MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids

J Clin Invest. 2015 Jun;125(6):2497-509. doi: 10.1172/JCI75438. Epub 2015 May 11.


Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet-fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology
  • Disease Models, Animal
  • Fatty Acids / genetics
  • Fatty Acids / metabolism*
  • Female
  • Glucose / genetics
  • Glucose / metabolism*
  • Humans
  • Insulin / genetics
  • Insulin / metabolism
  • Insulin Resistance*
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Obesity / chemically induced
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics


  • Dietary Fats
  • Fatty Acids
  • Insulin
  • MIRN26A microRNA, human
  • MicroRNAs
  • Mirn26 microRNA, mouse
  • Glucose