Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes.

Autor: Hill TG; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK., Gao R; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK., Benrick A; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden., Kothegala L; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden.; Department of Developmental Biology and Genetics (DBG), Indian Institute of Science (IISc), Bengaluru, India., Rorsman N; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK., Santos C; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden., Acreman S; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden., Briant LJ; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK., Dou H; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden., Gandasi NR; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden.; Department of Developmental Biology and Genetics (DBG), Indian Institute of Science (IISc), Bengaluru, India., Guida C; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK., Haythorne E; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK., Wallace M; Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford, UK.; The Royal Veterinary College, Hatfield, Hertfordshire, UK., Knudsen JG; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.; Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Miranda C; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden., Tolö J; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden., Clark A; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK., Davison L; Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford, UK.; The Royal Veterinary College, Hatfield, Hertfordshire, UK., Størling J; Steno Diabetes Center Copenhagen, Translational Type 1 Diabetes Research, Herlev, Denmark., Tarasov A; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.; Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK., Ashcroft FM; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK., Rorsman P; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. patrik.rorsman@drl.ox.ac.uk.; Metabolic Research Unit, Institute of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden. patrik.rorsman@drl.ox.ac.uk.; Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK. patrik.rorsman@drl.ox.ac.uk.; Oxford National Institute for Health Research, Biomedical Research Centre, Churchill Hospital, Oxford, UK. patrik.rorsman@drl.ox.ac.uk., Zhang Q; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. quan.zhang@ocdem.ox.ac.uk.; Center for Neuroscience and Cell Biology (CNC), Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal. quan.zhang@ocdem.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2024 Sep 23. Date of Electronic Publication: 2024 Sep 23.
DOI: 10.1038/s42255-024-01139-z
Abstrakt: Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion 1 . In healthy people, a fall in plasma glucose stimulates glucagon release and thereby increases counter-regulatory hepatic glucose production. This response is absent in many patients with type-1 diabetes (T1D) 2 , which predisposes to severe hypoglycaemia that may be fatal and accounts for up to 10% of the mortality in patients with T1D 3 . In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists 4-7 but both the underlying cellular mechanism and whether it can be extended to humans remain unestablished. Here, we show that glucagon secretion is not stimulated by low glucose in isolated human islets from donors with T1D, a defect recapitulated in non-obese diabetic mice with T1D. This occurs because of hypersecretion of somatostatin, leading to aberrant paracrine inhibition of glucagon secretion. Normally, K ATP channel-dependent hyperpolarization of β-cells at low glucose extends into the δ-cells through gap junctions, culminating in suppression of action potential firing and inhibition of somatostatin secretion. This 'electric brake' is lost following autoimmune destruction of the β-cells, resulting in impaired counter-regulation. This scenario accounts for the clinical observation that residual β-cell function correlates with reduced hypoglycaemia risk 8 .
(© 2024. The Author(s).)
Databáze: MEDLINE
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