Abstract 216: PCSK9 Loss-of-Function Mutation Q152H is Associated with Reduced Dietary Fat Clearance and Insulin Resistance in Humans

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Introduction: PCSK9 regulates plasma LDL-C concentrations. Loss-of-function (LOF) mutations are associated with cardiovascular protection via increased clearance of LDL particles. Work from our and other labs has shown that increased cellular uptake of LDL is proapoptotic for pancreatic β-cells and impairs adipose tissue function. Moreover, obese women with high concentration of LDL (ie plasma apoB) have lower insulin sensitivity and delayed dietary fat clearance. We recently identified a novel PCSK9 LOF mutation, Q152H, causing a 79% reduction of plasma PCSK9 and 48% reduction of plasma LDL-C. The impact of this mutation on the metabolic profile remains unexplored. Hypothesis: We hypothesize that despite a cardioprotective profile, carriers of Q152H have delayed dietary TG clearance and impaired insulin sensitivity similar to subjects with high apoB. Methods/Results: The heterozygous Q152H proband woman was compared to 2 groups of obese, age, sex and BMI-matched controls with low (n=6) and high (n=7) apoB. Fasting apoB, PCSK9, total cholesterol and LDL-C concentrations were lower in the proband (0.84g/l,126ng/ml, 4.22mM and 2.11mM, respectively) compared to low apoB (0.75 ± 0.05 g/l, 267 ± 18ng/ml, 5.1 ± 0.2mM and 2.8 ± 0.3nM, respectively) and high apoB (1.25 ± 0.09 g/l, 412 ± 79ng/ml, 6.9 ± 0.4mM and 4.3 ± 0.3nM, respectively). Women with high apoB had delayed dietary TG clearance over 6 hours as compared to women with low apoB (incremental TG AUC: 6.75 ± 1.65 vs 4.06 ± 0.77 mM/6h, p=NS). Incremental AUC TG in the proband was 106% greater than that of women with high apoB and 243% greater than that of low apoB. Botnia clamp was also conducted to measure insulin secretion and sensitivity. There was no difference in insulin secretion between the proband and the control groups measured via an intravenous glucose tolerance test. However, insulin sensitivity, as measured by glucose infusion rates (GIR) during a hyperinsulinemia clamp, was 7.5mg/kg/min in the proband, 32% lower than women with high apoB (11.1 ± 1.1 mg/kg/min) and 48% lower than women with low apoB (14.3 ± 0.9 mg/kg/min). Conclusion: PCSK9 deficiency favours a cardioprotective profile; however increased clearance of LDL by peripheral tissue may induce peripheral insulin resistance in obese subjects.