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Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats
The Goto Kakizaki (GK) rats which can spontaneously develop type 2 diabetes (T2D), are generated by repeated inbreeding of Wistar rats with glucose intolerance. The glucose intolerance in GK rat is mainly attributed to the impairment in glucose-stimulated insulin secretion (GSIS). In addition, GK ra...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335273/ https://www.ncbi.nlm.nih.gov/pubmed/30687391 http://dx.doi.org/10.3389/fgene.2018.00724 |
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author | Meng, Yuhuan Cui, Ying Zhang, Wenlu Fu, Shuying Huang, Lizhen Dong, Hua Du, Hongli |
author_facet | Meng, Yuhuan Cui, Ying Zhang, Wenlu Fu, Shuying Huang, Lizhen Dong, Hua Du, Hongli |
author_sort | Meng, Yuhuan |
collection | PubMed |
description | The Goto Kakizaki (GK) rats which can spontaneously develop type 2 diabetes (T2D), are generated by repeated inbreeding of Wistar rats with glucose intolerance. The glucose intolerance in GK rat is mainly attributed to the impairment in glucose-stimulated insulin secretion (GSIS). In addition, GK rat display a decrease in beta cell mass, and a change in insulin action. However, the genetic mechanism of these features remain unclear. In the present study, we analyzed the population variants of GK rats and control Wistar rats by whole genome sequencing and identified 1,839 and 1,333 specific amino acid changed (SAAC) genes in GK and Wistar rats, respectively. We also detected the putative artificial selective sweeps (PASS) regions in GK rat which were enriched with GK fixed variants and were under selected in the initial diabetic-driven derivation by homogeneity test with the fixed and polymorphic sites between GK and Wistar populations. Finally, we integrated the SAAC genes, PASS region genes and differentially expressed genes in GK pancreatic beta cells to reveal the genetic mechanism of the impairment in GSIS, a decrease in beta cell mass, and a change in insulin action in GK rat. The results showed that Slc2a2 gene was related to impaired glucose transport and Adcy3, Cacna1f, Bmp4, Fam3b, and Ptprn2 genes were related to Ca(2+) channel dysfunction which may responsible for the impaired GSIS. The genes Hnf4g, Bmp4, and Bad were associated with beta cell development and may be responsible for a decrease in beta cell mass while genes Ide, Ppp1r3c, Hdac9, Ghsr, and Gckr may be responsible for the change in insulin action in GK rats. The overexpression or inhibition of Bmp4, Fam3b, Ptprn2, Ide, Hnf4g, and Bad has been reported to change the glucose tolerance in rodents. However, the genes Bmp4, Fam3b, and Ptprn2 were found to be associated with diabetes in GK rats for the first time in the present study. Our findings provide a comprehensive genetic map of the abnormalities in GK genome which will be helpful in understand the underlying genetic mechanism of pathogenesis of diabetes in GK rats. |
format | Online Article Text |
id | pubmed-6335273 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-63352732019-01-25 Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats Meng, Yuhuan Cui, Ying Zhang, Wenlu Fu, Shuying Huang, Lizhen Dong, Hua Du, Hongli Front Genet Genetics The Goto Kakizaki (GK) rats which can spontaneously develop type 2 diabetes (T2D), are generated by repeated inbreeding of Wistar rats with glucose intolerance. The glucose intolerance in GK rat is mainly attributed to the impairment in glucose-stimulated insulin secretion (GSIS). In addition, GK rat display a decrease in beta cell mass, and a change in insulin action. However, the genetic mechanism of these features remain unclear. In the present study, we analyzed the population variants of GK rats and control Wistar rats by whole genome sequencing and identified 1,839 and 1,333 specific amino acid changed (SAAC) genes in GK and Wistar rats, respectively. We also detected the putative artificial selective sweeps (PASS) regions in GK rat which were enriched with GK fixed variants and were under selected in the initial diabetic-driven derivation by homogeneity test with the fixed and polymorphic sites between GK and Wistar populations. Finally, we integrated the SAAC genes, PASS region genes and differentially expressed genes in GK pancreatic beta cells to reveal the genetic mechanism of the impairment in GSIS, a decrease in beta cell mass, and a change in insulin action in GK rat. The results showed that Slc2a2 gene was related to impaired glucose transport and Adcy3, Cacna1f, Bmp4, Fam3b, and Ptprn2 genes were related to Ca(2+) channel dysfunction which may responsible for the impaired GSIS. The genes Hnf4g, Bmp4, and Bad were associated with beta cell development and may be responsible for a decrease in beta cell mass while genes Ide, Ppp1r3c, Hdac9, Ghsr, and Gckr may be responsible for the change in insulin action in GK rats. The overexpression or inhibition of Bmp4, Fam3b, Ptprn2, Ide, Hnf4g, and Bad has been reported to change the glucose tolerance in rodents. However, the genes Bmp4, Fam3b, and Ptprn2 were found to be associated with diabetes in GK rats for the first time in the present study. Our findings provide a comprehensive genetic map of the abnormalities in GK genome which will be helpful in understand the underlying genetic mechanism of pathogenesis of diabetes in GK rats. Frontiers Media S.A. 2019-01-10 /pmc/articles/PMC6335273/ /pubmed/30687391 http://dx.doi.org/10.3389/fgene.2018.00724 Text en Copyright © 2019 Meng, Cui, Zhang, Fu, Huang, Dong and Du. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Meng, Yuhuan Cui, Ying Zhang, Wenlu Fu, Shuying Huang, Lizhen Dong, Hua Du, Hongli Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats |
title | Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats |
title_full | Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats |
title_fullStr | Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats |
title_full_unstemmed | Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats |
title_short | Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats |
title_sort | integrative analysis of genome and expression profile data reveals the genetic mechanism of the diabetic pathogenesis in goto kakizaki (gk) rats |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335273/ https://www.ncbi.nlm.nih.gov/pubmed/30687391 http://dx.doi.org/10.3389/fgene.2018.00724 |
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