Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes
- Beth Israel Deaconess Medical Center, United States
- University of Copenhagen, Denmark
- University of Gothenburg, Sweden
- University of Oxford, United Kingdom
- University of Alberta, Canada
- Oxford University Hospitals, United Kingdom
- Imperial College London, United Kingdom
Abstract
Insulin-induced hypoglycemia is a major barrier to the treatment of type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon - the body's principal blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro) and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor(s) that stimulates glucagon secretion remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide, a stable surrogate marker of AVP) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. Exogenous injection of AVP in vivo increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with T1D, hypoglycemia failed to increase both plasma copeptin and glucagon levels. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
Data availability
The study data are available as a supplementary file.
Article and author information
Author details
Ingrid Wernstedt Asterholm
Funding
Wellcome Trust (201325/Z/16/Z)
- Linford JB Briant
National Institutes of Health (F31 DK109575)
- Angela Kim
Diabetes UK ((Harry Keen Clinical Fellowship))
- Victoria Salem
Diabetesförbundet
- Patrik Rorsman
H2020 European Research Council (322620)
- Patrik Rorsman
Leona M. and Harry B. Helmsley Charitable Trust
- Patrik Rorsman
- Linford JB Briant
Vetenskapsrådet ((Swedish Research Council))
- Ingrid Wernstedt Asterholm
- Patrik Rorsman
Wellcome Trust (095531)
- Patrik Rorsman
Wellcome Trust (884655)
- Patrik Rorsman
Canadian Institutes of Health Research (148451)
- Patrick E Macdonald
Knut och Alice Wallenbergs Stiftelse
- Patrik Rorsman
National Institutes of Health (R01 DK075632,R01 DK089044,R01 DK111401,R01 DK096010,P30 DK046200,P30 DK057521)
- Bradford B Lowell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were conducted in strict accordance to regulations enforced by the research institution. Experiments conducted in the UK were done so in accordance with the UK Animals Scientific Procedures Act (1986) (P0A6474AE, P0FA927F8) and University of Oxford and Imperial College London ethical guidelines, and were approved by the local Ethical Committee. All animal care and experimental procedures conducted in the U.S.A. were approved by the Beth Israel Deaconess Medical Center Institutional Animal Care and Use Committee. Animal experiments conducted in Goteborg University were approved by a local Ethics Committee.
Human subjects: Ethics statements are given in the Methods as follows:Clamping studies were conducted at Gentofte Hospital, University of Copenhagen. The studies were approved by the Scientific-Ethical Committee of the Capital Region of Denmark (registration no. H-D-2009-0078) and was conducted according to the principles of the Declaration of Helsinki (fifth revision, Edinburgh, 2000).Human pancreatic islets were isolated, with ethical approval and clinical consent, at the Diabetes Research and Wellness Foundation Human Islet Isolation Facility (OCDEM, Oxford, UK) or Alberta Diabetes Institute IsletCore (University of Alberta, AB, Canada).
Reviewing Editor
- Weiping Han, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore
Publication history
- Preprint posted: July 9, 2021 (view preprint)
- Received: August 9, 2021
- Accepted: November 16, 2021
- Accepted Manuscript published: November 17, 2021 (version 1)
- Version of Record published: December 8, 2021 (version 2)
Copyright
© 2021, Kim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes
eLife 10:e72919.
https://doi.org/10.7554/eLife.72919
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