miR-204 Controls Glucagon-Like Peptide 1 Receptor Expression and Agonist Function.
Diabetes
; 67(2): 256-264, 2018 02.
Article
in En
| MEDLINE
| ID: mdl-29101219
ABSTRACT
Glucagon-like peptide 1 receptor (GLP1R) agonists are widely used to treat diabetes. However, their function is dependent on adequate GLP1R expression, which is downregulated in diabetes. GLP1R is highly expressed on pancreatic ß-cells, and activation by endogenous incretin or GLP1R agonists increases cAMP generation, which stimulates glucose-induced ß-cell insulin secretion and helps maintain glucose homeostasis. We now have discovered that the highly ß-cell-enriched microRNA, miR-204, directly targets the 3' UTR of GLP1R and thereby downregulates its expression in the ß-cell-derived rat INS-1 cell line and primary mouse and human islets. Furthermore, in vivo deletion of miR-204 promoted islet GLP1R expression and enhanced responsiveness to GLP1R agonists, resulting in improved glucose tolerance, cAMP production, and insulin secretion as well as protection against diabetes. Since we recently identified thioredoxin-interacting protein (TXNIP) as an upstream regulator of miR-204, we also assessed whether in vivo deletion of TXNIP could mimic that of miR-204. Indeed, it also enhanced islet GLP1R expression and GLP1R agonist-induced insulin secretion and glucose tolerance. Thus, the present studies show for the first time that GLP1R is under the control of a microRNA, miR-204, and uncover a previously unappreciated link between TXNIP and incretin action.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gene Expression Regulation
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MicroRNAs
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Diabetes Mellitus, Experimental
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Insulin-Secreting Cells
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Glucagon-Like Peptide-1 Receptor
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Diabetes
Year:
2018
Document type:
Article
Affiliation country:
Albania
Publication country:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA