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Functional architecture of pancreatic islets identifies a population of first responder cells that drive the first-phase calcium response.

ABSTRACT: Insulin-secreting β-cells are functionally heterogeneous. Whether there exist cells driving the first-phase calcium response in individual islets, has not been examined. We examine "first responder" cells, defined by the earliest [Ca2+] response during first-phase [Ca2+] elevation, distinct from previously identified "hub" and "leader" cells. We used islets isolated from Mip-CreER; Rosa-Stop-Lox-Stop-GCamP6s mice (β-GCamP6s) that show β-cell-specific GCamP6s expression following tamoxifen-induced CreER-mediated recombination. First responder cells showed characteristics of high membrane excitability and lower electrical coupling to their neighbors. The first-phase response time of β-cells in the islet was spatially organized, dependent on the cell's distance to the first responder cell, and consistent over time up to approximately 24 h. When first responder cells were laser ablated, the first-phase [Ca2+] was slowed down, diminished, and discoordinated compared to random cell ablation. Cells that were next earliest to respond often took over the role of the first responder upon ablation. In summary, we discover and characterize a distinct first responder β-cell state, critical for the islet first-phase response to glucose.

SUBMITTER: Kravets V

PROVIDER: S-EPMC9506623 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Functional architecture of pancreatic islets identifies a population of first responder cells that drive the first-phase calcium response.

Kravets Vira V Dwulet JaeAnn M JM Schleicher Wolfgang E WE Hodson David J DJ Davis Anna M AM Pyle Laura L Piscopio Robert A RA Sticco-Ivins Maura M Benninger Richard K P RKP

PLoS biology 20220913 9

Insulin-secreting β-cells are functionally heterogeneous. Whether there exist cells driving the first-phase calcium response in individual islets, has not been examined. We examine "first responder" cells, defined by the earliest [Ca2+] response during first-phase [Ca2+] elevation, distinct from previously identified "hub" and "leader" cells. We used islets isolated from Mip-CreER; Rosa-Stop-Lox-Stop-GCamP6s mice (β-GCamP6s) that show β-cell-specific GCamP6s expression following tamoxifen-induce ...[more]

PMID: 36099294

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Project description:Lorcaserin is a serotonergic agonist specific to the 5-hydroxytryptamine 2c receptor (5-HT2CR) that is FDA approved for the long-term management of obesity with or without at least one weight-related comorbidity. Lorcaserin can restrain patients' appetite and improve insulin sensitivity and hyperinsulinemia mainly through activating 5-HT2CR in the hypothalamus. It is known that the mCPP, a kind of 5-HT2CR agonist, decreases plasma insulin concentration in mice and previous research in our laboratory found that mCPP inhibited glucose-stimulated insulin secretion (GSIS) by activating 5-HT2CR on the β cells. However, the effect of lorcaserin on GSIS of pancreatic β cell has not been studied so far. The present study found that 5-HT2CR was expressed in both mouse pancreatic β cells and β-cell-derived MIN6 cells. Dose-dependent activation of 5-HT2CR by lorcaserin suppressed GSIS and SB242084 or knockdown of 5-HT2CR abolished lorcaserin's effect in vitro. Additionally, lorcaserin also suppressed GSIS in high-fat diet (HFD)-fed mice in dose-dependent manner. Lorcaserin did not change insulin synthesis ATP content, but lorcaserin decrease cytosolic free calcium level [(Ca2+)i] in MIN6 cells stimulated with glucose and also inhibit insulin secretion and (Ca2+)i in MIN6 treated with potassium chloride. Furthermore, stimulation with the L-type channel agonist, Bay K8644 did not restore GSIS in MIN6 exposed to lorcaserin. Lorcaserin inhibits the cAMP generation of MIN6 cells and pretreatment with the Gα i/o inhibitor pertussis toxin (PTX), abolished lorcaserin-induced suppression of GSIS in β cells, while membrane-permeable cAMP analogue db-cAMP had same effect as PTX. These date indicated lorcaserin coupled to PTX-sensitive Gα i/o proteins in β cells reduced intracellular cAMP level and Ca2+ influx, thereby causing GSIS dysfunction of β cell. These results highlight a novel signaling mechanism of lorcaserin and provide valuable insights into the further investigation of 5-HT2CR functions in β-cell biology and it also provides guidance for the clinical application of lorcaserin.

Dataset Information

Functional architecture of pancreatic islets identifies a population of first responder cells that drive the first-phase calcium response.

Publications

Functional architecture of pancreatic islets identifies a population of first responder cells that drive the first-phase calcium response.

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