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.
(Less)
- author
- Taneera, Jalal
LU
; Dhaiban, Sarah
; Mohammed, Abdul Khader
; Mukhopadhyay, Debasmita
; Aljaibeji, Hayat
; Sulaiman, Nabil
; Fadista, Joao
LU
and Salehi, Albert
LU
- organization
- publishing date
- 2019-10-05
- 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
-
- pmid:31374326
- scopus:85071702972
- 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
- 2024-06-12 00:41:53
@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}},
keywords = {{GNAS; Human pancreatic islets; INS-1 cells; Insulin secretion; RNA sequencing; siRNA silencing}},
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}},
}