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

ABSTRACT: Diabetes is characterized by "glucotoxic" loss of pancreatic ? cell function and insulin content, but underlying mechanisms remain unclear. A mouse model of insulin-secretory deficiency induced by ? cell inexcitability (K(ATP) gain of function) demonstrates development of diabetes and reiterates the features of human neonatal diabetes. In the diabetic state, ? 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 ? cells after lowering of blood glucose by insulin therapy. We demonstrate here that ? 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 ? cell mass in long-standing diabetes and recovery of ? cell function and drug responsivity in type 2 diabetic patients following insulin therapy, and they suggest an approach to rescuing "exhausted" ? cells in diabetes.

SUBMITTER: Wang Z 

PROVIDER: S-EPMC4067979 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature