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Cell Rep. 2017 Mar 28;18(13):3192-3203. doi: 10.1016/j.celrep.2017.03.005.

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

Author information

1
Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
2
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland; Centre facultaire du diabète, University of Geneva, 1211 Geneva, Switzerland.
3
Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. Electronic address: marc.donath@usb.ch.

Abstract

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.

KEYWORDS:

DPP-4; GLP-1; diabetes; glucagon; glucose homeostasis; insulin; islet; paracrine; sitagliptin; α cell; β cell

PMID:
28355570
DOI:
10.1016/j.celrep.2017.03.005
[Indexed for MEDLINE]
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