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Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

Research output: Contribution to journalArticle

Helena C Barbosa-Sampaio, Bo Liu, Robert Drynda, Ana M Rodriguez de Ledesma, Aileen J King, James E Bowe, Cédric Malicet, Juan L Iovanna, Peter M Jones, Shanta J Persaud, Dany S Muller

Original languageEnglish
Pages (from-to)2477-2486
JournalDiabetologia
Volume56
Issue number11
Early online date31 Jul 2013
DOIs
E-pub ahead of print31 Jul 2013
PublishedNov 2013

King's Authors

Abstract

Aims/hypothesis
The stress-activated nuclear protein transcription regulator 1 (NUPR1) is induced in response to glucose and TNF-α, both of which are elevated in type 2 diabetes, and Nupr1 has been implicated in cell proliferation and apoptosis cascades. We used Nupr1 −/− mice to study the role of Nupr1 in glucose homeostasis under normal conditions and following maintenance on a high-fat diet (HFD).

Methods
Glucose homeostasis in vivo was determined by measuring glucose tolerance, insulin sensitivity and insulin secretion. Islet number, morphology and beta cell area were assessed by immunofluorescence and morphometric analysis, and islet cell proliferation was quantified by analysis of BrdU incorporation. Islet gene expression was measured by gene arrays and quantitative RT-PCR, and gene promoter activities were monitored by measuring luciferase activity.

Results
Nupr1 −/− mice had increased beta cell mass as a consequence of enhanced islet cell proliferation. Nupr1-dependent suppression of beta cell Ccna2 and Tcf19 promoter activities was identified as a mechanism through which Nupr1 may regulate beta cell cycle progression. Nupr1 −/− mice maintained on a normal diet were mildly insulin resistant, but were normoglycaemic with normal glucose tolerance because of compensatory increases in basal and glucose-induced insulin secretion. Nupr1 deletion was protective against HFD-induced obesity, insulin resistance and glucose intolerance.

Conclusions/interpretation
Inhibition of NUPR1 expression or activity has the potential to protect against the metabolic defects associated with obesity and type 2 diabetes.

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