Pancreatic β Cell Dedifferentiation in Diabetes and Redifferentiation Following Insulin Therapy

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blood Glucose / drug effects
  • Cell Dedifferentiation / drug effects*
  • Cell Differentiation / drug effects
  • Diabetes Mellitus / drug therapy*
  • Disease Models, Animal
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology*
  • Insulin-Secreting Cells / drug effects*
  • Mice
  • Nerve Tissue Proteins / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse