Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus.
Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting β-cells, we have generated mice with a β-c...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3246465?pdf=render |
| _version_ | 1811325284945756160 |
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| author | Martins Kalis Caroline Bolmeson Jonathan L S Esguerra Shashank Gupta Anna Edlund Neivis Tormo-Badia Dina Speidel Dan Holmberg Sofia Mayans Nelson K S Khoo Anna Wendt Lena Eliasson Corrado M Cilio |
| author_facet | Martins Kalis Caroline Bolmeson Jonathan L S Esguerra Shashank Gupta Anna Edlund Neivis Tormo-Badia Dina Speidel Dan Holmberg Sofia Mayans Nelson K S Khoo Anna Wendt Lena Eliasson Corrado M Cilio |
| author_sort | Martins Kalis |
| collection | DOAJ |
| description | Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting β-cells, we have generated mice with a β-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Δ/wt)), RIP-Cre(+/-)Dicer1(flox/flox) mice (RIP-Cre Dicer1(Δ/Δ)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased β-cell mass, reduced numbers of granules within the β-cells and reduced granule docking in adult RIP-Cre Dicer1(Δ/Δ) mice. β-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal β-cell development as 2-week old RIP-Cre Dicer1(Δ/Δ) mice showed ultrastructurally normal β-cells and intact insulin secretion. In conclusion, we have demonstrated that a β-cell specific disruption of the miRNAs network, although allowing for apparently normal β-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development. |
| first_indexed | 2024-04-13T14:31:36Z |
| format | Article |
| id | doaj.art-401b442bf0384c149901bab4723a6c12 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T14:31:36Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-401b442bf0384c149901bab4723a6c122022-12-22T02:43:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01612e2916610.1371/journal.pone.0029166Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus.Martins KalisCaroline BolmesonJonathan L S EsguerraShashank GuptaAnna EdlundNeivis Tormo-BadiaDina SpeidelDan HolmbergSofia MayansNelson K S KhooAnna WendtLena EliassonCorrado M CilioMature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting β-cells, we have generated mice with a β-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Δ/wt)), RIP-Cre(+/-)Dicer1(flox/flox) mice (RIP-Cre Dicer1(Δ/Δ)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased β-cell mass, reduced numbers of granules within the β-cells and reduced granule docking in adult RIP-Cre Dicer1(Δ/Δ) mice. β-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal β-cell development as 2-week old RIP-Cre Dicer1(Δ/Δ) mice showed ultrastructurally normal β-cells and intact insulin secretion. In conclusion, we have demonstrated that a β-cell specific disruption of the miRNAs network, although allowing for apparently normal β-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.http://europepmc.org/articles/PMC3246465?pdf=render |
| spellingShingle | Martins Kalis Caroline Bolmeson Jonathan L S Esguerra Shashank Gupta Anna Edlund Neivis Tormo-Badia Dina Speidel Dan Holmberg Sofia Mayans Nelson K S Khoo Anna Wendt Lena Eliasson Corrado M Cilio Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. PLoS ONE |
| title | Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. |
| title_full | Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. |
| title_fullStr | Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. |
| title_full_unstemmed | Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. |
| title_short | Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. |
| title_sort | beta cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus |
| url | http://europepmc.org/articles/PMC3246465?pdf=render |
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