A high-fat, ketogenic diet causes hepatic insulin resistance in mice


#1

I do not understand this study, if anyone can explain. This is an old study from 2010 if it has previously been discussed please point me to it.

One of the main points

“KD increases hepatic lipid content and impairs insulin signaling.
The KD-fed mice developed diet-induced NAFLD with elevated AST and significantly increased ALT plasma concentrations”

the ability of insulin to suppress endogenous glucose production was significantly impaired in the KD-fed mice

Seems to imply that a keto diet reduces insulin sensitivity rather than increasing it and promotes liver disease in mice

Another issue was that although the Keto mice weighed less, it was lean body mass that was lower and percentage of fat was the same

gained significantly less weight than the RC-fed mice but showed a significant increase in the percentage of fat mass, without change in percentage of lean body mass (Table 1), suggesting no increase in muscle proteolysis, despite the extreme composition of the KD. However, consistent with the decrease in body weight, total lean body mass was significantly decreased by 16% in the KD-fed mice, whereas total body fat was similar between groups.

Insulin sensitivity in other parts of the body increased but the liver showed a decrease leading potentially to liver disease


(Brian) #2

Hate to sound ugly but I am NOT a mouse!


(Mike Glasbrener) #3

Ummm. 17% fat, 60% carbs, 23% protein isn’t even remotely close to a ketogenic diet (KD)… It sounds much closer to a SAD diet. Once I read that I really struggled to read a whole little lot more.

EDIT:
Oops. My bad. I miss read the study. brownfat corrects me below… The KD diet was indeed extremely low carb…


(Todd Allen) #4

From the study the ketogenic diet fed to the mice was
95.1% fat, 0.4% carbohydrate, 4.5% protein

While that would be ketogenic it would not be considered a well formulated diet by the vast majority of people with any experience of ketogenic diets. They do not state what the actual foods used were but from looking at other studies I expect it was something like soybean oil, sugar and soy protein. The people conducting these studies put too much emphasis on the precision of the macro nutrient ratios and to attain that precision they tend to use combinations of highly processed “foods” that have each been reduced to a single macro component.

My expectation is that if you fed a mouse a somewhat high fat diet of foods they might eat in the wild, say insect grubs and a variety of seeds and nuts you would have very healthy mice but you would not be able to easily control or state the macro nutrient ratios.


(Todd Allen) #5

That was the control diet not the KD diet. The KD diet was in excess of 95% fat…


#6

Thank you for the replies.

I am concerned that this may be the reason for the rebound once you go off keto? That you no longer process carbs as well as others who were never keto. Simialr to how CICO people have lower BMR after weight loss than someone who has always been at that same weight. I have no plans to go off Keto but when at goal assuming I ever get there, I would like to follow more of a paleo plus dairy diet enjoying fruit and tubers in season

As to the quality of the fats, while I agree that soybean oil is not the best, it is still a keto diet and not a SAD diet and the mice are still better off, perhaps not as well off if they are eating free range grass fed organic but they should be healthier than the SAD mice. When I have to I will eat regular mayo for example and I still feel better than if I ate some carbage. Plus the SAD mice are eating SAD including seed oils and are not having ill effects.

If the theory on the feed is right, then perhaps this requires more scientific inquiry that NAFLD is caused by excess seed oils in addition to or instead of sugar?


(VLC.MD) #7

If I go off Keto, I’ll be a LCHF 30-40 carb a day person.
In a sense, I’m not going off too far.

:slight_smile:

This might interest some


(Todd Allen) #8

People eating keto tend to develop a condition called “physiological insulin resistance”. Basically it is a down regulation of the processes for glucose processing because they aren’t needed. But it is a short term thing similar to how eating high carb down regulates one’s ability to burn fats. After a short period of transitioning back to carbs, on the order of 2 or 3 days, carb processing is fully restored. And if one has reduced visceral fat while keto they are likely to have better insulin sensitivity than when they started.

I suspect the quality of the foods matter more than the macro nutrient ratio. I’d sooner eat sweet potatoes than soybean oil and it’s not that I’m a soy hater, I’m ok with edamame. Sweet potatoes are a whole food with their structure and all of their micro nutrients (vitamins, minerals, phyto chemicals, etc.) intact while soybean oil has been through a harsh refining process that has stripped it to just the oil minus most of the natural anti-oxidants such that the result is unstable and prone to degradation.


(Doug) #9

Great comments, Todd - fascinating stuff.


(VLC.MD) #10

That’s the real answer.


(Sjur Gjøstein Karevoll) #11

So there are many ketogenic diets and just because a diet is ketogenic doesn’t make it automatically healthy. You don’t have to make a diet high fat to make it ketogenic. You don’t even have to make it low carb. It’s important therefore to keep in mind which diet specifically you’re talking about, and in what context it was applied.

So I have no trouble believing a 95% fat 5% protein diet caused insulin resistance and lean body mass loss in mice even though it was ketogenic. In fact we have human studies showing similar trends in humans on similarly extreme diets, particularly decreased lean body mass is well documented in people on a classical ketogenic diet which is about 90% fat. Both hepatic insulin resistance and decreased lbm can be speculated to be caused by the low protein content in both this study and in the classical ketogenic diet. Ketogenic diets actually increase the need for protein in your diet since you now have to use proteins to cover some pathways that preferentially would use carbs in addition to the usual protein turnover that happens. This opens up avenues for new symptoms of protein deficiency that wouldn’t happen if you ate carbs.

The important part here is that most people on a modern ketogenic diet for weight loss or insulin resistance don’t typically have protein deficiency. Usually it’s the opposite (which would prevent you from getting into ketosis), which is why the focus is often on keeping the protein moderate.

Diets also don’t just consist of macronutrient ratios, that’s just one aspect of it. On a biochemical level insulin resistance is a sign of excessive oxidative stress which can have several causes and the contents of your diet can have a significant impact on that. Glucose is the main substrate for our anti-oxidant defense system and polyunsaturated fatty acids are a major source of oxidative stress, so if you put someone on a diet of no carbs and lots of vegetable oils it’s not a surprise if they become more insulin resistant, especially if they’re a mouse that’s more used to relying on glucose in their diet for their anti-oxidant needs.

The context here is really important and needs to be accounted for, and the truth of the matter is always more complicated than “X causes Y” when it comes to health.


#12

Thank you for the replies. I love the chart @VLC.MD. You are basically saying that feeding keto to the mice is analogus to feeding saturated fat to the rabbits, it does not have the same effect as in humans because our natural diets are different and keto in a mouse has a different result. Sounds like @Bellyman was correct.

@brownfat

is

similar to what happens to some people when they break a fast, their insulin spikes on the first meal?

@Berengal while I agree that the mice probably ate keto crap as opposed to SAD crap, I think that while keto crap may or may not be better than an organic whole grain diet with lots of vegetables, it will always be better than SAD crap. That is what it was compared to and it was not clearly better for the mice. I do accept the article quoted above that indicates that mice may not be the best study models for keto diets in humans


(Todd Allen) #13

I expect it is a similar thing. Many recommend breaking fasts gently with small meals and not immediately feasting. I experience gut discomfort if I eat very much too quickly after a fast which is strong incentive to transition gradually from fasting to feasting and I haven’t seen big blood glucose spikes after fasts.


#14

Thank you. I have not checked BG after a fast. I usually do psyllium on the last morning and again an hour before I break a 4 - 6 fast. The one time I forgot was not pleasant