GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion.

Autor: Gandasi NR; Metabolic Physiology Unit, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.; Cell Metabolism Lab (GA-08), Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, India., Gao R; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Kothegala L; Metabolic Physiology Unit, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden., Pearce A; Department of Pharmacology, University of Cambridge, Cambridge, UK., Santos C; Metabolic Physiology Unit, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden., Acreman S; Metabolic Physiology Unit, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Basco D; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Benrick A; Metabolic Physiology Unit, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden., Chibalina MV; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Clark A; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Guida C; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Harris M; Department of Pharmacology, University of Cambridge, Cambridge, UK., Johnson PRV; Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, UK.; Biomedical Research Centre, Oxford National Institute for Health Research, Churchill Hospital, Oxford, UK., Knudsen JG; Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Ma J; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Miranda C; Metabolic Physiology Unit, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden.; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Shigeto M; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Tarasov AI; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.; School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK., Yeung HY; Department of Pharmacology, University of Cambridge, Cambridge, UK., Thorens B; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Asterholm IW; Metabolic Physiology Unit, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden., Zhang Q; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Ramracheya R; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK., Ladds G; Department of Pharmacology, University of Cambridge, Cambridge, UK., Rorsman P; Metabolic Physiology Unit, Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg, Sweden. patrik.rorsman@drl.ox.ac.uk.; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK. patrik.rorsman@drl.ox.ac.uk.; Biomedical Research Centre, Oxford National Institute for Health Research, Churchill Hospital, Oxford, UK. patrik.rorsman@drl.ox.ac.uk.; School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK. patrik.rorsman@drl.ox.ac.uk.
Jazyk: angličtina
Zdroj: Diabetologia [Diabetologia] 2024 Mar; Vol. 67 (3), pp. 528-546. Date of Electronic Publication: 2023 Dec 21.
DOI: 10.1007/s00125-023-06060-w
Abstrakt: Aims/hypothesis: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes.
Methods: We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca 2+ and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36).
Results: GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC 50 of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by β-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca 2+ entry via voltage-gated Ca 2+ channels sensitive to ω-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content.
Conclusions/interpretation: We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action.
(© 2023. The Author(s).)
Databáze: MEDLINE
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