Comparative transcriptome and mutation analyses of the pancreatic islets of a rat model of obese type 2 diabetes identifies a frequently distributed nonsense mutation in the lipocalin 2 gene

Abstract

Type 2 diabetes (T2D) is a multifactorial disease caused by insulin resistance and impaired insulin secretion from pancreatic β-cells, but the precise mechanisms remain to be elucidated. To identify primary genetic factors of T2D in a rat model, we performed comparative transcriptome and mutation analyses of the pancreatic islets between the obese Zucker fatty rat and the Zucker fatty rat-derived T2D model Zucker fatty diabetes mellitus (ZFDM) rat. Among differentially expressed genes irrespective of obesity and glucose intolerance states, we identified a nonsense mutation, c.409C > T (p.Gln137X), in the lipocalin 2 (Lcn2) gene which encodes a secreted protein called neutrophil gelatinase-associated lipocalin, a well-known biomarker for inflammation. We examined the relevance of the Lcn2 mutation with T2D in the ZFDM rat by using genome editing and genetic linkage analysis and confirmed that the Lcn2 mutation exhibits no significant association with the onset of T2D. Interestingly, we found that the Lcn2 mutation is distributed widely in rat species, such as commonly used DA and F344 strains. Our data indicate that several rat strains would serve as Lcn2 deficient models, contributing to elucidate the pathophysiological roles of Lcn2 in a wide variety of phenotypes.