The insulinotropic effect of a high-protein nutrient preload is mediated by the increase of plasma amino acids in type 2 diabetes

Aims: Eating protein before carbohydrate reduces postprandial glucose excursions by enhancing insulin and glucagon-like peptide-1 (GLP-1) secretion in type 2 diabetes (T2D). We tested the hypothesis that this insulinotropic effect depends on the elevation of plasma amino acids (AA) after the digestion of food protein. Methods: In 16 T2D patients, we measured plasma AA levels through the course of two 75-g oral glucose tolerance tests (OGTT) preceded by either 500-ml water or a high-protein nutrient preload (50-g Parmesan cheese, one boiled egg, and 300-ml water). Changes in beta cell function were evaluated by measuring and modelling plasma glucose, insulin, and C-peptide through the OGTT. Changes in incretin hormone secretion were assessed by measuring plasma GLP-1. Results: Plasma AA levels were 24% higher after the nutrient preload (p < 0.0001). This increment was directly proportional to both the enhancement of beta cell function (r = 0.58, p = 0.02) and the plasma GLP-1 gradients (r = 0.57, p = 0.02) produced by the nutrient preload. Among single AA, glutamine showed the strongest correlation with changes in beta cell function (r = 0.61, p = 0.01), while leucine showed the strongest correlation with GLP-1 responses (r = 0.74, p = 0.001). Conclusions: The elevation of circulating AA that occurs after a high-protein nutrient preload is associated with an enhancement of beta cell function and GLP-1 secretion in T2D. Manipulating the meal sequence of nutrient ingestion may reduce postprandial hyperglycaemia through a direct and GLP-1-mediated stimulation of insulin secretion by plasma AA. Trial registration number: NCT02342834.