Pancreatic α-cells are functionally heterogeneous and sex-dependently regulated by neighboring endocrine cells
File(s)
Article in press
Author(s)
Huang, Ya-Chi
Rupnik, Marjan Slak
Rutter, Guy
Type
Journal Article
Abstract
Glucose and paracrine regulation of α-cells, particularly with respect to sex differences, is still poorly understood. Here, we imaged islets from GluCre:GCaMP6f mice in pancreatic slices, additionally loaded with a red Ca²⁺ indicator, to precisely interrogate Ca²⁺ dynamics in α-cells and the adjacent β- and δ-cells. During a glucose ramp (1.8-10.8 mM), α-cell Ca²⁺ oscillations were heterogeneous, antiphasic to β-cells, and inversely correlated with δ-cells. Selective inhibition of insulin receptor (InsR) and somatostatin receptor subtypes-2 and 3 (SSTR2/3) shifted the majority of α-cells to hyperactivity, delayed the decline of α-cell activity and onset of β-cell Ca²⁺ oscillations during the ramp. While female α-cells exhibited greater sensitivity to SSTR2/3 inhibition, male α-cells were more responsive to InsR blockade. Under complete SSTR2/3 and InsR antagonism, α-cells exhibited elevated Ca²⁺ oscillations but remained glucose-dependent. We conclude that intra-islet coordination fine-tunes α-cell glucose responses, with sex-specific paracrine signaling potentially shaping glucagon profiles in metabolic disease.
Date Issued
2026-06-23
Date Acceptance
2026-04-21
Citation
Communications Biology, 2026
ISSN
2399-3642
Publisher
Nature Portfolio
Journal / Book Title
Communications Biology
Copyright Statement
© The Atuthor(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1038/s42003-026-10163-6
Subjects
Huang
Y.-C.
Slak Rupnik
M.
Rutter
G.A. Pancreatic αcells are functionally heterogeneous and sex-dependently regulated by neighboring endocrine cells
Publication Status
Published online
Date Publish Online
2026-06-23