Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes
Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion<sup>1</sup>. 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)<sup>2</sup>, which predisposes to severe hypoglycaemia that may be fatal and accounts for up to 10% of the mortality in patients with T1D<sup>3</sup>. In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists<sup>4-7</sup> 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<sub>ATP</sub> 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<sup>8</sup>.
Authors
- Nils J. G. Rorsman
- Caroline Miranda (ORCID: https://orcid.org/0000-0002-4649-2093)
- Thomas G. Hill (ORCID: https://orcid.org/0000-0002-4637-3879)
- Anne M. Clark (ORCID: https://orcid.org/0009-0009-8195-8280)
- Cristiano Santos (ORCID: https://orcid.org/0000-0002-9972-5583)
- Lakshmi Kothegala (ORCID: https://orcid.org/0000-0002-6938-620X)
- Elizabeth Haythorne (ORCID: https://orcid.org/0000-0003-3097-9240)
- Anna Benrick (ORCID: https://orcid.org/0000-0003-4616-6789)
- Quan Zhang (ORCID: https://orcid.org/0000-0002-3626-4855)
- Claudia Guida (ORCID: https://orcid.org/0000-0001-9475-1064)
- Lucy J. Davison (ORCID: https://orcid.org/0000-0002-1920-0817)
- Andrei I. Tarasov (ORCID: https://orcid.org/0000-0002-8883-176X)
- Samuel Acreman (ORCID: https://orcid.org/0000-0001-5117-4447)
- Rui Gao (ORCID: https://orcid.org/0000-0002-0845-1370)
- Nikhil R. Gandasi (ORCID: https://orcid.org/0000-0001-9400-6494)
- Joachim Størling (ORCID: https://orcid.org/0000-0002-7529-4264)
- Frances M. Ashcroft (ORCID: https://orcid.org/0000-0002-6970-1767)
- Jakob G. Knudsen (ORCID: https://orcid.org/0000-0001-7237-8457)
- Johan Tolö (ORCID: https://orcid.org/0000-0001-9648-4721)
- Linford J.B. Briant (ORCID: https://orcid.org/0000-0003-3619-3177)
- Marsha D. Wallace
- Patrik Rorsman (ORCID: https://orcid.org/0000-0001-7578-0767)
- Haiqiang Dou (ORCID: https://orcid.org/0000-0002-1551-4114)
Institutions
- University of Copenhagen (DK)
- Royal Veterinary College (GB)
- Steno Diabetes Centers (DK)
- University of Ulster (GB)
- Churchill Hospital (GB)
- National Institute for Health and Care Research (GB)
- University of Oxford (GB)
- Oxford Centre for Diabetes, Endocrinology and Metabolism (GB)
- Indian Institute of Science Bangalore (IN)
- University of Coimbra (PT)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2024-09-23
- DOI
- https://doi.org/10.1038/s42255-024-01139-z
- Citations
- 24
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 13.75
Funders
- Wellcome
- Leona M. and Harry B. Helmsley Charitable Trust
- UK Research and Innovation
- Diabetes UK
- Novo Nordisk
- Vetenskapsrådet
- Medical Research Council