Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for β Cell Adaptation and Glucose Homeostasis

Publication date: 28 March 2017
Source:Cell Reports, Volume 18, Issue 13
Author(s): Shuyang Traub, Daniel T. Meier, Friederike Schulze, Erez Dror, Thierry M. Nordmann, Nicole Goetz, Norina Koch, Elise Dalmas, Marc Stawiski, Valmir Makshana, Fabrizio Thorel, Pedro L. Herrera, Marianne Böni-Schnetzler, Marc Y. Donath
Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes.

Graphical abstract

Teaser

Pancreatic α cells may process proglucagon to glucagon or GLP-1. Traub et al. find that α cell-derived GLP-1 is necessary for glucose homeostasis during aging and metabolic stress. Deficiency of α cell-derived glucagon-related peptides can be compensated by DPP-4 inhibition.


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