MicroRNA-7a regulates pancreatic β cell function.
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.
Mathieu
M
Latreille
Jean
J
Hausser
Ina
I
Stützer
Quan
Q
Zhang
Benoit
B
Hastoy
Sofia
S
Gargani
Julie
J
Kerr-Conte
Francois
F
Pattou
Mihaela
M
Zavolan
Jonathan L S
JL
Esguerra
Lena
L
Eliasson
Thomas
T
Rülicke
Patrik
P
Rorsman
Markus
M
Stoffel
D000818:Animals; D054337:Cell Dedifferentiation; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D005089:Exocytosis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism
D007328:Insulin; D035683:MicroRNAs; D050600:SNARE Proteins; C549242:MIRN7-1 microRNA, human; C549243:MIRN7 microRNA, mouse