title: Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for β Cell Adaptation and Glucose Homeostasis.
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.
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Traub
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meier
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Friederike
authors.initials: F
authors.lastname: Schulze
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Erez
authors.initials: E
authors.lastname: Dror
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Thierry M
authors.initials: TM
authors.lastname: Nordmann
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Goetz
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Norina
authors.initials: N
authors.lastname: Koch
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Elise
authors.initials: E
authors.lastname: Dalmas
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Stawiski
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Valmir
authors.initials: V
authors.lastname: Makshana
authors.affiliation: 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.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.affiliation: 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.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: Endocrinology, Diabetes, and Metabolism, University Hospital Basel, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Böni-Schnetzler
authors.affiliation: 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.
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
mesh_terms: D000222:Adaptation, Physiological; D000375:Aging / Q000473:pathology; D000818:Animals; D059305:Diet, High-Fat; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000150:complications / Q000473:pathology; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000473:pathology; D043484:Proprotein Convertases / Q000378:metabolism; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D004167:Diphtheria Toxin; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D043484:Proprotein Convertases; D005947:Glucose
keywords: DPP-4; GLP-1; diabetes; glucagon; glucose homeostasis; insulin; islet; paracrine; sitagliptin; α cell; β cell