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.
Traub, S., Meier, D. T., Schulze, F., Dror, E., Nordmann, T. M., Goetz, N., … Donath, M. Y. (2017). Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for β Cell Adaptation and Glucose Homeostasis. Cell Reports, 18(13), 3192–3203. https://doi.org/10.1016/j.celrep.2017.03.005