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 6

miR-7a levels correlate with β cell secretory function in insulin resistant and diabetic mouse models.

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miR-7a levels correlate with β cell secretory function in insulin resist...
(A and B) Pancreatic islets of mouse models of β cell compensation. (A) Relative miR-7a expression of 24-week-old male mice maintained on chow or HFD and 22-week-old male ob/ob mice (n = 4–5). (B) Relative miR-7a expression in islets of BKS db/db and WT control mice at the indicated ages (n = 5). (C) Ad libitum–fed blood glucose levels in Tg7a2 and littermate WT mice (n = 12–14). (D) Serum insulin levels in Tg7a2 and control mice (n = 5–6). (E) Insulin secretion assays performed with islets of 12-week-old Tg7a2 and control mice (n = 5). (F) Relative mRNA levels of exocytotic regulators in islets of Tg7a2 and control mice at 7 weeks of age (n = 5–6). (G) Average gene expression in islets of Rip-Cre Mir7a2fl/fl, ob/ob, Tg7a2, and BKS db/db mice, measured by quantitative PCR (n = 5–7 per group). Red and blue denote increases and decreases, respectively, in gene expression vs. respective controls; no difference in expression is depicted in white. ND, expression not detectable. Hierarchical clustering analysis showing the distance or similarity between the fold changes among mouse models was performed using unweighted pair group method with arithmetic mean (UPGMA). (H) Coimmunostaining of indicated proteins in mouse models at 15 weeks of age. Scale bar: 50 μm. Data are mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001.