Glucagon and beta-cell function changes before and after dietary weight loss-induced metabolic improvements in type 2 diabetes.

UNLABELLED: Hyperglucagonemia, beta-cell dysfunction and insulin resistance drive fasting and postprandial hyperglycemia in type 2 diabetes but their changes upon guideline recommended fasting induced weight loss > 10% remain unclear.

METHODS: Patients with type 2 diabetes treated without insulin underwent a 12-week very low-calorie formula diet (VLCD) aiming > 10 kg weight loss. Glucose, insulin, C-peptide and glucagon were determined fasting and after a standardized meal tolerance test (MTT) before, and after the diet without antidiabetic medication. We analyzed 35 participants achieving over 10 kg weight loss.

RESULTS: Fasting and postprandial glucose, insulin, and glucagon levels decreased significantly, accompanied by improved insulin sensitivity. Modeling of glucose, insulin and C-peptide during the MTT showed significant improvements in beta-cell glucose sensitivity (p = 0.001) and insulin clearance (p < 0.001), independent of glucagon levels. Fasting glucagon decreased significantly (p = 0.001) only in participants above median glucagon level. Changes in insulin sensitivity and beta-cell glucose sensitivity did not differ between groups. Postprandial insulin secretion decreased and potentiation factor increased only in the higher glucagon group, suggesting improved alpha- to beta-cell crosstalk. Fasting hyperglucagonemia was associated with male sex.

CONCLUSION: Weight loss > 10% improved insulin sensitivity and beta-cell function relative to baseline and normalized glucagon in participants with initial hyperglucagonemia.

Copyright © 2026 The Author(s). Published by Elsevier B.V. All rights reserved.

PMID: 42341884