miR-375 maintains normal pancreatic alpha- and beta-cell mass.
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 alpha-cell numbers, fasting and fed plasma glucagon levels, and increased gluconeogenesis and hepatic glucose output. Furthermore, pancreatic beta-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 beta-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, alpha- and beta-cell turnover, and adaptive beta-cell expansion in response to increasing insulin demand in insulin resistance.
Poy
Matthew N
MN
Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, ETH Zurich, CH-8093 Zurich, Switzerland.
Hausser
Jean
J
Trajkovski
Mirko
M
Braun
Matthias
M
Collins
Stephan
S
Rorsman
Patrik
P
Zavolan
Mihaela
M
Stoffel
Markus
M
D000818:Animals; D001786:Blood Glucose; D049109:Cell Proliferation; D050416:Glucagon-Secreting Cells / Q000166:cytology*; D006706:Homeostasis; D007328:Insulin; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D035683:MicroRNAs / Q000502:physiology*
D001786:Blood Glucose; D007328:Insulin; D035683:MicroRNAs; C540349:Mirn375 microRNA, mouse