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Albert Salehi

S Albert Salehi

Research team manager

Albert Salehi

GNAS gene is an important regulator of insulin secretory capacity in pancreatic β-cells

Author

  • Jalal Taneera
  • Sarah Dhaiban
  • Abdul Khader Mohammed
  • Debasmita Mukhopadhyay
  • Hayat Aljaibeji
  • Nabil Sulaiman
  • Joao Fadista
  • Albert Salehi

Summary, in English

BACKGROUND: Type 2 diabetes (T2D) is a complex polygenic disease with unclear mechanism. In an attempt to identify novel genes involved in β-cell function, we harness a bioinformatics method called Loss-of-function tool (LoFtool) gene score. METHODS: RNA-sequencing data from human islets were used to cross-reference genes within the 1st quartile of most intolerant LoFtool score with the 100th most expressed genes in human islets. Out of these genes, GNAS and EEF1A1 genes were selected for further investigation in diabetic islets, metabolic tissues along with their correlation with diabetic phenotypes. The influence of GNAS and EEF1A1 on insulin secretion and β-cell function were validated in INS-1 cells. RESULTS: A comparatively higher expression level of GNAS and EEF1A1 was observed in human islets than fat, liver and muscle tissues. Furthermore, diabetic islets displayed a reduced expression of GNAS, but not of EEF1A, compared to non-diabetic islets. The expression of GNAS was positively correlated with insulin secretory index, GLP1R, GIPR and inversely correlated with HbA1c. Diabetic human islets displayed a reduced cAMP generation and insulin secretory capacity in response to glucose. Moreover, siRNA silencing of GNAS in INS-1 cells reduced insulin secretion, insulin content, and cAMP production. In addition, the expression of Insulin, PDX1, and MAFA was significantly down-regulated in GNAS-silenced cells. However, cell viability and apoptosis rate were unaffected. CONCLUSION: LoFtool is a powerful tool to identify genes associated with pancreatic islets dysfunction. GNAS is a crucial gene for the β-cell insulin secretory capacity.

Department/s

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Islet Patophysiology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2019-10-05

Language

English

Publication/Series

Gene

Volume

715

Document type

Journal article

Publisher

Elsevier

Topic

  • Medical Genetics
  • Endocrinology and Diabetes

Keywords

  • GNAS
  • Human pancreatic islets
  • INS-1 cells
  • Insulin secretion
  • RNA sequencing
  • siRNA silencing

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology
  • Diabetes - Islet Patophysiology

ISBN/ISSN/Other

  • ISSN: 1879-0038