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EBioMedicine. 2019 Dec;50:306-316. doi: 10.1016/j.ebiom.2019.11.018. Epub 2019 Nov 26.

Abnormal regulation of glucagon secretion by human islet alpha cells in the absence of beta cells.

Author information

1
Department of Nephropathy, The Second Hospital of Jilin University, 218 Ziquiang Street, Nanguan District, Changchun, Jilin 130041, China; Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
2
Clinical Islet Laboratory, University of Alberta, Edmonton, Alberta, Canada.
3
Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
4
Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA.
5
Department of Nephropathy, The Second Hospital of Jilin University, 218 Ziquiang Street, Nanguan District, Changchun, Jilin 130041, China. Electronic address: luoping@jlu.edu.cn.
6
Columbia Center for Translational Immunology, Department of Surgery, Columbia University Medical Center, 650 West 168th Street, BB1701, New York, NY 10032, USA. Electronic address: xc2248@cumc.columbia.edu.

Abstract

BACKGROUND:

The understanding of the regulation of glucagon secretion by pancreatic islet α-cells remains elusive. We aimed to develop an in vitro model for investigating the function of human α-cells under direct influence of glucose and other potential regulators.

METHODS:

Highly purified human α-cells from islets of deceased donors were re-aggregated in the presence or absence of β-cells in culture, evaluated for glucagon secretion under various treatment conditions, and compared to that of intact human islets and non-sorted islet cell aggregates.

FINDINGS:

The pure human α-cell aggregates maintained proper glucagon secretion capability at low concentrations of glucose, but failed to respond to changes in ambient glucose concentration. Addition of purified β-cells, but not the secreted factors from β-cells at low or high concentrations of glucose, partly restored the responsiveness of α-cells to glucose with regulated glucagon secretion. The EphA stimulator ephrinA5-fc failed to mimic the inhibitory effect of β-cells on glucagon secretion. Glibenclamide inhibited glucagon secretion from islets and the α- and β-mixed cell-aggregates, but not from the α-cell-only aggregates, at 2.0 mM glucose.

INTERPRETATION:

This study validated the use of isolated and then re-aggregated human islet cells for investigating α-cell function and paracrine regulation, and demonstrated the importance of cell-to-cell contact between α- and β-cells on glucagon secretion. Loss of proper β- and α-cell physical interaction in islets likely contributes to the dysregulated glucagon secretion in diabetic patients. Re-aggregated select combinations of human islet cells provide unique platforms for studying islet cell function and regulation.

KEYWORDS:

Cell-to-cell contact; Glibenclamide; Human alpha cells glucagon; Insulin inhibition; Paracrine regulation; Somatostatin

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