Fructose causes insulin resistance – Hormonal Obesity XXXII

By Jason Fung, MD

The metabolism of excessive amounts of fructose leads to fatty liver, which is a key step in the development of insulin resistance, as we saw in our last post.  Is there evidence that consumption of fructose leads to insulin resistance?  In a word – yes.

As far back as 1980, there were studies linking the use of fructose, but not glucose to the development of insulin resistance in humans.  The study “Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects” examined the effect of adding 1000 kcal/day of excess calories as glucose vs fructose in healthy young people.  Body weight over the duration of the test did not change in either group.

Intravenous insulin was injected into the subjects after the overfeeding period and blood glucose was measured.  The group with excessive glucose intake did not show any statistical difference in sensitivity to insulin.  The fructose group, however, showed a 25% worsening of their insulin sensitivity.  After 7 days!  Remember that both groups had been overfed by the same amount of calories.  Fructose also caused a decrease in the binding of insulin to cells and this paralleled the increase in insulin resistance.

A more recent study “Effect of Fructose Overfeeding and Fish Oil Administration on Hepatic De Novo Lipogenesis and Insulin Sensitivity in Healthy Men” showed much the same effect.  Normal healthy subjects were overfed fructose.  De novo Lipogenesis (DNL) – or the production of new fat in the liver increased six fold accompanied by a 79% increase in plasma triglycerides.  A measure of insulin resistance in the liver increased by 28%.  After 6 days!  Muscle insulin resistance was not changed.

Since insulin resistance is the hallmark of type 2 Diabetes, this means that these previously healthy subjects were now well on their way to developing type 2 Diabetes in just 6 days.  The scariest demonstration of how overconsumption of fructose leads to insulin resistance and diabetes comes from the study “Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans”.  Here, healthy subjects were given 25% of their daily calories as Kool-Aid sweetened with either glucose or fructose for 8 weeks.  While this seems like a high percentage, there are many people who consume this high proportion of sugar in their diets.

The oral glucose tolerance test is a standard test for diabetes and pre-diabetes.  The blood sugar is measured in response to a sugary drink given to the patient.  The fructose, but not the glucose group has already developed pre-diabetes.  This is supported by the finding that the fructose group has developed significantly more insulin resistance than the glucose group.

Insulin levels are also significantly higher in the fructose group.  This is all despite the fact that both groups were given equal caloric amounts of glucose versus fructose.  The fructose, furthermore had much less effect on the blood glucose since it has a very low glycemic index.  This demonstrates yet another failure of the glycemic index classification system.

This is scary in so many ways.  First, the amount of fructose is certainly higher than most people consume.  But the study only lasted for 8 weeks.  What is going to happen after decades of high fructose consumption?  Fructose specifically will lead to fatty liver, insulin resistance and eventually type 2 diabetes.  But the accompanying concern is that the high insulin levels will also lead to obesity.

If we add this knowledge to our model of hormonal obesity, this is what we get.


The key driver to obesity is the increased insulin levels.  This depends upon the balance between dietary factors (particularly refined or fattening carbohydrates) and protective factors such as fibre and vinegar.  Another key driver of insulin levels is the time dependent effect of insulin resistance.  This sets up a vicious cycle whereby high insulin levels increase insulin resistance which leads to high insulin levels.  The longer this cycle goes around, the worse it becomes.

However, fructose also plays a key role in the development of insulin resistance aside from the high insulin levels.  This is at least partially explained by the induction of fatty liver and hepatic insulin resistance.

From here, it is easy to see why sugar is so fattening.    Sucrose is composed of a 50-50 mix of glucose and fructose.  HFCS is 55% fructose.  The glucose in the mixture acts as a refined carbohydrate and stimulates insulin.  The fructose acts on the liver to produce insulin resistance.  Therefore, the sugar is stimulating insulin production both in the short term and in the long term.  Over time, chronic overconsumption of sugar leads to high insulin levels.  This leads inevitably to obesity.

Sugars are not simply ’empty calories’.  They are not simply refined carbohydrates.  They are far more dangerous than that.  They stimulate both insulin as well as insulin resistance.  Is there much of a difference between sucrose and HFCS?  I don’t believe so.  Both are bad.  One may be slightly more bad, but that is splitting hairs.

The bottom line is this.  If you want to avoid weight gain – cut out sugars from the diet.  Do not replace them with sweeteners.  They are equally bad for you.  On this, at least, everybody can agree.

But the increased consumption of sugar does not fully explain the paradox of the Asian rice eater of the 1990s.  How did they consume so much carbohydrate without becoming obese?  There is one more thing to consider.  Wheat.

Continue to Populations in Transition – Hormonal Obesity XXXIII

Start here with Calories I – How Do We Gain Weight?

See the entire lecture – The Aetiology of Obesity 4/6 – The Fast Diet



By The Fasting Method

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Jason Fung, MD

By Jason Fung, MD

Jason Fung, M.D., is a Toronto-based nephrologist (kidney specialist) and a world leading expert in intermittent fasting and low-carb diets.

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