دورية أكاديمية
Legacy Effect of Foxo1 in Pancreatic Endocrine Progenitors on Adult β-Cell Mass and Function.
| العنوان: | Legacy Effect of Foxo1 in Pancreatic Endocrine Progenitors on Adult β-Cell Mass and Function. |
|---|---|
| المؤلفون: | Talchai SC; Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY Faculty of Science, King Mongkut's University of Technology Thonburi, Bangkok, Thailand., Accili D; Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY da230@columbia.edu. |
| المصدر: | Diabetes [Diabetes] 2015 Aug; Vol. 64 (8), pp. 2868-79. Date of Electronic Publication: 2015 Mar 17. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Diabetes Association Country of Publication: United States NLM ID: 0372763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1939-327X (Electronic) Linking ISSN: 00121797 NLM ISO Abbreviation: Diabetes Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Alexandria, VA : American Diabetes Association Original Publication: [New York, American Diabetes Association] |
| مواضيع طبية MeSH: | Forkhead Transcription Factors/*metabolism , Glucose Intolerance/*metabolism , Insulin-Secreting Cells/*metabolism , Islets of Langerhans/*metabolism, Animals ; Cell Size ; Forkhead Box Protein O1 ; Forkhead Transcription Factors/genetics ; Glucose Intolerance/genetics ; Insulin/metabolism ; Insulin-Secreting Cells/cytology ; Islets of Langerhans/cytology ; Mice ; Mice, Transgenic |
| مستخلص: | β-Cell dysfunction in diabetes results from abnormalities of insulin production, secretion, and cell number. These abnormalities may partly arise from altered developmental programming of β-cells. Foxo1 is important to maintain adult β-cells, but little is known about its role in pancreatic progenitor cells as determinants of future β-cell function. We addressed this question by generating an allelic series of somatic Foxo1 knockouts at different stages of pancreatic development in mice. Surprisingly, ablation of Foxo1 in pancreatic progenitors resulted in delayed appearance of Neurogenin3(+) progenitors and their persistence into adulthood as a self-replicating pool, causing a fourfold increase of β-cell mass. Similarly, Foxo1 ablation in endocrine progenitors increased their numbers, extended their survival, and expanded β-cell mass. In contrast, ablation of Foxo1 in terminally differentiated β-cells did not increase β-cell mass nor did it affect Neurogenin3 expression. Despite the increased β-cell mass, islets from mice lacking Foxo1 in pancreatic or endocrine progenitors responded poorly to glucose, resulting in glucose intolerance. We conclude that Foxo1 integrates cues that determine developmental timing, pool size, and functional features of endocrine progenitor cells, resulting in a legacy effect on adult β-cell mass and function. Our results illustrate how developmental programming predisposes to β-cell dysfunction in adults and raise questions on the desirability of increasing β-cell mass for therapeutic purposes in type 2 diabetes. (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.) |
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| معلومات مُعتمدة: | DK-63608 United States DK NIDDK NIH HHS; R01 DK064819 United States DK NIDDK NIH HHS; DK-64819 United States DK NIDDK NIH HHS; P30 DK026687 United States DK NIDDK NIH HHS; P30 DK063608 United States DK NIDDK NIH HHS |
| المشرفين على المادة: | 0 (Forkhead Box Protein O1) 0 (Forkhead Transcription Factors) 0 (Foxo1 protein, mouse) 0 (Insulin) |
| تواريخ الأحداث: | Date Created: 20150319 Date Completed: 20151009 Latest Revision: 20181113 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC4512230 |
| DOI: | 10.2337/db14-1696 |
| PMID: | 25784544 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1939-327X |
|---|---|
| DOI: | 10.2337/db14-1696 |