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Cell Metab. 2015 Aug 4;22(2):239-52. doi: 10.1016/j.cmet.2015.07.015.

Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes.

Author information

1
Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
2
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
3
Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
4
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
5
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
6
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
8
Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
9
Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
10
Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. Electronic address: rohit.kulkarni@joslin.harvard.edu.

Abstract

The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild complications (Medalist -C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist -C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.

PMID:
26244933
PMCID:
PMC4589213
DOI:
10.1016/j.cmet.2015.07.015
[Indexed for MEDLINE]
Free PMC Article

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