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Is the Paleo Diet Really Killing You? An Investigation into a Mouse Model

The press release for a recent study out of the University of Melbourne is titled, “Diabetes expert warns paleo diet is dangerous and increases weight gain.” These findings are reiterated by the lead author, Associate Professor Sof Andrikopoulos, in a YouTube video describing the experiment, which was done in New Zealand Obese (NZO) mice.

Much of the nutrition internet reacted in the expected way – people who are generally supporters of lower-fat diets liked it and people who follow low-carbohydrate diets did not. No surprise there.

But there is a greater question here when it comes to diet studies. Can outcomes from animal studies be extrapolated to humans? And if they can, how can it be done in a way that doesn’t distort the meaning?

I spoke with two experts in the field of mouse studies:

  • Donald Smith, Ph.D. in Veterinary Medicine, and Manager of the Comparative Biology Unit at the Tufts University Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA), and

  • Bill Lagakos, Ph.D. in Nutritional Biochemistry and Physiology

I wanted to find out what we can and can’t learn from a mouse study.

First: The Protocol

This study was done in New Zealand Obese (NZO) mice. These mice have multiple genes that cause them to rapidly become overweight and develop metabolic syndrome and diabetes very early in life. To give you an idea, the average mouse lifespan is about 100 weeks and the NZO mouse typically has diabetes by week 20, or 1/5 of the way through its lifespan. This would be equivalent to a human developing severe obesity and diabetes by around 16 years, assuming the typical life-expectancy in the United States.

To sum up:

  1. All NZO mice were raised on standard chow for 6 weeks. During this time they became pre-diabetic and obese, as is the norm for all NZO mice.

  2. After 6 weeks, half of the mice went on ad libitum LCHF diets and the other half continued to eat lab chow.

  3. At different points during the study, numerous data were collected from the mice:

  • Oral Glucose Tolerance Tests

  • Intravenous Glucose Tolerance Tests,

  • Weighed and fat mass measured

  • Blood glucose, insulin, and triglycerides measurements

  1. After mice are sacrificed, pancreases were removed and stained to measure beta cell mass.

This study is neat because it seeks to examine a tenet of the LCHF diet for diabetes that is often touted, but has not been conclusively proven: Macronutrient ratio, without subsequent weight loss, will delay or prevent diabetes.

A large, paleolithic segment of the internet might object to this diet being called "Paleo." The paper only refers to the diet as LCHF, though the press release and YouTube coverage call it paleo. Why the study was branded this way is outside the perview of this article - however, it's fair to note that there are a range of eating styles that self-identify as paleo.

As the study states in its introduction, numerous articles have been written advocating for using LCHF diets as a first defense in people with pre-diabetes and Type II Diabetes. In addition to the weight loss that typically comes with an LCHF diet, proponents believe that lowered blood glucose and insulin release after meals will allow diabetics to manage blood sugar levels and prevent further beta-cell burnout.

Why is this? Carbohydrates stimulate the release of insulin from the pancreas. When people decrease carbohydrate intake, this reduces post-meal blood sugar. A person with pre-diabetes has insulin resistance, so a post-meal increase in blood sugar forces beta-cells to produce extra insulin in order to bring blood sugar back into the normal range. When carbohydrates are removed, the lower post-meal blood sugar levels means lower need for insulin.

So it follows that less pressure on the beta-cells to produce insulin could preserve them and prevent the burnout that comes with Type 2 Diabetes.

In practice, genetically obese NZO mice given zero carbohydrates do manage to stay diabetes free, despite other metabolic risk factors. However, as soon as these mice are given access to carbohydrates, their disease progression resumes at an increased pace.

When human trials are done comparing various weight loss diets, low-carbohydrate diets have a tendency to come out on top or tie for first. But the problem here is that all of these diets focus on weight loss as an outcome, and weight loss inevitably causes increased insulin sensitivity and sometimes diabetes prevention or reversal. The individual effect of macronutrient ratio is hopelessly confounded when weight loss is involved.

So the team at University of Melbourne attempted to see if LCHF diets without weight loss could have the same diabetes-preventing effect as the same diet with weight loss. This would essentially prove that a LCHF diet could prevent diabetes merely by lowering blood glucose after a meal and reducing insulin load.

As you can see, that did not happen. In fact, mice on the diet (which was extremely high in saturated fat) experienced greater insulin resistance, higher fasting blood glucose, and accumulated more fat mass than the NZO mice on the high-carbohydrate, low-fat diet. They also had the same beta-cell mass as the high-carbohydrate group, disproving the hypothesis that lower post-meal insulin secretion would preserve beta-cell function.

Despite eating the same number of calories, the LCHF mice also gained more weight. Authors concluded this must have been due to lower activity levels, though activity wasn’t explicitly measured.

So What Does This Prove?

A 6% carbohydrate diet with 81% fat (55% from saturated fat) will exacerbate insulin resistance and weight gain in NZO mice.

Can This Be Applied to Humans?

Here is where interpretation gets tricky. How much of this study can we reasonably say is true for humans? Can you really say that a LCHF diet, let alone a Paleo diet, could be unhealthy for humans?

Donald Smith, Ph.D. said, “The study suggested that it could,” but added some caveats, “It’s a pretty important statement to be making and I think you’d want to have it confirmed by others.” The next step would be to repeat it in higher order primates. However, he did explain that disease progress is similar in these mice and in humans:

"The whole thing with insulin resistance is that increased fatness (obesity) leads to lower insulin sensitivity, so the body needs to produce more insulin and beta cells are blasting to release enough insulin. But, you reach the point where the beta cells cannot produce any more insulin, enough to keep up with the demand, and you get a loss of beta cell function. [As seen with THIS low-carb diet] you can have a low post-prandial blood glucose, which would require less insulin secretion, but at the same time be insulin resistant.”

“Is this physiology the same between mice and humans?” I asked.

“Generally yes.”

But, he pointed out, “A lot of obese models are artificial [bred to develop a specific disease] models, and many animals or people with the same problems don’t necessarily respond similarly to the same interventions. So that’s why you go to clinical trials or a higher order of animals.”

And, despite the popularity of ketogenic diets on the internet, Smith added, “It’s an artificial diet, I don’t think anyone eats an 81% fat diet.”

Smith believed obesity was the driver for the glucose intolerance and greater insulin resistance seen with LCHF mice. “They’re more resistant,” he said, “because of the [increased] obesity.” In his opinion, if both experimental and control mice had been the same weight, he would have expected them to experience the same amount of insulin resistance.

Though email correspondence, Bill Lagakos, Ph.D., agreed in no uncertain terms: “LCHF and keto [ketogenic] research in mice can be very informative, but not for studying the regulation of body weight or fat mass (in which you can get a different outcome in every study, seriously).”

If the worsened insulin resistance is a result of increased body fat, then this study failed to show that a LCHF diet produces significantly worse results due to its fat composition. However, the study did show that a LCHF diet without weight loss is NOT protective against type II diabetes.

And this could likely apply to humans, since the disease progression is similar between humans and NZO mice, except for the pesky fact that LCHF diets in people usually lead to lower caloric intake and weight loss.

So, while the study doesn’t go so far as to prove that LCHF diets are dangerous in humans, it creates compelling evidence that the beneficial effects of LCHF diets seen in humans are due to weight loss caused by lowered intake and not because there is an ideal fat-to-carb ratio that will prevent disease.

Finally, it is worth pointing out that mice are HDL animals. This means that increasing their fat intake even to 90% won’t cause atherosclerosis or heart disease in mice that aren’t specifically bred to develop heart disease. In humans, a huge increase in saturated fat leads to increased total cholesterol, HDL and LDL. High LDL is linked to the development of heart disease and so is another reason why humans, not mice, want to monitor saturated fat intake even if they are on a higher fat diet.

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