<b>Mechanistic insights into postprandial insulin-glucagon interactions and their impact on glucose flux following protein-glucose co-ingestion in humans</b>

<p dir="ltr">Despite stimulating glucagon secretion, the mechanism(s) by which protein ingestion lowers glucose excursions remain unclear. We investigated this using the triple stable isotope glucose tracer technique to measure postprandial glucose fluxes. Eleven healthy adults completed three trials, ingesting 25g glucose (25G; 100 kcal), 50g glucose (50G; 200 kcal), or 25g glucose plus 25g whey protein (25WG; 200 kcal). Glucose excursions were lowest for 25WG. Glucagon increased ~3-fold with 25WG but was suppressed with 25G and 50G. Insulin and GIP were higher for 25WG vs 25G, while GLP-1 was similar. Compared to 50G, 25WG produced a greater GIP but similar GLP-1 response, with a trend for higher early-phase insulin. Endogenous glucose production (EGP) was less suppressed with 25WG (~50%) vs 25G (~70%) or 50G (~80%). Compared to 25G, 25WG did not enhance glucose disposal (Rd) but reduced early-phase (30-60 min) glucose absorption. These findings confirm that protein-glucose co-ingestion robustly stimulates glucagon while enhancing GIP and insulin, leading to lower postprandial glucose excursions. Despite greater insulin secretion, the net glycemic benefit appears to stem from reduced early glucose absorption rather than increased Rd. This provides novel insight into the mechanisms by which protein improves postprandial glucose handling despite interfering with EGP suppression.</p>