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Endocr Pathol. 2018 Sep;29(3):207-221. doi: 10.1007/s12022-018-9523-x.

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

Author information

1
Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia. njabraham78@gmail.com.
2
School of Medicine And Pharmacology, University of Western Australia, Carwley, WA, Australia. njabraham78@gmail.com.
3
Islet Cell Development Program, Harry Perkins Institute of Medical Research, Nedlands, Verdun St, Perth Western, 6009, Australia. njabraham78@gmail.com.
4
Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia.
5
School of Medicine And Pharmacology, University of Western Australia, Carwley, WA, Australia.
6
Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia. fang-xu.jiang@perkins.uwa.edu.au.
7
School of Medicine And Pharmacology, University of Western Australia, Carwley, WA, Australia. fang-xu.jiang@perkins.uwa.edu.au.

Abstract

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.

KEYWORDS:

Db/db islets; Network analysis; β-cell dedifferentiation

PMID:
29542001
DOI:
10.1007/s12022-018-9523-x
[Indexed for MEDLINE]

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