Research

Pancreatic islet expression profiling in diabetes-prone C57BLKS/J mice reveals transcriptional differences contributed by DBA loci, including Plagl1 and Nnt

Abraham A Anderson¹ , Joan Helmering² , Todd Juan³ , Chi-Ming Li³ , Jocelyn McCormick² , Melissa Graham² , Daniel M Baker⁴ , Michael A Damore⁴ , Murielle M Véniant² and David J Lloyd²

¹  Department of Computational Biology, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320, USA

²  Department of Metabolic Disorders, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320, USA

³  Department of Protein Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320, USA

⁴  Department of Molecular Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA 91320, USA

author email corresponding author email

PathoGenetics 2009, 2:1doi:10.1186/1755-8417-2-1

Published:	22 January 2009

Abstract

Background

C57BLKS/J (BLKS) mice are susceptible to islet exhaustion in insulin-resistant states as compared with C57BL6/J (B6) mice, as observed by the presence of the leptin receptor (Lepr) allele, Lepr^db/db. Furthermore, DBA2/J (DBA) mice are also susceptible to β-cell failure and share 25% of their genome with BLKS; thus the DBA genome may contribute to β-cell dysfunction in BLKS mice.

Results

Here we show that BLKS mice exhibit elevated insulin secretion, as evidenced by improved glucose tolerance and increased islet insulin secretion compared with B6 mice, and describe interstrain transcriptional differences in glucose response. Transcriptional differences between BLKS and B6 mice were identified by expression profiling of isolated islets from both strains. Genomic mapping of gene expression differences demonstrated a significant association of expression differences with DBA loci in BLKS mice (P = 4×10^-27).

Conclusion

Two genes, Nicotinamide nucleotide transhydrogenase (Nnt) and Pleiomorphic adenoma gene like 1 (Plagl1), were 4 and 7.2-fold higher respectively in BLKS islets, and may be major contributors to increased insulin secretion by BLKS islets. Contrary to reports for B6 mice, BLKS mice do not harbor a mutant Nnt gene. We detected 16 synonymous polymorphisms and a two-amino acid deletion in the Plagl1 gene in BLKS mice. Several inflammatory glucose-responsive genes are expressed at a higher level in BLKS, suggesting an inflammatory component to BLKS islet dysfunction. This study describes physiological differences between BLKS and B6 mice, and provides evidence for a causative role of the DBA genome in β-cell dysfunction in BLKS mice.