The study that lead to this surprising headline was published in August 2018 (Short-term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high-fat diet, Grandl et al., 2018).
What Did Study Actually Show?
Mice were divided into 3 groups:
- standard chow (control group);
- a high fat diet based on 60% kcals coming from lard and refined soybean oil; and
- a very high fat (ketogenic) diet based on 90% kcals coming from Crisco and corn oil.
The mice were fed with refined soybean oil, Crisco, and corn oil are some of the least healthy dietary fats possible. More accurately, they are likely harmful. Inflammatory, more susceptible to oxidative damage, and promoting oxidative stress.
Also, the use of different sources of fats in all 3 diets is a confounding variable. It would be more appropriate to use the same source of carbohydrate and fat, and just vary the ratio to achieve the desired level of fat:carb. All fats are not alike and are expected to have different metabolic effects independent from total level of dietary fat.
Ketogenic Group Had the Lowest Basal Insulin
After 3 days, compared to the other 2 groups, the high fat diet-fed mice (the mice in the second group) required more insulin to maintain normal fasting blood glucose levels indicating insulin resistance. The ketogenic diet-fed mice (the third group) had the lowest basal insulin of all 3 groups and insulin levels were similar to the control group.
Triacylglycerols, free fatty acids, cholesterol, and body weight were largely unchanged after 3 days.
Part of the point of this 3-day duration was to determine if the fat content of the diet could induce any metabolic effects before changes in body weight could set in. Both intervention groups (second and third group) were ingesting slightly more calories so it may be safe to assume elevated body weights in the future.
It is important to mention that this is an animal study and it is not what happens in humans on whole food-based low carb and/or ketogenic diets. See: Appetite Control and Caloric Intake on Low-carb Ketogenic Diets.
Glucose Tolerance and Insulin Sensitivity Results
The results also showed reduced glucose tolerance in the ketogenic diet-fed group and impaired insulin sensitivity in both intervention groups during an intraperitoneal glucose tolerance test.
An intraperitoneal glucose tolerance test consists of injecting 1.5 grams of glucose per kilogram body weight. In humans that’s roughly the amount of sugar in 3 cans of soda directly into the abdomen. (I suspect the dose of glucose was intentionally high because after only 3 days on the respective diets, the researchers figured the animals wouldn’t be very insulin resistant.)
Don’t do that. Oral glucose tolerance tests are more relevant although somewhat debatable in the context of ketogenic diets. That is, ketogenic dieters are never exposed to high carb meals, so the relevance of glucose tolerance has been questioned in the context.
Everyone has better glucose tolerance to orally administered glucose than intraperitoneal (mice) or intravenous (humans) glucose due to the incretin effect. The incretin effect is an augmenting of insulin secretion by glucose that comes from the gut (via oral administration) as opposed to glucose that came from the liver, peritoneum, or blood vessels.
The hyperinsulinemic-euglycemic clamp, which was also used in this study, is a more targeted way to determine insulin sensitivity. It’s the gold standard. Insulin is infused at the same rate in all groups, and the rate of glucose infusion to maintain euglycemia (normal concentration of glucose in the blood) determines insulin sensitivity: the more glucose required to maintain euglycemia, the more insulin sensitive.
In this study, and in line with earlier results, the ketogenic diet-fed mice required significantly less glucose to maintain euglycemia indicating insulin resistance.
There was no difference in glucose production by the liver in the basal state although it was significantly increased during insulin infusion in the ketogenic diet-fed group which led to the article title: “Short-term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high-fat diet” which is not entirely accurate.
Glucose production by the liver was significantly higher in ketogenic diet-fed mice than controls, but not statistically significantly higher than “obesogenic high-fat diet”. It is not entirely accurate to use the term “obesogenic” which implies more fat mass or elevated body weight, neither of which occurred.
In an admittedly somewhat clever follow-up experiment, they repeated the hyperinsulinemic-euglycemic clamp with a lower insulin infusion rate and higher glucose target which exposed reduced glucose infusion rates in both the ketogenic and high fat diet-fed groups. In agreement with the first clamp study, there were no differences in basal endogenous glucose production, and elevated glucose production during hyperinsulinemia in the ketogenic diet-fed group compared to controls and high fat diet-fed mice… which, again, is incongruous with the title of the paper.