MicroRNA-7a regulates pancreatic β cell function
Mathieu Latreille, … , Patrik Rorsman, Markus Stoffel
Mathieu Latreille, … , Patrik Rorsman, Markus Stoffel
Published May 1, 2014
Citation Information: J Clin Invest. 2014;124(6):2722-2735. https://doi.org/10.1172/JCI73066.
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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 1

β cell–specific Mir7a2 loss-of-function mouse models display increased glucose tolerance due to improved secretory function.

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β cell–specific Mir7a2 loss-of-function mouse models display increased g...
(A) Relative miR-7a and miR-7b expression in pancreatic islets of Rip-Cre Mir7a1fl/fl, Rip-Cre Mir7a2fl/fl, and control mice at 8 weeks of age (n = 5–6). (B) Body weight of Rip-Cre Mir7a2fl/fl and control mice (n = 8–13). (C) Ad libitum–fed blood glucose levels in Rip-Cre Mir7a2fl/fl and control mice (n = 8–13). (D) IPGTT (3 g/kg) in overnight fasted Rip-Cre Mir7a2fl/fl and control mice at 10 weeks of age (n = 11). (E) In vivo insulin excursions in overnight fasted Rip-Cre Mir7a2fl/fl and controls at 15 weeks of age during an IPGTT (n = 6–11). (F) IPITT (0.75 U/kg) in 6-hour fasted Rip-Cre Mir7a2fl/fl and control mice at 11 weeks of age (n = 11). (G) Islet organization of Rip-Cre Mir7a2fl/fl and control pancreas at 10 weeks of age. Shown are staining for insulin and glucagon. Scale bar: 50 μm. (H) Pancreatic β cell mass in 25-week-old Rip-Cre Mir7a2fl/fl and control mice (n = 5–6). (I and J) Static insulin secretion performed with islets from 5- (I) and 35-week-old (J) Rip-Cre Mir7a2fl/fl and control mice (n = 5) at indicated glucose and KCl concentrations. All data are mean ± SEM except I and J (mean ± SD). *P < 0.05; **P < 0.01; ***P < 0.001.