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01.11.2013 | Article

Nupr1 deletion protects against glucose intolerance by increasing beta cell mass

verfasst von: 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

Erschienen in: Diabetologia | Ausgabe 11/2013

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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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Titel: Nupr1 deletion protects against glucose intolerance by increasing beta cell mass
verfasst von: 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
Publikationsdatum: 01.11.2013
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 11/2013
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-3006-x

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