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

Taneera, Jalal LU ; Dhaiban, Sarah ; Mohammed, Abdul Khader ; Mukhopadhyay, Debasmita ; Aljaibeji, Hayat ; Sulaiman, Nabil ; Fadista, Joao LU and Salehi, Albert LU (2019) In Gene 715.
Abstract

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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
GNAS, Human pancreatic islets, INS-1 cells, Insulin secretion, RNA sequencing, siRNA silencing
in
Gene
volume
715
article number
144028
publisher
Elsevier
external identifiers
  • scopus:85071702972
  • pmid:31374326
ISSN
1879-0038
DOI
10.1016/j.gene.2019.144028
language
English
LU publication?
yes
id
89ffa343-cca7-40b5-a760-a936561130ab
date added to LUP
2019-09-16 13:03:55
date last changed
2019-10-08 03:57:39
@article{89ffa343-cca7-40b5-a760-a936561130ab,
  abstract     = {<p>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.</p>},
  author       = {Taneera, Jalal and Dhaiban, Sarah and Mohammed, Abdul Khader and Mukhopadhyay, Debasmita and Aljaibeji, Hayat and Sulaiman, Nabil and Fadista, Joao and Salehi, Albert},
  issn         = {1879-0038},
  language     = {eng},
  month        = {10},
  publisher    = {Elsevier},
  series       = {Gene},
  title        = {GNAS gene is an important regulator of insulin secretory capacity in pancreatic β-cells},
  url          = {http://dx.doi.org/10.1016/j.gene.2019.144028},
  doi          = {10.1016/j.gene.2019.144028},
  volume       = {715},
  year         = {2019},
}