Choline and Fatty Liver

I've been writing about non-alcoholic fatty liver disorder (NAFLD) since the early days of this blog, because it's an alarmingly common disorder (roughly a quarter of Americans affected) that is typically undiagnosed. It often progresses into its more serious cousin non-alcoholic steatohepatitis (NASH), an inflammatory condition that causes liver damage and can progress to cancer. In a number of previous posts, I pinpointed excess sugar and seed oil consumption as culprits in NAFLD and NASH (1, 2, 3, 4, 5).

Chris Masterjohn recently published two very informative posts on NAFLD/NASH that add a major additional factor to the equation: choline (6, 7). Choline is an essential nutrient that's required for the transport of fat out of the liver (8). NAFLD can be caused, and cured, simply by removing or adding dietary choline, and it appears to be dominant over other dietary factors including fat, sugar and alcohol. Apparently, certain researchers have been aware of this for some time, but it hasn't entered into the mainstream consciousness.

Could that be because the richest dietary sources are liver and eggs*? Choline is also found in smaller amounts in a variety of whole animal and plant foods. Most people don't get the officially recommended amount. From a recent review article (9):

Mean choline intakes for older children, men, women, and pregnant women are far below the adequate intake level established by the [Institute of Medicine]. Given the importance of choline in a wide range of critical functions in the human body, coupled with less-than-optimal intakes among the population, dietary guidance should be developed to encourage the intake of choline-rich foods.

I've dubbed beef liver the Most Nutritious Food in the World, Nature's Multivitamin, and I'll probably invent other titles for it in the future. Add yours to the comments. Learn to love liver! I think it's an excellent food to eat on a weekly basis.

Head over to Chris's blog and read about the classic studies he unearthed. And add The Daily Lipid to your RSS reader, because there's more interesting material to come!

The Sweet Truth about Liver and Egg Yolks
Does Choline Deficiency Contribute to Fatty Liver in Humans?


* For the brave: brain is actually the richest source of choline.

Copper in Food

Sources of Copper

It isn't hard to get enough copper-- unless you live in an industrial nation. I've compiled a chart showing the copper content of various refined and unrefined foods to illustrate the point. The left side shows industrial staple foods, while the right side shows whole foods. I've incorporated a few that would have been typical of Polynesian and Melanesian cultures apparently free of cardiovascular disease. The serving sizes are what one might reasonably eat at a meal: roughly 200 calories for grains, tubers and whole coconut; 1/4 pound for animal products; 1/2 teaspoon for salt; 1 cup for raw kale; 1 oz for sugar.

Note that beef liver is off the chart at 488 percent of the USDA recommended daily allowance. I don't know if you'd want to sit down and eat a quarter pound of beef liver, but you get the picture. Beef liver is nature's multivitamin: hands down the Most Nutritious Food in the World. That's because it acts as a storage depot for a number of important micronutrients, as well as being a biochemical factory that requires a large amount of B vitamins to function. You can see that muscle tissue isn't a great source of copper compared to other organs, and this holds true for other micronutrients as well.

Beef liver is so full of micronutrients, it shouldn't be eaten every day. Think of it in terms of the composition of a cow's body. The edible carcass is mostly muscle, but a significant portion is liver. I think it makes sense to eat some form of liver about once per week.

Modern Agriculture Produces Micronutrient-poor Foods

The numbers in the graph above come from NutritionData, my main source of food nutrient composition. The problem with relying on this kind of information is it ignores the variability in micronutrient content due to plant strain, soil quality, et cetera.

The unfortunate fact is that micronutrient levels have declined substantially over the course of the 20th century, even in whole foods. Dr. Donald R. Davis has documented the substantial decline in copper and other micronutrients in American foods over the second half of the last century (1). An even more marked decrease has occurred in the UK (2), with similar trends worldwide. On average, the copper content of vegetables in the UK has declined 76 percent since 1940. Most of the decrease has taken place since 1978. Fruits are down 20 percent and meats are down 24 percent.

I find this extremely disturbing, as it will affect even people eating whole food diets. This is yet another reason to buy from artisanal producers, who are likely to use more traditional plant varieties and grow in richer soil. Grass-fed beef should be just as nutritious as it has always been. Some people may also wish to grow, hunt or fish their own food.

Fatty Liver: It's not Just for Grown-ups Anymore

The epidemic of non-alcoholic fatty liver disease (NAFLD) is one of my favorite topics on this blog, due to the liver's role as the body's metabolic "grand central station", as Dr. Philip Wood puts it. The liver plays a critical part in the regulation of sugar, insulin, and lipid levels in the blood. Many of the routine blood tests administered in the doctor's office (blood glucose, cholesterol, etc.) partially reflect liver function.

NAFLD is an excessive accumulation of fat in the liver that impairs its function and can lead to severe liver inflammation (NASH), and in a small percentage of people, liver cancer. An estimated 20-30% of people in industrial nations suffer from NAFLD, a shockingly high prevalence (1).

I previously posted on dietary factors I believe are involved in NAFLD. In rodents, feeding a large amount of sugar or industrial seed oils (corn oil, etc.) promotes NAFLD, whereas fats such as butter and coconut oil do not (2). In human infants, enteric feeding with industrial seed oils causes severe liver damage, whereas the same amount of fat from fish oil doesn't, and can even reverse the damage done by seed oils (3).

So basically, I think sugar and industrial oils are major contributors to NAFLD, and if you look at diet trends in the US over the last 40 years, they're consistent with the idea. Industrial oils are harmful due (at least in part) to their high omega-6 content, which is problematic partially because it disturbs normal omega-3 metabolism. A potential solution to fatty liver is to reduce sugar, replace industrial oils with natural fats, and ensure a regular source of omega-3. I've posted two anecdotes of people rapidly healing their fatty livers using diet changes* (4, 5).

I recently came across a study that examined the diet of Canadian children with NAFLD (6). The children had a high sugar intake, a typical (i.e., high) omega-6 intake, and a low omega-3 intake. The authors claimed that the children also had a high saturated fat intake, but at 10.5% of calories, they were almost eating to the American Heart Association's "Step I" diet recommendations**. Busted! Total fat intake was also low.

High sugar consumption was associated with a larger waist circumference, insulin resistance, lower adiponectin and elevated markers of inflammation. High omega-6 intake was associated with markers of inflammation. Low omega-3 intake was associated with insulin resistance and elevated liver enzymes. Saturated fat intake presumably had no relation to any of these markers, since they didn't mention it in the text.

These children with NAFLD, who were all insulin resistant and mostly obese, had diets high in omega-6, high in sugar, and low in omega-3. This is consistent with the idea that these three factors, which have all been moving in the wrong direction in the last 40 years, contribute to NAFLD.


* Fatty liver was assessed by liver enzymes, admittedly not a perfect test. However, elevated liver enzymes do correlate fairly well with NAFLD.

** Steps I and II were replaced by new diet advice in 2000. The AHA now recommends keeping saturated fat below 7% of calories. Stock up on those skinless chicken breasts! Make sure there isn't any residual fat sticking to the meat, it might kill you. I do have to give the AHA credit however, because their new recommendations focus mostly on eating real food rather than avoiding saturated fat and cholesterol.

Another Fatty Liver Reversal, Part II

A month ago, I wrote about a reader "Steve" who reversed his fatty liver using a change in diet. Non-alcoholic fatty liver disease (NAFLD) is a truly disturbing modern epidemic, rare a few decades ago and now affecting roughly a quarter of the adult population of modern industrialized nations. Researchers cause NAFLD readily in rodents by feeding them industrial vegetable oils or large amounts of sugar.

Steve recently e-mailed me to update me on his condition. He also passed along his liver test results, which I've graphed below. ALT is a liver enzyme that enters the bloodstream following liver damage such as hepatitis or NAFLD. It's below 50 units/L in a healthy person*. AST is another liver enzyme that's below 35 units/L in a healthy person*.

Steve began his new diet in November of 2008 and saw a remarkable and sustained improvement in his ALT and AST levels:

Here's how Steve described his diet change to me:

I totally eliminated sugar, heavy starches, and grains. Started eating more whole, real foods, including things like grass-fed beef and pastured pork and eggs, began supplementing with good fats and omega-3 (pastured butter, coconut oil, cod liver oil). Ate more fruits and vegetables instead of refined carbs. Also completely gave up on the idea that I had to eat only "lean" meats. After my last results, the GI doc said that I wouldn't need the biopsy at all, that things were great, and that if I kept it up I "would live forever."

He did experience some side effects from this diet though:

My triglycerides also went from pre-diet measures of 201 and 147 to post diet 86, 81, and 71.

The added bonus, of course, was that my weight went from 205 pounds to 162 pounds and my body fat percentage from 24% to 12% in the matter of five months--all without the typically excessive cardio I used to try unsuccessfully for weight loss.

The liver is the body's "metabolic grand central station". It's essential for nutrient homeostasis, insulin sensitivity, detoxification, and hormone conversion, among other things. What's bad for the liver is bad for the rest of the body as well. Don't poison your liver with sugar and industrial vegetable oils.


* The cutoff depends on who you ask, but these numbers are commonly used.

How to Fatten Your Liver
Excess Omega-6 Fat Damages Infants' Livers
Health is Multi-Factorial
Fatty Liver Reversal
Another Fatty Liver Reversal

The Diet-Heart Hypothesis: Oxidized LDL, Part II

In the last post, I presented the evidence that oxidized LDL (oxLDL) is a dominant factor in the arterial disease known as atherosclerosis, although probably not the only factor. In this post, I'll describe some of the major contributors to oxLDL.

Polyunsaturated Fats Increase LDL Oxidation

The serum concentration of oxLDL is strongly influcenced by diet. One dietary determinant of oxLDL is dietary polyunsaturated fat (PUFA). PUFA are inherently susceptible to oxidative damage, compared to monounsaturated and saturated fats. The predominant PUFA in the modern diet is linoleic acid, found excessively in industrial seed oils like corn oil, sunflower oil, safflower oil, cottonseed oil and soy oil. LDL is naturally rich in linoleic acid, even in cultures such as the Kitavans who have a very low dietary intake of it. However, LDL content of linoleic acid does correlate with dietary intake, and the Kitavans have a comparatively small amount of linoleic acid in their LDL, relative to industrial cultures.

There have been a number of media reports in the last few years proclaiming that monounsaturated fat reduces LDL oxidation compared to saturated and polyunsaturated fat. This is rather implausible on the surface, so let's take a closer look. There are two ways to measure oxLDL:

1. Measure it directly from the blood
   
2. Take normal LDL from the blood, expose it to copper in a test tube, and see how fast it oxidizes

The first reflects actual oxLDL in the blood, whereas the second reflects "susceptibility to oxidation" and has a dubious relationship with actual oxidized LDL in the bloodstream. This results in statements like the following (ref):

LDL resistance to copper-induced oxidation, expressed as lag time, was highest during the MUFA-rich diet (55.1±7.3 minutes) and lowest during the PUFA(n-3)– (45.3±7 minutes) and SFA- (45.3±6.4 minutes) rich diets.

This was published in a paper by P. Mata and colleagues in 1996. They fed 42 volunteers one of four different diets for 5 weeks each: one rich in saturated fat, one rich in monounsaturated fat, one rich in linoleic acid PUFA, and one rich in linoleic acid plus omega-3 PUFA. They emphasized the finding quoted above, as did the media. But there's an embarrassing piece of data buried in the paper that the authors, and the media, ignored (thanks to Chris Masterjohn for pointing this out). Here's what they saw when they looked directly at LDL oxidation in their volunteers:

Oops! LDL oxidation in the two PUFA groups was increased by more than 31%. The difference between the leftmost two groups and the rightmost two was statistically significant. As one would expect, oxidized LDL is proportional to the amount of PUFA in LDL, which is proportional to dietary PUFA. This somehow got left out of the abstract and media reports. The same investigators published a similar report a year later.

In another diet trial, participants were placed on one of two diets for 5 weeks: a low-fat, high PUFA diet low in vegetables; or a low-fat, high PUFA diet high in vegetables. The authors were forthright about their findings, so I'll let them summarize:

The median plasma OxLDL-EO6 increased by 27% (P less than 0.01) in response to the low-fat, low-vegetable diet and 19% (P less than 0.01) in response to the low-fat, high-vegetable diet. Also, the Lp(a) concentration was increased by 7% (P less than 0.01) and 9% (P=0.01), respectively.

This is the diet mainstream cardiologists have been prescribing to heart attack patients for 40 years. The trials I mentioned above are the only three I'm aware of in which fat quality was manipulated and oxLDL was directly measured (the first two were based on subsets of the same data). They all suggest that replacing saturated fat with PUFA increases oxLDL.

I suspect that the effect has less to do with the decrease in saturated fat and more to do with the increase in PUFA, although there's no way to know for sure. In the Lyon Diet-Heart trial, which I believe was the most successful diet trial of all time, linoleic acid was reduced to 3.6% of calories, but saturated fat was also reduced. Another reason is that there are numerous low-fat, low PUFA, high-carbohydrate cultures that have low levels of atherosclerosis and heart attacks. The Kitavans, for example, don't seem to have heart attacks or strokes (although no autopsies have been done so we don't know how much atherosclerosis they have).

They get 69% of their calories from high-glycemic starchy tubers, and their 21% fat comes mostly from coconut so it's highly saturated. Their blood lipids are low in omega-6 linoleic acid and very saturated. But there's a little surprise in the data: their lipids are full of palmitic acid (saturated), despite the fact that their diet contains very little of it. The reason is that their livers are turning all that carbohydrate into saturated fat, which is what happens when you eat more carbohydrate than you can burn immediately or store as glycogen. The moral of the story is that you don't need to eat saturated fat to have saturated LDL: a high-carbohydrate diet can accomplish the same thing, especially if it has a high glycemic index.

Fat-Soluble Antioxidants Decrease LDL Oxidation

LDL carries fat-soluble antioxidants, predominantly vitamin E and coenzyme Q10 (CoQ10). One form of vitamin E, alpha-tocopherol, slows atherosclerosis in most animal models but has shown equivocal results in human trials. There is even the suggestion that it may increase LDL oxidation under some circumstances. I don't recommend supplementing with vitamin E. However, the first line of antioxidant defense in LDL is provided by CoQ10. CoQ10 unequivocally reduces LDL oxidation in human subjects, and potently reduces atherosclerosis in animal models.

CoQ10 has a special relationship with cardiovascular health. Levels are reduced in individuals with cardiovascular disease and high oxLDL. Whether this is cause or effect, it's difficult to say. However, supplementing with CoQ10 has been repeatedly shown to be effective for high blood pressure and congestive heart failure. There has been one controlled trial of CoQ10 (120 mg/day) supplementation for the prevention of heart attacks, which reduced cardiac events including deaths by 45%, compared to a group receiving B vitamins. The CoQ10 group showed a large reduction in plasma lipid oxidation. This is a promising result and the experiment should be repeated.

CoQ10 is not an essential nutrient, although food does contribute a small portion of our total CoQ10 use. The large majority of CoQ10 is synthesized by the body itself, and this is dependent on a number of essential nutrients, including vitamin B2, B3, B5, B6, B12, vitamin C and folic acid. Thus, the body's synthesis of CoQ10 is dependent on overall nutritional status. Sub-clinical deficiency of any of these vitamins can hypothetically contribute to reduced CoQ10 production and thus oxLDL. This is potentially a big problem since modern Americans get more than half their calories from nutrient-poor refined foods. Liver is the single best source of many of these vitamins, and also holds the title of Most Nutritious Food on the Planet. It's also rich in CoQ10.

CoQ10 synthesis declines with age and is reduced in people with disorders involving oxidative stress, like cardiovascular disease. It's also greatly reduced by the cholesterol-lowering drugs statins. I'm not generally in favor of supplements, but CoQ10 seems to have a lot of promise and nothing but positive side effects that I'm aware of. CoQ10 deficiency may be a common theme in a number of modern disorders.

Excess Blood Sugar and Fructose Increase LDL Oxidation

Both type I and type II diabetes are associated with higher levels of oxLDL, therefore, prolonged high blood glucose may contribute to LDL oxidation due to glycosylation of the LDL protein ApoB. Fructose consumption increases oxLDL relative to glucose. Fructose is a very powerful glycosylating agent (binds non-specifically to other molecules, causing damage). Although it isn't present at high levels in the general circulation, it does interact with blood lipids in the hepatic portal vein as it moves from the digestive tract to the liver to be turned into fat (palmitic acid). Peter at Hyperlipid has written extensively about the role of glycosylation in LDL oxidation.

The Diet-Heart Hypothesis: The Verdict

The diet-heart hypothesis, the idea that dietary saturated fat and cholesterol raise blood cholesterol and thus increase heart attack risk, is a half-century embarrassment to the international scientific community. It requires willful ignorance of the fact that saturated fat does not increase total cholesterol or LDL in humans, in the long term. It requires a simplistic view of blood lipids that ignores the potentially harmful effects of replacing animal fats with carbohydrate or industrial seed oils. Worst of all, it requires selective citation of the literature on diet modification trials.

I have to conclude that if dietary saturated fat and cholesterol play any role whatsoever in cardiovascular disease, it's a minor one that's trumped by other factors. Industrial seed oils and sugar are likely to play an important role in cardiovascular disease.

Another Fatty Liver Reversal

Just to show it wasn't a fluke, reader "Steve" replicates the experiment:

I had a similar problem as what Sam described, and it just happened to coincide with my discovery of and commitment to a new eating plan (based on low/good carb, high in good fat and omega 3, and good protein--basically a mix of paleo, primal, low carb, whatever they call it). I consider myself lucky to have had great fortune in my timing of finding out about my fatty liver.

My ALT and AST [markers of liver damage] had been at 124 and 43 respectively, and then still at 80 and 30 in a follow up a few months later. I weighed in at about 205 (I'm 6'1.5" on a slimmish frame), which was my heaviest. I had been on a basic American (bad) diet. The whole thing shocked me, especially after a CT with contrast showed the fatty deposits on my liver (and prior to that, when the muddy ultrasound revealed a fatty liver and a possible pancreatic mass, later ruled out by the CT). Like Sam, though I was surely overweight, I was not fat or heavy. (Most people have noticed I look leaner, but are shocked when I disclose how much weight I have lost since they say "I cannot believe you had that much to lose.")

At about the same time I found out about my liver issue, I had been getting into reading about diet and health (something I had done once when I read the Zone stuff from Sears many years ago). I practically dove through Taubes, Eades, Cordain, and a bunch of blogs (including yours), and I made a commitment to fix my problem.

I started a pretty severe regimen at first, which included only protein and good fats with a minimal amount of non-starchy fruits and vegetables. Almost immediately, I started losing weight and body fat (as measured by an electrical impedance scale). I have always supplemented with fish oil, but I added krill oil and I also started eating grass-fed beef and pastured eggs and pastured pork as much as possible. I have added some coconut oil and pastured butter to my diet as well. I have dropped almost 40 pounds, I am down to about 10-11% body fat (from 24%), and my ALT/AST on my last test was 24/14 [normal]. I am getting another test soon, and I expect similar results.

And a later comment:

I can add to the story that I first found out about the fatty liver on a routine new patient blood screening when I moved to a new town. I can also add that it took a bit of initiative on my part to get to the right diagnosis. The first doctor suspected hepatitis, but when blood work ruled that out, he ordered the imagining tests. Once I was referred to a GI specialist, it was a quick diagnosis. Still, I had to undertake myself to figure out the best diet. The GI recommended eliminating white bread, rice, pasta, starches, etc. but also recommended lowering fat intake. Having done some of my reading on diet and health, I knew to follow the former advice and to modify the latter to be "get plenty of fat, but make sure its the right kind."

Steve took the initiative and fixed his damaged liver. He modified his GI doctor's advice based on what he had read about nutrition, with excellent results. I suspect his doctor will be all ears next time Steve comes into his office.

The liver is a remarkable organ. Besides being your "metabolic grand central station", it's the only organ in the human body that can regenerate almost completely. It can be 75% obliterated, and it will grow back over time. Fatty liver and NASH are largely reversible.

Letter to the Editor

I just got a letter to the editor published in the journal Obesity. It's a comment on an article published in October titled "Efficiency of Intermittent Exercise on Adiposity and Fatty Liver in Rats Fed With High-fat Diet."

In the study, they placed rats on a diet composed of "commercial rat chow plus peanuts, milk chocolate, and sweet biscuit in a proportion of 3:2:2:1," and then proceeded to simply call it a "high-fat diet" in the title and text body, with no reference to its actual composition outside the methods section. We can't tolerate this kind of fudging if we want real answers from nutrition science. Rats eating the "high-fat diet" developed abdominal obesity, fatty liver and hyperphagia, but this was attenuated by exercise.

As I like to say, the problem isn't usually in the data, it's in the interpretation of the data. The result is interesting and highly relevant. But you can't use terminology that tars and feathers all fat when your diet was in fact high in linoleic acid (omega-6), low in omega-3 and high in sugar and refined grains. Especially when butter and coconut oil don't cause the same pathology. I pointed out in the letter that we need to be more precise about how we define "high-fat diets". I also pointed out that the study is highly relevant to the modern U.S., because it supports the hypothesis that a junk food diet high in linoleic acid and sugar causes metabolic disturbances and fatty liver, and exercise may be protective.

Fatty Liver Reversal

On April 15th, I received an e-mail from a reader who I'll call Sam. Sam told me that he had elevated levels of the liver enzyme ALT (alanine transaminase) in his blood, which indicates liver damage. ALT is an enzyme contained in liver cells that's released into the bloodstream when they rupture. Sam also had fatty liver confirmed by biopsy.

Liver damage with fat accumulation is very common in the United States. According to the NHANES health and nutrition surveys, in the time period 1999-2002, 8.9% of Americans had elevated ALT. Just 10 years earlier (1988-1994), the number was 4.0%. Fatty liver is a growing epidemic that currently affects roughly a quarter of Americans. Sam told me he had been trying to reverse his fatty liver for nearly a decade without success, and asked if I had any thoughts. He was not overweight, and from what I could gather, his diet was already better than most. I believe Sam knew intuitively that the right diet would improve his condition. With the usual caveats that this is not advice and I'm not a doctor, here's what I told him:

The quality of fat you eat has a very large influence on health, and especially on the liver. Excess omega-6 is damaging to the liver. This type of fat is found primarily in refined seed oils such as corn oil, soybean oil, and safflower oil... Sugar is also a primary contributor to fatty liver. Reducing your sugar intake will go a long way toward reversing it. Omega-3 fats also help reverse fatty liver if an excess of omega-6 is present. There was a clinical trial using fish oil that was quite effective. You might try taking 1/2 teaspoon of fish oil per day.

On May 11, I received another e-mail from him:

The day after your recommendations, less than a month ago, I started a regimen of 1200 mg/day of fish oil concentrate.

At the same time, I significantly reduced or even eliminated all forms of sugar from my diet. I did have a half glass of orange juice for breakfast every few days or so, and some fruits, and maybe a taste of dessert or a small candy bar here and there. I never exceeded the 30 g/day sugar limit you suggested.

I completely eliminated any and all fried foods and avoided most oils. I also avoided high glycemic index foods to some degree, e.g. white bread and potatoes. I did eat quite a bit more protein, including red meat, eggs, fish, chicken, and pork.

The balance of my diet and lifestyle was largely unchanged. I do drink a couple of beers every two to three weeks, but never more than three drinks in day. I have been doing more yard work, simply because of the season. Other than that, I don't get much more exercise than a typical inactive office worker.

In the same e-mail, he sent me his new ALT test results. He had been getting tested since 2002. The latest result, reflecting his progress since adopting the new diet, followed the previous test by less than a month. Here's a graph of his ALT levels. Below 50 is considered normal: The latest test was 52, just on the cusp of normal. That's nearly 50% lower than his next lowest result over the past 7 years, in less than one month of eating well. I suspect that his next ALT test will be well within the normal range, and the fat in his liver will gradually disappear, if he continues this diet. When I asked him how he was feeling, he said:

I did feel different after adjusting my diet. It's hard to describe, but overall I just felt better. I wasn't as tired when I woke up in the morning and I became a little slimmer, not a lot, maybe 3-5 pounds [note: he was not overweight to begin with]. I figured it was a placebo effect, but I think the fish oil has made a real difference.

Yesterday I had a few potato chips, corn chips, and some others. I didn't like it at all. Today I had half of a brownie for an afternoon snack and I completely crashed after an hour or so. I had a hard time keeping my eyes open. I no longer have much of a craving for snack food, I prefer to eat a full meal with more protein, e.g. beans, meat etc.

Fatty liver is a serious problem that responds readily to diet. I believe the main culprits are excess omega-6 from industrial vegetable oils; insufficient omega-3 from seafood, leafy greens and pastured animal foods; and excess sugar. The liver is your "metabolic gatekeeper", so it pays to take care of it.

How to Fatten Your Liver
Excess Omega-6 Fat Damages Infants' Livers
Health is Multi-Factorial

Eicosanoids, Fatty Liver and Insulin Resistance

I have to take a brief intermission from the heart disease series to write about a very important paper I just read in the journal Obesity, "COX-2-mediated Inflammation in Fat is Crucial for Obesity-linked Insulin Resistance and Fatty Liver". It's actually related to cardiovascular disease, although indirectly.

First, some background. Polyunsaturated fatty acids (PUFA) come mostly from omega-6 and omega-3 sources. Omega-6 and omega-3 are precursors to eicosanoids, a large and poorly understood class of signaling molecules that play a role in basically everything. Eicosanoids are either omega-6-derived or omega-3-derived. Omega-6 and omega-3 compete for the enzymes that convert PUFA into eicosanoids. Therefore, the ratio of omega-6 to omega-3 in tissues (related to the ratio in the diet) determines the ratio of omega-6-derived eicosanoids to omega-3-derived eicosanoids.

Omega-6 eicosanoids are very potent and play a central role in inflammation. They aren't "bad", in fact they're essential, but an excess of them is probably not good. Omega-3 eicosanoids are generally less potent, less inflammatory, and tend to participate in long-term repair processes. So in sum, the ratio of omega-6 to omega-3 in the diet will determine the potency and quality of eicosanoid signaling, which will determine an animal's susceptibility to inflammation-mediated disorders.

One of the key enzymes in the pathway from PUFA to eicosanoids (specifically, a subset of them called prostanoids) is cyclooxygenase (COX). COX-1 is expressed all the time and serves a "housekeeping" function, while COX-2 is induced by cellular stressors and contributes to the the formation of inflammatory eicosanoids. Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen inhibit COX enzymes, which is why they are effective against inflammatory problems like pain and fever. They are also used as a preventive measure against cardiovascular disease. Basically, they reduce the excessive inflammatory signaling promoted by a diet with a poor omega-6:3 balance. You wouldn't need to inhibit COX if it were producing the proper balance of eicosanoids to begin with.

Dr. Kuang-Chung Shih's group at the Department of Internal Medicine in Taipei placed rats on five different diets:

1. A control diet, eating normal low-fat rat chow.
2. A "high-fat diet", in which 45% of calories came from a combination of industrial lard and soybean oil, and 17% of calories came from sucrose*.
3. A "high-fat diet" (same as above), plus the COX-2 inhibitor celecoxib (Celebrex).
4. A "high-fat diet" (same as above), plus the COX-2 inhibitor mesulid.
5. An energy-restricted "high-fat diet".

The "high-fat diets", besides being high in sucrose (table sugar), also presumably had a poor omega-6:3 ratio, in the neighborhood of 10:1 or possibly higher. Weight and fat mass in rats and humans increases with increasing omega-6 in the diet, and also increases with a high 6:3 ratio. I wrote about that here. Rats eating the high-fat diets (groups 2- 4) gained weight as expected**.

Rats in group 2 not only gained weight, they also experienced increased fasting glucose, leptin, insulin, triglycerides, blood pressure and a massive decline in insulin sensitivity (seven-fold relative to group 1). Rats in groups 3 and 4 gained weight, but saw much less of a deterioration in insulin and leptin sensitivity, and blood pressure. Group 2 also developed fatty liver, which was attenuated in groups 3 and 4. If you're interested, group 5 (energy restricted high-fat) was similar to groups 3 and 4 on pretty much everything, including insulin sensitivity.

So there you have it folks: direct evidence that insulin resistance, leptin resistance, high blood pressure and fatty liver are mediated by excessive inflammatory eicosanoid signaling. I wrote about something similar before when I reviewed a paper showing that fish oil reverses many of the consequences of a high-vegetable oil, high-sugar diet in rats. I also reviewed two papers showing that in pigs and rats, a high omega-6:3 ratio promotes inflammation (mediated by COX-2) and lipid peroxidation in the heart. Are you going to quench the fire by taking drugs, or by reducing your intake of omega-6 and ensuring an adequate intake of omega-3?

*Of course, they didn't mention the sucrose in the methods section. I had to go digging around for the diet's composition. This is typical of papers on "high-fat diets". They load them up with sugar, and blame everything on the fat. This kind of shenanigans wouldn't fly in a self-respecting field, but it's typical of nutrition-health papers.

**Rats gain fat mass when fed a high-fat diet (even if it's not loaded with sugar), although when the fat is butter or coconut oil, they gain less than if it's vegetable oil. But humans don't gain weight on a high-fat diet (i.e. low-carb diet); to the contrary. What's the difference? It may have to do with the fact that rats eat more calories when they have ad libitum access to high-fat food, while humans don't. In fact, most low-carbohydrate diet trials indicate that participants spontaneously reduce their caloric intake when eating high-fat food.

Excess Omega-6 Fat Damages Infants' Livers

A nurse friend of mine sent me an e-mail a few weeks ago with a very interesting observation:

On the unit I work on we get lots of babies who have "short gut syndrome" due to a variety of causes who have to be on parenteral nutrition to supplement their nutrition while their GI system grows and hopefully heals fast enough. The big problem (among many) with TPN (total parenteral nutrition) is that it destroys the liver and kids get horribly jaundiced (which also causes brain damage) and often they die of liver failure or need a liver transplant before their GI system grows enough to take them off TPN.

Boston Children's has done some amazing work showing that this is largely due to the fact that the lipids part of the TPN was a soybean based oil so they started using Omegaven instead which is a fish oil based IV lipid solution. So far the results have been amazing and reversed the damage in lots of kids livers and prevented it in those started on Omegaven at birth.

Babies born with short gut syndrome can't absorb nutrients properly due to their unusually short small intestine. They're temporarily fed intravenously (total parenteral nutrition; TPN), until their intestines can develop enough to digest food normally.

The typical TPN formula contains soybean and safflower oils as the fat, both of which are over 50% omega-6 linoleic acid. Soybean oil also contains 7% omega-3 alpha-linolenic acid. You can't get the kids started too early on a "heart-healthy" diet!

The solution was to replace the vegetable oil with fish oil, which prevents or rapidly reverses the severe liver damage caused by TPN rich in omega-6 vegetable oils. I don't think this is a great solution, but it certainly beats vegetable oil. The ideal solution would be to replace the vegetable oil with a fat that approximates the composition of breast milk: mostly monounsaturated and saturated fat, with a little bit of linoleic acid, alpha-linolenic acid and long-chain fats such as AA and DHA. You could do this pretty easily with a mix of lard and fish oil; or palm oil and fish oil; or coconut oil, olive oil and fish oil. Breast milk composition varies with diet, and the amount of linoleic acid in the breast milk of Western populations is unusually high.

Excess linoleic acid, particularly when combined with excess fructose and insufficient omega-3 fat, is toxic to the liver. Modern Western nations are experiencing an epidemic of non-alcoholic fatty liver disease (NAFLD), which animal studies indicate is probably the result of replacing animal fats with polyunsaturated vegetable oils and increasing sugar intake (see links below for more detail). Fatty liver was seen primarily in alcoholics three decades ago. An estimated 1/4 of Americans now have NAFLD. It's the number one cause of liver damage in the U.S.

Where the liver goes, the rest of the body follows.

How to Fatten Your Liver
Nonalcoholic Fatty Liver Disease
The Liver: Your Metabolic Gatekeeper
More Liver Functions

Peripheral vs. Ectopic Fat

I went to an interesting presentation the other day by Dr. George Ioannou of the University of Washington, on obesity and liver disease. He made an interesting distinction between the health effects of two types of body fat. The first is called subcutaneous fat (or peripheral fat). It accumulates right under the skin and is evenly distributed over the body's surface area, including extremities. The second is called ectopic fat. Ectopic means "not where it's supposed to be". It accumulates in the abdominal region (beer belly), the liver, muscle tissue including the heart, the pancreas, and perhaps in lipid-rich deposits in the arteries. Subcutaneous fat can be measured by taking skinfold thickness in different places on the body, or sometimes by measuring arm or leg circumference. Ectopic fat can be measured by taking waist circumference.

It's an absolutely critical distinction, because ectopic fat associates with poor health outcomes while subcutaneous fat does not. In this recent study, waist circumference was associated with increased risk of death while arm and leg circumference were associated with a reduced risk of death. I think the limb circumference association in this particular study is probably confounded by muscle mass, but other studies have also shown a strong, consistent association between ectopic fat and risk of death, but not subcutaneous fat. The same goes for dementia and a number of other diseases. I think it's more than an epidemiological asssociation. Surgically removing the abdominal fat from mice prevents insulin resistance and prolongs their lifespan.

People with excess visceral fat are also much more likely to have fatty liver and cirrhosis. It makes sense if you think of them both as manifestations of ectopic fat. There's a spectrum of disorders that goes along with excess visceral fat and fatty liver: it's called the metabolic syndrome, and it affects a quarter of Americans (NHANES III). We already have a pretty good idea of what causes fatty liver, at least in lab animals: industrial vegetable oils and sugar. What's the most widely used animal model of metabolic syndrome? The sugar-fed rat. What are two of the main foods whose consumption has increased in recent decades? Vegetable oil and sugar. Hmm... Fatty liver is capable of causing insulin resistance and diabetes, according to a transgenic mouse that expresses a hepatitis C protein in its liver.

You want to keep your liver happy. All those blood tests they do in the doctor's office to see if you're healthy-- cholesterol levels, triglycerides, insulin, glucose-- reflect liver function to varying degrees.

Abdominal fat is a sign of ectopic fat distribution throughout the body, and its associated metabolic consequences. I think we know it's unhealthy on a subconscious level, because belly fat is not attractive whereas nicely distributed subcutaneous fat can be. If you have excess visceral fat, take it as a sign that your body does not like your current lifestyle. It might be time to think about changing your diet and exercise regime. Here are some ideas.

Is Vitamin A Toxicity a Concern?

Several commenters have asked for my opinion on recent statements by prominent health researchers that many Americans are suffering from unrecognized vitamin A toxicity. Dr. John Cannell of the Vitamin D Council is perhaps the most familiar of them. Dr. Cannell's mission is to convey the benefits of vitamin D to the public. The Vitamin D Council's website is a great resource.

Vitamin A is a very important nutrient. Like vitamin D, it has its own nuclear receptors which alter the transcription of a number of genes in a wide variety of tissues. Thus, it is a very fundamental nutrient to health. It's necessary for proper development, vision, mineral metabolism, bone health, immune function, the integrity of skin and mucous membranes, and many other things. Vitamin A is a fat-soluble vitamin, and as such, it is possible to overdose. So far, everyone is in agreement.

The question of optimal intake is where opinions begin to diverge. Hunter-gatherers and healthy non-industrial cultures, who almost invariably had excellent dental and skeletal development and health, often had a very high intake of vitamin A (according to Dr. Weston Price and others). This is not surprising, considering their fondness for organ meats. A meager 2 ounces of beef liver contains about 9,500 IU, or almost 200% of your U.S. and Canadian recommended daily allowance (RDA). Kidney and eye are rich in vitamin A, as are many of the marine oils consumed by the Inuit and other arctic groups.

If we can extrapolate from historical hunter-gatherers, our ancestors didn't waste organs. In fact, in times of plenty, some groups discarded the muscle tissue and ate the organs and fat. Carnivorous animals often eat the organs first, because they know exactly where the nutrients are. Zookeepers know that if you feed a lion nothing but muscle, it does not thrive.

This is the background against which we must consider the question of vitamin A toxicity. Claims of toxicity must be reconciled with the fact that healthy cultures often consumed large amounts of vitamin A without any ill effects. Well, you might be surprised to hear me say that I do believe some Americans and Europeans suffer from what you might call vitamin A toxicity. There is a fairly consistent association between vitamin A intake and bone mineral density, osteoporosis and fracture risk. It holds true across cultures and sources of vitamin A. Chris Masterjohn reviewed the epidemiology here. I recommend reading his very thorough article if you want more detail. The optimum intake in some studies is 2-3,000 IU, corresponding to about 50% of the RDA. People who eat more or less than this amount tend to suffer from poorer bone health. This is where Dr. Cannell and others are coming from when they say vitamin A toxicity is common.

The only problem is, this position ignores the interactions between fat-soluble vitamins. Vitamin D strongly protects agains vitamin A toxicity and vice versa. As a matter of fact, "vitamin A toxicity" is almost certainly a relative deficiency of vitamin D. Vitamin D deficiency is also tightly correlated with low bone mineral density, osteoporosis and fracture risk. A high vitamin A intake requires vitamin D to balance it. The epidemiological studies showing an association between high-normal vitamin A intake and reduced bone health all sported populations that were moderately to severely vitamin D deficient on average. At optimal vitamin D levels, 40-70 ng/mL 25(OH)D, it would take a whopping dose of vitamin A to induce toxicity. You might get there if you eat nothing but beef liver for a week or two.

The experiment hasn't been done under controlled conditions in humans, but if you believe the animal studies, the optimal intake for bone mineral density is a high intake of both vitamins A and D. And guess what? A high intake of vitamins A and D also increases the need for vitamin K2. That's because they work together. For example, vitamin D3 increases the secretion of matrix Gla protein and vitamin K2 activates it. Is it any surprise that the optimal proportions of A, D and K occur effortlessly in a lifestyle that includes outdoor activity and whole, natural animal foods? This is the blind spot of the researchers who have warned of vitamin A toxicity: uncontrolled reductionism. Vitamins do not act in a vacuum; they interact with one another. If your theory doesn't agree with empirical observations from healthy cultures, it's back to the drawing board.

High-vitamin cod liver oil is an excellent source of vitamins A and D because it contains a balanced amount of both. Unfortunately, many brands use processing methods that reduce the amount of one or more vitamins. See the Weston Price foundation's recommendations for the highest quality cod liver oils. They also happen to be the cheapest per dose. I order Green Pasture high-vitamin cod liver oil through Live Superfoods (it's cheaper than ordering directly).

So is vitamin A toxicity a concern? Not really; the concern is vitamin D deficiency.

How to Give a Rat Metabolic Syndrome

I was doing my usual journal rounds today when I came across an article in the American Journal of Hypertension that caught my eye. It's called "Metabolic Syndrome: Comparison of the Two Commonly Used Animal Models." Metabolic syndrome is a cluster of symptoms including large waist circumference, elevated triglycerides, elevated blood pressure, and insulin resistance. It's the quintissential modern metabolic disorder, and it affects 24% of Americans (NHANES III). So what are the two most commonly used animal models of metabolic syndrome?

• A strain called the spontaneously hypertensive rat (SHR), fed a high-sucrose (table sugar, 50% fructose) diet.
• Sprague-Dawley (generic lab strain) rats fed a high-fructose diet.

When fed sugar, these rats develop insulin resistance, impaired glucose tolerance, elevated triglycerides and hypertension. Fructose causes leptin resistance in rats. Leptin resistance causes metabolic syndrome in rats. These studies trace a line directly from sugar to the metabolic syndrome.

On to humans. Total sugar and fructose consumption have been increasing in the U.S. in recent decades, along with metabolic syndrome. I think the average numbers may hide some important information, because there is a fraction of the population that consumes far more than the average amount of sugar through soda. Leptin resistance seems to be central to the metabolic syndrome, and typically precedes the other symptoms. The evidence suggests that the rat research on metabolic syndrome is applicable to humans.

I don't think sugar acts alone in causing the metabolic syndrome in humans. I believe the liver is a central player in the disorder, as many of the markers used to diagnose it are measures of processes that occur in the liver (triglyceride synthesis, glucose and insulin disposal). Insulin resistance in the liver is sufficient to cause many of the hallmarks of the metabolic syndrome in mice. The fructose portion of sugar and high-linoleic (omega-6) vegetable oils act synergistically to cause liver dysfunction in rats and probably humans.

I also believe wheat contributes to the process, perhaps through its ability to cause hyperphagia (overeating) or intestinal damage. So we're back to the three big killers in the modern diet:

• Refined vegetable oils
• Sugar
• Wheat
  

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is milder form of NASH, in which the liver becomes enlarged and accumulates fat. Ready for a shocker? The prevalence of NAFLD is thought to be between 20 and 30 percent in the Western world, and rising. It's typically associated with insulin resistance and often with the metabolic syndrome. This has lead some researchers to believe it's caused by insulin resistance. It's a chicken and egg question, but I believe it's the other way around if anything.

There are certain animal models of human disease that are so informative I keep coming back to them again and again. One of my favorites is the LIRKO mouse, or liver-specific insulin receptor knockout mouse. The LIRKO mouse is missing its insulin receptor in the liver only, so it is a model of severe insulin resistance of the liver. It accumulates a small amount of fat in its liver in old age, but nothing that resembles NAFLD. So liver insulin resistance doesn't lead to NAFLD or NASH, at least in this model.

What else happens to the LIRKO mouse? It develops severe whole-body insulin resistance, impaired glucose tolerance, high fasting blood glucose and hyperinsulinemia (chronically elevated insulin). So insulin resistance in the liver is sufficient to cause whole-body insulin resistance, hyperinsulinemia and certain other hallmarks of the metabolic syndrome, while liver and whole-body insulin resistance are not sufficient to cause NAFLD or NASH. This is consistent with the fact that nearly everyone with NAFLD is insulin resistant, while many who are insulin resistant do not have NAFLD.

In all fairness, there are reasons why NAFLD is believed to be caused by insulin resistance. For example, insulin-sensitizing drugs improve NAFLD. However, that doesn't mean the initial metabolic 'hit' wasn't in the liver. One could imagine a scenario in which liver insulin resistance leads to insulin resistance in other tissues, which creates a positive feedback that aggravates NAFLD. Or perhaps NAFLD requires two 'hits', one to peripheral insulin sensitivity and another directly to the liver.

In any case, I feel that the most plausible mechanism for NAFLD goes something like this: too much n-6 from polyunsaturated vegetable oil (along with insufficient n-3), plus too much fructose from sweeteners, combine to cause NAFLD. The liver becomes insulin resistant at this point, leading to whole-body insulin resistance, hyperinsulinemia, impaired glucose tolerance and general metabolic havoc.

How to Fatten Your Liver

Steatohepatitis is a condition in which the liver becomes inflamed and accumulates fat. It was formerly found almost exclusively in alcoholics. In the 1980s, a new condition was described called nonalcoholic steatohepatitis (NASH), basically steatohepatitis without the alcoholism. Today, NASH is thought to affect more than 2% of the adult American population. The liver has many important functions. It's not an organ you want to break.

This week, I've been reading about how to fatten your liver. First up: industrial vegetable oil. The study that initially sent me on this nerd safari was recently published in the Journal of Nutrition. It's titled "Increased Apoptosis in High-Fat Diet–Induced Nonalcoholic Steatohepatitis in Rats Is Associated with c-Jun NH₂-Terminal Kinase Activation and Elevated Proapoptotic Bax". Quite a mouthful. The important thing for the purpose of this post is that the investigators fed rats a high-fat diet, which induced NASH.

Anytime a study mentions a "high-fat diet", I immediately look to see what they were actually feeding the animals. To my utter amazement, there was no information on the composition of the high-fat diet in the methods section, only a reference to another paper. Apparently fat composition is irrelevant. Despite the fact that a high-fat diet from coconut oil or butter does not produce NASH in rats. Fortunately, I was able to track down the reference. The only difference between the standard diet and the high-fat diet was the addition of a large amount of corn oil and the subtraction of carbohydrate (dextrin maltose).

Corn oil is one of the worst vegetable oils. You've eaten corn so you know it's not an oily seed. To concentrate the oil and make it palatable, manufacturers use organic solvents, high heat, and several rounds of chemical treatment. It's also extremely rich in n-6 linoleic acid. The consumption of corn oil and other n-6 rich oils has risen dramatically in the US in the last 30 years, making them prime suspects in NASH. They have replaced the natural (more saturated) fats we once got from meat and milk.

Next up: fructose. Feeding rats an extreme amount of fructose (60% of calories) gives them nonalcoholic fatty liver disease (NAFLD), NASH's younger sibling, even when the fat in their chow is lard. Given the upward trend of US fructose consumption (mostly from high-fructose corn syrup), and the refined sugar consumed everywhere else (50% fructose), it's also high on my list of suspects.

Here's my prescription for homemade foie gras: take one serving of soybean oil fried french fries, a basket of corn oil fried chicken nuggets, a healthy salad drenched in cottonseed oil ranch dressing, and wash it all down with a tall cup of soda. It's worked for millions of Americans!

Real Food VI: Liver

Liver was a highly regarded food among many hunter-gatherer and traditional agricultural societies. It's not surprising once you realize it's quite literally the most nutritious food in the world. It's because the liver is a storage depot, into which important nutrients are deposited in case of later need. A modest 4-oz serving of calf's liver contains 690% of your RDA of B12, 610% of preformed vitamin A, 215% of folate, 129% of B2, 24.5 g protein, and the list goes on. The nutrients found in liver are particularly important for development, but are also helpful for continued health in adulthood.

Preformed vitamin A is one of the nutrients Weston Price suggested was responsible for the glowing health of the cultures he studied in his book Nutrition and Physical Degeneration. It's an essential nutrient, but it's different from most vitamins (except D) because it acts like a hormone, entering cells and altering gene transcription. Thus, it has its hand in many important bodily processes.

"Vitamin A" from plant sources such as carrots is actually a group of vitamin A precursors called carotenes, which the body inefficiently converts to actual vitamin A. The efficiency of conversion varies around 10%, depending on the carotene and how much fat is ingested along with it. Nutrition labels in the US do not reflect this. When a nutrition label on a plant-based product says "30% vitamin A", you can assume you will get about 3% of your RDA from it. This doesn't apply to eggs, dairy and liver, which contain preformed vitamin A.

I'm not sure how this happened, but somewhere along the line we decided in the US that muscle is the only proper animal tissue to eat. We are missing out on the most nutritious parts of the animal, and our health is suffering.

I recommend purchasing organic calf's liver, 100% grass-fed if possible. Chicken livers are also nutritious but ruminant livers are the most concentrated in vitamins by far.

Here is a recipe for a liver pate. I recognize that many people don't like the taste of liver, which is why I chose this recipe because it is very mild.

Ingredients

• 1/2 to 1 lb calf's liver, chopped into 1-in strips
  
• 3 eggs
• 1/2 stick butter
• 1/2 onion
• 1-2 carrots (optional)
• Sage and/or rosemary (optional)
• Salt to taste
  

Recipe

1. Saute the onions and carrots in 1 tbsp butter until they're soft.
2. Add liver and herbs and cook until the liver is just done.
3. Crack the eggs right into the pan and stir them until they're cooked.
4. Turn off the heat, add the remaining butter.
5. Blend until smooth.

Enjoy!

More Liver

It's time to celebrate your liver. It's a hard-working organ and it deserves some credit.

One of the liver's most important overall functions is maintaining nutrient homeostasis. It controls the blood level of a number of macro- and micronutrients, and attempts to keep them all at optimal levels.

Here's a list of some of the liver's functions I'm aware of:

• Buffers blood glucose by taking it up or releasing it when needed
• A major storage site for glycogen (a glucose polymer)
  
• Clears insulin from the blood
• Synthesizes triglycerides
• Secretes and absorbs lipoprotein particles ("cholesterol")
• Stores important vitamins: B12, folate, A, D, E, K (that's why it's so nutritious to eat!)
• Stores minerals: copper and iron
  
• Detoxifies the blood
• Produces ketone bodies when glucose is running low
• Secretes blood proteins
• Secretes bile
• Converts thyroid hormones
• Converts vitamin D (D3 --> 25(OH)D3)
  

The liver is an all-purpose metabolic powerhouse and storage depot. In the next post, I'll give you a recipe for it...

The Liver: Your Metabolic Gatekeeper

As I've been learning more about the different blood markers of metabolic dysfunction, something suddenly occurred to me. Most of them reflect liver function! Elevated fasting glucose, low HDL cholesterol, high LDL cholesterol, high triglycerides and high fasting insulin all reflect (at least in part) liver function. The liver is the "Grand Central Station" of cholesterol and fatty acid metabolism, to quote Philip A. Wood from How Fat Works. It's also critical for insulin and glucose control, as I'll explain shortly. When we look at our blood lipid profile, fasting glucose, or insulin, what we're seeing is largely a snapshot of our liver function. Does no one talk about this or am I just late to the party here?!

I read a paper today from the lab of C. Ronald Kahn that really drove home the point. They created a liver-specific insulin receptor knockout (LIRKO) mouse, which is a model of severe insulin resistance in the liver. The mouse ends up developing severe whole-body insulin resistance, dramatically elevated post-meal insulin levels (20-fold!), impaired glucose tolerance, and elevated post-meal and fasting glucose. Keep in mind that this all resulted from nothing more than an insulin resistant liver.

LIRKO mice had elevated post-meal blood glucose due to the liver's unresponsiveness to insulin's command to take up sugar. Apparently the liver can dispose of one third of the glucose from a meal, turning it into glycogen and triglycerides. The elevated fasting glucose was caused by insulin not suppressing gluconeogenesis (glucose synthesis) by the liver. In other words, the liver has no way to know that there's already enough glucose in the blood so it keeps on pumping it out. This is highly relevant to diabetics because fasting hyperglycemia comes mostly from increased glucose output by the liver. This can be due to liver insulin resistance or insufficient insulin production by the pancreas.

One of the interesting things about LIRKO mice is their dramatically elevated insulin level. Their pancreases are enlarged and swollen with insulin. It's as if the pancreas is screaming at the body to pick up the slack and take up the post-meal glucose the liver isn't disposing of. The elevated insulin isn't just due to increased output by the pancreas, however. It's also due to decreased disposal by the liver. According to the paper, the liver is responsible for 75% of insulin clearance from the blood in mice. The hyperinsulinemia they observed was both due to increased secretion and decreased clearance. Interestingly, they noted no decline in beta cell (the cells that secrete insulin) function even under such a high load.

Something that's interesting to note about these mice is they have very low blood triglyceride. It makes sense since insulin is what tells the liver to produce it. Could this have something to do with their lack of beta cell dysfunction?

The really strange thing about LIRKO mice is that their blood glucose becomes more normal with age. Strange until you see the reason: their livers are degenerating so they can't keep up glucose production!

LIRKO mice reproduce many of the characteristics of type II diabetes, without degenerating completely into beta cell death. So insulin resistance in the liver appears to reproduce some elements of diabetes and the metabolic syndrome, but the full-blown disorders require other tissues as well. As a side note, this group also has a skeletal muscle-specific insulin receptor knockout which is basically normal. Interesting considering muscle tissue seems to be one of the first tissues to become insulin resistant during diabetes onset.

So if you want to end up like your good pal LIRKO, remember to drink high-fructose corn syrup with every meal! You'll have fatty liver and insulin resistance in no time!

I have a lot more to say about the liver, but I'll continue it in another post.