Is the Carbohydrate-Insulin Model Dead? The Rumors Have Been Exaggerated

A version of this post is available on PubMed, linked here.

In a new review, Kevin Hall claims to have “falsified” the Carbohydrate-Insulin Model (CIM) of obesity as iterated by Mark Friedman and me in 2014. Hall describes this achievement as “rare” in nutritional science, like refuting the “luminiferous ether” hypothesis of the 19th century. Elsewhere, he argues that the published data are so definitive as to warrant curtailment of further funding for macronutrient-focused obesity research.

To loosely paraphrase Mark Twain, rumors of CIM’s demise have been greatly exaggerated.

Hall bases his case mainly on his two feeding studies, one small and short (6 days), the other small, non-randomized (i.e., observational) and designated a pilot.

In the discussion section of the 6-day study, Hall and colleagues write: “Our relatively short-term experimental study has obvious limitations in its ability to translate to fat mass changes over prolonged durations” (NB, it can take the body weeks to adapt to a high fat diet). This appropriately cautious interpretation was evidently abandoned in the current review. Indeed, the study has numerous limitations beyond short duration, as reviewed elsewhere, including: 1) lack of a difference in actual fat mass by DXA (p=0.78); 2) use of an exceptionally low fat content for the low-fat diet (< 8% of total energy), arguably without precedent in any population consuming natural diets; 3) use of a relatively mild restriction of carbohydrate (30% of total energy), well short of typical very-low-carbohydrate diets; and 4) experimental errors and exclusions of data that could confound findings. In addition, the investigators failed to verify biologically available energy of the diet (e.g., by analysis of the diets and stools for energy content). Rates of fat oxidation, the primary endpoint, are exquisitely sensitive to energy balance. A miscalculation of available energy for each diet of 5% in opposite directions could explain the study’s findings — and this possibility can’t be ruled out in studies of such short duration.

Hall’s non-randomized pilot potentially suffers from all the well-recognized limitations of small observational studies, importantly including confounding by any time-varying covariate. One such factor is miscalculation of energy requirements, leading to progressive weight loss that would have introduced bias against the very-low-carbohydrate diet. Other major design and interpretive limitations have been considered elsewhere.

Furthermore, Hall sets the bar for the CIM unrealistically high (i.e., 400 to 600 kcal/d greater total energy expenditure), citing speculative claims by non-scientists like Robert Atkins. In fact, effects estimates of 100 to 300 kcal/day — as demonstrated by Hall himself and by us using doubly-labeled water — would be of major scientific and clinical significance if real, and do not represent “ad hoc modifications” to evade “falsification.” (For comparison, Hall previously argued that the actual energy imbalance underlying the entire obesity epidemic is < 10 kcal/d.)

To test the CIM, we need high-quality studies of adequate duration to eliminate transient biological adaptations (ideally ≥ 1 month); using a randomized-controlled design; with definitive measurements of body composition (e.g. DXA or MRI); and including appropriate process measures to assure that the diets are properly controlled for biologically available energy content. No such studies have yet been published. Thus, the CIM is neither proven nor “falsified” by existing data. In view of the complexity of diet, many high-quality studies will likely be needed to provide a complete answer to this question, versions of which have been debated for a century.

The CIM aims to explain a paradox: Body weight is controlled (“defended”) by biological factors affecting fat storage, hunger and energy expenditure. However, the average defended body weight has increased rapidly throughout the world among genetically stable populations. Lacking a definitive explanation for the ongoing obesity epidemic, or effective non-surgical treatment, we should not casually dismiss CIM, especially in light of many studies suggesting benefits of carbohydrate-modified/higher-fat diets for obesity, cardiovascular disease and possibly longevity.

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