RNA-Seq Analysis of Islets to Characterise the Dedifferentiation in Type 2 Diabetes Model Mice db/db



Type 2 diabetes (T2D) is a global health issue and dedifferentiation plays underlying causes in the pathophysiology of T2D; however, there is a lack of understanding in the mechanism. Dedifferentiation results from the loss of function of pancreatic β-cells alongside a reduction in essential transcription factors under various physiological stressors. Our study aimed to establish db/db as an animal model for dedifferentiation by using RNA sequencing to compare the gene expression profile in islets isolated from wild-type, db/+ and db/db mice, and qPCR was performed to validate those significant genes. A reduction in both insulin secretion and the expression of Ins1, Ins2, Glut2, Pdx1 and MafA was indicative of dedifferentiation in db/db islets. A comparison of the db/+ and the wild-type islets indicated a reduction in insulin secretion perhaps related to the decreased Mt1. A significant reduction in both Rn45s and Mir6236 was identified in db/+ compared to wild-type islets, which may be indicative of pre-diabetic state. A further significant reduction in RasGRF1, Igf1R and Htt was also identified in dedifferentiated db/db islets. Molecular characterisation of the db/db islets was performed via Ingenuity analysis which identified highly significant genes that may represent new molecular markers of dedifferentiation.


Db/db islets β-cell dedifferentiation Network analysis 



Mouse insulinoma 6


Vitamin D receptor


Insulin 1


Insulin 2


Glucose transporter 2


Pancreatic and duodenal homebox1


Paired Box 6






V-Maf avian musculoaponeurotic fibrosarcoma oncogene homologue


β-cell dedifferentiation


Type 2 diabetes

−/− mice

Wild-type mice

db/− mice

Heterozygous mice

db/db mice

Homozygous mice


Vitamin D binding protein


Aldehyde dehydrogenase


Thyroxin-binding globulin


MicroRNA 6236


Insulin receptor substrate 1


Solute carrier family 2 (facilitated glucose transporter)


Signal transducer and activator of transcription


Free fatty acid receptor


Insulin-like growth factor 1 receptor


Protein kinase AMP-activated non-catalytic beta-2




Neuronal PAS domain protein 4


Ras protein-specific guanine nucleotide releasing factor 1


Huntington gene


Peroxisome proliferator-activated receptor


Fos-like antigen 1


Gastric inhibitory polypeptide receptor


Nuclear receptor subfamily 4






Urocortin III


Protein phosphatase 1


Prime phosphoadenosine 5 prime phosphosulfate synthase 2


Gnas complex locus


Endoplasmic reticulum oxidorectin 1-like beta



We also thank the support of Diabetes Research (WA). Thanks to Dr. Angela Abraham and Leah Simmons for their suggestions.

Authors’ Contributions

ANJ wrote the manuscript, all the laboratory works and part of the bioinformatic analysis; RR performed the bioinformatics analysis and FXJ supervised this work.

Compliance with Ethical Standards

The Animal Resource Centre Ethics Committee, Murdoch University approved the use of mice for islet purification of wild-type, db/+ and db/db.

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Harry Perkins Institute of Medical Research, Centre for Medical ResearchUniversity of Western AustraliaNedlandsAustralia
  2. 2.School of Medicine And PharmacologyUniversity of Western AustraliaCarwleyAustralia
  3. 3.Islet Cell Development ProgramHarry Perkins Institute of Medical ResearchPerth WesternAustralia

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