In their comment letter in this issue of Diabetes, Ragozzino et al. (1) raise several points regarding our recent publication (2) that “warrant further clarification to strengthen the translational impact of the work.” They indicate that “several mechanistic interpretations . . . are inferred from indirect behavioral and metabolic proxies,” mainly that “meal size and meal number are treated as readouts of satiation and satiety, although these constructs traditionally require direct assessment through preload paradigms, hormonal profiling, or neural activity mapping” and that “shifts in substrate oxidation are interpreted as coordinated metabolic adaptations, yet they derive solely from gas-exchange calculations that do not account for protein turnover and lack isotopic validation.” We absolutely agree with these points. Indeed, we dedicated a section in the Discussion to describing study limitations, including the following statements:
- “Satiation and satiety were drawn from ad libitum meal patterns and not from direct measures of satiation or satiety (e.g., preload experiments)”
- “Similarly, lipid and carbohydrate oxidation rates were derived from gas exchange measurements”
- “Changes to protein synthesis/degradation were not included in our calculations”
- “Future studies will use isotopic tracers to derive direct measurements of fuel oxidation”
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