IGFBP7 is upregulated in islets from T2D donors and reduces insulin secretion

Efraim Westholm; Alexandros Karagiannopoulos; Nicole Kattner; Yara Al-Selwi; George Merces; James A M Shaw; Anna Wendt; Lena Eliasson

doi:10.1016/j.isci.2024.110767

IGFBP7 is upregulated in islets from T2D donors and reduces insulin secretion

iScience. 2024 Aug 20;27(9):110767. doi: 10.1016/j.isci.2024.110767. eCollection 2024 Sep 20.

Authors

Efraim Westholm^{1

2}, Alexandros Karagiannopoulos^{1

2}, Nicole Kattner³, Yara Al-Selwi³, George Merces⁴, James A M Shaw³, Anna Wendt^{1

2}, Lena Eliasson^{1

2}

Affiliations

¹ Islet Cell Exocytosis, Lund University Diabetes Centre (LUDC), Department of Clinical Sciences-Malmö, Lund University, Malmö, Sweden.
² Clinical Research Centre (CRC), Skåne University Hospital, Malmö, Sweden.
³ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
⁴ Image Analysis Unit, Newcastle University, Newcastle upon Tyne, UK.

Abstract

Intra-islet crosstalk has become a focus area to fully understand the regulation of insulin secretion and impaired β-cell function in type 2 diabetes (T2D). Here, we put forward evidence for insulin-like growth factor binding protein 7 (IGFBP7) as a potential protein involved in autocrine and paracrine β-cell regulation. We showed presence of IGFBP7 in granules of both human α- and β-cells and measured elevated gene expression as well as IGFBP7 protein in T2D. Insulin secretion was reduced in human islets, and the human β-cell line EndoC-βH1, after 72-h incubation with IGFBP7. Mechanistically reduced insulin secretion by IGFBP7 is attributed to reduced p21-activated kinase 1 (PAK1) protein, and decreased oxygen consumption and ATP-production. Knockdown of IGFBP7 in EndoC-βH1 cells verified reduced IGFBP7 levels in the medium, as well as improved insulin secretion. Finally, IGFBP7 knockdown in islets from T2D donors improved insulin secretion, making IGFBP7 a potential drug target in diabetes.

Keywords: Cell biology; Cellular physiology; Physiology.