Eating Fat and Diabetes — Response to Bix Weber

Melissa McEwen recently brought to my attention a blog post by Bix Weber, the Fanatic Cook, “Diabetes is a Disorder of Fat Metabolism.”

Weber cites a 2009 study published in The Journal of Clinical Investigation entitled “Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans” that purports to show that eating too much fat contributes to insulin resistance not only in our furry little lab rat friends but also in humans.

The paper contains an animal study and a human study.  The animal study is useful and informative, while the human study is poorly designed.  This paper is important and does shed some light on the causes of insulin resistance, but to conclude from this paper that humans will become diabetic from eating too much fat is a serious misuse and misinterpretation of the paper.

The researchers fed rats a control diet or a 60% lard diet from Research Diets.  The authors don't state what the control diet was, but if it was similar to the standard control diet that Research Diets offers, the 60% lard diet would yield not only a high content of saturated fat, but a 50% increase in total PUFA.  They fed this diet with or without an antioxidant that targets the mitochondria, scavenges reactive oxygen species, and prevents the oxidative destruction of PUFA.

The high-fat diet did not produce any oxidative destruction of PUFA in rats:

No evidence of mitochondrial dysfunction or oxidative stress, at least with respect to the levels of the lipid peroxide derivative 4-hydroxy-nonenal (data not shown) was found in muscle of high-fat diet-fed rats with or without SS31 [the antioxidant] treatment.

However, when they isolated the muscles from these rats and provided them with energy sources, there was a 2-3-fold increase in the maximal production of hydrogen peroxide, which is used as a signaling molecule but can induce oxidative damage at high doses or when combined with certain metal ions.  This effect was abolished when the rats were treated with the mitochondrial antioxidant.

The high-fat diet also reduced concentrations of the master antioxidant of the cell, glutathione, and led to impaired glucose tolerance.  It is typical for this type of high-fat diet to produce these metabolic effects in rats, so this is not surprising.  Treatment with the mitochondrial antioxidant helped prevent the decrease in glutathione and completely abolished the impairment of glucose tolerance.

When they repeated the experiment in mice, they genetically engineered some of them to produce more of the enzyme catalase, which converts hydrogen peroxide to water.  Overproduction of catalase completely prevented the negative metabolic effects of the high-fat diet.

Quite obviously, this paper shows that high-fat diets are not inherently harmful to rodents.  Simply providing an antioxidant nearly abolishes all their negative effects.

Health-conscious humans do not eat high-fat diets made of refined, purified ingredients or obtain 60% of their calories as lard.  A diet based on organ meats such as liver, shellfish, muscle meats, fish, fruits, vegetables, starches, and animal fats from healthy animals or selected traditional plant oils bears no resemblance to this type of diet and is instead loaded with antioxidants.

Nevertheless, I actually really like this paper.  In the discussion section, they point out that glutathione is not just an antioxidant, but is actually a master control switch responsible for regulating the activity of a whole host of different proteins and that insulin resistance is not so much a result of damage to the organism, but a way of homeostatically regulating energy balance.  I'll write more on this topic in the future.

Their hypothesis is basically that the supply of fat exceeds the metabolic demand for fat, and that the cell responds by creating a more oxidized environment in order to deliberately reduce its sensitivity to insulin, which will stop the flood of more incoming fuel in the form of glucose.

By providing an antioxidant, they increase the mitochondria's ability to process the fats, and thus increase the cell's tolerance for incoming fuel.  So the cell will take up more glucose in response to insulin.

The only problem with the paper is they never explain why fat would constitute “excess” whereas carbohydrate would not. It's possible that fats just burn a little less cleanly than glucose.  For example, a large excess of energy provided to mitochondria will tend to cause glucose to get converted to fat, but could tend to increase the burning of fatty acids in the endoplasmic reticulum, which generates a lot more oxidative stress than the mitochondria.  They provided no evidence of this, however.

But it's also quite possible that the 50% excess PUFA made all fuels burn less cleanly by increasing the mitochondrial content of vulnerable PUFAs.  Since they didn't find oxidative destruction of PUFAs, this hypothesis is not very well supported.It's also possible that this simply reflects an adaptation to fat-burning.  As the cell adapts to fat, it stops taking up glucose.

Regardless, the antioxidant improved mitochondrial efficiency enough to handle the fat and to be able to respond to insulin sensitively.

The big problem with this paper is that they try to extrapolate this to humans with an incredibly poorly designed study.

Here is what they report for methods:

Nine healthy lean (BMI, <25 kg/m2) men (aged 18-25 years) of a variety of races participated in an acute high-fat diet study.  Subjects reported to the laboratory following a 12-hour overnight fast.  After muscle samples were obtained, subjects consumed a single high-fat meal (35% daily kcal intake; >60% kcal from fat), and a second muscle biopsy was taken 4 hours later.  Subjects then consumed a high-fat diet (isocaloric; >60% kcal from fat) for 5 days and returned 12-hour fasted on the morning of the sixth day, when a final muscle biopsy was obtained.

Hmm, can you spot the control group?

Picture borrowed from here.

I think Waldo might be in there, but there's no control group in this study.  Nor is there a control trial where the people consumed a low-fat diet.

Nor is the diet described.

Their animal study would seem to suggest that the effects of the high-fat diet — if in fact there were any effects — could be mitigated simply by including appropriate antioxidants, perhaps the type that are included abundantly in traditional, nutrient-dense fatty foods.