The impact of a single dose of whey protein on glucose flux and metabolite profiles in normoglycemic males: insights into glucagon and insulin biology

Protein ingestion concurrently stimulates euglycemic glucagon and insulin secretion, a response that is particularly robust with rapidly absorbing proteins. Previously, we have shown that ingestion of repeated doses of rapidly absorbing whey protein equally stimulated endogenous glucose production (EGP) and glucose disposal (Rd), thus explaining the preservation of euglycemia. Here, we aimed to determine if a smaller single dose of whey could elicit a large enough glucagon and insulin response to stimulate glucose flux. Therefore, in normoglycemic young adult males (n = 10; age ∼26; BMI ∼25), using [6,6-2H2] glucose tracing and quantitative targeted metabolite profiling, we determined the metabolic response to a single 25 g "standard" dose of whey protein. Whey protein ingestion did not alter glycemia, but increased circulating glucagon (peak 4-fold basal), insulin (peak 6-fold basal), amino acids, and urea while also reducing free fatty acid (FFA) and glycerol concentrations. Interestingly, the postprandial insulin response was driven by both a stimulation of insulin secretion and marked reduction in hepatic insulin clearance. Whey protein ingestion resulted in a modest stimulation of EGP and Rd, both peaking at ∼20% above baseline 1 h after protein ingestion. These findings demonstrate that the ingestion of a single standard serving of whey protein can induce a euglycemic glucagon and insulin response that stimulates glucose flux. We speculate on a theory that could potentially explain how glucagon and insulin synergistically provide hardwired control of nitrogen and glucose homeostasis.NEW & NOTEWORTHY Protein ingestion concurrently stimulates glucagon and insulin secretion. Here we show that in normoglycemic males, ingestion of a single "standard" 25 g serving of rapidly absorbing whey protein drives a sufficiently large glucagon and insulin response, such that it simultaneously increases endogenous glucose production and glucose disposal. We speculate on a novel theory that could potentially explain how the antagonistic/synergistic actions of glucagon and insulin simultaneously provide tight control of glucose and nitrogen homeostasis.