MicroRNA-7 Regulates the mTOR Pathway and Proliferation in Adult Pancreatic β-Cells

Wang, You; Liu, Jiangying; Liu, Chengyang; Naji, Ali; Stoffers, Doris A.

doi:10.2337/db12-0451

Cited by 181 publications

(135 citation statements)

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“…The role of miRNAs in regulating pancreatic beta cell proliferation and insulin secretion has been demonstrated extensively (27,28,(31)(32)(33). We show here that menin plays a role in the processing of let-7a, a member of the let-7 family of miRNAs that regulates glucose metabolism in multiple organs (41).…”

Section: Discussionmentioning

confidence: 71%

“…miRNA-mediated regulation of pancreatic islet cell proliferation and insulin secretion has previously been demonstrated (31)(32)(33)(34). Conditional deletion of Dicer1 early in pancreas development results in dramatic reduction of insulin-producing beta cells (31).…”

Section: Multiple Endocrine Neoplasia Type I (Men1)mentioning

confidence: 96%

“…Similarly, Dicer1-deficient adult beta cells show dramatic decrease in insulin content, insulin-promoter activity, and insulin mRNA levels resulting in development of diabetes in these animals (32). Furthermore, miR-7a inhibition leads to activation of mTOR signaling and promotes adult beta cell replication in mouse primary islets (33). Analysis of miRNAs showing differential expression between normal pancreas and pancreatic endocrine tumors (PET) identified 87 up-regulated and 8 down-regulated miRNA in PETs (34).…”

Section: Multiple Endocrine Neoplasia Type I (Men1)mentioning

confidence: 99%

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Menin Is Required for Optimal Processing of the MicroRNA let-7a

Gurung

Muhammad

Hua

2014

Journal of Biological Chemistry

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Background: Menin represses pancreatic beta cell proliferation. Results: Menin promotes processing of let-7a, whose target IRS2 plays an important role in insulin signaling and beta cell proliferation. Conclusion: Menin represses beta cell proliferation partly via regulation of miRNA biogenesis. Significance: Understanding how menin represses beta cell proliferation will aid toward improving therapies targeting endocrine tumors and metabolic diseases including diabetes.

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Section: Discussionmentioning

confidence: 71%

Section: Multiple Endocrine Neoplasia Type I (Men1)mentioning

confidence: 96%

Section: Multiple Endocrine Neoplasia Type I (Men1)mentioning

confidence: 99%

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Menin Is Required for Optimal Processing of the MicroRNA let-7a

Gurung

Muhammad

Hua

2014

Journal of Biological Chemistry

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“…Among other miRNAs, miRNA-7a [95] has been reported to limit adult beta cell proliferation by inhibiting mammalian target of rapamycin (mTOR) signalling. Mice lacking miR-375 exhibit reduced beta cell mass as a result of impaired proliferation, hyperglucagonaemia and increased alpha cell numbers suggesting regulation of both beta and alpha cells [96].…”

Section: Contributors To Maintenance Of Islet Cell Mass In Adult Rodentsmentioning

confidence: 99%

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Mezza

Kulkarni

2014

Diabetologia

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Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and agedependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.

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“…Downregulation of miR-7 in mouse embryos results in a reduction in the number of beta cells and diminished insulin production, leading to glucose intolerance in the postnatal period [23]. Inhibition of miR-7 using antisense oligonucleotides in isolated adult mouse islet cells was found to activate the mechanistic target of rapamycin (mTOR) pathway and promote beta cell proliferation [24]. However, beta cell-specific MiR-7 knockout mice did not show significant differences in beta cell survival or proliferation, but displayed enhanced insulin release as a result of increased expression of key components of the exocytotic machinery, permitting an improved response to a glucose challenge [25].…”

Section: Micrornas As Regulators Of Beta Cell Differentiation and Funmentioning

confidence: 99%

Role of islet microRNAs in diabetes: which model for which question?

Guay

Regazzi

2014

Diabetologia

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MicroRNAs are important regulators of gene expression. The vast majority of the cells in our body rely on hundreds of these tiny non-coding RNA molecules to precisely adjust their protein repertoire and faithfully accomplish their tasks. Indeed, alterations in the microRNA profile can lead to cellular dysfunction that favours the appearance of several diseases. A specific set of microRNAs plays a crucial role in pancreatic beta cell differentiation and is essential for the fine-tuning of insulin secretion and for compensatory beta cell mass expansion in response to insulin resistance. Recently, several independent studies reported alterations in microRNA levels in the islets of animal models of diabetes and in islets isolated from diabetic patients. Surprisingly, many of the changes in microRNA expression observed in animal models of diabetes were not detected in the islets of diabetic patients and vice versa. These findings are unlikely to merely reflect species differences because microRNAs are highly conserved in mammals. These puzzling results are most probably explained by fundamental differences in the experimental approaches which selectively highlight the microRNAs directly contributing to diabetes development, the microRNAs predisposing individuals to the disease or the microRNAs displaying expression changes subsequent to the development of diabetes. In this review we will highlight the suitability of the different models for addressing each of these questions and propose future strategies that should allow us to obtain a better understanding of the contribution of microRNAs to the development of diabetes mellitus in humans.Keywords Animal models of Diabetes . Diabetes . Human islet donors . Insulin . Islets of Langerhans . MicroRNAs . Pancreatic beta cells . Review MicroRNAs as regulators of beta cell differentiation and functionType 2 diabetes is a chronic metabolic disorder characterised by major alterations in gene expression, which affects several organs, including the islets of Langerhans. A growing number of studies demonstrate that these changes are not only caused by deregulation of key transcription factors such as v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MafA) or pancreatic and duodenal homeobox 1 (PDX1) but are also driven by modifications in the level of another group of molecules regulating gene expression, the microRNAs [1][2][3][4]. MicroRNAs are small non-coding RNAs (typically 21-23 nucleotides long) that pair to the 3′ untranslated region of target mRNAs leading to translational repression and/or a decrease in messenger stability [5].The importance of the microRNA regulatory network for proper differentiation and function of beta cells is highlighted by the phenotypic traits of mice lacking Dicer1, an enzyme essential for the generation of most microRNAs [5]. Deletion of Dicer1 at different stages of pancreas development or of the pancreatic endocrine lineage results in a dramatic loss of microRNAs, accompanied by severe defects in pancreas m...

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MicroRNA-7 Regulates the mTOR Pathway and Proliferation in Adult Pancreatic β-Cells

Cited by 181 publications

References 50 publications

Menin Is Required for Optimal Processing of the MicroRNA let-7a

Menin Is Required for Optimal Processing of the MicroRNA let-7a

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Role of islet microRNAs in diabetes: which model for which question?

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