Báo cáo khoa học: Sirt1 and mir-9 expression is regulated during glucose-stimulated insulin

Sirt1 and mir-9 expression is regulated during

glucose-stimulated insulin secretion in pancreatic b-islets

Deepti Ramachandran*, Upasana Roy*, Swati Garg, Sanchari Ghosh, Sulabha Pathak and

Ullas Kolthur-Seetharam

Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai, India

Introduction

MicroRNAs (mirs) regulate protein expression due to

their ability to target the 3¢UTRs of mRNAs [1].

Although, in the recent past, there have been numer￾ous studies reporting mir targets and their physiologi￾cal implications, we still do not understand fully the

mechanisms that regulate their expression. This is cru￾cial as they are now known to play diverse roles and

are being considered as potential therapeutic targets.

Mirs have also been found to be important modulators

of changes in metabolic response, including endocrine

functions [2]. Several mirs involved in the control of

pancreatic development and insulin secretion have

been discovered recently [3,4]. Mir-375 was one of the

first mirs to be identified as a key factor affecting insu￾lin secretion by inhibiting glucose-stimulated insulin

secretion (GSIS) [4]. Another mir that has been impli￾cated in the control of insulin secretion is mir-9 [5].

Plaisance et al. [5] indicated a possible role for mir-9

in insulin secretion by showing that mir-9 targets

Onecut-2 (OC-2) mRNA and down-regulates its

expression in insulin-secreting cells. This decrease in

OC-2 consequently leads to an increase in the levels of

its target gene, granuphilin. Granuphilin has been well

characterized as a key player in insulin secretion and is

known to negatively regulate insulin exocytosis [6].

Therefore, on the basis of these results in INS-1E cells,

using exogenously expressed human growth hormone,

mir-9 has been proposed to negatively regulate insulin

exocytosis [5]. However, it is unclear whether altera￾tions in mir-9 levels and targeting are physiologically

Keywords

glucose-stimulated insulin secretion; mir-9;

Sirt1; b-islets

Correspondence

U. Kolthur-Seetharam, B-306, Department of

Biological Sciences, Tata Institute of

Fundamental Research, Homi Bhabha Road,

Colaba, Mumbai 400 005, India

Fax: +91 22 2280 4610

Tel: +91 22 2278 2721

E-mail: [email protected]

*These authors contributed equally to this

work

(Received 17 November 2010, revised 5

January 2010, accepted 31 January 2011)

doi:10.1111/j.1742-4658.2011.08042.x

MicroRNA mir-9 is speculated to be involved in insulin secretion because

of its ability to regulate exocytosis. Sirt1 is an NAD-dependent protein

deacetylase and a critical factor in the modulation of cellular responses to

altered metabolic flux. It has also been shown recently to control insulin

secretion from pancreatic b-islets. However, little is known about the regu￾lation of Sirt1 and mir-9 levels in pancreatic b-cells, particularly during glu￾cose-dependent insulin secretion. In this article, we report that mir-9 and

Sirt1 protein levels are actively regulated in vivo in b-islets during glucose￾dependent insulin secretion. Our data also demonstrates that mir-9 targets

and regulates Sirt1 expression in insulin-secreting cells. This targeting is

relevant in pancreatic b-islets, where we show a reduction in Sirt1 protein

levels when mir-9 expression is high during glucose-dependent insulin secre￾tion. This functional interplay between insulin secretion, mir-9 and Sirt1

expression could be relevant in diabetes. It also highlights the crosstalk

between an NAD-dependent protein deacetylase and microRNA in pancre￾atic b-cells.

Abbreviations

ARBP, acidic ribosomal binding protein; GSIS, glucose-stimulated insulin secretion; LNA, locked nucleic acid; mir, microRNA; OC-2,

Onecut-2; pS, pSuper vector; pS9, pSuper mir-9 vector.

FEBS Journal 278 (2011) 1167–1174 ª 2011 The Authors Journal compilation ª 2011 FEBS 1167