Is it in the liver or pancreas after all?

I am getting confused now. Where does the fructose cause diabetes then? 

Dr Lustig explained the mechanism of oxidation stress and how this affects the binding of proteins inside the liver cell compartments at 55:20 of the video. It was illustrated with a picture: 

I agree with what he said, but then what caught my attention, was that he suddenly talked not about the liver cells but about the pancreatic cells instead. This pointed at how bad fructose is for pancreas. Well, did he not say some while ago, that fructose can, after consumption of excess sugar, occur in the blood in 5 micromoles concentration, which is 1000 times lower than of normal glucose concentration? He said that this was enough to trigger insulin response, too... 

My question is: if little fructose is good for the liver (certainly at higher concentration than 5 micromoles), but this small concentration in the systemic circulation can damage pancreas to such extend it can lead to diabetes and insulin resistance, where glucose comes into this picture? Pancreas responds primarily to glucose levels in blood... glucose, albeit 7-times slower in browning reaction (in vitro), has more capacity for this damage because it appears in blood in 1000 times higher concentrations than fructose. And diabetics with a poorly managed blood glucose levels are known to have increased concentrations of glycosylated haemoglobin. It is not the fructose that causes it. 

My other question is: how much insulin can fructose make the pancreas producing so that the insulin concentration raises to the level classified as hyperinsulinemia? Dr Lustig suggested this as well but he did not explain it further.  

The mechanism of insulin resistance development - which one is correct?

In one of my previous articles you could read my discussion on the possible causes of hyperinsulinemia in people. This condition is closely related to insulin resistance, whether as a cause or a consequence and it also is connected with metabolic syndrome on which I did my research for dissertation. People with elevated glucose concentration in blood, when having pancreas functioning, secrete more insulin and this helps to keep blood glucose under control. But after time, as this condition persists, especially when being overweight or even obese, insulin resistance can develop in muscles or elsewhere in the body. And, as the animal studies suggest, high fat diet can promote insulin resistance in the hypothalamus and this could eventually lead to overeating and overweight. This requires more research. Nonetheless, Dr Lustig proudly presented to the audience how he managed to fix obesity in otherwise healthy patient just by simply lowering the high insulin levels by using a drug. 

What I would like to discuss in this lengthy article (make yourself comfortable, a cup of tea or coffee might be useful, too), is the alleged origin of insulin resistance promoted by Dr Lustig. When discussing the causes or origin of metabolic syndrome, he highlighted few points: 

Then he asks a question WHERE this insulin resistance happens?

He again presented quite an amount of biochemistry and recent advancements in research.

Firstly he refused the traditional adipocentric view of the metabolic syndrome development. This traditional view operates with a gradual accumulation of the excess adipose tissue leading to insulin resistance, which metabolically affects other organs and body systems: 

The background of this Dr Lustig's refusal was that the obesity is not an issue, because 1 in 5 obese people are metabolically normal. Read more on my comments about this here.

Here he provides a different scenario: 

In order to go deeper into this problem he firstly presented how the scientists bred animals lacking insulin receptors in eight various tissues and examining how their metabolism was affected: 

Dr Lustig pointed ad the PODIRKO mouse, which was insulin resistant in its kidneys, although the blood glucose were normal. In this breed the insulin caused severe damage to the animal kidneys, similar to those of poorly managed diabetics. Dr Lustig concluded that it was not the glucose causing the tissue damage, it was insulin. Of course it was insulin, because their blood glucose was NORMAL, I add. In diabetic patients the blood glucose is elevated, often together with insulin - can we say that in these it is again only the insulin that causes kidney (and other organs) damage? Dr Lustig said nothing about that but you could repeatedly hear how fructose is a browning agent and damages the cells and tissues. Except the fact that the fructose concentrations in blood are 10-1000 times lower than the concentrations of glucose. In one video Dr Lustig announced that 6 micromoles of fructose concentrations can occur in blood, which is 1000 times less than a physiological concentration of glucose measured in millimoles. 

Now please look at the MIRKO mouse, which is of interest for me. These animals were insulin resistant in their muscles, but protected from obesity. I am fine with that, except the fact, as I have mentioned elsewhere, a lack of physical activity while overeating can result in the signs of prediabetes within 1 or 2 days. So, does the focus on the liver and brain insulin resistance, when associated with obesity, matter that much? What is more: does not the insulin resistance induced by non-exercising muscles affect the brain, which then fails to read the leptin? I guess it does. Although the study reports that MIRKO mice were not sufficiently affected in terms of glucose homeostasis (which drives insulin higher for some time), it also stated that: 

" muscle...communicates with and regulates insulin sensitivity in other tissues."

The study also mentioned in their conclusion, that: "...primary insulin resistance in muscle may lead to increased adiposity and development  of obesity." This seems to be in contrast with the content mentioned by Dr Lustig in the slide. Moreover, the group of 6 traits was only presented as immune against obesity, but nothing was indicated how prone they were to the metabolic syndrome. 

Overall, the slide above  does not disprove my point that a person can become insulin resistant when overeating and not being physically active; and this can emerge from the diet lacking fructose. Please bear this in mind as you will read further, because Dr Lustig will try to convince you that it is the fructose that is the absolute villain in the development of hepatic insulin resistance and as such it drives the metabolic syndrome development, insulin resistance in the whole body or even type 2 diabetes. 

Secondly, you could see a brief overview of how the body functions under different conditions in relation to insulin sensitivity or resistance:

When the liver is functional and insulin sensitive, in the presence of insulin it stops producing glucose and at the same time it produces fat (triglycerides) which are released into the blood. This happens primarily after glucose consumption, no fructose was mentioned here. Fructose has very little insulin stimulating activity because it almost does not occur in the blood. This fat stimulating effect can easily happen in fructose-free diet, based on processed starches of a high glycaemic index. 

Dr Lustig also said at 17:55 minute that the produced VLDL from the hepatic DNL can "CAUSE atherogenesis as a direct effect". The fact is that the presence of VLDL is only a risk factor, not a direct cause of atherosclerosis. Other factors must be present, such as hypertension, damaging the delicate epithelium of the arteries, being oxidized by elevated glucose concentrations and other processes such as inflammation. The circulating lipoproteins on their own are not as bad, it is what acts upon them that makes them a time bomb. 

A similar diagram, illustrating the LIRCO (liver insulin resistant mouse), shows how the liver is blind to the insulin stimulated triglycerides production and the inhibition of gluconeogenesis is not stimulated either, so the animal has a high blood glucose, but allegedly not the metabolic syndrome. 

Well, since for the metabolic syndrome at least the three of five main features of the clinical definition must be present, while this scenario does not support it, I must agree. But is the elevated glucose harmless? Hardly so. 

Then Dr Lustig moves to a third scenario. where there is a selective insulin resistance because although the glucose is high, also the triglycerides are high. 

In this case a metabolic syndrome, along obesity, were the result while in the previous case there was only the obesity without the metabolic syndrome (albeit the hepatic insulin resistance was present), on which Dr Lustig has probably built his own new theory: obesity is not enough and insulin resistance is also not enough, as you could see in the first slide in this article. 

Well, for me and also for the diabetics it is enough to have a high blood glucose to go blind, having kidney failure or have a leg amputated. But Dr Lustig apparently pushes the boat towards the more complex condition - metabolic syndrome so that he can make fructose the captain.

One thing I would like to highlight here: these mechanisms were studied on mice which were bred to lack the insulin receptors at specific tissues while other insulin receptors remained functional. Is this representative for the general population? I do not think so. Moreover, as several genes normally affect one metabolic pathway, one gene can influence several metabolic processes, too. This is how our biology is complicated. 

Let's continue. I have already outlined my concerns about how the inactive muscles are not able to take in any more glucose or fats for energy and this can lead to prediabetic condition within a couple of days in humans. These people have elevated glucose and also can have elevated lipids, upon which the glucose will act and make them atherogenic. 

Do you think that the insulin resistance due to a positive energy balance develops in isolation on specific organs in normal free-living humans? I mean those without a genetic predisposition, because those with some genetic trait would be similar to the selectively bred mice in their risks. The study I mentioned earlier suggested that the metabolism in normal organisms is interconnected and the insulin resistance of one organ (adipose tissue, muscles) can affect the metabolism of other organs (liver) and the whole glucose homeostasis. 

According to Dr Lustig, the scenario is the opposite: excess dietary fructose makes liver to store fat and AFTER THAT it becomes insulin resistant while still producing extra triglycerides - leading to metabolic syndrome and affecting the rest of the body as a consequence - just because 20% of obese people are metabolically healthy and there are non-obese (albeit half of them overweight) who also express metabolic syndrome... Think.  

Before I end this post I would like you to look at the adipocentric picture at the beginning of the post again. There you can see that it was published in 2005. In my other article you could also read, that in the same year a scientific paper supported the peripheral insulin resistance as a more likely reason for developing fatty liver condition than the insulin resistance of the liver itself, which Dr Lustig advocates. They basically said that the NAFLD was a consequence of the peripheral insulin resistance and not the other way round, according to the available evidence. But Dr Lustig does not seem to accept this in 2014 and focuses on hepatic insulin resistance only, supporting his theory by the research on the genetically manipulated animals and persistently blaming the fructose in the diet as an ubiquitous factor that explains all the following aspects: 

What followed after this slide I have discussed in another article. 

To conclude and answer the question in the title: I do not have the answer. You could see how complicated the issue is, but from my point of view I tend to contradict Dr Lustig, at least in part, because the metabolism is really complicated and things do not tend to happen on isolated tissues or organs at once unless there is a genetic condition that makes it happen on a single tissue or organ. Maybe both of these opinions are partly true and the mechanism of insulin resistance can have different scenario in different people, depending on their genetic traits, lifestyle, exposure to different factors, etc. 

Are we having presented the whole picture or is there something missing?

At about 38:30 Dr Lustig says that liver is the only site for energy metabolism. He presented a slide showing: 

During that time, as he did not want to appear a fructocentric, he pointed out at these four food substrates that drive the metabolic disease by overloading the mitochondria in the liver and producing fat. Well, where is glucose? Is glucose not an energy molecule? Is it not metabolized by the liver? And, more importantly: is it not converted to fat when in excess? Of course it is. But Dr Lustig has some sort of sympathy for glucose and blaming only fructose for everything, with the recent addition of these three substrates on top of it. 

Yes, I agree that about 80% of glucose is metabolized in the rest of the body, but the truth also is that the isotopes of labelled fructose were found in breath in higher concentrations than of labelled glucose (Chong et al 2007). This means that more fructose was burned straight away than of glucose and other isotope tracer studies confirmed this as well: non-exercising people proportionally burned more fructose while exercising subject burned more glucose, according to the concentrations of recovered labelled carbons (originating from each sugar) in their breath. 

Of course, liver can store unlimited amount of glycogen, from glucose molecules - when there is a genetic disorder present which prevents liver to release free glucose, called glycogen storage disease. However, in healthy people the liver can store glycogen, forming about 5% of its total mass. However, some amount of fructose is also converted to glucose in the liver and even stored as glycogen especially when the glycogen stores are not full (in a fasted state, especially morning). We know it because the isotopic tracer studies have been examining the different fates of labelled fructose as I have discussed earlier and in more detail here. 

There is also no pop-off in glycogen from glucose, when the glycogen stores are full. Mitochondria has to deal with excess substrates from either the fructose or glucose (which they have common, interconvertible) and now you already know that it was glucose based carbohydrates the consumption of which has increased much more than of sugar and since 2000, when sugar intake started to decrease in the U.S., while the non-fructose virtually carbohydrates stayed the same. 

In this article you can learn how flawed were the conclusions about the de-novo lipogenesis (DNL) of fructose, based on rather indirect assessment methods and how the addition of the same amount of glucose tripled the allegedly measured DNL as a result of fructose intake. 

I am glad Dr Lustig pointed at alcohol. He said that little is OK, but too much is not. However, that applies to the fructose, too. In one of my articles I criticized his statement that alcohol is better than sugar because it sends you under the table only once a day. He stated that about 20% of people are addicted to alcohol (1 in 5). Well, have a look at this diagram about the trends in sugar sweetened beverages (SSB) consumption and alcohol consumption among the U.S. adults. *Alcohol is not part of the SSB. The study of Duffy and Popkin (2012) can be found here. 

So, if fructose is an alcohol without the buzz, which allegedly led the metabolic diseases in the U.S. population, how about the alcohol? Even many teenagers have drink problems. While alcohol is not responsible for the NAFLD, do you think this trend has not affected the population somehow? Just a reminder: from the number of calories within the total SSB fructose forms only about half, which brings it very close to the amount of calories obtained from alcohol. Moreover, fructose is converted to many other compounds (glucose, lactate, glycogen, fat), not just the toxic glyceraldehyde. In comparison, alcohol is temporarily broken down to also a toxic compound - acetaldehyde, but it has not such capacity to be converted to the other compounds as fructose does - except of fats. 

This diagram above is a very crude overview of the trends, and the data may not be absolutely representative of the real situation, but it gives you a hint about what was going on. Many people do not report their guilty pleasures and this is one of the many weaknesses of the dietary surveys. Moreover, this refers to date before 2002 and it would be interesting to see the newer trends. I also sense some weakness in the data of the NAFLD that it partially could be due to alcohol consumption among youth (or even adults), but because they are under-age their alcohol intake may not have been captured and their liver problems only ascribed to other dietary components (to sugars by Dr Lustig and also to fats by other, more realistic, scientists). 

Moving on, I particularly appreciate the mention of the corn-fed beef that has a higher profile of branched chain amino acids (and also less healthy fatty acids profile). Is it a news for you that the cheap fast-food has boomed in the western countries in the past decades? What they put into the burgers? Cheap corn fed beef! While the sugar consumption in the U.S. has been decreasing since 2000, the added fats and oils have been increasing, and the consumption of cheap meat as well, while the grass-fed beef and pasture raised chicken meat is rather expensive and not commonly consumed by ordinary people. The same applies to farmed salmon while the wild salmon is rather rare and expensive. I am not saying that people consume significantly more meat than they used to decades ago, I am saying that there was a shift from healthy meat to the cheap meat produced on a massive scale today. 

These people today also cook less at home and they rather go to the fast-food and take-away, which often serve as cheap ingredients as possible, including the cheap food items such as fries and soft drinks. This cocktail of unhealthy foods is responsible for the poor health of the Western population, not only sugar or fructose alone. 

And, regarding the trans-fats: yes their intake has slowly decreased. But what is the real picture? Have you heard about the interesterified fats? Probably not. But you will, in the future. For now, please check what these fats actually are and make your own opinion about this particular statement for this nutrient made by Dr Lustig. I think that even he should update his knowledge about the diet, at least within his own country. This article was published in 2007 but his lecture delivered in 2013.

So, I completely agree with his statement: A calorie is not a calorie. Especially after finding out that these interesterified fats actually increase blood sugar (glucose), too. 

This article aimed to show five main things: 

• Alcohol followed the curve with sugary drinks for adults
• there is no glycogen pop-off when the liver or any glycogen stores (muscles) are full, even from glucose. 
• Fructose can also be converted to glucose and glycogen, when the glycogen stores are not full. 
• Since glucose and fructose have common metabolic intermediates, they both in excess can choke mitochondria in any cell in the body, not just the liver. It only happens that fructose has more capacity for this in the liver. 
• Although the trans-fats were reduced, they were replaced with equally bad fats.

The processed food doom continues... 

PS: Every body cell is a site for energy metabolism.