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.
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Mouse insulinoma 6
Vitamin D receptor
Glucose transporter 2
Pancreatic and duodenal homebox1
Paired Box 6
V-Maf avian musculoaponeurotic fibrosarcoma oncogene homologue
Type 2 diabetes
- −/− mice:
- db/− mice:
- db/db mice:
Vitamin D binding protein
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
Peroxisome proliferator-activated receptor
Fos-like antigen 1
Gastric inhibitory polypeptide receptor
Nuclear receptor subfamily 4
Protein phosphatase 1
Prime phosphoadenosine 5 prime phosphosulfate synthase 2
Gnas complex locus
Endoplasmic reticulum oxidorectin 1-like beta
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We also thank the support of Diabetes Research (WA). Thanks to Dr. Angela Abraham and Leah Simmons for their suggestions.
We thank Telethon and the Perth Child Research Fund and the University of Western Australia for their financial support.
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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Neelankal John, A., Ram, R. & Jiang, FX. RNA-Seq Analysis of Islets to Characterise the Dedifferentiation in Type 2 Diabetes Model Mice db/db. Endocr Pathol 29, 207–221 (2018). https://doi.org/10.1007/s12022-018-9523-x
- Db/db islets
- β-cell dedifferentiation
- Network analysis