miR-375 maintains normal pancreatic α- and β-cell mass

Matthew N. Poy, Jean Hausser, Mirko Trajkovski, Matthias Braun, Stephan Collins, Patrik Rorsman, Mihaela Zavolan, Markus Stoffel

Research output: Contribution to journalArticlepeer-review

Abstract

Altered growth and development of the endocrine pancreas is a frequent cause of the hyperglycemia associated with diabetes. Here we show that microRNA-375 (miR-375), which is highly expressed in pancreatic islets, is required for normal glucose homeostasis. Mice lacking miR-375 (375KO) are hyperglycemic, exhibit increased total pancreatic α-cell numbers, fasting and fed plasma glucagon levels, and increased gluconeogenesis and hepatic glucose output. Furthermore, pancreatic β-cell mass is decreased in 375KO mice as a result of impaired proliferation. In contrast, pancreatic islets of obese mice (ob/ob), a model of increased β-cell mass, exhibit increased expression of miR-375. Genetic deletion of miR-375 from these animals (375/ob) profoundly diminished the proliferative capacity of the endocrine pancreas and resulted in a severely diabetic state. Bioinformatic analysis of transcript data from 375KO islets revealed that miR-375 regulates a cluster of genes controlling cellular growth and proliferation. These data provide evidence that miR-375 is essential for normal glucose homeostasis, α- and β-cell turnover, and adaptive β-cell expansion in response to increasing insulin demand in insulin resistance.

Original languageEnglish (US)
Pages (from-to)5813-5818
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number14
DOIs
StatePublished - Apr 7 2009
Externally publishedYes

Keywords

  • Diabetes
  • Glucagon
  • Islet
  • Proliferation
  • microRNA

ASJC Scopus subject areas

  • General

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