The carbohydrate-insulin model: a physiological perspective on the obesity pandemic

David S Ludwig, Louis J Aronne, Arne Astrup, Rafael de Cabo, Lewis C Cantley, Mark I Friedman, Steven B Heymsfield, James D Johnson, Janet C King, Ronald M Krauss, Daniel E Lieberman, Gary Taubes, Jeff S Volek, Eric C Westman, Walter C Willett, William S Yancy, Cara B Ebbeling, David S Ludwig, Louis J Aronne, Arne Astrup, Rafael de Cabo, Lewis C Cantley, Mark I Friedman, Steven B Heymsfield, James D Johnson, Janet C King, Ronald M Krauss, Daniel E Lieberman, Gary Taubes, Jeff S Volek, Eric C Westman, Walter C Willett, William S Yancy, Cara B Ebbeling

Abstract

According to a commonly held view, the obesity pandemic is caused by overconsumption of modern, highly palatable, energy-dense processed foods, exacerbated by a sedentary lifestyle. However, obesity rates remain at historic highs, despite a persistent focus on eating less and moving more, as guided by the energy balance model (EBM). This public health failure may arise from a fundamental limitation of the EBM itself. Conceptualizing obesity as a disorder of energy balance restates a principle of physics without considering the biological mechanisms that promote weight gain. An alternative paradigm, the carbohydrate-insulin model (CIM), proposes a reversal of causal direction. According to the CIM, increasing fat deposition in the body-resulting from the hormonal responses to a high-glycemic-load diet-drives positive energy balance. The CIM provides a conceptual framework with testable hypotheses for how various modifiable factors influence energy balance and fat storage. Rigorous research is needed to compare the validity of these 2 models, which have substantially different implications for obesity management, and to generate new models that best encompass the evidence.

Keywords: dietary carbohydrate; endocrinology; energy balance; glucagon; incretins; insulin; macronutrients; obesity; scholarly discourse; weight loss.

© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Dynamic phase of obesity development in the carbohydrate-insulin model. The relation of energy intake and expenditure to obesity is congruent with the conventional model. However, these components of energy balance are proximate, not root, causes of weight gain. In the compensatory phase (not depicted), insulin resistance increases, and weight gain slows, as circulating fuel concentration rises. (Circulating fuels, as measured in blood, are a proxy for fuel sensing and substrate oxidation in key organs.) Other hormones with effects on adipocytes include sex steroids and cortisol. Fructose may promote hepatic de novo lipogenesis and affect intestinal function, among other actions, through mechanisms independent of, and synergistic with, glucose. Solid red arrows indicate sequential steps in the central causal pathway; associated numbers indicate testable hypotheses as considered in the text. Interrupted red arrows and associated numbers indicate testable hypotheses comprising multiple causal steps. Black arrows indicate other relations. ANS, autonomic nervous system; GIP, glucose-dependent insulinotropic peptide.

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