SummaryPancreatic β cells adapt to compensate for increased metabolic demand during insulin resistance. Although the microRNA pathway has an essential role in β cell proliferation, the extent of its contribution is unclear. Here, we report that miR-184 is silenced in the pancreatic islets of insulin-resistant mouse models and type 2 diabetic human subjects. Reduction of miR-184 promotes the expression of its target Argonaute2 (Ago2), a component of the microRNA-induced silencing complex. Moreover, restoration of miR-184 in leptin-deficient ob/ob mice decreased Ago2 and prevented compensatory β cell expansion. Loss of Ago2 during insulin resistance blocked β cell growth and relieved the regulation of miR-375-targeted genes, including the growth suppressor Cadm1. Lastly, administration of a ketogenic diet to ob/ob mice rescued insulin sensitivity and miR-184 expression and restored Ago2 and β cell mass. This study identifies the targeting of Ago2 by miR-184 as an essential component of the compensatory response to regulate proliferation according to insulin sensitivity.

MicroRNAs (miRNAs) are a novel group of universally present small non-coding RNAs that have been implicated in wide ranging physiological processes and thereby are critical in the manifestation of diverse diseases. Since their discovery as developmental regulators in C.elegans, they have come a long way and are currently associated with normal and diverse pathophysiological states including Parkinson's syndrome, cardiac hypertrophy, viral infection, diabetes and several types of cancer. Of special significance is their involvement in diabetes, an area in which several emerging reports point to the fact that these small RNA species could be special and critical in this complex disease and they or their specific inhibitors may be exploited as targets for therapeutic intervention. The stable nature of these miRNAs over mRNAs is an added advantage of them being projected for the same. This review focuses on and discusses the current diabetic epidemic and the potential role(s) of these miRNAs in various physiological processes that lead to the diabetic phenotype with an objective of better understanding the emerging mechanisms of these small molecules in the development and progression of diabetes and its complications.

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