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

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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.