MicroRNA-7a regulates pancreatic β cell function
Mathieu Latreille, Jean Hausser, Ina Stützer, Quan Zhang, Benoit Hastoy, Sofia Gargani, Julie Kerr-Conte, Francois Pattou, Mihaela Zavolan, Jonathan L.S. Esguerra, Lena Eliasson, Thomas Rülicke, Patrik Rorsman, Markus Stoffel
Mathieu Latreille, Jean Hausser, Ina Stützer, Quan Zhang, Benoit Hastoy, Sofia Gargani, Julie Kerr-Conte, Francois Pattou, Mihaela Zavolan, Jonathan L.S. Esguerra, Lena Eliasson, Thomas Rülicke, Patrik Rorsman, Markus Stoffel
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Research Article Endocrinology

MicroRNA-7a regulates pancreatic β cell function

Abstract

Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic β cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of β cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in β cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates β cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in β cells developed diabetes due to impaired insulin secretion and β cell dedifferentiation. Interestingly, perturbation of miR-7a expression in β cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine β cell mass. Furthermore, we found that miR-7a levels are decreased in obese/diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated β cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic β cells and support a role for miR-7 in the adaptation of pancreatic β cell function in obesity and type 2 diabetes.

Authors

Mathieu Latreille, Jean Hausser, Ina Stützer, Quan Zhang, Benoit Hastoy, Sofia Gargani, Julie Kerr-Conte, Francois Pattou, Mihaela Zavolan, Jonathan L.S. Esguerra, Lena Eliasson, Thomas Rülicke, Patrik Rorsman, Markus Stoffel

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Figure 2

miR-7a controls exocytosis in primary pancreatic β cells.

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miR-7a controls exocytosis in primary pancreatic β cells. (A and B) Calc...
(A and B) Calcium responses in (A) control (Ad-GFP) and miR-7a–overexpressing (Ad–miR-7a) and (B) control (LNA-C) and miR-7a–inhibited (LNA-7a) β cells under basal conditions and after addition of 20 mM glucose (20G) or 35 mM KCl (35K). Traces are representative of 40 (Ad-GFP), 22 (Ad–miR-7a), 14 (LNA-C), or 16 (LNA-7a) different cells from 3 different animals and expressed as ΔF/F0 (i.e., change relative to basal fluorescence [dashed horizontal lines]). (C and E) Exocytosis, monitored as increases in membrane capacitance, in (C) miR-7a–overexpressing and (E) miR-7a–inhibited β cells. Exocytosis was elicited by progressively longer (10–500 ms) depolarization from –70 to 0 mV (shown above traces). For clarity, only responses to 50-, 100-, and 200-ms depolarizations are shown. (D and F) Relationship between pulse duration and exocytosis (quantification of results in C and E, respectively). n = 14 (Ad–miR-7a2); 16 (Ad-GFP); 14–16 (LNA-7a and LNA-C). (G) As in F, but experiments were performed on human β cells (n = 18–20). (H and I) Docked granule density in (H) miR-7a–overexpressing and (I) miR-7a–inhibited cells. Data are from 15–23 cells obtained from 2 (H) or 3 (I) mice after a 15-minute incubation with 1 or 20 mM glucose. All data are mean ± SEM. *P < 0.05; **P < 0.01.