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

Jiudan Zhang; Sylva Mareike Schäfer; Stefan Kabisch; Marta Csanalosi; Bettina Schuppelius; Margrit Kemper; Mariya Markova; Nina Marie Tosca Meyer; Olga Pivovarova-Ramich; Farnaz Keyhani-Nejad; Sascha Rohn; Andreas F H Pfeiffer

doi:10.1016/j.clnu.2023.02.011

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

Clin Nutr. 2023 Apr;42(4):467-476. doi: 10.1016/j.clnu.2023.02.011. Epub 2023 Feb 21.

Affiliations

¹ Department of Endocrinology, Diabetes and Nutrition, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
² Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; Institute of Nutritional Science, Justus-Liebig University of Giessen, Giessen, Germany.
³ Department of Endocrinology, Diabetes and Nutrition, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; German Center for Diabetes Research (Deutsches Zentrum Für Diabetesforschung e.V.), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
⁴ Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
⁵ Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; German Center for Diabetes Research (Deutsches Zentrum Für Diabetesforschung e.V.), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
⁶ Department of Endocrinology, Diabetes and Nutrition, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany; German Center for Diabetes Research (Deutsches Zentrum Für Diabetesforschung e.V.), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany; Reseach Group Molecular Nutritional Medicine, Dept. of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbrücke, 14558, Nuthetal, Germany.
⁷ Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146, Hamburg, Germany; Institute of Food Technology and Food Chemistry, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355, Berlin, Germany.
⁸ Department of Endocrinology, Diabetes and Nutrition, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany; German Center for Diabetes Research (Deutsches Zentrum Für Diabetesforschung e.V.), Ingolstädter Landstraße 1, 85764, Neuherberg, Germany. Electronic address: andreas.pfeiffer@charite.de.

PMID: 36857956
DOI: 10.1016/j.clnu.2023.02.011

Abstract

Aims: Amino acids powerfully release glucagon but their contribution to postprandial hyperglucagonemia in type 2 diabetes remains unclear. Exogenously applied GIP stimulates, while GLP-1 inhibits, 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.

Keywords: Alpha-cell dysfunction; GIP; GLP-1; Glucagon; Isomaltulose; Protein intake.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blood Glucose / metabolism
Caseins
Diabetes Mellitus, Type 2* / metabolism
Glucagon
Glucagon-Like Peptide 1 / metabolism
Humans
Incretins*
Insulin
Meals
Obesity
Sucrose
Sugars

Substances

Incretins
Glucagon
Sugars
Caseins
Glucagon-Like Peptide 1
Insulin
Sucrose
Blood Glucose

Associated data

ClinicalTrials.gov/NCT04564391
ClinicalTrials.gov/NCT03806920
ClinicalTrials.gov/NCT02219295