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. 2020 Jul 6;9(7):1621.
doi: 10.3390/cells9071621.

miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1

Alessandro Matarese  1   2 , Jessica Gambardella  1   3 , Angela Lombardi  1   4 , Xujun Wang  1   5 , Gaetano Santulli  1   3   5
Affiliations

miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1

Alessandro Matarese et al. Cells. .

Abstract

Glucagon-like peptide-1 (GLP-1) has been shown to potentiate glucose-stimulated insulin secretion binding GLP-1 receptor on pancreatic β cells. β-arrestin 1 (βARR1) is known to regulate the desensitization of GLP-1 receptor. Mounting evidence indicates that microRNAs (miRNAs, miRs) are fundamental in the regulation of β cell function and insulin release. However, the regulation of GLP-1/βARR1 pathways by miRs has never been explored. Our hypothesis is that specific miRs can modulate the GLP-1/βARR1 axis in β cells. To test this hypothesis, we applied a bioinformatic approach to detect miRs that could target βARR1; we identified hsa-miR-7-5p (miR-7) and we validated the specific interaction of this miR with βARR1. Then, we verified that GLP-1 was indeed able to regulate the transcription of miR-7 and βARR1, and that miR-7 significantly regulated GLP-1-induced insulin release and cyclic AMP (cAMP) production in β cells. Taken together, our findings indicate, for the first time, that miR-7 plays a functional role in the regulation of GLP-1-mediated insulin release by targeting βARR1. These results have a decisive clinical impact given the importance of drugs modulating GLP-1 signaling in the treatment of patients with type 2 diabetes mellitus.

Keywords: cAMP; diabetes; epigenetics; glucose-stimulated insulin secretion (GSIS); miRNA-7; β-arrestin 1.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Identification of miR-7 as modulator of βARR1. (A) Complementary nucleotides between the target region of βARR1 3′-UTR (in yellow) and hsa-miR-7-5p (miR-7) are conserved across different species. Luciferase activity was measured 48 h after transfection, using the vector without βARR1 3′-UTR (empty vector), the vector containing the wild-type βARR1 3′-UTR, and the vector containing a mutated βARR1 3′-UTR (βARR1 MUT); (B) A non-targeting miR (scramble) has been employed as further control. Means ± S.E.M. are shown alongside actual values; * p < 0.05.
Figure 2
Figure 2
GLP-1 regulates miR-7 and βARR1 transcription in pancreatic β cells. Stimulation of INS-1 β cells with GLP-1 (100 nM) induces an upregulation of miR-7 (A); and a downregulation of βARR1 (B). Means ± S.E.M. are shown alongside actual values. * p < 0.05.
Figure 3
Figure 3
Mechanistic role of miR-7 in GLP-1-mediated insulin secretion. INS-1 cells treated with miR-7 mimic, inhibitor, or scramble (negative control) were stimulated for 2 h with GLP-1 (100 nM) or vehicle and insulin release was measured (A); No significant differences were observed in terms of insulin release in response to KCl (B) or insulin content (C). Means ± S.E.M. are shown alongside actual values. * p < 0.05 vs. miR-scramble.
Figure 4
Figure 4
Effects of miR-7 on GLP-1-mediated cAMP production. INS-1 cells treated with miR-7 mimic, inhibitor, or scramble (negative control) were stimulated for 2 h with GLP-1 (100 nM) or vehicle and cAMP was measured. Means ± S.E.M. are shown alongside actual values. Basal, vehicle + miR-scramble; * p < 0.05 vs. miR-scramble, # p < 0.05 vs. vehicle.
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