Heterogeneity in the coordination of delta cells with beta cells is driven by both paracrine signals and low- density Cx36 gap junctions

• 成果类型: Article
• 署名作者: Pourhosseinzadeh, Mohammad S.; Huang, Jessica L.; Shin, Donghan; Hart, Ryan G.; Framroze, Luhaiza Y.; Guillen, Jaresley, V; Sanchez, Joel; Tirado, Ramir, V; Unanwa, Kelechi; Huising, Mark O.
• 署名单位: University of California System; University of California Davis; University of California System; University of California Davis
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9851
• DOI: 10.1073/pnas.2504151122
• 发表日期: 2025-09-23
• 关键词: antagonism improves glucagon; insulin-secretion; somatostatin release; islet; glucose; oscillations; alpha; ca2+; hypoglycemia; responses

摘要

Insulin potently decreases blood glucose; thus, tight control is required to prevent excessive insulin release and hypoglycemia. Central to this inhibition is somatostatin released from delta cells that are clustered with beta cells in pancreatic islets. This communication is of interest because the loss of functional beta cells in diabetes leads to uncontrolled delta cell activity that disrupts islet paracrine crosstalk. While it is established that insulin and somatostatin secretion are coordinated, the specific mechanism is unsettled. We have previously demonstrated that beta cells release the hormone Urocortin 3 to stimulate delta cells at high glucose, demonstrating a paracrine negative feedback loop. Others have proposed direct coordination via gap junctions. To resolve this conundrum, we used the genetically encoded fluorescent Ca2+ reporter GCaMP6s to simultaneously record the activity of hundreds of beta and delta cells in low (2.8 mM) (LG) and high (16.8 mM) glucose (HG). Surprisingly, while many delta cells exhibit Ca2+ oscillations in HG that are coordinated with beta cells, the activation of these delta cells precedes beta cells and is more variable than beta cell responses. The selective delta cell knockout of connexin 36 confirmed the involvement of gap junctions. However, blockade of vesicle release with the Rho-GTPase inhibitor ML-141 completely removed coupling between beta and most delta cells in HG. Our data reveal considerable functional heterogeneity among delta cells, where most delta cells are entrained by oscillatory Ca2+ behaviors of beta cells that are mediated by a combination of paracrine signaling and low-density gap junction coupling.