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Greetings everyone.

Before we get into the meat of this post, I would like to discuss some interesting poll responses from last week’s Arrow.

First, this one.

Then this one.

I found this an interesting dichotomy.

As most of you probably know, I write The Arrow at warp speed once I’ve figured out what I’m going to write about. And, as you might imagine, typos abound. I then pass it off to MD to edit and look for typos. She finds a lot of them, but also misses some as well. She is an excellent editor and has actually edited other people’s work. But she’s so used to my writing that she sometimes knows what I’m trying to say and reads typos I might have made as what they should be and not what they are. For instance, I might write tha instead of than. When she reads it, she reads the tha as than because she knows that’s what I’m trying to say and her brain fills it in. And thus misses a typo.

I always write my posts in the platform I use to publish it. This last time I defied tradition and wrote it offline in a Google document. In doing so, I discovered that Google docs uses much better technology to discover typos than does the platform I use to publish. Google docs is superior in picking up the typos. And the grammatical errors as well.

I decided to use my old friend Perplexity dot ai to check for typos. I can’t just grab the text out of the publishing platform and run it through AI. I would have to copy it to some other format before uploading. Which is why I decided to write it in Google docs to begin with.

After I wrote it, but before pasting it into the platform, I ran the Google doc version through Perplexity. I asked it to search for typos and grammatical screw-ups. What I expected was a list of the errors I could use to correct the typos along with a list of any grammatical screw-ups. Sometimes writers, myself included, purposely use improper grammar to either be humorous or to make a point.

What I got back was not what I expected. 

What I got back was a message saying, basically, that Perplexity had rewritten my post fixing all the typos it had found and changing the grammar and style as needed, and as far as I was concerned, it was my style, so it didn’t need fixing. It did not give me a list of the typos and errors so I could correct them myself.

As those of you who read last week’s Arrow know, it was a lengthy technical post. Much though I was tempted to simply copy and paste the ‘revised’ Perplexity version, I didn’t. I went through the whole thing line by line looking for typos and comparing it to what I had originally written. It took forever. But in doing so, I discovered that the stylistic changes made were not to my liking. So I went with what I had written. Which one of the poll respondents thought “reads like a product of AI.” Oh, well…

Next time I will ask Perplexity to search for typos and grammatical errors, list them separately, and not rewrite.

One other issue that came up in the poll responses:

I’ve had variations of this complaint for a long time. I’ve racked my brain trying to figure out what was going on. I couldn’t come up with a solution, so I figured it was an issue of outdated browsers or older computers on ancient operating systems or something of that nature.

This time, I copied the poll response and sent it to customer service. As it turns out, it was an easy fix. And it was all my fault. Not old browsers or old operating systems. When I set up my configurations of the platform, I neglected to click a button that I should have clicked. I’ve clicked it now, so the problem should be solved. Now, onward!

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Fatty Liver and the Low-Carb Diet

I came across a new paper I think many of you will find of value. I certainly did.

Before we get to the nuts and bolts of the article, let me give you a little history. Over 20 years ago, I was undertaking my daily trawl through the medical literature when I came upon a paper that grabbed me from a number of perspectives. The paper, titled Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity, showed that almost a third of Americans had what at the time was called non-alcoholic fatty liver disease (NAFLD).

I knew NAFLD was problematic in obese subjects, but I had no idea a third of the population suffered from it. When I tested blood samples from my patients (before I had ever seen the above article) I commonly got back lab results showing elevated liver enzymes indicating damage. Which I took to be because of fatty infiltration of the liver. But these were generally obese patients. The study above was just average people – not just the obese.

The study was published in 2004. I can only imagine what the researchers would find if they did this same study today. Given the huge rise in obesity, instead of almost a third of the subjects having fatty liver (as measured by proton magnetic resonance spectroscopy, a much more sensitive measure than a simple blood test) I would instead guess the number would be closer to almost half. A distressing finding, to say the least.

Just to make a point, here are the CDC’s obesity statistics for 2004 followed by those from 2024 (the latest stats available):

And just to provide another perspective, below are the obesity statistics for those in the 40-59-year-old range. The statistics shown above include all age groups, whereas the one below shows just those statistics for the age group when obesity really sets in.

Is this terrifying or what?

Before we go on, let’s define NAFLD.

A pathologist taking a look at a liver tissue sample from a long-time abuser of alcohol will find a degree of fat infiltration. The degree of liver damage can run the gamut from mild fatty infiltration all the way to actual cirrhosis and everything in between. The pathologist would list these findings as evidence for alcoholic liver disease (ALD).

The same exact findings can be present in those who don’t abuse alcohol. In that case, the diagnosis is non-alcoholic fatty liver disease (NAFLD), simply based on the subject's denial of heavy drinking. Or it used to be.

Now, for some reason, the name has been changed to metabolic dysfunction-associated steatotic liver disease (MASLD). Which is probably a better name since it describes what the issue really is: steatotic liver disease (fatty liver disease) caused by metabolic dysfunction. 

Going back and rereading this paper really got my blood up as it reminded me of one of my major sources of agitation.

Diversity in Scientific Studies

This is probably going to be a politically incorrect thing to say in today’s woke world, but the races of people differ and men and women differ. It is very well known that the different races have different degrees of a multitude of disorders. Just as do men and women.

There seems to be a movement to democratically select members of study groups to be diverse. It’s the stupidest thing in the world.

I am a white male.* I would much prefer that any study I relied on for treatment for some medical issue I might fall victim to be conducted on white males. Not a mishmash of white, black, Asian, and Hispanic males along with white, black, Asian, and Hispanic females. There are plenty of all the above to conduct studies on different races and different sexes. Granted, it would be more expensive, but the findings would be vastly more valuable.

For instance, it is well known that men lose weight more easily than do females. If I were to conduct a weight-loss study with a group of subjects composed of 100 males and 100 females, I can guarantee you that the weight loss would be greater in the males than in the females. If I combine the results, it would not be an accurate study. It would indicate that females would lose more easily than they really do, and that males would have more difficulty in losing than they really do.

It’s the same with age. Younger people lose weight more easily than older people. So why group old and young together in a weight-loss study? The results of the group won’t be accurate for the individual age groups.

Let’s look at part of the abstract of the study above.

As you can see, there are differences between Hispanics, whites, and blacks in terms of their tendency to develop fatty liver. And a big difference between men and women.

Let me get off my soapbox about the diversification of medical studies and back to the topic at hand.

NAFLD in 2004 and The Book That Wasn’t

When I first read the study above back in 2004, it inspired me to take a deeper look into fatty liver disorder.

As I began to go through the papers available then, I noticed that the ones I found most interesting were all rodent studies. A number of researchers had discovered that polyunsaturated fats, especially linoleic acid, enhanced the development of fatty liver disease.

You might be wondering how the researchers gave the rodents fatty liver disease. They did it by either giving them alcohol or large doses of fructose or both.

If they gave rodents linoleic acid along with their alcohol or fructose, it accelerated the development of fatty liver disease. If, on the other hand, they gave the rodents long-chain saturated fats, they almost couldn’t make them develop fatty liver no matter how much alcohol or fructose they gave them. In other words, saturated fats, especially long-chain saturated fats, such as those found in beef tallow, were protective.

At that time, I couldn’t find any studies on humans for obvious reasons. At that time, saturated fat was considered a major risk factor for cardiovascular disease (much as it is still considered so by the unenlightened). It would have been deemed unethical to force alcohol on people who don’t drink much and have them take large doses of polyunsaturated fat to see if they developed fatty livers. It would probably also have been thought unethical to give human subjects large doses of beef tallow and have them drink alcohol in large quantities in an effort to determine if the saturated fat was protective against the booze.

Wasn’t going to happen.

After I had done the research, it occurred to me that there might be a book in all this. So I called our agent and pitched her on the idea. I told her about the fact that almost a third of people have NAFLD, and that it was bound to increase in parallel with the skyrocketing obesity statistics. It won’t be long, said I, before half the population will have fatty liver disease. And since it will take two years to write and get such a book published, we would be right there with the only popular book in print about NAFLD. 

Our agent, who is a New Yorker from birth, asked me if it had been written about in the Times, meaning, of course, the New York Times. I told her no, that is the beauty of it. We would be there first. She asked if there had been an article in the New Yorker about NAFLD. She told me that unless it was already an epidemic that everyone was talking about (she meant New Yorkers, whom she considers the center of the universe), there would be no interest in such a book in the publishing world.

She said when NAFLD is on the lips of everyone, then we can sell a book on it. I replied that by that time there would be fifty people out there pitching books on it. She told me I didn’t have to worry about selling it to the public – that was the publisher’s job. My job was to sell it to the publisher, and if no one has heard of it (since, after all, it hadn’t been written about in the Times), we would be wasting our time. No editor would be interested in a book on any disease process that hadn’t been recognized by the paper of record for the world.

Thus my plans were thwarted.

Old Paper Versus New Papers

But my interest in fatty liver disease hasn’t flagged. I just haven’t been as diligent in my literature reading as I was in those early days.

I went back and looked at the papers I had saved showing polyunsaturated fats to enhance liver fat accumulation and saturated fat preventing liver fat accumulation. I then uploaded these papers to Perplexity and asked it to take a look for recent papers on fatty liver to see if the old papers (from my 2004 search) had been refuted. Or if they had been confirmed.

Here was my actual query:

Here is what I got back.

Perplexity did include citations for more recent studies, all of which I looked at. There was one human study from Sweden showing that those subjects consuming polyunsaturated fats had better outcomes than those consuming saturated fats. And that gave me a moment of pause — hmmm? So I looked deeper into that one.

The study randomized subjects into two groups. Both groups were instructed to consume their regular diets for the duration of the study. Subjects in both groups were instructed to consume as many of a particular (provided) large muffin as they wanted in addition to their regular diets. These muffins, baked in an institutional kitchen, contained either saturated fat or polyunsaturated fat in equal proportions.

The group of subjects consuming the muffins baked with polyunsaturated fats had better outcomes in terms of liver fat accumulation than did those eating the muffins made with saturated fat. Subjects in both groups ate an average of almost three muffins daily in addition to their regular diets.

I went through this paper carefully for a couple of reasons. First, it was a human study. Second, because it showed an outcome that was the opposite of what all the other studies had confirmed. After my careful reading, I had some major issues with this study.

First, there was no indication whatsoever of the actual diets these subjects ate during the study. It would have been easy enough to have had them keep diet diaries or to have a staff member call them and simply ask about their diets. This is a real confounding factor, which would have been simple enough to collect the data on. The fact that nothing was mentioned about the regular diets makes me suspicious. If they didn’t collect the data, it was a mistake. More than likely, they did collect the data, but failed to report it. If this was the case, it likely screwed up the case they were trying to make. Most of the research community is of the opinion that polyunsaturated fats are good and saturated fats are bad. If something arose that contradicted this, then that might have been a factor in having the paper peer reviewed and could possibly have led to its not being accepted for publication.

In any event, as published, it was a sloppy study. Later studies may confirm it, but I have my doubts.

Now, with all this prelude, let’s get to the real study I want to discuss.

Your Liver Has a Bedtime Problem That’s Worsening Every Night

A groundbreaking new study from the prestigious journal Cell Metabolism (one of my favorite journals) reveals that fatty liver disease is mostly a nighttime disease. 

According to the paper titled Human MASLD is a diurnal disease driven by multisystem insulin resistance and reduced insulin availability at night, published by researchers from the University of Oxford. The article argues that MASLD is fundamentally a nighttime disease in which multiple organs become more insulin resistant, and insulin itself becomes relatively scarce, even after weight loss lowers liver fat.

Which means – assuming the study holds up to replication – MASLD isn’t just a metabolic disease, it’s a time-of-day disease.

Let’s take a look.

First, from the introduction:

(I wrote earlier that MASLD (or NAFLD) probably affected almost 50 percent of people in the US by now. This paper reports that it affects ~ 40% of the global population. When it comes to metabolic disorders, the US leads the pack. So I’ll stick with my almost 50% prediction.)

This study was not a simple survey or observational study. The researchers put 12 people with MASLD and 12 overweight people without it through a grueling but carefully controlled protocol. And they did it twice. Once during the day (7 AM to 1 PM), and once at night (7 PM to 1 AM). They used sophisticated techniques involving stable isotopes –essentially harmless chemical tracers – to track exactly what the liver, muscle, and fat tissue were doing metabolically at each time of day. They also collected tissue biopsies and analyzed thousands of proteins across multiple organs.

The research team used insulin-clamps, which I’m not a fan of, but which have become the gold standard for determining insulin resistance. (I don’t like insulin-clamp studies because they are not physiologic.)

Here is how they work. 

Researchers infuse insulin via IV until insulin levels are higher than normal. Then they keep the insulin infusion at a steady state at this high level. As glucose levels begin to fall, the techs begin infusing glucose to bring glucose levels to normal. If it takes a lot of glucose to maintain normal levels, then it can be said that the subject undergoing the insulin-clamp study is not insulin resistant. It means a fixed level of insulin drives a lot of glucose into the cells, which is the definition of insulin sensitivity.

If, on the other hand, it doesn’t take much glucose to keep blood glucose normal, that means the subject is insulin resistant. In other words, it takes a lot of insulin to maintain a normal blood sugar level because the high insulin levels provided by the clamp are not able to drive sugar into the cells, therefore it takes little infused glucose to keep the blood glucose at the normal level.

The primary focus of this study was on de novo lipogenesis (DNL) — i.e., the liver's ability to convert carbohydrates and other precursors into fat. But the researchers also measured insulin sensitivity, glucose production, fat breakdown, and much more.

Here’s what they found.

The Liver Misbehaves at Night

In healthy people, metabolism naturally slows down at night. But in MASLD patients, it doesn't just slow, it malfunctions.

The liver keeps pumping out glucose all night long (called endogenous glucose production, or EGP), even when insulin is screaming for it to stop. Muscle tissue becomes resistant to insulin and refuses to absorb glucose. Fat cells release fatty acids into the bloodstream uncontrollably. The liver keeps building new fat via de novo lipogenesis (DNL) even in a fasted state. And perhaps most surprisingly, the body actually produces less insulin at night in MASLD patients while simultaneously clearing insulin faster, which leaves cells double-exposed to metabolic chaos.

The end result? MASLD patients wake up with higher morning blood sugar (called the "dawn phenomenon") from more fat flooding their liver overnight. And tissues that have spent the night marinating in a metabolic storm.

Why is this study different from everything before?

Previous research on circadian rhythms and liver disease was almost entirely done in rodents. This study is the first to use functional metabolic measurements – not just gene expression or blood tests – to map this nighttime dysfunction in living humans. That's a huge difference.

Even more striking, the researchers had 11 of the MASLD patients complete a 12-week weight-loss program, losing about 6% of their body weight. Their liver fat dropped significantly. But when the nighttime clamp studies were repeated, the nighttime metabolic dysfunction was still there. The daytime improved, but the nighttime didn't budge. This strongly suggests that the nighttime metabolic pattern isn't just a result of fatty liver – it might be a cause of it, baked in deeper than simple weight loss can fix.

Here's where this research gets exciting for anyone who eats low-carb or keto, which is why I’m so fired up about this study. 

The nighttime problems in MASLD are, at their core, a failure to manage carbohydrate and insulin signaling at night. 

Here’s what we find if we break the study down.

The liver is overproducing glucose. On a ketogenic diet, carbohydrate intake is so low that the liver's glucose-producing machinery is already operating in a restrained, fat-burning mode. The big driver of runaway nighttime glucose production –gluconeogenesis being overstimulated by excess glucose substrate – is naturally reduced when there are fewer carbohydrates and sugars flooding the system throughout the day.

The liver is making fat from scratch (DNL) at night. DNL requires carbohydrate precursors, especially fructose and glucose. When you're eating a low-carbohydrate diet, you're cutting off the primary raw material for this process. The study actually found that nighttime DNL was a hallmark distinguishing MASLD from healthy controls – something a ketogenic diet directly targets.

Fat is being released uncontrollably from fat cells. Interestingly, the study found that nighttime free fatty acids correlated strongly with the degree of liver fat accumulation. On a ketogenic diet, the body becomes efficient at using fatty acids for energy. It converts them into ketone bodies rather than shuttling them back to the liver to be stored as fat. The study even measured ketones (3-hydroxybutyrate, or 3OHB) and found that both groups had elevated nighttime ketones, which is the body's natural attempt to burn off excess fat. A ketogenic diet essentially amplifies and sustains this fat-burning mode.

Per this study, the central problem is that insulin is low and ineffective at night. Low-carb/ketogenic diets are the most powerful dietary tool known for improving insulin sensitivity. By keeping carbohydrate intake low, you reduce the insulin demand on the body around the clock – including at the nighttime window when MASLD patients are most vulnerable.

The study also found a protein called GDF-15 was elevated at night in MASLD patients, which animal studies suggest may be a protective signal trying to ramp up fat burning in the liver. Ketogenic diets are associated with elevated GDF-15 and enhanced hepatic beta-oxidation, indicating that low-carb/ketogenic dieting is likely working with this natural protective mechanism.

What Are the Takeaways From this Study?

The researchers point to three key implications of their findings: when you eat, when you exercise, and when medications are taken may all matter enormously for MASLD patients. They note that the biggest single meal in their participants' day was dinner – 40% of daily calories – eaten right at the time when metabolic dysfunction is peaking.

From a low-carb/ketogenic perspective, this supports what I always recommend: keep evening meals small and low in carbohydrates. If you're eating low-carb/keto, a dinner heavy in protein and healthy fats, with minimal or no starchy carbohydrates, may help keep nighttime DNL and glucose overproduction in check. Evening exercise, the researchers suggest, may also be particularly beneficial for improving that nighttime glucose disposal that is so impaired in MASLD. And remember moderate aerobic exercise is a fat burning endeavor; high intensity and resistance exercise (really working the muscles against a load) calls on those type 2B fibers that suck up glucose. That’s their go-to fuel.)

Importantly, this study is a reminder that fatty liver disease is not just about what you eat, it's also about when your body is most vulnerable, and what you can do to protect it during that window. Low-carb and ketogenic diets, by their very mechanism of action, address the nighttime metabolic chaos at its roots.

Try to eat dinner a little earlier and if you’re going to eat carbs, eat them earlier in the day when you are more insulin sensitive.

* My 23 and Me genetic test showed that I was mainly Scottish and Irish with a little Scandinavian and northern England thrown in. And I’m 1.5% black. Apparently, one of my relatives a number of generations back was Cameroon.

"Vaccines Do Not Cause Autism!" The Science is Settled. Right?

Aaron Siri, the attorney who has been suing over vaccine injuries for years has a book out titled Vaccines, Amen that I have recommended a few times. It’s an excellent book well worth reading from cover to cover.

One of the chapters presents the science concerning vaccines and autism. In a post just today, Mr. Siri generously provided a free download of his entire chapter about vaccines and autism.

If you’re interested, click here to see his post and access the free chapter.

Odds and Ends

• What was the first novel ever written? Take a guess, then take a look.

• Why do cats purr? Personally I grew up with dogs as pets; I'm not a cat person. MD grew up with cats and loves them, but we've never owned one jointly. It's not that I dislike cats, but I am seriously allergic to their dander, far beyond sneezing and red eyes to the point of asthmatic wheezing as is our eldest son, so we never had cats at Casa Eades.

• Aspirin's 4000 year history. A not so modern miracle.

• I love village pubs -- the history, the patina, the ambience, the whisky. MD and I have happily dined and imbibed in them all over Ireland and Scotland. Haven't had the pleasure of this one ... yet. Supposedly the oldest pub in Ireland, and possibly the world. How many St. Paddy’s days has it seen?

• The Bride and I have traveled a lot on trains throughout Europe and the UK but never anything remotely like these opulent train trips. Not saying we would object to doing so, of course. Should the opportunity arise, our roller bags would be packed in the twinkling of an eye!

• Ancient Egyptian correction fluid? Even artisan scribes can make a mistake, it seems.

• References to food and drink in Shakespeare's plays reveal more about the characters and story than I ever imagined.

• Here's a good little brain-stretching, time-wasting activity if you simply have too much of it on your hands. Though even if you learn it, it will still leave you far short of the world record of reciting 100,000 digits of Pi.

• Did you ever wonder if animals have accents? MD once told me a story about her sister, who back 60-plus years ago in high school babysat for a French family; at dinner one night she commented that even the cat meowed in French. Maybe it was so, according to this article about the phonology of animal sounds.

Newsletter Recommendations

Video of the Week

I may have posted this video years ago. I just can’t remember. It’s one of those videos that fascinates me because I can’t imagine doing what these folks are able to do. After I first watched this video years and years ago, I tried this in the privacy of my own backyard. I didn’t come anywhere remotely close.

Cover the bottom half of these dancers’ bodies with your hand or a card or something. The top half doesn’t move, while the bottom half goes to town. Amazing! To me, at least.

I had actually forgotten about this video, when, all of a sudden, it popped up in my feed when I opened my YouTube app. I’ve watched it in amazement at least ten times since then. I’m mesmerized by how this dance—if that’s what it’s called—can be done.

Enjoy! And my apologies if I’ve posted it in the past. Still worth a watch. And if you enjoyed it the first time, you’re welcome again!

Time for the poll, so you can grade my performance this week.

That’s about it for this week. Keep in good cheer, and I’ll be back soon.

Please help me out by clicking the Like button, assuming, of course, that you like it.

This newsletter is for informational and educational purposes only. It is not, nor is it intended to be, a substitute for professional medical advice, diagnosis, or treatment and should never be relied upon for specific medical advice.

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