Understanding the Metabolic and Endocrine Effects of Macronutrient Boluses in the Context of a Low-Carbohydrate Diet: A Randomized Crossover Study

Background/Objectives: Adherence to a low-carbohydrate diet induces distinct metabolic adaptations, yet the acute endocrine responses to individual macronutrients within this adapted state remain incompletely characterized. This study aimed to determine the acute, postprandial endocrine and glycemic kinetics following isolated isocaloric carbohydrate, protein, and fat boluses in healthy adults adapted to a low-carbohydrate diet. Methods: Participants (13 female, 11 male) completed three interventions which consisted of consuming an isovolumetric 300 kcal drink of either whey protein (PRO), dextrose (CHO), or olive oil (FAT) mixed with water. Blood was taken immediately prior to drink consumption and then every 30 min afterwards for 2 h in each condition. Continuous glucose monitoring occurred during each intervention. Results: Postprandial glucose remained stable following the FAT and PRO conditions, whereas the CHO condition significantly increased glucose concentrations over time (p < 0.01). Glucagon did not differ between FAT and CHO (p = 0.28) but increased following PRO compared to both FAT and CHO (p < 0.01). Insulin, C-peptide and amylin rose in the CHO condition, with smaller increases in PRO and minimal changes in FAT (p < 0.01). GLP-1 was elevated in the PRO condition compared to both FAT and CHO (p < 0.01), while GIP increased most in the CHO condition and differed across all treatments (p < 0.01). Ghrelin decreased after CHO and PRO, leptin did not significantly change across conditions, and both PP and PYY were lower in the CHO condition at later time points relative to FAT and PRO. Inflammatory markers showed minimal acute changes across conditions, although MCP-1 increased over time following PRO. Conclusions: In low-carbohydrate-adapted individuals, isolated macronutrient boluses elicit highly distinct, divergent endocrine signatures. The robust, acute glucagon response to pure protein does not cause short-term glycemic excursions, indicating that counter-regulatory incretin and insulinotropic pathways remain highly capable of preserving immediate glucose homeostasis.