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dc.contributor.author | Vieira, Elaine |
---|---|
dc.contributor.author | Marroquí, Laura |
dc.contributor.author | Figueroa, Ana Lucia |
dc.contributor.author | Merino, Beatriz |
dc.contributor.author | Fernandez-Ruiz, Rebeca |
dc.contributor.author | Nadal, Angel |
dc.contributor.author | Burris, Thomas P. |
dc.contributor.author | Gomis, Ramon, 1946- |
dc.contributor.author | Quesada, Ivan |
dc.date | 2018-09-27T13:41:13Z |
dc.date | 2018-09-27T13:41:13Z |
dc.date | 2013-07-25 |
dc.date | 2018-09-27T13:41:13Z |
dc.identifier | 1932-6203 |
dc.identifier | 632142 |
dc.identifier | 23936124 |
dc.identifier.uri | http://hdl.handle.net/2445/124881 |
dc.description | Disruption of pancreatic clock genes impairs pancreatic beta-cell function, leading to the onset of diabetes. Despite the importance of pancreatic alpha-cells in the regulation of glucose homeostasis and in diabetes pathophysiology, nothing is known about the role of clock genes in these cells. Here, we identify the clock gene Rev-erb alpha as a new intracellular regulator of glucagon secretion. Rev-erb alpha down-regulation by siRNA (60-70% inhibition) in alphaTC1-9 cells inhibited low-glucose induced glucagon secretion (p<0.05) and led to a decrease in key genes of the exocytotic machinery. The Rev-erb alpha agonist GSK4112 increased glucagon secretion (1.6 fold) and intracellular calcium signals in alphaTC1-9 cells and mouse primary alpha-cells, whereas the Rev-erb alpha antagonist SR8278 produced the opposite effect. At 0.5 mM glucose, alphaTC1-9 cells exhibited intrinsic circadian Rev-erb alpha expression oscillations that were inhibited by 11 mM glucose. In mouse primary alpha-cells, glucose induced similar effects (p<0.001). High glucose inhibited key genes controlled by AMPK such as Nampt, Sirt1 and PGC-1 alpha in alphaTC1-9 cells (p<0.05). AMPK activation by metformin completely reversed the inhibitory effect of glucose on Nampt-Sirt1-PGC-1 alpha and Rev-erb alpha. Nampt inhibition decreased Sirt1, PGC-1 alpha and Rev-erb alpha mRNA expression (p<0.01) and glucagon release (p<0.05). These findings identify Rev-erb alpha as a new intracellular regulator of glucagon secretion via AMPK/Nampt/Sirt1 pathway. |
dc.format | 15 p. |
dc.format | application/pdf |
dc.language | eng |
dc.publisher | Public Library of Science (PLoS) |
dc.relation | Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0069939 |
dc.relation | PLoS One, 2013, vol. 8, num. 7, p. e69939 |
dc.relation | https://doi.org/10.1371/journal.pone.0069939 |
dc.rights | cc-by (c) Vieira, Elaine et al., 2013 |
dc.rights | http://creativecommons.org/licenses/by/3.0/es |
dc.rights | info:eu-repo/semantics/openAccess |
dc.subject | Glucosa |
dc.subject | Citoquines |
dc.subject | Genètica humana |
dc.subject | Pàncrees |
dc.subject | Glucose |
dc.subject | Cytokines |
dc.subject | Human genetics |
dc.subject | Pancreas |
dc.title | Involvement of the clock gene Rev-erb alpha in the regulation of glucagon secretion in pancreatic alpha-cells |
dc.type | info:eu-repo/semantics/article |
dc.type | info:eu-repo/semantics/publishedVersion |