title: Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy.
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.
authors.affiliation: 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.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: York
authors.affiliation: 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.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.affiliation: 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.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Remedi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects; D054337:Cell Dedifferentiation / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009419:Nerve Tissue Proteins; C407737:Neurog3 protein, mouse
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