Verification That Mouse Chromosome 14 Is Responsible for Susceptibility to Streptozotocin in NSY Mice

Abstract

Introduction Streptozotocin- (STZ-) induced diabetes is under polygenic control, and the genetic loci for STZ susceptibility are mapped to chromosome (Chr) 11 in Nagoya-Shibata-Yasuda (NSY) mice. In addition to Chr11, other genes on different chromosomes may contribute to STZ susceptibility in NSY mice. The aim of this study was to determine whether NSY-Chr14 contributes to STZ susceptibility and contains the STZ-susceptible region. Materials and Methods A consomic C3H-14NSY strain (R0: homozygous for NSY-derived whole Chr14 on the control C3H background), two congenic strains (R1: the region retained proximal and middle segments of NSY-Chr14 and R2: the region retained a proximal segment of NSY-Chr14), and parental NSY and C3H mice were intraperitoneally injected with a single injection of STZ at a dose of 175 mg/kg body weight at 12 weeks of age. Blood glucose levels and body weights were measured at days 0, 1, 2, 4, 5, 7, 8, and 14 after STZ injection. At day 14 after STZ injection, pancreata were dissected and fixed. Results After STZ injection, blood glucose levels were significantly higher in R0 mice than in C3H mice. However, blood glucose levels in R0 mice were not as severely affected as those in NSY mice. In R1 and R2 mice, blood glucose levels were similar to those in C3H mice and were significantly lower than those in R0 mice. Body weights were decreased in NSY and R0 mice; however, this change was not observed in R1, R2, and C3H mice. Although islet tissues in all strains exhibited degeneration and cellular infiltration, histological changes in NSY and R0 mice were more severe than those in R1, R2, and C3H mice. Conclusions These data demonstrated that NSY-Chr14 was a STZ-susceptible chromosome and that STZ susceptibility was mapped to the distal segment of NSY-Chr14.

Novel loci for hyperglycemia identified by QTL mapping of longitudinal phenotypes and congenic analysis

“…Since type 2 diabetes is a polygenic disease and each locus was identified in crosses of two strains by the relative strength of the locus on each phenotype, it is possible that some genes may induce opposite effects. For example, previous studies have reported contradictory effects of Nidd2nsy and Nidd3nsy on visceral fat weight; alleles from disease-prone NSY mice decreased visceral fat pad weight, whereas alleles from disease-resistant C3H mice increased visceral fat pad weight 16,17 . Such loci effects were also previously reported in NOD mice, a www.nature.com/scientificreports/ well-known animal model of another polygenic disease, type 1 diabetes [31][32][33] .…”

“…One of the possible reasons for this discrepancy may be the difference in phenotyping age: 52 weeks in QTL mapping and 28 weeks in the congenic study. Another possibility is that the congenic mice were affected by Nidd2nsy on Chr14 and Nidd3nsy on Chr6 from C3H-derived alleles, which increased visceral fat 16 , 17 .…”

“…Construction of a congenic strain and phenotypic characterization. A novel congenic strain (C3H.NSY-Nidd5nsy) was constructed with the genomic region identified in QTL analysis using a markerassisted speed-congenic method 38 , as previously described 11,12,16,39,40 . Namely, (NSY × C3H) F1 male mice were backcrossed with female C3H mice.…”

Role of Fibrinogen in Type-2 Diabetes Mellitus with Diabetic Neuropathy and its Preliminary Mechanism

“…[ 14 ]. Streptozotocin acts on and destroys islet β cells and the function of pancreatic islets in animal models according to the injection dose [ 15 ]. High-dose injections of STZ can increase blood sugar in animal models, but there is no significant neuropathy [ 16 ].…”