Abstract
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 Ca2+ 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.
Highlights
The number of people suffering from diabetes worldwide in 2017 was 451 million, with over one in four cases in China (121 million) (Cho et al, 2018)
It has been reported that the impaired glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells is a major factor responsible for glucose intolerance in Goto Kakizaki (GK) rats (Portha et al, 2012) in which the beta cell mass is reduced by 60% (Portha et al, 2001)
The results show that enriched pathways were significantly related to diabetes indicating that few specific amino acid changed (SAAC) genes are influenced by diabetes in GK rats
Summary
The number of people suffering from diabetes worldwide in 2017 was 451 million, with over one in four cases in China (121 million) (Cho et al, 2018). It has been reported that the impaired glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells is a major factor responsible for glucose intolerance in GK rats (Portha et al, 2012) in which the beta cell mass is reduced by 60% (Portha et al, 2001). The genetic mechanism of these features including the impairment in GSIS, a decrease in beta cell mass and a change in insulin action in GK rats remain unexplored. We integrated GK specific amino acid changed (SAAC) genes, the PASS region genes, and pancreatic differential expression genes to explore the genetic mechanism of the impairment in GSIS, decrease in beta cell mass, and the change in insulin action of GK rat
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