Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion

Iwona Szczerbinska*, Annamaria Tessitore, Lena Kristina Hansson, Asmita Agrawal, Alejandro Ragel Lopez, Marianne Helenius, Andrzej R. Malinowski, Barak Gilboa, Maxwell A. Ruby, Ramneek Gupta, Carina Ämmälä

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

13 Downloads (Pure)

Abstract

Type 2 diabetes (T2D) is a chronic metabolic disorder affecting almost half a billion people worldwide. Impaired function of pancreatic β-cells is both a hallmark of T2D and an underlying factor in the pathophysiology of the disease. Understanding the cellular mechanisms regulating appropriate insulin secretion has been of long-standing interest in the scientific and clinical communities. To identify novel genes regulating insulin secretion we developed a robust arrayed siRNA screen measuring basal, glucose-stimulated, and augmented insulin secretion by EndoC-βH1 cells, a human β-cell line, in a 384-well plate format. We screened 521 candidate genes selected by text mining for relevance to T2D biology and identified 23 positive and 68 negative regulators of insulin secretion. Among these, we validated ghrelin receptor (GHSR), and two genes implicated in endoplasmic reticulum stress, ATF4 and HSPA5. Thus, we have demonstrated the feasibility of using EndoC-βH1 cells for large-scale siRNA screening to identify candidate genes regulating β-cell insulin secretion as potential novel drug targets. Furthermore, this screening format can be adapted to other disease-relevant functional endpoints to enable large-scale screening for targets regulating cellular mechanisms contributing to the progressive loss of functional β-cell mass occurring in T2D.
Original languageEnglish
Article number103
JournalBiomedicines
Volume10
Issue number1
Number of pages13
ISSN2227-9059
DOIs
Publication statusPublished - 2022

Keywords

  • siRNA screen
  • T2D
  • β-cell
  • EndoC-βH1
  • EndoC-βH5
  • Text mining
  • Glucose-stimulated insulin secretion
  • GSIS
  • Large-scale

Fingerprint

Dive into the research topics of 'Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion'. Together they form a unique fingerprint.

Cite this