2682-P: Targeting APOC3 Preserves β-Cell Function in a Mouse Model of Type 2 Diabetes

Introduction and Objective: Apolipoprotein C3 (APOC3) is a component of triglyceride-rich lipoproteins (TRLs) that delays their clearance, leading to elevated triglyceride (TG) and TRL levels and accelerated cardiovascular disease (CVD), particularly in people with type 2 diabetes (T2D). APOC3 suppression may be a strategy for mitigating CVD risk in people with elevated TRLs; however, its effects on the pancreas remain unclear. Methods: To determine whether APOC3 suppression preserves β-cell function, we treated diabetic BTBR Lep-/- (OB) mice and non-diabetic (ND) littermates with an APOC3 antisense oligonucleotide (ASO) or control ASO for 12 weeks in a model of elevated TRLs (LDL receptor ASO). Metabolic phenotyping included glucose and insulin tolerance tests (GTT and ITT) and intravenous glucose tolerance (IVGTT) testing to assess β-cell function. Direct effects of TRLs on β-cells were examined in βTC3 cells. Results: APOC3 ASO dramatically suppressed plasma TG and cholesterol in (TGs reduced by 60% in OB APOC3 vs OB cASO, p<0.001, N=11-14). Glucose tolerance and insulin sensitivity were improved (GTT; p<0.001, N=15-17; ITT; p=0.02, N=4-8 OB APOC3 ASO vs cASO). In examining β-cell function by IVGTT, the acute insulin response tended to be higher in OB APOC3 ASO mice, even after adjustment for prevailing glucose and insulin sensitivity. Histologically, APOC3 ASO partially reversed the loss of pancreatic islet insulin staining in OB mice (23.5±4.7% vs 7.9±1.7% insulin/islet area in APOC3 ASO vs cASO, p=0.03, N=10-12), but not to levels in non-diabetic controls (71% insulin/islet area, N=11). Exposing βTC3 cells to elevated TRL levels induced apoptosis and cell death (2.3-fold with TRLs vs vehicle, p<0.001, N=8). Conclusion: Together, lowering plasma TRLs via APOC3 silencing improves glycemic control in diabetes-prone mice, in part by preserving β-cells, which appear sensitive to TLR-induced cell death. Disclosure A. Tran: None. F. Kramer: None. E. Giering: None. J. Cervantes: None. A.E. Mullick: Employee; Current; Ionis Pharmaceuticals.