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.
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