Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes

Aston-Mourney, K., Wong, N., Kebede, M., Zraika, S., Balmer, L., McMahon, J. M., Fam, B. C., Favaloro, J., Proietto, J., Morahan, G. and Andrikopoulos, S. 2007, Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes, Diabetologia, vol. 50, no. 12, pp. 2476-2485.

Attached Files
Name Description MIMEType Size Downloads

Title Increased nicotinamide nucleotide transhydrogenase levels predispose to insulin hypersecretion in a mouse strain susceptible to diabetes
Author(s) Aston-Mourney, K.
Wong, N.
Kebede, M.
Zraika, S.
Balmer, L.
McMahon, J. M.
Fam, B. C.
Favaloro, J.
Proietto, J.
Morahan, G.
Andrikopoulos, S.
Journal name Diabetologia
Volume number 50
Issue number 12
Start page 2476
End page 2485
Total pages 10
Publisher Springer
Place of publication Heidelberg, Germany
Publication date 2007
ISSN 0012-186X
1432-0428
Keyword(s) genetic predisposition
insulin secretion
intravenous glucose tolerance test
Islet beta cell function
quantitative trait locus
Summary Aims/hypothesis Insulin hypersecretion may be an independent predictor of progression to type 2 diabetes. Identifying genes affecting insulin hypersecretion are important in understanding disease progression. We have previously shown that diabetes-susceptible DBA/2 mice congenitally display high insulin secretion. We studied this model to map and identify the gene(s) responsible for this trait.

Methods Intravenous glucose tolerance tests followed by a genome-wide scan were performed on 171 (C57BL/6 × DBA/2) × C57BL/6 backcross mice.

Results A quantitative trait locus, designated hyperinsulin production-1 (Hip1), was mapped with a logarithm of odds score of 7.7 to a region on chromosome 13. Production of congenic mice confirmed that Hip1 influenced the insulin hypersecretion trait. By studying appropriate recombinant inbred mouse strains, the Hip1 locus was further localised to a 2 Mb interval, which contained only nine genes. Expression analysis showed that the only gene differentially expressed in islets isolated from the parental strains was Nnt, which encodes the mitochondrial proton pump, nicotinamide nucleotide transhydrogenase (NNT). We also found in five mouse strains a positive correlation (r 2  = 0.90, p < 0.01) between NNT activity and first-phase insulin secretion, emphasising the importance of this enzyme in beta cell function. Furthermore, of these five strains, only those with high NNT activity are known to exhibit severe diabetes after becoming obese.

Conclusions/interpretation Insulin hypersecretion is associated with increased Nnt expression. We suggest that NNT must play an important role in beta cell function and that its effect on the high insulin secretory capacity of the DBA/2 mouse may predispose beta cells of these mice to failure.
Language eng
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2007, Springer-Verlag
Persistent URL http://hdl.handle.net/10536/DRO/DU:30047463

Document type: Journal Article
Collection: School of Medicine
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 25 times in TR Web of Science
Scopus Citation Count Cited 26 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 19 Abstract Views, 1 File Downloads  -  Detailed Statistics
Created: Thu, 30 Aug 2012, 09:32:25 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.