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题名:Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion.
作者:LOCKE JM; DA SILVA XAVIER G; DAWE HR; RUTTER GA; HARRIES LW;
来源:Diabetologia. 2013 Oct 23. [ IF= 6.49 ] ]
URL :10.1007/s00125-013-3089-4
日期:20131104
摘要:AIMS/HYPOTHESIS: Type 2 diabetes is characterised by progressive beta cell
dysfunction, with changes in gene expression playing a crucial role in its
development. MicroRNAs (miRNAs) are post-transcriptional regulators of gene
expression and therefore alterations in miRNA levels may be involved in the
deterioration of beta cell function. METHODS: Global TaqMan arrays and individual
TaqMan assays were used to measure islet miRNA expression in discovery (n = 20)
and replication (n = 20) cohorts from individuals with and without type 2
diabetes. The role of specific dysregulated miRNAs in regulating insulin
secretion, content and apoptosis was subsequently investigated in primary rat
islets and INS-1 cells. Identification of miRNA targets was assessed using
luciferase assays and by measuring mRNA levels. RESULTS: In the discovery and
replication cohorts miR-187 expression was found to be significantly increased in
islets from individuals with type 2 diabetes compared with matched controls. An
inverse correlation between miR-187 levels and glucose-stimulated insulin
secretion (GSIS) was observed in islets from normoglycaemic donors. This
correlation paralleled findings in primary rat islets and INS-1 cells where
overexpression of miR-187 markedly decreased GSIS without affecting insulin
content or apoptotic index. Finally, the gene encoding homeodomain-interacting
protein kinase-3 (HIPK3), a known regulator of insulin secretion, was identified
as a direct target of miR-187 and displayed reduced expression in islets from
individuals with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our findings
suggest a role for miR-187 in the blunting of insulin secretion, potentially
involving regulation of HIPK3, which occurs during the pathogenesis of type 2
diabetes.

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