Argonaute2 Mediates Compensatory Expansion of the Pancreatic β Cell

Abstract

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: An adaptive mechanism in the pancreatic β-cell…and beyond?

“…This result provided the first in vivo evidence that miRNAs could play a binary role in regulating both exocytosis and cellular proliferation. β-cell specific knockout mouse of Ago2, a key mediator of the miRNA pathway, exhibited a similar phenotype underlining an important role for small RNAs in the compensatory response of this cell type as the demand for insulin increases [8]. As potent regulators of both secretion and cell proliferation, together these results highlight the potential for studying how this pathway contributes to the most fundamental aspects of β-cell physiology.…”

“…To date, 2588 mature human miRNAs have been annotated in the miRBase database V20 which now catalogs 206 different plant and animal species [6]. While several sequences including miR-375, miR-7, and miR-184 appear to be enriched in the endocrine pancreas, profiling results from mouse and human tissues have shown that none of these miRNAs are entirely specific to the islet [7] [8]. In the case of miR-375, expression of this miRNA has been reported in numerous tissue types including the pituitary gland, adrenal gland, intestine, lung, and several types of cancer [9] [10].…”

“…Similarly, miR-7 and miR-184 have been shown to be highly enriched in the central nervous system and eye, respectively [11]. Recent studies using mouse knockouts have shown that loss of these three abundant miRNAs will increase β-cell exocytosis however it still remains unclear whether all miRNAs present in the β-cell are committed to an identical functional role and whether they perform the same function in all cell types where they are present [12] [9] [8]. For example, while miR-375 regulates exocytosis and compensatory proliferation of the β-cell, it has not been determined whether it functions in these capacities in the other neuroendocrine cell types where it is expressed [8] [13].…”

“…Recent studies using mouse knockouts have shown that loss of these three abundant miRNAs will increase β-cell exocytosis however it still remains unclear whether all miRNAs present in the β-cell are committed to an identical functional role and whether they perform the same function in all cell types where they are present [12] [9] [8]. For example, while miR-375 regulates exocytosis and compensatory proliferation of the β-cell, it has not been determined whether it functions in these capacities in the other neuroendocrine cell types where it is expressed [8] [13]. Meanwhile for miRNAs which are abundant in the β-cell however are ubiquitously expressed across many tissues such as the let-7 family, it is not clear whether there is functional overlap to sequences like miR-375.…”

“…The chronic hyperglycemia characteristic of diabetes has long been established the result of inadequate insulin action making one of the prime directives of the β-cell field to identify genes and mechanisms which contribute to reduced growth and function of this cell type. Since the first gain and loss of function studies on miR-375, several subsequent reports have identified a number of additional miRNAs as negative regulators of β-cell function including miR-7, miR-184, miR-21, miR-29a and miR-33a [5] [12] [8] [17] [18]. Importantly, the role of several miRNAs as negative regulators has been substantiated using specific genetic mouse knockouts [19].…”