Format

Send to

Choose Destination
Cell Metab. 2014 May 6;19(5):872-82. doi: 10.1016/j.cmet.2014.03.010. Epub 2014 Apr 17.

Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy.

Author information

1
Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA; Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
2
Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
3
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA; Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
4
Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA; Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Electronic address: mremedi@wustl.edu.

Abstract

Diabetes is characterized by "glucotoxic" loss of pancreatic β cell function and insulin content, but underlying mechanisms remain unclear. A mouse model of insulin-secretory deficiency induced by β cell inexcitability (K(ATP) gain of function) demonstrates development of diabetes and reiterates the features of human neonatal diabetes. In the diabetic state, β cells lose their mature identity and dedifferentiate to neurogenin3-positive and insulin-negative cells. Lineage-tracing experiments show that dedifferentiated cells can subsequently redifferentiate to mature neurogenin3-negative, insulin-positive β cells after lowering of blood glucose by insulin therapy. We demonstrate here that β cell dedifferentiation, rather than apoptosis, is the main mechanism of loss of insulin-positive cells, and redifferentiation accounts for restoration of insulin content and antidiabetic drug responsivity in these animals. These results may help explain gradual decrease in β cell mass in long-standing diabetes and recovery of β cell function and drug responsivity in type 2 diabetic patients following insulin therapy, and they suggest an approach to rescuing "exhausted" β cells in diabetes.

PMID:
24746806
PMCID:
PMC4067979
DOI:
10.1016/j.cmet.2014.03.010
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center