The Arrow #124
Greetings from Montecito.
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Okay, you’ve probably heard this before, but let me reinforce it. If you’ve got one three word sentence filled with wisdom to pass on to kids, grandkids, friends, anyone, it is this: Don’t store shit.
MD and I are immersed in the hell of cleaning out a relatively small (10X10) storage unit. When we sold our house in Boulder, which had a ton of storage space, we intended to move all of the stored stuff to Santa Fe, where we spent a lot of down time. At the last minute, we decided to cart a bunch of it to Santa Barbara and stick it in a storage unit. Most of the stuff was from our house in Little Rock, which we moved away from in 1997. It went to Boulder first for a number of years, then ultimately to California.
We figured when we were here we would go through it a bit at a time. Well, as you’ve probably guessed, that never happened. Then about a month ago, we get a notice from the storage place that they are remodeling and we have to get our stuff either moved to another unit in the same place or out of there altogether.
We decided this would be a good time to go through all the stuff we had stored there and dispose of the part of it we wanted to ditch and figure out what to do with the rest.
Bear in mind that when we moved from Little Rock, we were not there to oversee the packing and loading. We were in Boulder, and for reasons I can’t recall, we weren’t able to get back to Little Rock in time for the move. We had sold our house there, and the buyer wanted a fast escrow.
On our behalf, MD’s sister (RIP) hired a company to pack all our stuff and ready it for the move. Whoever did the packing was a total F#&#ng idiot. He/she/they threw disparate stuff in all kinds of boxes and labeled it whatever the last thing thrown in was. For example, in one of the boxes labeled “Lamps, etc.” there was a part of a lamp (the lamp, but no lampshade) and a frigging houseplant. We had nice cushions for our dining room chairs, which these morons used for padding in eight different boxes.
I could go on and on, but you get the picture.
When we sold our Boulder house, we had the movers move one of the many little storage spots to Santa Barbara. And they’ve been there for a little over 20 years.
Once we got in to see what we had there, we found a large proportion of the stuff to be ancient—and I mean ancient—tax records, check stubs, bank statements which we no longer need. And we had clinic employee records going back to 40 years ago. All this stuff needs to be shredded, because it contains SS numbers, names, addresses, etc. We even had a few boxes of very old patient records we somehow kept. They really need to be shredded.
As we were going through the boxes, we would occasionally come across some family treasure we had saved. It happened often enough that we couldn’t just say, Screw it, let’s set fire to the whole mess. We had to go through it all.
With the Arrow bearing down on me, I said let’s just go get the stuff, bring it all back to our place in Montecito, which is not large, and put a tarp over it. Then we can go through it at our leisure and shred what needs to be shredded with our new industrial-strength shredder. Which I’m listening to as I write these words. MD is right outside the door on the patio shredding her little heart out.
We’ve still got two giant, massively heavy, steel lateral file cabinets we’ve got to get rid of in the next couple of days. I guess we’ll take them to the dump. Sooner or later, it will all be over.
The worst part.
I went back over how much we’ve spent to store all this crap for over 20 years. It totaled up to $38,400! It started out at $80 per month and has now topped out at $240.
I would have gladly sold every bit of it for $2,000 had someone made me the offer. And that includes the family treasures.
Don’t. Store. Shit.
Cognitive Dissonance and Confirmation Bias
Given what’s happened over the past couple of days, I’d like to take a little time to go over cognitive dissonance and the confirmation bias. We’re seeing matchless examples of how they work in real time.
First, let’s consider cognitive dissonance, which is the uncomfortable feeling we all get when trying to hold two opposing or clashing ideas in our brains at the same time.
Let me give you an example. Let’s say you have a favorite politician, one who is the exemplar of your own party. He pretty much seems to be in lock step with you in all things political. And not only that, you’re actually so much a fan that you’ve even worked with him in one of his campaigns. You met him personally, and he is a warm, open, friendly person, who treated you like he was your best friend.
Then, out of the blue, you read in the newspaper that he was found with hundreds of photos of child pornography on his computer. And many of the photos show him in compromising situations with children. The FBI had him targeted for a sting, and they finally struck.
More evidence starts to stack up, but you just can’t reconcile this warm, friendly man who embodies all your political beliefs with pedophilia. It just can’t be true.
You are experiencing cognitive dissonance in a big way. You are not a happy camper.
Now let’s assume this guy is a member of a political party you despise. He comes across nice and friendly enough in interviews, but you hate his views and you hate the fact that he always votes the party line, even though it sometimes seems to be not in his state’s best interest.
Now you learn that this guy is a pedophile. No cognitive dissonance there. You always knew something had to be wrong with him.
Now let’s go back to the first example. You have two options to reconcile the unpleasant cognitive dissonance you’re experiencing. One way is to realize, based on the evidence you’ve seen, that the guy really is a swine. You were totally sold a bill of goods on him by his warm gracious behavior toward you. But now he’s been unmasked. And he is awful. And now that you think about it, he did show signs if you looked closely. But you didn’t, and that makes it even worse. He should be in jail. And you hope he goes there for life.
There is another way to deal with the situation.
You can cast about looking for any information that shows he was falsely accused. You seek out some far (right or left; take your pick) internet site or talk radio show and sure enough you find someone who informs you that your guy is being persecuted by the other side, or that he was set up, or whatever.
Now your confirmation bias jumps in and you think, Ah, I knew it all along. Your uncomfortable cognitive dissonance dissolves, and you feel a lot better.
Don’t think for a minute that politicians don’t understand this situation perfectly.
When bad news emerges about one of their own, they quickly confab and come up with talking points to say themselves and release to their favored journalists to amplify. They know that all those folks on their side want their cognitive dissonance resolved, so they throw them something their confirmation bias can latch onto.
The above are admittedly extreme examples, but we see less extreme examples all the time.
For instance, the Durham report just came out a few days ago. What you think of it probably sorts you out pretty well on the political spectrum. Not only did the Durham report come out, but a few days before that the House Committee on Oversight and Accountability reported that the Biden family (but not Joe Biden himself) had engaged in all sorts of dubious financial shenanigans with foreign entities resulting in their harvesting of many millions of dollars. However you feel about the Durham report, you probably feel the same way about this one.
If you are not outraged, then you should look at it from the other side’s perspective. In fact, whichever side you’re on in anything, you should consider how you would feel if you were on the other side.
One of the best books I’ve read over the past few years is The Scout Mindset, which suggests that very thing. If you want to think logically, look at everything as if you were on the other side.
Before I get into this, let me tell you my thoughts on The Donald, a man who does not fail to provoke intense emotion. When he first declared his intention to run, I disliked him intensely and thought his candidacy was a joke. (If you have the time, you can go back through my old Facebook posts from before 2016 to see what I thought about him back then. Don’t look for anything current, I haven’t been on FB for years.)
I didn’t figure he had a chance, anyway, until I happened to catch him on TV at a press conference. The only reason I even saw it was because I was at a conference in Chicago, and walked into my hotel room after I checked in to find the TV on. Folks don’t believe me, but I don’t even know how to turn a TV on these days. We have two TVs; one in each of our places. And I can’t turn either of them on. MD is the AV person in our household.
Anyway, I walk into my hotel room, and there is Trump on TV. I watch for a bit, and it takes me about two minutes to realize he’s going to win the election. How did I know? Because of two questions he was asked.
First, a reporter asked him about his wealth. The reporter started his question by saying that Romney’s great wealth handicapped him in his election against Obama in 2012. He then asked if Trump thought his own wealth was a problem.
Trump answered in true Trumpian fashion, though I hadn’t really known what that was until that moment. Trump said something along the lines of, ‘first let’s get something straight: Romney’s not wealthy. What’s his net worth? Maybe $400M? I make more than that every year. Trust me; Romney’s not wealthy.’
I thought right then that he had it in the bag. I had never seen anyone in politics talk like that. I figured others hadn’t either, so Trump was something different, and I suddenly wasn’t so sure the foreordained Hillary win was such a slam dunk after all.
Then they ask Trump about McCain. He says he prefers people who don’t get caught. I couldn’t believe it. Everyone—including Democrats—seems to be deferential to McCain’s captivity and ordeal, and here is Trump not just dismissing it, but dissing it.
At that moment, I was really worried for the first time that he really might win.
When Trump did get elected, I was scared to death. I had no idea how he was going to govern. I really don’t think he did either.
But he ended up governing like a moderate Republican, which was fine with me. Like almost everyone, I got tired of his constant fights with the press, but I’ve got to say, he put himself out there. How many press conferences has Joe Biden had? You can count them on one hand. Maybe one finger. Maybe even no fingers.
Trump had a press conference every day. Sometimes multiple times per day. No one can accuse him of not taking questions from the press.
If I had my way right now, I would like for him to evaporate, but that’s not going to happen. I would also like Biden to evaporate, corporally. He’s already kind of evaporated mentally. But Joe’s going to run. At least he’s declared. The Dems may have other plans for him. They are not idiots like the Republicans back in 1996, when they searched throughout the country and picked Bob Dole, probably the only person alive who could not beat Clinton that year. All because McCain said, “It’s Bob’s turn.” Jesus wept.
My vote would be for the both of them to go away and have some fresh faces. And that might happen over time—not the evaporation, but the fresh faces. Eighteen months is a lifetime in politics, so who knows who we’ll end up with.
But I suspect it will be Trump on the GOP side. If he somehow loses in the primaries, I wouldn’t be surprised to see him run as a third party candidate, which would ensure whoever runs on the Dem side of a victory.
Anyway, other than his caving to Fauci, Birx, Redfield, et al, when he never really caved to anyone else, I thought he did an okay job. The stock market was at an all-time high, the US was a net exporter of petroleum and gas prices were low, inflation was in check, and by any other metric things were going fine. Until the pandemic.
We all know what happened since.
But back to the Durham report, which showed Team Hillary to be behind the entire idea of a Trump-Russia connection. Matt Taibbi has a great substack report on it that hits the high points of the report (and unlike most of his stuff is not behind a paywall).
I hate to stop this abruptly, but I’ve droned on about this long enough. I’ll pick it back up at a later date, because I think it’s really interesting in terms of cognitive dissonance and confirmation bias. I don’t want you to think I’m beating a drum here for Trump, because I’m not. As I said, I wish he would just go away, but he won’t. I just intend to explore what happened during the Trump administration from a little different perspective.
I’ll leave this as an intro, and get into some real nutritional goodies.
But first, this on climate change, another non-controversial subject.
More Storms and Other Extreme Weather
As climate change increases the severity of heat waves, cold spells and other extreme weather, blackouts are becoming more common.
Now there was no equivocating here. It’s an out and out statement of fact. Or purported fact. But reported as fact. No, As proponents of climate change believe blah, blah, blah. Instead “As climate change increases…extreme weather [is] becoming more common.”
I decided to fact check it out with the National Atmospheric and Oceanic Administration (NAOA), the government agency that tracks this sort of thing.
Here’s what they had to say about changes in storms and other extreme weather over the past 30 years.
At least in terms of severe storms, doesn’t look like much of a change to me.
Okay, on to some nutritional info.
Sarcobesity and the VLCKD
Sarcobesity is the deadly combination of obesity and sarcopenia.
We’ve discussed sarcopenia a number of times in these pages, but for new readers, let’s briefly review.
Sarcopenia is muscle wasting with disease or, more commonly, aging and disuse. As we age and become less active, we lose muscle mass, which gets replaced with fat. Visceral obesity generates a host of inflammatory chemicals that tend to waste muscle in the arms and legs. Which is why you see a lot of older people at the beach with big bellies and skinny arms and legs.
Sarcopenia is relentless. We all begin to lose muscle mass after about age 30. There are various estimates of how much, but as a rule of thumb, you can count on about 0.5-1 percent per year. Which over a long life adds up. Or subtracts, if you’re talking about muscle mass.
Prior to age 30, muscle mass is pretty much under the control of various metabolic hormones. These hormones will mobilize the protein you eat into muscle mass almost irrespective of how you eat it. If you nibble a bit here and there, as long as you’re getting some dietary protein, these hormones will make sure it goes to the right spot.
After age 30, your muscle mass is dependent upon larger quantities of protein per meal in combination with resistance exercise.
That’s just a fact of metabolic life. Ignore it at your peril.
As we’ve also discussed, you need about 30-40 grams of animal protein at a meal to stimulate mTOR, which is the system that turns on muscle synthesis. If you consume plant-based protein, you need at least double that amount at a meal, because plant protein contains way less leucine, the particular amino acid that triggers mTOR. As you might imagine, it’s difficult to eat 60-80 grams of plant protein at a sitting.
You start out at age 30+ with plenty of muscle mass to do most everything you want to do. But over time, you become weaker and weaker. As time progresses, you start to be unable to do simple things you could do easily before. Say, for example, emptying your grocery sack and putting heavy items on upper shelves. And innumerable other tasks you could have done without a thought at age 30.
If you’re obese, it makes it all the worse as you’re having to move all your excess weight around with a gradually diminishing muscle mass.
In order to make later years more comfortable and yourself more independent, you’ve absolutely got to pay attention to your muscle mass and do all you can to maintain it. Or even increase it, which is tough, but can be done.
With all this in mind, let’s take a look at an Italian pilot study I came across a few days ago.
The study, titled Very low calorie ketogenic diet combined with physical interval training for preserving muscle mass during weight loss in sarcopenic obesity: A pilot study, looks at a potential method for treating sarcobesity. It is a pilot study, which means it has a small number of subjects. Researchers use pilot studies to see if the generated data is strong enough to get funding for a larger study. Data from these kinds of pilot studies must be interpreted with caution.
I think this one provides some interesting information despite the small number of subjects. Just remember as I go through it that these findings could all be artifacts and not replicable with a larger group of subjects. But based on my hands-on experience with a whole lot of patients, I strongly suspect these findings would hold up if they tested a large number of patients.
The researchers winnowed down a fairly large number of volunteers—almost 500—to get to the 24 who ultimately participated.
The inclusion conditions were as follows:
Women and men, age between 50 and 70 years old, BMI between 30 and 40 kg/m2 with stable BW in the previous 6 months, WC ≥ 102 cm for men and ≥88 cm for women, sarcopenia, insulin resistance (Homeostasis Model Assessment-Insulin Resistance, HOMA-IR ≥ 2.5) or type 2 diabetes mellitus treated only with metformin.
The presence of SO [sarcopenic obesity] was considered when the following conditions were satisfied:
- FM [fat mass] > 39–41% for woman and > 29–31% for man
- Five times Sit-to-Stand Chair test > 15 s according to EWGOP2
- Short physical performance battery (SPPB) < 8, according to EWGSOP2
The fat mass part is pretty obvious. If you’ve got a fat mass anywhere near the numbers above, you are obese. The other two parts of the selection criterion determine the presence of sarcopenia.
The chair stand test (CST) looks at the amount of time needed for a subject to rise five times from a seated position without using his/her arms. If it took longer than 15 seconds to do this, the researchers diagnosed sarcopenia.
To better evaluate physical performance, the researchers added a couple of other components from the Short Physical Performance Battery (SPPB)
consisting of three components of physical performance: (1) standing balance, (2) chair stands, and (3) gait speed. A score from 0 (poorest) to 4 (best) was assigned for each of these three components. The sum of the scores provided a composite score ranging from 0 to 12; physical performance was considered impaired when the total SPPB score was ≤ 8
Once the 24 subjects who met all the criteria were selected, they were randomized into two groups of 12. One group went on a very-low-calorie ketogenic diet (VLCKD) while the other group went on the same VLCKD but with twice-per-week interval training added starting in week 2.
What kind of interval training? Take a look.
What is a bird dog exercise, you might ask? Well, I was clueless myself, so I looked it up. It’s a core exercise you can read about here if you’re interested.
The VCLKD was the same for both groups and was as follows:
All patients followed a VLCKD [780–800 kcal/day, with the following composition in macronutrients, percentage of caloric intake, and g/kg of ideal BW of proteins (derived by the BMI set at 25 kg/m2), respectively: carbohydrates 26 g (13.5%), fats 35 g (40.4%) and proteins 80–90 g (1.2–1.4 g/Kg of ideal BW)
The subjects got their meals parceled out five times per day. The protein—were it of animal origin—was enough to stimulate muscle growth, but only if about half of it were provided at one time. Preferentially an early meal. But since it was divided into five meals, I doubt any one meal had a large enough protein content to do much in terms of muscle mass. Since the fat content of the diet was 15 percent saturated, I suspect they did use animal protein. And this was done in Italy. Italians are Italians, but they haven’t been stupid enough to fall for the plant-based BS like the rest of the world has.
They followed these folks for six weeks. Let’s see what happened.
When I started reading the study, I made my own predictions based on my own years of experience with many patients.
I predicted that both groups would lose muscle mass. The group without the exercise would lose more. And I predicted both groups would lose about the same amount of weight.
I was wrong. And sort of right.
Here are the results.
If you look at the FFM, which stands for fat-free mass, you can see that the group on the VLCKD lost 2.3 kg (5.06 lb) of muscle mass while those with the added exercise actually gained a bit of FFM: 0.3 kg (0.66 lb).
Which means the exercise prevented the loss of a little over 5 pounds of lean body mass and even added a tiny bit. And these subjects did not do what anyone would call brutal episodes of resistance training.
Frankly, I was surprised to see such robust results. But, remember, these could be artifacts due to the small number of subjects.
In terms of overall fat loss, you can see right above the red rectangle above that the subjects on the VLCKD lost an average of 6.5 kg (14.3 lb) of fat while those on the VLCKD with exercise added lost 11 kg (24.2 lb). That’s almost double what the group who did not exercise lost. And, remarkably, that loss is over six weeks, which equates to a bit over four pounds of fat lost per week, a huge loss. Especially when you consider a gallon of fat weighs a bit less than eight pounds, which equates to a half gallon of fat loss per week.
You always hear the expression, You can’t outrun a bad diet. And you read that exercise isn’t all that potent in terms of weight loss. Well, this study seems to disprove that, at least the second half of it. Bearing in mind the small number of subjects and all.
You can see the remarkable difference in fat loss in this graphic from the paper.
The figure above shows the results for each study participant in the program. You can see there is some overlap. In other words, some of the subjects on the diet plus exercise arm lost less fat mass than a few on the diet alone, but overall it’s pretty clear the diet plus exercise was more effective.
It gets even more impressive when you see the difference in fat free mass (FFM), which is essentially a proxy for muscle mass.
In terms of muscle mass, you can see that there is almost no overlap. Three of the subjects on the VLCKD alone lost very little muscle mass, but the rest lost a significant amount. And a few on the exercise regimen lost a little muscle mass, but overall the results show you’re more likely to gain, or at least fail to lose, muscle mass if you exercise along with your diet.
There are a few other things that jumped out at me as I read this paper and looked at the data.
Here are the lab results before and after for each group. I can’t believe they didn’t measure ketones, but apparently they didn’t. Or didn’t include them if they did.
I apologize for the size of the image, but that’s the only way I could get the entire thing on the screen. You can go to the full study linked above if you’re having trouble reading the small numbers.
First thing I noticed when I saw this was the increase in the GFR, which is the glomerular filtration rate, a function of how well the kidneys are working. It improved a bit in both groups, with the improvement in the exercise group almost doubling that in the non-exercise group.
The protein intake in both diets was about 90 grams per day. I’m not sure these folks were getting that much before they went on the diet. The fact that their GFR improvement indicates that a ketogenic diet doesn’t harm the kidneys. Just the opposite, in fact.
It was nice to see vitamin D go up in both groups. Subjects in both groups lost fat. Vitamin D is fat soluble and stored in fat, so it was definitely released and increased the blood levels.
Next thing I noticed was that HDL went up markedly in the diet plus exercise group. It barely moved in the non-exercise group. But because of the wide variance between subjects, I don’t give this one a lot of credence. One outlier could make a big difference. And the way they listed it as a range instead of the ± way the others are listed kind of spooked me.
The triglyceride levels also troubled me. To qualify for entry into the study, these subjects all had to be either insulin resistant or have type 2 diabetes. I’ve taken care of a lot of overweight insulin resistant and/or type 2 diabetic patients, and they almost all have elevated triglycerides. In fact, high triglycerides are almost a proxy for insulin resistance. These subjects all had triglyceride levels at the start that weren’t all that abnormal. I don’t think in a group of 24 supposedly insulin resistant, type 2 diabetics you would find more than a couple who didn’t have way elevated trigs.
Finally, I wish they had used DEXA instead of bio-impedance analyzer for body composition. But, it’s a pilot study. I hope they can use these results to get funding for a study with a lot more subjects.
All in all, the most important finding in this small study was that it appears that folks 50-70, at least, can maintain their muscle mass in the face of a very low calorie diet (with a decent amount of protein) if they do resistance exercise a couple of times a week.
I’ve always been a bit hesitant to put older people on very-low-calorie ketogenic diets because I’ve always been worried they would lose muscle mass, which I thought they would have real trouble regaining.
It has always been a real conundrum. It’s better for older folks to not be obese. But it’s also better for them to maintain—and even gain—muscle mass. So, you try to thread the needle and do both.
If I were advising patients today, I would tell them to go on a very-low-carb diet, which is a ketogenic diet, but have them eat when hungry. And particularly eat protein and fat. I would suggest one big protein meal early in the day to activate mTOR. And I would encourage resistance exercise at least a couple of times per week.
Okay, on to an even more interesting study
G protein-coupled receptors and Ketones
Now there is a click-bait-y title if I’ve ever seen one. How could one not read on?
I want to start out by quoting a good part of the abstract of this article, which pretty much represents conventional thinking. Then I want to discuss what I think about it, which is not conventional thinking. Before you read it, let me define a couple of terms you may not be familiar with. A ligand is a part of one molecule that attaches to another molecule or complex. (It’s a little more specific than that, but my definition is close enough.) And a G coupled-protein receptor (GCPR) is simply a receptor in a cell membrane that, once stimulated by attachment of a ligand, sends a signal to the interior of the cell to do something.
Ketogenesis takes place in hepatocyte mitochondria where acetyl-CoA derived from fatty acid catabolism is converted to ketone bodies (KB), namely β-hydroxybutyrate (β-OHB), acetoacetate and acetone. KB represent important alternative energy sources under metabolic stress conditions. Ketogenic diets (KDs) are low-carbohydrate, fat-rich eating strategies which have been widely proposed as valid nutritional interventions in several metabolic disorders due to its substantial efficacy in weight loss achievement. Carbohydrate restriction during KD forces the use of FFA, which are subsequently transformed into KB in hepatocytes to provide energy, leading to a significant increase in ketone levels known as “nutritional ketosis”. The recent discovery of KB as ligands of G protein-coupled receptors (GPCR) - cellular transducers implicated in a wide range of body functions - has aroused a great interest in understanding whether some of the clinical effects associated to KD consumption might be mediated by the ketone/GPCR axis. [My bold emphasis]
Where I differ from these authors (and most authors, I suspect) is in considering ketones as alternative energy sources under metabolic stress.
If you go back to Paleolithic times, the time before agriculture came on the scene, our ancestors were primarily hunters who cut their teeth, so to speak, on a basically carnivore diet. They would have been in what we now call nutritional ketosis virtually all the time. It would not have been an “alternative energy source under metabolic stress conditions;” it would have been normal. Had there been a cave man version of a chem scan unit, our cave man doc would have discovered that all his fellow cave men, women, people, zhey, whatever, would have had ketones cranking along at 2-4 mmol/l levels…maybe even more 24/7.
If one of our cave doc’s patients had come down with something and it was found that ketone levels were 0.5, the cave doc might have made the diagnosis of hypoketonemia, a serious disorder of low ketones. Our doc might tell the patient that he/she was in metabolic stress and using glucose, an alternative energy source (at least back then), for fuel. Gotta get those ketones up, our Doc would say, then you’ll feel a lot better.
I’m being a bit facetious here, but the more I read about the benefits of ketones, the more I’m convinced that the forces of natural selection would not have built us to use them as just an alternative source of energy when we’re metabolically stressed. My presumption is that they—along with the fats from which they came—were (and are) the primary fuels for the human body.
The problem came in when lab equipment was invented. Once we could check levels of all kinds of blood chemistry, we, as a species, had already been on agricultural diets for centuries. When scientists started measuring blood, almost everyone was on a high-carbohydrate diet, at least as compared to our Paleolithic ancestors. So when blood values came back, in one subject after another, we took those as normal.
When we started measuring ketones, they weren’t there. Except in diabetic patients, who sometimes went into ketoacidosis, which was often fatal. We came to consider ketones as being dangerous, not just a regular fuel.
As time went on and more lab values accumulated, they tended to follow a bell-shaped curve. Someone somewhere along the way decided that a measure of normal was two standard deviations around the mean. And that’s how what is considered normal in a lab value came to be.
Since then, things have refined a bit. Many lab values are still considered normal at the two standard deviations level. But others have been deemed as normal, but unhealthy, so they’ve been reclassified.
Take total cholesterol, for example. When I was in medical school many years ago, the upper limit of normal for total cholesterol was 300 mg/dl. That was two standard deviations from the mean. Then that became a number thought to be unhealthful, so it has dropped over the years until the upper limit of healthful/normal became 200 mg/dl. This lowering of the upper limit was driven in large part by those companies that had a cholesterol-lowering drug to sell.
Had these chem scan units been developed 25,000 years ago, we would doubtless have a different idea of what is normal and what is not. Yet physiologically we are just about the same now as we were then.
Okay, so with that preface, let’s take a look at the study in question.
The study, Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders, pretty much lives up to its title. Most of what it reviews are positive outcomes when ketones are elevated, so, in accordance with my views on the subject, I would call it what happens to people when they return to a normal diet, at least from the perspective of the couple million years we were on a ketogenic diet.
When I starting thinking about writing on this study, I realized I would have to explain what G protein-coupled receptors are, which can be a long discussion. Then I took a look at some videos and found a short one (just a couple of minutes) that describes these receptors in enough detail that the name at least makes sense. You’ll never know how many of these I went through to sift this one out for you. There are dozens and dozens out there, so if you want a more in-depth discussion, just go to YouTube and enter GPCR in the search function. Then have fun.
You can think of these as just regular receptors despite the more complex name. They are located in the cell membrane, and when something (a ligand) attaches to them, they send a signal to the inside of the cell telling it to do something.
The insulin receptor is not a GPCR, but it acts in a similar way. Insulin attaches to the receptor in the cell membrane, the receptor thus activated sends a signal into the cell to send GLUT4 receptors to the cell surface to grab glucose molecules and bring them into the cell.
The insulin receptor responds to only insulin, but GPCRs respond to many different stimuli.
One of the tidbits I ran across in plowing through this study was the following one.
Most of β-OHB [beta-hydroxyutyrate, the main ketone body] actions seem to be mediated by the activation of a specific GPCR, namely GPR109A, also known as Hydroxycarboxylic Acid Receptor 2 (HCAR2). GPR109A is classically recognized as the receptor for butyrate and nicotinic acid and is abundantly expressed in adipocytes, macrophages, and neutrophils. The plasma concentrations of β-OHB able to engage GPR109A (EC50 = 0.77 ± 0.06 mM) are those achievable after ∼2–3 days of starvation, or following a ketogenic diet regimen.
The GPR109A receptor jumped out at me because of some freelance writing MD did years ago. Acting as a writer for hire, she pounded out one of those giant family medical guides under the name of a prestigious university. She ended up having to phone conference with most of the department chairmen, who were far far removed from patient care, to discuss why she wrote what she did. Many of them wanted to change what she wrote, so she did not want her name mentioned anywhere on the book. And per her request it isn’t.
As an aside and just to show you how far removed these folks are from day to day patient care, I’ll describe one incident. She had written a paragraph in the urology chapter on blood in an ejaculation. The chairman of the department said to her, Why are you putting that in there. Everyone knows it’s harmless. She countered with, No, everyone doesn’t. If some guy sees blood in his ejaculate, he’ll be scared shitless and will be in his doctor’s office as soon as he can. The guy relented, and that paragraph remained. She had conflicts like this throughout the project.
This all took place before statins had come on the market in full force. When she was doing the research for her writing, she reviewed a ton of papers on drugs and supplements that prevent heart disease. She concluded that the only single supplement or drug that reliably prolonged life was niacin, or nicotinic acid. I’ve always been interested in it since.
After reading the section I quoted above, I remembered a paper I had read a few years back titled It ain’t over till the fat lady sings.
I remembered this paper because it had a great graphic on how nicotinic acid works through the GPR109A receptor. (Strangely, this paper was cited in the paper under discussion, but totally out of context.)
Here is the graphic.
Beta-hydroxybutryrate (BOHB) stimulates this same receptor. And it has the same effect niacin does except for the flushing.
BOHB has an anti-lipolytic effect in that it prevents fat from being released from the fat cells. But this is basically a feedback effect. If there is plenty of BOHB around, the body doesn’t need to release more fat. The anti-lipolytic effect keeps the ketones in check, which is why it’s virtually impossible to go into ketoacidosis while on a ketogenic diet…as long as you don’t have type 1 diabetes.
BOHB also inhibits the activation of the inflammasome, a complex system that activates all kinds of pro-inflammatory processes that contribute to the pro-atherogenic environment. Although this article doesn’t specifically say it, keeping the inflammasome tamped down gets rid of all kinds of aches and pains.
You can read the article yourself to see what all ketones do to make us better. When you do, read it from my perspective that ketones are regular fuels and not just something summoned when we starve or don’t eat carbs, and I think you’ll have a different view of the situation.
Here is a summary of all the good things ketones do acting through GPCRs.
Reduces atherosclerosis and inflammation through GRP109A
May protect against stroke, also through GRP109A
May protect against Parkinson’s disease, also through GRP109A
Protective against alcoholic liver disease, which means it also doubtless protects against NAFLD.
Protects via GRP109A against inflammation associated with insulin resistance and obesity, which are both inflammatory disorders.
May protect against other types of inflammation acting through GPR41
Acetoacetate (another ketone) may modulate inflammation and metabolism via gut microbiome through GPR43
Although the paper is about how ketones affect the various GCPRs, it goes on to discuss how effective a ketogenic diet is in treating multiple disorders in ways that are not GCRP involved.
Type 1 diabetes
Type 2 diabetes
Polycystic Ovary Disease
I encourage you to read the article as it’s pretty easy to understand once you know what these receptors are. The last part about the four disorders above is very understandable. As is the discussion. Just blot from your mind, when you come across them, the parts in the paper about the ketogenic diet being an unnatural diet. It is not.
Video of the Week
I’ve got what I think is a great one this week. And it’s silent. No music involved.
The Titanic, lying on the ocean floor at a depth of 12,500 feet, has been extensively explored since it was located in 1985. But the depth and darkness have prevented anything but close up photos.
The scan was carried out in summer 2022 by Magellan Ltd, a deep-sea mapping company, and Atlantic Productions, who are making a documentary about the project. They took 700,000 different photos from all angles and precisely measured the length and width of the ship. They then took the digital photos and created an exact 3-D reconstruction.
You can watch the short, haunting video at this link. I found it fascinating. I think you will too, if you’ve ever had any interest in the sinking of the Titanic.
That’s about it for today. Keep in good cheer, and I’ll see you next Thursday.
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