The more FAs you have in the cell, the more resistant that cell will be to translocating GLUT4 to the cell surface to take up glucose. Thus, the activity of the PDH complex will be impaired as the cell begins to preferentially burn FAs as fuel [1]. This impairs oxidative glucose disposal and increases non-oxidative glucose disposal [2]. Essentially, when you eat a high-fat diet, you lose glycogen in your liver, your cells will make the switch to FA-burning, and oxidative disposal of glucose will go down. When you finally do get a bolus of glucose, it will serve to replete glycogen stores and will be disposed of through non-oxidative pathways. More astute individuals in the low-carb community will recognize this whole situation as "physiological insulin resistance", which they rightly state is a non-pathological state.

However, since merely increasing the availability of FAs to a cell will powerfully reduce its sensitivity to insulin [3], we can surmise that the relative insulin sensitivity of a cell is dictated by its FA burden. As such, if one's cells are overburdened with FAs, glucose concentrations in the blood will be higher due to the Randle cycle's effects on insulin sensitivity and glucose disposal [4]. When you challenge the body with glucose while the body is attempting to burn through a surplus of FAs, glucose is going to have to wait outside the cell in the blood until those FAs are burned. When we see this happen in T2DM, it is very tempting to blame the carbs in the diet as being the ultimate cause of the persistently elevated glucose we see in the blood. But the glucose isn't actually to blame. The elevated BG is merely reflecting the competition between energy substrates based on the relative availability of each substrate to the body's cells, particularly the adipocytes. When there is too much fat, glucose cannot be burned.

Am I attempting to imply that a high-fat diet causes T2DM? No, not at all. But the effects of high-fat feeding on glucose metabolism gives us insight into the roles of carbs and fats in T2DM. Which leads me to my next point.

2. Diabetes is a disease of excess calories.

We can confidently say that the symptoms of T2DM are made uniquely worse by carbohydrates, as removing them has profound utility with regards to symptom management [5]. Nobody can really dispute this credibly at this point. However, there is a massive amount of evidence indicating that the primary source of insulin resistance in T2DM at the cellular level is the FA burden of the actual cell [6]. So, what determines the FA burden of a cell? By and large, the answer is every Taubesian acolyte's least favourite word—calories. Calories, calories, calories. 

But isn't insulin a fat storage hormone? Aren't the carbohydrates responsible for sequestering fat into our fat tissue? Yes and no. Insulin stores fat and displaces lipolysis proportionate to the energy provided by the carbohydrates that stimulated the insulin. So yes, if you were somehow able to learn the history of each TG in your adipose tissue, you'd discover that the vast majority of those TGs originated as FAs consumed in the diet. However, insulin wasn't really required to store any of them. If we refer back to the diagram of the Randle cycle for a moment, we discover that merely overburdening an adipocyte with FAs will stimulate TG synthesis. Whether those TGs were stored in the adipocyte through insulin or stored passively by merely consuming fat, it is the total calorie balance of the diet that determines the TG content of the adipocyte at the end of the day [7].

There is a growing body of evidence that suggests that sufficient caloric restriction leads to the remission and perhaps the reversal of T2DM in a manner that is entirely predicted by fat mass loss [8][9]. Fat mass loss is dictated by caloric intake. No more, no less. 

So, to recap. If you overeat carbohydrates, you will indeed store every ounce of fat you consume. However, calorie for calorie, if you overconsume fat, you will drive up TG synthesis and store every ounce of excess fat you consume as well. At the end of the day, total calorie intake minus your total energy expenditure determines fat loss or fat gain. If you overeat enough calories chronically, eventually your adipocytes become so overloaded with FAs that they're indefinitely stuck in the FA-burning position. It is similar to only being able to turn one handle on a faucet, when you should be able to turn both.

3. Carbohydrate restriction is therapeutic, not curative.

Let's go back to BG for a moment. Why is carbohydrate restriction beneficial for T2DM? If it's the fat inside the cell that's causing the problem, why should there be benefits to restricting carbohydrates at all? The short answer is that consuming excess fat carries fewer short-term negative symptoms when compared to glucose in the context of T2DM. When we consume excess fat, it may be readily stored in a number of places. Even though some of these storage depots are problematic, like the liver or even the blood, fat stored in these places causes very few noticeable symptoms under certain conditions. Don't get me wrong, though. It's still not a good thing to store ectopic fat, or to store fat in the blood. However, when you consume glucose while adipocytes and visceral fat stores are experiencing an overload of fat (as with T2DM), all hell breaks loose.

The body does not prefer to store glucose as fat [10]. It never has, and it never will. Glucose that can't be burned is shunted out of cells as lactate. Once the lactate is in the blood it goes to the liver and participates in the Cori cycle to be recycled into glucose. It is then sent back into the blood [11]. Typically, lactate is returned to the liver to be converted to glucose to replete hepatic glycogen. The body knows that while you're burning FAs as fuel, the liver needs extra glucose. But T2DM typically presents with a scenario wherein both subcutaneous fat stores as well as hepatic fat stores are maxed. This impairs the liver's ability to store glycogen. The liver and the adipose are both paddles in a game of Pong, with glucose and lactate as the ball. This is confirmed by the higher levels of plasma and urinary lactate associated with T2DM [12]. As one would expect, this effect can be observed in people with certain glycogen storage disorders as well [13]. In T2DM, this merry-go-round repeats itself indefinitely, until the FA burden on the adipocytes can be resolved. 

But, at this point you might be wondering why this merry-go-round is damaging. Personally, I don't actually think the glucose itself is damaging, but what inevitably results from that glucose is damaging. In this state, you cannot have a glut of BG without a glut of blood lactate, and that is problematic. Lactate can cause anything from hypoxia to tissue necrosis, and pretty much any of the comorbidities associated with T2DM. In fact, some people with T2DM have experienced acute lactic acidosis from taking metformin, a drug that inhibits the Cori cycle [14]. Inhibiting the Cori cycle increases lactate levels in the blood [15][16]. I'm not trying to scare diabetics out of taking metformin. Not at all. In fact, one of the reasons metformin is beneficial is because it opens the loop. If the lactate can't go to the liver to be converted to glucose, it may be redirected to the kidney to be excreted in the urine. This is because the liver and the kidney are two of the body's largest lactate disposal sites. If you take the liver out of the equation, you may very well urinate the excess lactate more easily, or even metabolize it in the kidney more easily. 

I suspect that a combination of metformin and a low-carbohydrate diet could be a powerful tool for reducing many of the comorbidities associated with T2DM. In my estimation, the lactate probably has more to do with these comorbidities than does the glucose itself. But removing the glucose removes the lactate. So, removing the glucose has tremendous utility in T2DM symptom management. Until the FA burden on the adipocytes can be rectified, one cannot expect to be able to tolerate a glucose challenge. It is for this reason that I'm willing to say that the reduction in diabetic symptoms associated with carbohydrate-restriction may very well constitute T2DM remission. However, this is not T2DM reversal. Reversal would imply that one has restored glucose tolerance. Mechanistically, the only durable path toward genuine T2DM reversal would be rigorous calorie restriction, regardless of the macronutrient ratio of the diet. Though, a low carbohydrate diet would likely be less rocky along the way. 

Additionally, as a consequence of the body not preferring to store glucose as fat, you have an innate preference to dispose of glucose through oxidative pathways. This generates a lot of metabolites and byproducts of metabolism that are inherently damaging, and even more damaging in the context of T2DM. Substances like methylglyoxal, reactive oxygen species, and other breakdown products. These products disrupt metabolism and can damage a number of tissues. They can also further disrupt insulin signalling through oxidative damage of the insulin receptor substrate proteins. When you swap the carbohydrates for fat in the diet, there is a greater opportunity to safely store the energy you've consumed. Because the body can safely store this energy, and there is no pressing need to burn it immediately, there is considerably greater leeway with carbohydrate-restrictive diets when we're considering T2DM and its associated comorbidities. 

4. Ketosis is functional diabetes, therefore also therapeutic.

This statement may seem provocative and hyperbolic, but I'm absolutely serious. If you compare ketotic metabolism to diabetic metabolism, there are some spooky similarities.

Pretty much all of the hallmarks of T2DM overlap with the hallmarks of nutritional ketosis, with the exception of glucose, insulin, and lactic acid. This is why ketosis is therapeutic for T2DM. Ketosis removes the primary source of the bulk of the comorbidities associated with T2DM, but the underlying pathology still remains. The insulin resistance persists. The high energy status, and many of its long-term consequences, likely persists as well. In short, ketosis is T2DM without the hyperglycemia. Ketosis takes a dysfunctional state, and makes it more functional by removing the challenge to the glucose disposal system while it is impaired. It doesn't reverse the dysfunctional state. It merely improves the situation by masking some of the associated symptoms.

PS. If you like what you've read and want me to continue writing, consider supporting me on Patreon. Every little bit helps! Thank you for reading!

References:

[1] Chokkalingam K., et al. High-fat/low-carbohydrate diet reduces insulin-stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans: An important role for skeletal muscle pyruvate dehydrogenase kinase 4. J Clin Endocrinol Metab. January 2007. https://www.ncbi.nlm.nih.gov/pubmed/17062764

[2] Bisschop P.H., et al. Dietary fat content alters insulin-mediated glucose metabolism in healthy men. Am J Clin Nutr. March 2001. https://www.ncbi.nlm.nih.gov/pubmed/11237931

[3] Stephen F. Burns, Sheryl F. Kelsey, and Silva A. Arslanian. Effects of an Intravenous Lipid Challenge and Free Fatty Acid Elevation on In Vivo Insulin Sensitivity in African American Versus Caucasian Adolescents. Diabetes Care. February 2009. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628707

[4] Siôn A. Parry, Rachel M. Woods, Leanne Hodson, and Carl J. Hulston. A Single Day of Excessive Dietary Fat Intake Reduces Whole-Body Insulin Sensitivity: The Metabolic Consequence of Binge Eating. Nutrients. August 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579612/

[5] Sarah J. Hallberg, et al. Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. Diabetes Ther. April 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104272/

[6] Taylor R., et al. Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for β Cell Recovery. Cell Metab. October 2018. https://www.ncbi.nlm.nih.gov/pubmed/30078554

[7] Kevin D. Hall and Juen Guo. Obesity Energetics: Body Weight Regulation and the Effects of Diet Composition. Gastroenterology. May 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568065/

[8] Lean M.E., et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. February 2018. https://www.ncbi.nlm.nih.gov/pubmed/29221645

[9] Roy Taylor. Calorie restriction for long-term remission of type 2 diabetes. Clin Med (Lond). January 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399621/

[10] Acheson K.J., Schutz Y., Bessard T., Anantharaman K., Flatt J.P., Jéquier E. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am J Clin Nutr. August 1988. https://www.ncbi.nlm.nih.gov/pubmed/3165600

[11] Chen Y.D., Varasteh B.B., and Reaven G.M. Plasma lactate concentration in obesity and type 2 diabetes. Diabetes Metab. August 1993. https://www.ncbi.nlm.nih.gov/pubmed/8293860

[12] Jean L. J. M. Scheijen, et al. L(+) and D(−) Lactate Are Increased in Plasma and Urine Samples of Type 2 Diabetes as Measured by a Simultaneous Quantification of L(+) and D(−) Lactate by Reversed-Phase Liquid Chromatography Tandem Mass Spectrometry. Exp Diabetes Res. March 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310144/

[13] Hagen T., Korson M.S., and Wolfsdorf J.I. Urinary lactate excretion to monitor the efficacy of treatment of type I glycogen storage disease. Mol Genet Metab. July 2000. https://www.ncbi.nlm.nih.gov/pubmed/10924273

[14] E. Fitzgerald. Metformin associated lactic acidosis. BMJ. September 2009. https://www.bmj.com/content/339/bmj.b3660

[15] Huang W., Castelino R.L., and Peterson G.M. Lactate Levels with Chronic Metformin Use: A Narrative Review. Clin Drug Investig. November 2017. https://www.ncbi.nlm.nih.gov/pubmed/28836132

[16] DeFronzo R., Fleming G.A., Chen K., and Bicsak T.A. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. February 2016. https://www.ncbi.nlm.nih.gov/pubmed/26773926

The Sapien Diet: Peak Human or Food Lies?

I am a fan of Brian Sanders' podcast, Peak Human. I don't agree with much of his particular outlook on food and nutrition, but I do enjoy most of the guests that he interviews. It wasn't until recently that I gave his website a look. It was a bizarre experience to say the least. His site builds a case for something he calls the Sapien Diet. In addition to advocating for carbohydrate-restriction and time-restricted feeding, the diet is oddly focused on minimizing conditions that can negatively affect nutrient absorption and bioavailability. However, despite claiming that his perspective is evidence-based and non-biased, his personal biases toward food are quite transparent. I didn't have to look far.

This image is one such example, which implies that healthy foods like apples and bananas are both toxic and nutrient poor, or at least that they have diminished nutrient bioavailability.

While it is true that plant foods contain natural toxins like insect antifeedants, there is no clear evidence that nutritional doses of these toxins from whole foods pose a health risk to humans sufficient enough to justify specific food avoidance as a general recommendation. It is particularly odd to use this speculation to buttress something as pretentious as the "Sapien Diet", which he asserts is the optimal human diet. Profound claims require profound evidence. 

Using plant foods like bananas, apples, bell peppers, strawberries, and even butternut squash to demonstrate the dangers of anti-nutrients is very bizarre, as those plant foods are typically extremely low in anti-nutrients. Not only that, but edible plant ovaries like fruit contain some of the lowest concentrations of plant toxins specifically because they evolved to be eaten by animals like humans. Whereas foods like broccoli actually can contain high amounts of these toxins. However, on balance these plant toxins seem to exert a net positive effect on human health, not negative. The dangers of broccoli to human health are not clearly born out in any prospective, epidemiological, or experimental data. So it makes absolutely no sense to me to scare people away from plants, or suggest that general plant avoidance is supposedly a hallmark of the optimal human diet. It's antithetical to the vast majority of our evolutionary history.

Some of the only evidence cited for the acute dangers of anti-nutrients is a paper wherein a 65-year old woman drank nothing but smoothies containing an enormous amount of leafy green vegetables for ten days straight. The total oxalate content of the smoothie was 1.3g. This is 940% more oxalate than the average person consumes on a typical Western diet. This is not a nutritional dose. She used her blender to turn healthy leafy green vegetables into a drug that had a pharmacological effect on her body. Not only this, but this woman was also dosing relatively high amounts of calcium citrate (1200mg) and vitamin D (1000 IU). The authors of the paper also remark that it was likely the recent gastric bypass surgery she'd undergone in addition to a regimen of antibiotics she was taking at the time that predisposed her to the effect. The only common whole food on the market that has been shown to generate this effect all by itself is star fruit. One star fruit can contain up to 10g of oxalate. But that is the exception. Most fruit contains less than 10mg of oxalate.

Furthermore, it is implied on the opposite side of the infographic that butter is low in toxins with high nutrient bioavailability. It's ironic, considering that one of butter's primary nutrients, saturated fat, associates more consistently with poor health outcomes than broccoli, but I suppose that's a separate discussion. The point is, at the end of the day the health implications of butter are still largely up for legitimate academic debate. However, the health-promoting aspects of broccoli and even high-sugar fruit are exceedingly consistent and well supported by multiple lines of evidence. This alone suggests that there is more to a food than merely its micronutrient bioavailability. Lastly, while it is probably true that the bioavailability of nutrients in butter is probably higher than something like carrots, it is still the case that butter is one of the most nutrient-poor foods available on the market. It is hardly more nutritious than brown sugar when matched for calories. If I had to choose between butter or chocolate chip cookies as a means of furthering my nutrition, I'd be utterly foolish to choose the butter. I invite anyone to credibly challenge this statement.

It is also not always the case that animal foods are superior sources of nutrients. It is not even true that plant foods always have poorer bioavailability of nutrients when compared to animal foods. Calcium is a good example. The bioavailability of calcium from cruciferous vegetables is around fifty percent, whereas the bioavailability of calcium from either any sort of dairy product or even edible bones is typically around thirty percent. 

Sure, someone could point out that the absolute amount of calcium in the animal foods will be so high that they're still a better choice. Yes, I agree. However, I'll refer you back to my example between butter and carrots. It is true that the bioavailability of a nutrient like vitamin A will likely be higher with butter. It is also true you'll probably never get as much vitamin A from butter as you could get from carrots, despite the poorer bioavailability and the metabolic conversion inefficiencies. 

Moving on. The Sapien diet is essentially based on three basic principles. These principles are prefaced by the statement that the Sapien Diet is "how homo sapiens should eat". So, henceforth I will be rightly assuming that these are specific and unwavering rules for optimal nutrition for all human beings. Lofty claims, but that is essentially how it is stated. Let's begin.

The first principle encourages us to consume minimally processed, nutrient dense, whole foods. I actually agree with this recommendation, and see little to argue against in general. In the details we're encouraged to embrace a number of animal foods, which I also agree with. We're further encouraged to favour low-sugar fruit, though it is not explicitly stated why at this point. I strongly disagree with this recommendation for reasons I have stated above.

The last section of the blurb goes on to state that processed foods, sugar, refined grains, and vegetable oil should be utterly avoided. At this point, it is not explained why. We're merely expected to take for granted that these foods are valueless and best excluded from our diet. I simply don't agree with that.

It is puzzling that nuts and seeds are included in the list of foods we're encouraged to embrace. Yet, these are the exact foods that are typically highest in anti-nutrients, plant toxins, and the plant oils we're encouraged to avoid. These foods actually do associate more strongly with health problems than most other plant foods (especially fruit), as they are typically more allergenic and more strongly associated with mineral deficiency syndromes due to their high phytate content and their dense polyphenol content. I'm not saying they're bad foods. I'm merely pointing out an apparent inconsistency with regards to the Sapien Diet's priorities.

The second principle first encourages us to target protein, include protein with every meal, and make sure protein adequacy is met. I agree with this. It then states that we should favour animal protein over plant protein. I agree with this, too. It's a surer bet that you'll meet your protein requirements if you're favouring animal foods. However, some of us actually can't satisfy the second principle thus far without violating the first principle, even if we're sticking to animal protein. The elderly are a good example. It is prohibitively difficult for some elderly people to meet their protein requirements due to common decrements in appetite that tend to result from old age. Highly processed foods like whey protein isolate can step in to ensure these people get what they need. As trivial of an example as that may appear, it is nonetheless one level of nuance with far-reaching implications that can easily break the Sapien Diet's core heuristics. Not everyone can do what this diet is asking them to do, which again cuts against the notion that the Sapien Diet is how homo sapiens should eat.

It is then implied that we're to favour animal protein over plant protein on the basis that animal protein is more bioavailable. Again, I agree. However, this isn't ample justification for plant protein avoidance, if that is actually what is being suggested. A diet of steak and butter will have less protein and less overall nutrition than a diet of steak and, say, lentils when matched for calories. Why would we want to avoid the lentils in this case? Lentils can not only provide added protein, but they can also augment the overall nutritional profile of the diet. A better recommendation might be to simply target protein generally, and don't be afraid of your food.

As we continue reading, we'll see that he plays to a dubious yet bizarrely popular low-carb trope⁠— that fat is the preferred fuel of the body and provides unique health benefits, therefore carbohydrate-restriction is both advised and optimal. I wholeheartedly disagree. I'm not going to go into all of the reasons as to why right now, but perhaps we could further explore my disagreement if I were invited onto the Peak Human podcast to discuss them verbally. Carbohydrate-deprivation could have some unique benefits, but there is no clear evidence that these benefits aren't equally offset by decrements elsewhere. Everything has a cost. Not only that, but the notion that fat is the preferred fuel for the human body is completely at odds with what is gleamed by even the most cursory evaluation of human metabolism and physiology. The whole idea is dead-on-arrival. It doesn't make sense.

I also find it very strange that we're to be guided specifically away from plant foods like bananas because they "provide a ton of energy (empty calories) and not a lot of nutrients", but also guided toward foods like coconut oil. Coconut oil is one of the most calorie-dense, nutrient-devoid foods someone could consume. One extra large Ron Jeremy-sized banana has the same calories as a single tablespoon of coconut oil, and the banana's nutritional profile absolutely crushes the coconut oil. Hands down. No contest. No argument. I'm not saying bananas are awesome or that coconut oil is bad. I'm saying the Sapien Diet contains many internal contradictions that make it seem more than just a little silly.

The last principle is time-restricted feeding. I'm actually surprised at this, since there is virtually no large scale validation of this practice as an effective modality for, well, anything. Some studies suggest that compressing your feeding window merely shortens the amount of time you have to shove food in your face during the day, and thus can induce a caloric deficit in some people. I agree that if you're looking to lose body fat, this strategy can be effective for some people, but not all. It also has a tendency to hinder muscle hypertrophy in athletes when matched against time-unrestricted feeding, and probably isn't optimal as a general recommendation. I don't have much more to say than that. 

Here's my overall perspective and response to what I've read. I view all of nutrition essentially as a great big bin-packing problem. There are many satisfactory solutions to the problem that encourage health and meet our needs, spanning a huge array of different foods and food combinations. To me, the question isn't about which foods everyone should staunchly avoid or staunchly include in their diet, because that cancels many legitimate, safe opportunities for personalized nutrition. I just don't feel that this is the best way to pack the bin. The question should be about which foods best encourage optimal health for the individual, and on top of that which foods can be enjoyed without compromising that individual's optimal health. Maybe there are some core fundamental characteristics of the bin packing that should be conserved across all possible solutions. Things like achieving nutritional adequacy, staying in calorie balance, exercising, etc. But there is likely always room for flexibility that doesn't compromise the bin itself.

The blood-boiling thing that diet zealots just can't accept about this outlook is that it literally allows for the inclusion of all foods. Even junk foods. Is there some amount of liver or egg consumption that directly promotes optimal health? For most people I think the answer would probably be yes. Most people would probably be better off consuming some amount of liver or eggs as opposed to consuming none. However, is there some amount of banana that is compatible with optimal health? For the vast majority of people, absolutely! Banana is a healthy food. Furthermore, is there some amount of chocolate cake that is also compatible with optimal health? For most people who would be consuming it against the background of a diet that already maximally satisfies their personal nutritional needs, the answer would probably be yes as well.

Say you're going on a trip and you're packing a suitcase. Chances are good that regardless of the nature of your trip you will fill your suitcase with a core assortment of indispensable items. But then, you will likely have at least some leeway to customize and personalize much of whatever else it is that you will take with you. I look at nutrition the same way. Once the fundamentals have been optimally satisfied, you have at least some liberty to enjoy yourself and enjoy your foods. For one person, they might fill their extra suitcase space with bananas and mangoes. Others might fill that space with avocados and almonds. If either of them can pack a cookie or two without perturbing the essentials, I think that is perfectly fine and can possibly even be health-promoting in and of itself.

This is a typical example of my diet:

My diet breaks down to around 55% carbs, 15% fat, and 30% protein. At this moment I consume just shy of 2300 kcal per day. I can achieve nutritional adequacy of all essential vitamins, minerals, and amino acids within the first 1500 kcal of my day. If I wanted to fill the remainder with sugary fruit, starchy plants, and refined grains, what does their relative nutrient bioavailability or sugar content matter? Are there better options? Perhaps marginally for some of those things, sure. Would it make an appreciable difference? I doubt it. I enjoy my nutrient dense diet, and I enjoy the flexibility that it grants me. I'm granted the liberty to indulge more frequently by virtue of the fact that my overall dietary pattern is profoundly nutrient dense. That is part of the advantage of a nutrient dense diet, and the indulgences need not be a detraction.

We shouldn't devalue entire foods based on one context-sensitive aspect of those foods. No matter how tempted we are to do so. Be it phytate, toxins, lectins, processed food, carbohydrates, bioavailability, etc. All foods have value. If they didn't have value, people wouldn't eat them. Likely there is a place for nearly all foods in a healthy diet. Food avoidance may be a powerful heuristic that some people can use to lose weight and keep it off. For others, not so much. Some people would likely prefer moderation, however moderation might lead some other people directly to ruin. But I don't think either heuristic reigns supreme as a default approach. Nutrition is personal. I'm not persuaded that the Sapien Diet is the diet that all homo sapiens should be eating.

PS. If you like what you've read and want me to continue writing, consider supporting me on Patreon. Every little bit helps! Thank you for reading!

The Inversion Pattern: Cholesterol Code or Cholesterol Slowed?

Dave Feldman is a prominent voice in the low-carb community. He is a software engineer who decided to try a low carbohydrate, ketogenic diet (KD) as a nutritional strategy to regain control of his health when he was diagnosed as being borderline pre-diabetic in 2015 [1]. However, this led to an increase in his low-density lipoprotein cholesterol (LDL-C) that left him concerned about his heart disease risk. He then decided to have his LDL-C measured more regularly than most for an extended period of time, even once per day for a while. He was also tracking his fat intake and was able to compare this data to his LDL-C data. From this he discovered that for which he is arguably most famous⁠— the Inversion Pattern [2]. His LDL-C was inversely correlated with his fat intake. His LDL-C on average was higher than before, but it dynamically responded to the fat in his diet.

He infers that his LDL-C is inversely tracking his fat intake because it is a reflection of energy distribution. That is to say that the more fat we have coming in from our diet, the fewer very low-density lipoproteins (VLDL) we have being secreted by our liver. He remarks that he's seen this before as a software engineer. This pattern resembles a network to him—a distribution network of objects that dynamically respond to inputs. He suggests that being fat-adapted allows us to uniquely tap into this energy distribution network [3]. Perhaps if we're "powered by fat", the average bump in LDL-C experienced by some on low-carb diets might not be a sign of a pathological state after all. Additionally, perhaps eating fat isn't so bad if eating more of it reduces LDL-C. Not a totally unreasonable hypothesis, in my opinion. However, I'm not at all persuaded by this. Let's explore why.

Before we dig into the Inversion Pattern, we need a crash course in basic lipid metabolism. This means we need to understand how the body moves lipids from one compartment to another, and how they're eventually broken down to make energy. Since every lipid in your body got there as a result of something you shoved in your mouth, let's start at ground zero: your diet.

You just ate a glob of fat. What happens now? Aside from the heart palpitations and anxiety you might experience if you're a fan of typical Western dietary guidelines, of course. Well, the fat hits your stomach and signals to the gallbladder to release bile acids (BA), phospholipids (PL) (also known as lecithins), and free cholesterol (FC). These are all components necessary to capture the dietary fat in a self-assembling structures called mixed micelles (MM). The MM is composed of, you guessed it; BAs, PL, FC, and dietary fat.

There is an uncountable number of these structures when you consume fat, and the sum of all of them forms what is known as an emulsion. An emulsion is a sticky substance consisting of both hydrophobic and hydrophilic components. Have you ever made mayonnaise at home? It requires a liquid fat and an egg. That's it. The egg contains PLs and CE, FC, and the fat contains, well, fat. You blend them together, and it produces an abundance of these self-assembling lipid structures. The sum of which is an emulsion. The same thing happens in your small intestine when you consume dietary fat. Your gut basically turns into a mayonnaise factory.

The MM migrates to your enterocytes. These are the cells that comprise the surface of the small intestine. The MM encounters a layer of higher acidity between the intestinal lumen and the enterocytes. The MM is readily disassembled by a series of proteins and its components are absorbed. The dietary fat and PLs are broken down by lipases and is taken up by transporter proteins. FC and some BAs are absorbed through the Niemann-Pick C-1 like 1 transporter protein (NPC1L1). Excess FC (and BAs that were accidentally taken up) are ejected back out into the lumen by ATP-binding cassette sterol transporters, G5 and G8 (ABCG5/G8). However, up to 95% of BAs are taken up by another portion of the intestine called the ileum and are taken to the liver via the portal vein. The net effect is that most of the dietary fat and PLs are absorbed, a regulated amount of FC is absorbed, and almost all BAs are eventually absorbed.

At this point, all of these lipids are reconstituted through a series of metabolic pathways that aren't important to understand. But, essentially the enterocyte will take in the materials from the MM on the lumen side of the cell and will use those materials to rebuild a similar structure on the basal side of the cell called a chylomicron (CM). A CM is similar to a MM, but it is in many ways very different. A CM is a lipoprotein (Lp). Lps are different sorts of structures. They contain special proteins called apolipoproteins (Apo) that play regulatory roles and help facilitate Lp metabolism in different ways. There are about a dozen or so Apo proteins that have been identified and characterized. Only a handful of them are relevant to this discussion, but we'll come back to that.

The CM is essentially a spherical layer of PLs, FC, and Apo proteins shrouding a core of triglycerides (TG) and cholesteryl esters (CE). The CM is secreted from the enterocyte into the lymphatic system. From there, it travels upward and is released from the thoracic duct into general circulation. This is where the CM's journey really begins. As it travels through the blood, it interacts with various tissues and delivers its main cargo, TGs. The CM will leave a little bit of TGs in the fat tissue, in the muscle tissue, the cardiac tissue, organ tissue, etc. Any tissues requiring energy at that moment will have a fair crack at the TG content of the CM. The way these tissues take up TGs is through interacting with one of the Apo proteins on the CM, apolipoprotein C-II (ApoC-II). ApoC-II interacts with an enzyme found on tissues all over the body called lipoprotein lipase (LPL), this enzyme acts like a drinking straw, using ApoC-II to pull TGs out of the CM.

After the CM has made the rounds and delivered the bulk of its TGs to peripheral tissues (tissues other than the liver), the change in its TG content causes the CM to shed its ApoC-II. This reduces the CM to a chylomicron remnant (CMR). It is now unable to further donate TGs directly to peripheral tissues. However the CMR is still able to trade TGs from high-density lipoproteins (HDL) in exchange for CE with the use of cholesteryl ester transfer protein (CETP). It is also hydrolyzed by hepatic lipase (HL). However, these are not major fates of CMR-TGs. This is because the loss of ApoC-II facilitates the binding of apolipoprotein B-48 (ApoB-48), a major structural protein of CMs and CMRs, with apolipoprotein E (ApoE), another structural protein that is present on nearly all Lps. This then makes ApoB-48 and ApoE a single ligand for the low-density lipoprotein receptor (LDLr) on the liver. LDLrs are responsible for pulling CMRs, and a few other Lps out of circulation. The CMR only has the opportunity to donate any of its remaining TGs to HDL or HL if hepatic LDLr expression is diminished. But, even if those were major pathways for CM-TG, those pathways are carrying TGs to the liver anyway. Nevertheless, pretty much all CMRs are TG-rich upon reaching the liver.

Once the CMR is inside the liver it is catabolized and all of its contents are released. The TGs now have one of two fates. Either they're burned for energy or exported from the liver back into circulation. Just to keep the story moving, let's assume the TGs are being released back into circulation. This occurs similarly to how TGs are exported from the enterocyte. The TGs are packaged up into a Lp called a VLDL. This Lp is a little more complicated than a CM. It has a long and complex life cycle. It has its own specialized Apo proteins and interactions with tissues in a very different manner. However, the means by which the VLDL sheds its TGs is identical to that of the CM.

The VLDL traverses the blood, and the ApoC-II interacts with LPL all over the body to deliver TGs. Once the VLDL sheds a certain amount of TGs, it sheds its ApoC-II and becomes an intermediate-density lipoprotein (IDL). An IDL is very similar to a CMR. It is TG-rich, lacks ApoC-II, and it can also be taken up by hepatic LDLr the same way as the CMR. The IDL has three possible fates. Either it will lose its TGs and become a low-density lipoprotein particle (LDLp), or it will be catabolized by the liver. At least half of IDLs are pulled out of circulation by the liver. The other half will be hydrolyzed by HL or CETP, lose their TGs and thus become LDLp.

Now we have ourselves a bunch of LDLp. LDLp are primarily responsible for carrying out reverse cholesterol transport (RCT). Contrary to Dave Feldman's claim that the primary job of LDLp is to deliver fat-based energy, LDLp are actually TG-depleted. They collect cholesterol (CL) from HDL through CETP and help HDL carry CL back to the liver. LDLp have many potential functions, but generally LDLp have two possible fates. They can be taken up by the liver via LDLr, or they can be taken up by peripheral tissues. Only about one fifth of LDLp are taken up by peripheral tissues, and the remainder are taken up by the liver. Once in the liver, the LDLp are catabolized and their contents are released. Most of the contents are FC and CEs.

The FC and CEs can then be metabolized to FC as well as BAs⁠—ready to emulsify more dietary fat. Now we've come full circle. We've gone from dietary fat metabolism to Lp metabolism and back again, and observed a bird's eye, macro-level view of the entire pathway. Unfortunately, we're not quite ready to reconcile this information with the Inversion Pattern just yet. I mean, we are. At least I feel as though we are. But I know I won't be able to escape certain baseless criticisms unless I explore nutritional ketosis. So, let's take a moment to review the basics of the fat-burning metabolism and ketogenesis. Don't worry, this will be brief.

When we consume glucose, there are generally three different things we can do with it. First, to whatever extent we can we replete our glycogen⁠— a storage form of glucose similar to starch. This glucose is stored primarily in our liver and muscle tissue. Secondly, if glycogen is replete we burn the carbohydrates (CHO) as fuel. Lastly, if we are in a calorie surplus and can't burn the glucose, we can convert it to TGs through a process called de novo lipogenesis (DNL) [4].

Let's focus on liver glycogen, since this is the crux of ketogenesis. Glycogen is used by the liver to maintain euglycemia between meals and during sleep. When we sleep, we are fasting. There is no glucose coming into the body from outside, so the body must rely on the liver to stabilize blood glucose during this time. But let's say we decide to replace nearly all of the of CHO in our diet with dietary fat. This type of glucose-deprivation causes hypoglycemia, and the liver is called upon to defend our blood glucose until we run out of liver glycogen. Falling blood glucose signals to the pancreas to release glucagon, which acts on the liver to hydrolyze its stored glycogen and release glucose into general circulation.

However, this counter-regulatory hormone can only do so much. As glucose-deprivation continues, soon the liver's glycogen gets so low that glucagon is no longer able to maintain blood glucose by itself. When liver glycogen is sufficiently depleted, the adrenal cortex is called upon to secrete cortisol. Cortisol acts on skeletal muscle to liberate particular amino acids called gluconeogenic amino acids. These amino acids travel to the liver and make unique contributions to a process called gluconeogenesis (GNG). GNG uses non-glucose substrates to generate glucose. These amino acids are used to synthesize pyruvate and a number of intermediates necessary to the TCA cycle that would normally require glucose. In the initial phase of ketosis, most of the gluconeogenic substrates are amino acids from skeletal muscle and lactate shunted out of the cell by the deactivation of the pyruvate dehydrogenase complex (PDH). As time goes on the body can learn to rely on other substrates, like, glycerol from the adipose or the liver, and and even small aldehydes generated by normal metabolism.

The same loss of liver glycogen that leads to GNG also leads to ketogenesis. As blood glucose falls to a steady state, insulin also falls. As insulin falls, adipocytes release more free fatty acids (FFA). These FFAs traverse the blood stream, bound to a serum protein called albumin. They're taken up by tissues to provide energy when both glucose and insulin are low. But they're also taken to the liver along with dietary fat from CMRs. Once in the liver, these fatty acids (FA) and CMR-TGs are fed into the TCA cycle to generate acetyl-CoA, and then that acetyl-CoA is carried down through a pathway to generate acetoacetate and beta-hydroxybuterate. These are the water-soluble "ketone bodies" that enter the circulation and serve as an alternative fuel when glucose availability is low.

Well, maybe that wasn't very brief after all. Oh well. Let's continue. Just kidding. Now we have to discuss why ketosis is irrelevant to the Inversion Pattern. Believe me, I don't want to type this. But I will.

To understand what is really going on with ketosis and the Inversion Pattern, we have to understand three variables relevant to the liver: fat uptake, FA utilization, and TG export— fat in, fat used, and fat out. Ketosis will generally only independently affect one of these variables, FA utilization. Ketosis will conditionally affect TG export. Dietary fat will generally only independently affect one of these variables, TG uptake. Dietary fat will conditionally affect TG export as well. But, your overall energy status generally affects all three variables together. This is why I'm not convinced that ketosis is relevant to the Inversion Pattern. Especially as it relates to fat overfeeding, which we will discuss in a moment. Not only are you suppressing the amount of ketosis that is necessary to support energy metabolism, but the amount of FAs that contribute to ketosis is capped regardless of dietary fat intake.

Ketogenesis only requires somewhere between 4-44g of fat per day for the average person [5]. More if starved; less if fed. On a 2000 kcal ketogenic diet that is 75% fat, only 26% of that fat is committed to ketogenesis. So, even if we are very generous and assume that 100% of the FAs being used for ketogenesis are coming directly from CMR-TG (coming from the diet directly), that's still only 26% of the amount of fat one would typically eat on a ketogenic diet. This doesn't explain or contribute anything revelatory to understanding the Inversion Pattern.

For example, if you consume no fat, ketogenesis will be supported by FFAs liberated from your adipose tissue. If you consume a large amount of dietary fat, TG uptake from CMR will increase, and TG export through VLDL will increase, but you need not commit any of those TGs to supporting ketogenesis while those TGs are in the liver. That is determined by the liver's perception of whole body energy status at that moment. At best there will be a slight decrease in TG export if your fat intake is perfectly eucaloric. But a marginal decrease in TG export under eucaloric conditions isn't what is being explored by the Inversion Pattern. The Inversion Pattern demonstrates a decrease in LDL-C that is inversely proportional to dietary fat intake, with a correlation of approximately 0.9.

Because the conversion of CMs to CMRs is based on the absolute TG content, there will be no difference in the number of TGs reaching the liver on a KD when compared to a mixed diet with the same amount of fat. The only thing that will change is the time-scale involved. CMs will be converted to CMRs and then taken up by the liver faster on the KD under eucaloric conditions with fat clamped. The CMs will become CMRs and will be taken up by the liver slower on the mixed diet. However, total hepatic TG uptake from CMRs will be equal in both scenarios and have an equal area under the curve (AUC). As far as the liver is concerned the fat-in side of the equation is unaffected by ketosis. This means the burden of fat on your liver will be proportional to your fat intake. Ketogenesis is also not necessarily limiting for TG export, because FA utilization need not change as a function of TG uptake. But your liver will take up those TGs no matter what, and it will export some proportion of them no matter what. Ketosis doesn't matter here. Sorry, I just can't emphasize it enough.

We're powered by VLDL-TG regardless of ketosis or our CHO intake. Our overall energy status dictates just how much of our dietary fat is going to be retained by the liver to support ketogenesis. In a high energy state, the liver will commit fewer-to-none of those TGs toward supporting ketogenesis, and may even re-esterify incoming FFAs from the blood to form new TGs. In a low energy state, the liver will commit more of those TGs as well as incoming FFAs toward supporting ketogenesis. Sure, if ketogenesis is maximally suppressed with dietary CHO, you will have fewer TGs that entered the liver being committed to supporting energy metabolism in that way. Under eucaloric, fat-clamped conditions, you may have a slightly greater amount of TGs leaving the liver with the CHO-inclusive diet. This isn't relevant to the Inversion Pattern, which is why I didn't even want to bring ketosis into this discussion. It's just straight up irrelevant.

The state of ketosis will not effect the flux of dietary fat through the liver more than marginally in eucaloric conditions, and probably more if fewer fat calories are consumed. But ultimately you're looking at a relatively small change in either case. However, Dave Feldman's Cholesterol-Drop Protocol (CDP) (a short-term dietary protocol designed to maximally leverage the Inversion Pattern) encourages you to eat approximately 1.38kg of dietary fat, equating 82% of calories, in three days [6]. I think everyone can agree that this generates a hypercaloric state in most people. Further emphasizing just how irrelevant ketosis is to this discussion. Under these conditions, potentially less than 1% of dietary fat would be contributing to ketogenesis. Being "powered by fat" does not fundamentally alter the physiology of hepatic TG uptake or export, and claiming that it does is tantamount to admitting that you believe in magic.

Alright. Now we're ready to reconcile what we've discussed with the Inversion Pattern. As disappointing as it may be, this is likely to be the shortest part of this blog post. Here we go.

Let's talk about Dave Feldman's CDP. This protocol is designed to fully reveal the Inversion Pattern, and encourages one to eat an enormous amount of dietary fat. Dave Feldman suggests that dietary TGs downregulate the release of VLDL-TGs. He postulates this is because there is no need to mobilize stored fat as VLDL-TGs when you have an abundance of CM-TGs coming in from the diet. The CDP is meant to be the ultimate example of this principal in action— eat a massive amount of fat, hepatic TG export decreases, LDL-C naturally decreases in tandem. Or so the story goes.

Sounds compelling. However, this is not actually how the liver works, as we've discussed. With regards to dietary fat, the liver simply takes in TGs from CMRs, HDLs, IDLs, and LDLp to a lesser extent, and decides what the do with them. The liver exports some proportion of them (or all of them) back into circulation as TGs in VLDLs. That's actually it. You eat fat, your body takes what it wants, the liver gets the remainder, the liver takes what it wants, and sends the rest out into the blood. Simple.

But wait, this actually sounds like eating dietary fat should increase VLDL secretion. So, why does LDL-C tend to go down proportionate to the amount of fat consumed as seen in the Inversion Pattern? This is because the liver does not generally have the resources on hand to export very much dietary fat at a given moment. The more fat you eat, the worse it gets. In fact it can take many hours to mobilize all of the dietary TGs from the liver after a single high-fat meal [7][8]. I'm not saying KDs cause fatty liver. In fact, experiments have revealed reductions in hepatic steatosis among human subjects following KDs [9]. Not my point. Those findings can be explained by variables unrelated to nutritional ketosis itself. Adiposity and high energy status are overwhelmingly the largest predisposing risk factors for hepatic steatosis, and a mere change in protein intake can have huge effects on this. However, the KD is a useful weight loss tool in free-living humans, and animals, due to its effects on appetite. But what happens if you deliberately overeat fat on a KD?

Let's refer back to earlier in our discussion. When we eat fat, the gallbladder secretes an assortment of lipids that are essentially raw materials for building MMs and Lps. These raw materials include: PLs, FC, and BAs. The PLs are mostly reabsorbed, the FC is only partially reabsorbed, and the BAs are almost completely reabsorbed in the ileum of the small intestine. However, these are under normal conditions.

Eating over a pound of fat per day is hardly representative of normal conditions. In fact, eating more than 77-83g of fat per day would be considered abnormal by national standards [10]. Under normal conditions BAs are typically reabsorbed, sure. But, it has been well documented that merely feeding a high-fat diet (an extreme condition from my perspective) can significantly increase bile acid loss in the stool [11][12][13][14][15][16][17].

I surmise that this is actually the cause of the Inversion Pattern. The rapid BA excretion and loss of BA turnover leads to hepatic BA and CL depletion. BAs are synthesized from CL. In this state, the liver is forced to work overtime, doubling down on CE and FC synthesis to support VLDL production as well as BA production. Every time you eat dietary fat, you lose a little CL as BAs, as well as FC, in the stool. The effect is highly sensitive to the amount of fat in the diet. It is even sensitive to a particular high-fat meal, as the body can often need several cycles of enterohepatic BA circulation to handle just a single high-fat meal. 

But, this isn't a single high-fat meal under normal conditions. This is balls-the-wall-inhale-over-three-blocks-of-butter-in-three-days level fat overfeeding here. There is no reason to believe that the established effect of BA loss due to high-fat feeding wouldn't hold true at even higher levels of fat intake. Keto isn't magic. It is highly likely that you're going to lose more BAs in the stool when you do this protocol.

In essence, the Inversion Pattern is likely a reflection of hepatic BA and CL depletion, which means the CDP is actually a BA/CL-depletion protocol first and foremost. The Inversion Pattern is not correlating with energy distribution as Dave Feldman sees it. It's correlating with the liver's struggle to handle the fat burden of the diet within a given period of time. The liver is not recruiting fewer TGs from storage in response to incoming dietary fat as Dave Feldman suggests. The TGs from the diet are the first ones on the scene in the liver, and that amount of fat can back up hepatic lipid metabolism such that LDL-C drops in tandem. This is a very easy mechanism to understand, it is well-documented, and as such it requires very little speculation.

But, let's hammer this point home a little more. Let's take a look at Dave Feldman's TGs compared to his fat intake. 

Notice how his TGs have a poorer correlation with fat intake than does his LDL-C? 

Interesting, considering that his argument is that the Inversion Pattern represents the inverse relationship between dietary fat and fat recruited from "storage" being mobilized from the liver as VLDL-TG. Presumably this graph is a representation of fasting TGs held primarily in VLDLs, IDLs, LDLs, and HDLs. Pretty odd if you ask me. He even remarks that this is a disappointing finding in his article. Probably because it cuts against his hypothesis so sharply. Why he maintains this hypothesis in light of this is a mystery to me. If his claim is that the Inversion Pattern is tracking energy (not necessarily CL availability or synthesis), you'd expect the Inversion Pattern to track with TGs far more tightly than LDL-C. But it doesn't.

The truth is you can't manufacture VLDL in the liver without either CL or PLs, but PLs become limiting much sooner than CL. You can export enormous amounts of fat from the liver using very little CL, but you can't export ANY fat from the liver without PLs. Dave Feldman's protocol also involves eating 194g of protein per day. This is only 15% of calories, but it is a LOT of protein. In this blog post, I explain how protein is a source of methionine (and is often a source of choline), which the body uses to synthesize PLs. It is also likely that the diet itself is very high in PLs. As far as I can tell, Dave Feldman's protocol is designed to lower LDL-C by overburdening hepatic CL synthesis. Whether or not transient steatosis is also a contributor is likely anyone's guess at this point. Essentially, in high-fat overfeeding you may see TGs go up or down inconsistently. You may see HDL fluctuate. You may see LDLp go up or down. But, the actual blood CL itself maintains a tight inverse correlation with fat intake.

At this point someone might argue that Dave Feldman's protocol could actually be pretty high in dietary CL, so CL-depletion may not be a sufficient explanation for the finding. Maybe. But, CL-uptake in the gut is tightly controlled by your enterocytes. Not to mention that most dietary CL is esterified and is less bioavailable. I find it highly unlikely that exogenous CL contributes meaningfully to the hepatic CL pool in normal people. I mean, heck, isn't dietary CL's poor absorption rate a typical low-carb talking point anyway? However, there are subsets of people for whom I'd expect CL to be less limiting in this way. For example, people with familial hypercholesterolemia (FH) resulting from impaired ABCG5/G8 activity in the gut [18]. These people have accelerated and highly indiscriminate sterol uptake in the gut, and as a result maintain a state of hyperlipidemia. I would suspect that the Inversion Pattern would not hold true as tightly for these people.

Unfortunately, I could only find one study investigating changes in hepatic lipids in the context of high-fat overfeeding [19]. Doubly unfortunate⁠— it's a rodent study. The study was performed on a special kind of mouse called an ob/ob mouse. This is what is known as a "knock out" mouse. Basically, the researchers select genes they want to "knock out" and essentially deactivate them. This has different effects depending on the genes we want to knock out. In ob/ob mice, their leptin genes have been deactivated (another name for an ob/ob mouse is a "leptin-deficient" mouse). This causes them to overeat drastically. Since it is overeating we wish to investigate, they're a reasonable choice.

Essentially there were two groups of mice in the experiment. The control group were standard 6J mice fed an ad libitum (as much as desired) diet of either rodent chow or high-fat chow (60% of calories as fat). The experimental group was the ob/ob mice fed the same two diets. As predicted, the ob/ob mice overate both diets. They were killed at different time points and their livers were removed, frozen with liquid nitrogen, and their hepatic lipids were analyzed. Lipids were measured by molar weight, and were represented as percentages of hepatic lipid droplets.

What they discovered was that the ob/ob mice consuming the high-fat diet had significantly lower hepatic FC, CE, impaired VLDL secretion, steatosis, a minor decrease to hepatic PLs, and a higher loss of BAs in the stool. Not only this, but the ob/ob mice eating the high-fat diet had diminished HMG-CoA reductase (HMGCR) activity as compared to the ob/ob mice eating the control diet. This means the ob/ob mice eating the high-fat diet had impaired CL synthesis compared to the same mice eating the control diet. Lastly, the ob/ob mice eating the high-fat diet also had lower CYP7A1 activity as compared to the control mice eating the same diet. Which means that their BA synthesis was lower as a function of them having overeaten fat. Which is an illustration of the BA/CL-depletion I speculated about earlier. Essentially, what they're investigating here is the lipid milieu of the liver in the context of high-fat, diet-induced BA and CL depletion.

This is the only data I could find that investigated anything even remotely close to Dave Feldman's CDP. It coheres with my original interpretation of what is likely occurring in the liver during both the CDP protocol and the Inversion Pattern. High-fat diets may not necessarily lead to steatosis in human livers, but it is highly likely that both the BA pool and CL synthesis takes a hit from the sheer volume of fat overall. Keeping in mind that steady-state blood CL levels will be on average higher while on virtually any high-fat diet. But, in essence Dave Feldman's Inversion Pattern, as well as his CDP, merely reflect the liver's struggle to handle the burden of dietary fat over time. They are not a reflection of a dynamic energy distribution system that turns VLDL-TG export up or down like a faucet in response to dietary fat. Dave Feldman's model is reasonable if one lacks certain critical knowledge about lipid metabolism. But, ultimately the model as it is currently described makes very little sense, and it is completely at odds with the basic physiology of lipid metabolism.

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References:

[1] Cholesterol Code. About Dave Feldman. https://cholesterolcode.com/about/

[2] Cholesterol Code. Cholesterol Code – Part I : More Fat, Less LDL-C. https://cholesterolcode.com/cholesterol-code-part-i/

[3] Low Carb Down Under. Dave Feldman - It's About Energy, Not Cholesterol. https://www.youtube.com/watch?v=y8pybQjVeiQ

[4] Acheson KJ1, Schutz Y, Bessard T, Anantharaman K, Flatt JP, and Jéquier E. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am J Clin Nutr. Aug 1988. https://www.ncbi.nlm.nih.gov/pubmed/3165600

[5] Patrycja Puchalska and Peter A. Crawford. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. February 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

[6] Cholesterol Code. Cholesterol Drop Protocol (“Feldman Protocol”). https://cholesterolcode.com/extreme-cholesterol-drop-experiment/

[7] B. O. Schneeman, L. Kotite, K. M. Todd, and R. J. Havel. Relationships between the responses of triglyceride-rich lipoproteins in blood plasma containing apolipoproteins B-48 and B-100 to a fat-containing meal in normolipidemic humans. Proc Natl Acad Sci U S A. March 1993. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC46022/

[8] Cohn JS, McNamara JR, Krasinski SD, Russell RM, and Schaefer EJ. Role of triglyceride-rich lipoproteins from the liver and intestine in the etiology of postprandial peaks in plasma triglyceride concentration. Metabolism. May 1989. https://www.ncbi.nlm.nih.gov/pubmed/2725288

[9] Jeffrey D. Browning, Jonathan A. Baker, Thomas Rogers, Jeannie Davis, Santhosh Satapati, and Shawn C. Burgess. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr. May 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076656/

[10] Susan K. Raatz, Zach Conrad, LuAnn K. Johnson, Matthew J. Picklo, and Lisa Jahns. Relationship of the Reported Intakes of Fat and Fatty Acids to Body Weight in US Adults. Nutrients. May 2007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452168/

[11] Kasbi Chadli F., Nazih H., Krempf M., Nguyen P., and Ouguerram K. Omega 3 fatty acids promote macrophage reverse cholesterol transport in hamster fed high fat diet. PLoS One. April 2013. https://www.ncbi.nlm.nih.gov/pubmed/23613796

[12] Müller V.M., Zietek T., Rohm F., Fiamoncini J., Lagkouvardos I., Haller D., Clavel T., and Daniel H. Gut barrier impairment by high-fat diet in mice depends on housing conditions. Mol Nutr Food Res. April 2016. https://www.ncbi.nlm.nih.gov/pubmed/23613796

[13] Yoshitsugu R., Kikuchi K., Iwaya H., Fujii N., Hori S., Lee D.G., and Ishizuka S. Alteration of Bile Acid Metabolism by a High-Fat Diet Is Associated with Plasma Transaminase Activities and Glucose Intolerance in Rats. J Nutr Sci Vitaminol (Tokyo). 2019. https://www.ncbi.nlm.nih.gov/pubmed/30814411

[14] Reddy B.S., Hanson D., Mangat S., Mathews L., Sbaschnig M., Sharma C., and Simi B. Effect of high-fat, high-beef diet and of mode of cooking of beef in the diet on fecal bacterial enzymes and fecal bile acids and neutral sterols. J Nutr. September 1980. https://www.ncbi.nlm.nih.gov/pubmed/7411244

[15] Sakaguchi M., Minoura T., Hiramatsu Y., Takada H., Yamamura M., Hioki K., and Yamamoto M. Effects of dietary saturated and unsaturated fatty acids on fecal bile acids and colon carcinogenesis induced by azoxymethane in rats. Cancer Res. January 1986. https://www.ncbi.nlm.nih.gov/pubmed/3940210

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