Altered Glucose Metabolism in Sbp2 Deficient Mice Manifesting a Multi Organ Syndrome
Presentation Number: OR13-4
Date of Presentation: April 2nd, 2017
Haruki Fujisawa*1, Jiao Fu1, Xiao-Hui Liao1, Honggang Ye2, Natalia A Tamarina1, Scott Olehnik1, Manami Hara2 and Alexandra M Dumitrescu1
1The University of Chicago, Chicago, IL, 2University of Chicago, Chicago, IL
Selenocysteine is incorporated into selenoproteins via recoding of a UGA stop codon in a process requiring selenocysteine insertion sequence binding protein 2, SBP2. The consequences of impaired selenoprotein synthesis became apparent with the identification of the first SBP2 mutations in humans (1). Partial SBP2 deficiency results in a syndrome with multisystem manifestations including growth delay, a unique thyroid phenotype, congenital myopathy and impaired coordination (1, 2). The study of a model organism is required to dissect the pathophysiology responsible for the various phenotypes. To bypass the embryonic lethality of lacking Sbp2, we used a CreER/loxP approach to generate induced conditional knockout, iCKO mice. Tamoxifen was injected around P35 and mice were analyzed 4-5 weeks later. The pathognomonic thyroid phenotype of SBP2 deficiency was replicated in this mouse model (3) thus validating it as a tool to elucidate the selenoprotein-mediated pathology.
As patients with SBP2 deficiency also manifest a metabolic phenotype with low fasting blood glucose (BG), we set out to investigate this in our mouse model. Sbp2 iCKO had significantly lower body weight compared to Wt (15.8±0.6 vs 20.8±0.4g in males, 13.4±0.6 vs 18.2±0.7g in females) and significantly lower fat mass compared to Wt (2.3±0.1 vs 2.7±0.2g in males and 1.8±0.1 vs 2.3±0.1g in females). In metabolic cages, Sbp2 iCKO showed 24.8% lower motor activity during daytime in males and 34.1% lower during nighttime in females, suggestive of a neuromuscular phenotype as reported in SBP2 deficient patients. Food and water intake, O2 consumption, CO2 production, RER and heat production per lean body mass were similar in both genotypes. Sbp2 iCKO also had significantly lower fasting BG compared to Wt (120±3.9 vs 152±3.2 mg/dL in males and 114±6.8 vs 148±6.8 mg/dL in females), while fasting insulin levels were similar in both genotypes. In the pyruvate challenge test, both male and female Sbp2 iCKO had significantly lower BG than Wt indicating impaired gluconeogenesis. The analysis of the pancreatic islets in-situ using large scale image capture of the endocrine cells showed increased beta and delta cell mass with larger islets in Sbp2 iCKO compared to Wt. Additional tests in these mice are underway to uncover the underlying mechanisms. Lacking specific selenoproteins can manifest as increased insulin sensitivity (Gpx1 KO), insulin resistance (SelM KO) or impaired insulin secretion (SelT KO). Multiple selenoproteins are deficient in Sbp2 defects and the contribution of specific selenoproteins needs to be investigated.
Sbp2 iCKO mice replicate phenotypes reported in patients with SBP2 deficiency. This model of global Sbp2 deficiency offers a unique opportunity to study in vivo the cross talk of multiple pathways involving selenoproteins and advance our understanding of the role of SBP2 in cellular metabolism.
Nothing to Disclose: HF, JF, XHL, HY, NAT, SO, MH, AMD