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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.

Integrative Analysis of Genome and Expression Profile Data Reveals the Genetic Mechanism of the Diabetic Pathogenesis in Goto Kakizaki (GK) Rats