There are few topics more divisive in medicine than low-fat versus low-carbohydrate diets.

And last week, that divide was thrown into sharp focus with the publishing of a study partly funded by the Nutrition Science Initiative, a group formed by prominent low-carb advocates including journalist Gary Taubes and Peter Attia, MD, the group's former president, who can still be found online sporting a t-shirt that reads "Praise the Lard."

NuSI, as the group is known, is funding several studies, but the results from the first one were just published in the American Journal of Clinical Nutrition last week. It was a small trial, with only 17 participants, but it eliminated the usual problems with diet studies by controlling everything that the participants ate by keeping them in metabolic wards and taking measurements in very precise "metabolic chambers."

Most remarkably, the study results did not clearly support one of NuSI's central precepts. The researchers leading it -- who were chosen by NuSI but who otherwise had no ties with the organization – found that an isocaloric, low-carbohydrate ketogenic diet was not associated with increased body fat loss compared with a higher carbohydrate diet, but was associated with a slight increase in energy expenditure that was barely detectable.
The results were, in other words, less than spectacular.

In fact, they were so underwhelming that Kevin Hall, MD, the lead author of the study and a researcher at NIH, proclaimed that the evidence, when added to an earlier study on carbohydrate restriction, showed that the insulin carbohydrate model -- which holds that carbs are behind the obesity epidemic because they increase circulating insulin -- was essentially dead.

"The combination of the two studies, on the metabolic side of things, basically falsifies the carbohydrate-insulin hypothesis," said Hall in a popular YouTube video earlier this year, discussing preliminary results from the study.



But in an email to MedPage Today, Hall was more circumspect. "I think it is fair to say that the interpretation of the study results by the investigators, especially when combined with the results from the non-NuSI funded study published last year in Cell Metabolism, are not in line with the predictions of carbohydrate-insulin model that have been promoted by Gary Taubes and others," he wrote.

But other researchers -- including David Ludwig, MD, a Harvard University researcher who is a prominent advocate of the carbohydrate-insulin model and is receiving research funding from NuSI -- say that the study was far from definitive, and in fact that the evidence from the study supports their model.

The Numbers
The 17 patients, all of whom were obese or overweight men, spent the first 4 weeks of the study on a high-carb baseline diet and the last 4 weeks on the ketogenic diet. The patients lost weight and body fat throughout the whole study, and had a negative energy balance of around 300 kcal per day. Compared with the baseline diet, the ketogenic diet was associated with increased energy expenditure (57±13 kcal/day; P=0.0004) and sleeping energy expenditure (89±14 kcal/day; P<0.0001). They also had decreased respiratory quotient (-0.111±0.003; P<0.00001), and energy expenditure -- as measured by doubly labeled water -- increased by 151±63 kcal/day (P=0.03). The rate of loss of body fat slowed during the ketogenic diet part of the study, and it coincided with the loss of fat-free mass and increased protein utilization, Hall and colleagues reported.

The participants were ages 18 to 50 and had a body mass index of somewhere from 25 to 35. Ten of the patients were black; five were white; one was Asian; and one was Hispanic. Participants were told to cycle for 90 minutes per day, and on two days per week they were confined to the metabolic chamber.

They were excluded if their body weight had changed more than 5% during the last 6 months, if their current weight was less than 92% of their lifetime maximum weight, if they had blood pressure greater than 140/90 mm Hg, or if they had other diseases or disabilities that would have interfered with their ability to complete the study.

The food was prepared in a lab, frozen, then shipped to the study sites, where it was then prepared along with fresh produce. The baseline diet didn't have a large amount of sugar, so it may have "differed somewhat from the customary diets" of the participants, wrote the authors.

The participants were not allowed to leave or to eat other foods, and were told they had to eat all of the food in front of them. They were allowed to meet with visitors, but only under the supervision of a nurse or research staff. The metabolic chamber measurement times were all at least 23 hours. Blood and urine measurements were also taken.

"Our data do not support the carbohydrate-insulin model predictions of physiologically relevant increases in energy expenditure or greater body fat loss in response to an isocaloric ketogenic diet," concluded Hall and colleagues.

The Rashomon Effect
Some researchers found the results unsurprising. Marion Nestle, PhD, MPH, an influential blogger at New York University, wrote that there are two takeaways from the study: When it comes to weight loss, "the relative proportions of fat, protein, and carbohydrate do not matter much (although low-carb diets may help with eating less)," she wrote. But when it comes to health, "the food sources of calories matter very much indeed."

The carbohydrate–insulin model predicts a greater rate of body fat loss during the ketogenic diet period," wrote the authors, but they didn't see that play out in the results -- the rate of fat loss during the last two weeks was similar to the baseline period. This may have been because the increased fat consumption that replaced the carbs led to higher circulating postprandial triglyceride concentration, "which may have stimulated adipose tissue fat uptake and/or inhibited adipocyte lipolysis," they wrote.

Hall said in the YouTube video that the results, along with another of his studies in Cell Metabolism -- which found that when calories were compared to calories, fat restriction led to more body fat loss than carbohydrate restriction among obese people -- were not encouraging for the carbohydrate insulin model.

And obesity researcher and blogger Stephan Guyenet, PhD, wrote that the study "serves up disappointment" for the carbohydrate-insulin model.

But at least two other researchers see the results in fundamentally different ways. Ludwig noted in a blog post that, according to the trial's registration page on ClinicalTrials.gov, the study was only a pilot study, and thus strong conclusions -- like that it falsifies the model that Ludwig is a proponent of -- couldn't be drawn from it.

But even taking the study at face value, he wrote, the results were still remarkable. "The results showed that carbohydrate reduction increased energy expenditure as predicted!" he wrote. "Beyond expectations for pilot studies, their results were statistically significant."

An energy gap of 100 to 150 kcal per day could go a long way in solving the obesity epidemic, he added. Ludwig argued that the report's conclusion should have read: "We found preliminary evidence for an exceptional effect of a very-low-carbohydrate diet on energy metabolism. This finding suggests that reducing carbohydrate may be advantageous to conventional approaches for weight loss maintenance. Because of fundamental study limitations, these data should be interpreted cautiously pending longer-term, definitive randomized controlled trials."

And Michael Eades, MD, wrote on his Proteinpower.com site that there's a disparity between the conclusions that Hall drew in the YouTube video and in the paper and the actual results of the study.

"That's a hell of a lot of energy considering all the things we don't know," wrote Eades of the significant increase of 150 kcal/day in the study, which was the minimum amount detectable by the chamber. "Enough to roll back the obesity epidemic and bring people's weights to 19th century levels if it was maintained day in and day out."

Additionally, according to Eades, the study was "sloppy" in letting participants spend most of each week outside the metabolic chambers, which apparently led to unintentional weight loss: the participants had relatively low energy expenditure during chamber days, but dramatically higher expenditure on non-chamber days. The result was an overall negative energy balance that amounted to 300 kcal per day, likely because the patients were choosing to spontaneously exercise on non-chamber days.

"We actually were surprised by the magnitude of how many more calories they were burning outside the chambers," said Hall in the YouTube video. "So what that meant was that we were feeding them more or less in balance in the chamber but we were underfeeding them outside the chamber." (In the final version of the study, Hall and colleagues listed this as a limitation of the research.)

But the objections raised by Hall's critics probably won't win over many people who had not previously accepted the carbohydrate-insulin model. Studies of a longer duration would be welcome, wrote Ludwig, and Hall and colleagues noted that there's an aspect of the model that they didn't test for: whether restricting carbs leads to decreased ad libitum energy intake.

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