A pancreatic islet-specific microRNA regulates insulin secretion.
MicroRNAs (miRNAs) constitute a growing class of non-coding RNAs that are thought to regulate gene expression by translational repression. Several miRNAs in animals exhibit tissue-specific or developmental-stage-specific expression, indicating that they could play important roles in many biological processes. To study the role of miRNAs in pancreatic endocrine cells we cloned and identified a novel, evolutionarily conserved and islet-specific miRNA (miR-375). Here we show that overexpression of miR-375 suppressed glucose-induced insulin secretion, and conversely, inhibition of endogenous miR-375 function enhanced insulin secretion. The mechanism by which secretion is modified by miR-375 is independent of changes in glucose metabolism or intracellular Ca2+-signalling but correlated with a direct effect on insulin exocytosis. Myotrophin (Mtpn) was predicted to be and validated as a target of miR-375. Inhibition of Mtpn by small interfering (si)RNA mimicked the effects of miR-375 on glucose-stimulated insulin secretion and exocytosis. Thus, miR-375 is a regulator of insulin secretion and may thereby constitute a novel pharmacological target for the treatment of diabetes.
Poy
Matthew N
MN
Laboratory of Metabolic Diseases and Laboratory of RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Eliasson
Lena
L
Krutzfeldt
Jan
J
Kuwajima
Satoru
S
Ma
Xiaosong
X
Macdonald
Patrick E
PE
Pfeffer
Sébastien
S
Tuschl
Thomas
T
Rajewsky
Nikolaus
N
Rorsman
Patrik
P
Stoffel
Markus
M
D000818:Animals; D020013:Calcium Signaling; D002460:Cell Line; D003001:Cloning, Molecular; D003920:Diabetes Mellitus / Q000235:genetics / Q000628:therapy; D005089:Exocytosis / Q000187:drug effects; D015870:Gene Expression; D020868:Gene Silencing; D015316:Genetic Therapy; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011189:Potassium Chloride / Q000494:pharmacology; D013379:Substrate Specificity; D014044:Tolbutamide / Q000494:pharmacology
D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; C065700:myotrophin; D011189:Potassium Chloride; D014044:Tolbutamide; D005947:Glucose