Implication of sugar, protein and incretins in excessive glucagon secretion in type 2 diabetes after mixed meals

Aims: Amino acids powerfully release glucagon but their contribution to postprandial hyper-glucagonemia in type 2 diabetes remains unclear. Exogenously applied GIP stimulates, while GLP-1 in-hibits, glucagon secretion in humans. However, their role in mixed meals is unclear, which we therefore characterized.Methods: In three experiments, participants with type 2 diabetes and obese controls randomly received different loads of sugars and/or proteins. In the first experiment, participants ingested the rapidly cleaved saccharose (SAC) or slowly cleaved isomaltulose (ISO) which is known to elicit opposite profiles of GIP and GLP-1 secretion. In the second one participants received test meals which contained saccharose or isomaltulose in combination with milk protein. The third set of participants underwent randomized oral protein tests with whey protein or casein. Incretins, glucagon, C-peptide, and insulin were profiled by specific immunological assays.Results: 50 g of the sugars alone suppressed glucagon in controls but slightly less in type 2 diabetes patients. Participants with type 2 diabetes showed excessive glucagon responses within 15 min and lasting over 3 h, while the obese controls showed small initial and delayed greater glucagon responses to mixed meals. The release of GIP was significantly faster and greater with SAC compared to ISO, while GLP-1 showed an inverse pattern. The glucagon responses to whey or casein were only moderately increased in type 2 diabetes patients without a left shift of the dose response curve.Conclusions: The rapid hypersecretion of glucagon after mixed meals in type 2 diabetes patients compared to controls is unaffected by endogenous incretins. The defective suppression of glucagon by glucose combined with hypersecretion to protein is required for the exaggerated response. Clinical trials numbers: NCT03806920, NCT02219295, NCT04564391.(c) 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Automated summary

This study investigates the contribution of amino acids to postprandial hyper-glucagonemia in type 2 diabetes patients. The research shows that type 2 diabetes patients have excessive glucagon responses after mixed meals, while the obese control group only shows small initial and delayed greater glucagon responses. The role of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in mixed meals is unclear.