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

Thomas G Hill, Rui Gao, Anna Benrick, Lakshmi Kothegala, Nils Rorsman, Cristiano Santos, Samuel Acreman, Linford J Briant, Haiqiang Dou, Nikhil R Gandasi, Claudia Guida, Elizabeth Haythorne, Marsha Wallace, Jakob G Knudsen, Caroline Miranda, Johan Tolö, Anne Clark, Lucy Davison, Joachim Størling, Andrei TarasovFrances M Ashcroft, Patrik Rorsman, Quan Zhang

Abstract

Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion1. 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 T1D3. In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists4-7 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, KATP 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 risk8.

OriginalsprogEngelsk
TidsskriftNature metabolism
Vol/bind6
Udgave nummer11
Sider (fra-til)2070-2081
Antal sider12
ISSN2522-5812
DOI
StatusUdgivet - nov. 2024

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