ABSTRACT
Diabetes is associated with ß cell failure. But it remains unclear whether the latter results from reduced ß cell number or function. FoxO1 integrates ß cell proliferation with adaptive ß cell function. We interrogated the contribution of these two processes to ß cell dysfunction, using mice lacking FoxO1 in ß cells. FoxO1 ablation caused hyperglycemia with reduced ß cell mass following physiologic stress, such as multiparity and aging. Surprisingly, lineage-tracing experiments demonstrated that loss of ß cell mass was due to ß cell dedifferentiation, not death. Dedifferentiated ß cells reverted to progenitor-like cells expressing Neurogenin3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient ß cells adopted the α cell fate, resulting in hyperglucagonemia. Strikingly, we identify the same sequence of events as a feature of different models of murine diabetes. We propose that dedifferentiation trumps endocrine cell death in the natural history of ß cell failure and suggest that treatment of ß cell dysfunction should restore differentiation, rather than promoting ß cell replication.
Subject(s)
Cell Dedifferentiation , Diabetes Mellitus, Type 2/pathology , Insulin-Secreting Cells/pathology , Animals , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Forkhead Box Protein O1 , Forkhead Transcription Factors/metabolism , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Male , Mice , Pancreas/pathologyABSTRACT
Restoration of regulated insulin secretion is the ultimate goal of therapy for type 1 diabetes. Here, we show that, unexpectedly, somatic ablation of Foxo1 in Neurog3(+) enteroendocrine progenitor cells gives rise to gut insulin-positive (Ins(+)) cells that express markers of mature ß cells and secrete bioactive insulin as well as C-peptide in response to glucose and sulfonylureas. Lineage tracing experiments showed that gut Ins(+) cells arise cell autonomously from Foxo1-deficient cells. Inducible Foxo1 ablation in adult mice also resulted in the generation of gut Ins(+) cells. Following ablation by the ß-cell toxin streptozotocin, gut Ins(+) cells regenerate and produce insulin, reversing hyperglycemia in mice. The data indicate that Neurog3(+) enteroendocrine progenitors require active Foxo1 to prevent differentiation into Ins(+) cells. Foxo1 ablation in gut epithelium may provide an approach to restore insulin production in type 1 diabetes.
Subject(s)
Enteroendocrine Cells/metabolism , Forkhead Transcription Factors/physiology , Insulin/biosynthesis , Neuroendocrine Cells/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/biosynthesis , Basic Helix-Loop-Helix Transcription Factors/genetics , C-Peptide/biosynthesis , C-Peptide/metabolism , Cell Differentiation , Diabetes Mellitus, Experimental/metabolism , Enteroendocrine Cells/cytology , Forkhead Box Protein O1 , Forkhead Transcription Factors/deficiency , Forkhead Transcription Factors/genetics , Gastrointestinal Tract/cytology , Gastrointestinal Tract/metabolism , Glucose/pharmacology , Hyperglycemia/therapy , Insulin/genetics , Insulin/metabolism , Insulin Secretion , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/physiology , Mice , Mice, Transgenic , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Stem Cells/cytology , Streptozocin/pharmacology , Sulfonylurea Compounds/pharmacology , Wnt Signaling PathwayABSTRACT
The New York Stem Cell Foundation's "Fifth Annual Translational Stem Cell Research Conference" convened on October 12-13, 2010 at the Rockefeller University in New York City. The conference attracted over 400 scientists, patient advocates, and stem cell research supporters from 16 countries. In addition to poster and platform presentations, the conference featured panels entitled "Road to the Clinic" and "Regulatory Roadblocks."
