2042-P: Loss of Apoptosis Repressor with Caspase Recruitment Domain Promotes High-Fat Diet Induced Hyperglycemia In Vivo

Abstract

Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of apoptosis signaling. We previously showed ARC is expressed in β cells and ameliorates amyloid-induced β-cell death in vitro. More recently, we found that wild type (WT) and whole-body ARC knockout (KO) mice on an FVB background fed a normal chow diet exhibit no differences in islet area, β-cell area, or α-cell area at 16 (n=5) or 35 weeks (n=7-8) of age. In the present study, we sought to determine whether ARC plays a role in maintaining glycemia in response to the challenge of high fat diet (HFD, 60% kcal from fat) feeding in vivo. At 12 weeks of age, just prior to starting 24 weeks of HFD, ARC KO mice displayed lower body weight than WT mice (0 wks: 26.2±0.6 vs. 30.6±0.8 g; p<0.01; n=13), and this weight difference persisted throughout the HFD study (24 wks: 44.7±2.5 vs. 51.9±1.0 g; p=0.04, n=4-9). Random plasma glucose (PG) was not different between genotypes prior to HFD feeding. With HFD challenge, PG increased significantly in ARC KO but not WT mice (see Table). This elevation in PG in ARC KO mice was observed after 4 weeks of HFD and remained throughout the study. These data indicate that loss of ARC promotes hyperglycemia in response to HFD feeding in vivo. Whether this hyperglycemia in ARC KO mice arises from impaired β-cell compensation due to reduced β-cell mass or function remains to be determined. Disclosure A.T. Templin: None. C.R. Schmidt: None. M.F. Hogan: None. N. Esser: None. R.N. Kitsis: None. R.L. Hull: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. Funding U.S. Department of Veterans Affairs (I01-BX001060, IK2-BX004659); National Institutes of Health (P30DK017047)