A Pancreatic Islet-Specific microRNA Regulates Insulin Secretion

Nature. 2004 Nov 11;432(7014):226-30. doi: 10.1038/nature03076.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling
  • Cell Line
  • Cloning, Molecular
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / therapy
  • Exocytosis* / drug effects
  • Gene Expression
  • Gene Silencing
  • Genetic Therapy
  • Glucose / metabolism
  • Glucose / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / ultrastructure
  • Mice
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Organ Specificity
  • Potassium Chloride / pharmacology
  • Substrate Specificity
  • Tolbutamide / pharmacology

Substances

  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • MicroRNAs
  • myotrophin
  • Potassium Chloride
  • Tolbutamide
  • Glucose