Abstract Body: Introduction: APOE4 (which encodes apolipoprotein E4) is a common genetic risk factor for cardiovascular disease (CVD), and the underpinnings are poorly understood. In small clinical studies APOE4 is also associated with type 2 diabetes mellitus (T2DM), which increases CVD risk by up to 4-fold. However, if and how APOE4 impacts glucose homeostasis is unknown.
Hypothesis: This study tests the hypothesis that APOE4 promotes insulin resistance and glucose intolerance.
Methods: GWAS data from two large independent cohorts were analyzed. Glucose homeostasis was evaluated in mice with murine Apoe replaced by human APOE3 or APOE4 (hE3 or hE4 mice, respectfully). Glucose and insulin tolerance tests (GTT or ITT) and hyperinsulinemic clamps were done, skeletal muscle glucose disposal and insulin delivery were quantified, and contrast-enhanced ultrasound assessed muscle capillary recruitment. Direct actions of APOE3 versus APOE4 on endothelial cells (EC) were studied in cultured human aortic EC.
Results: In both GWAS cohorts APOE4 was associated with increased T2DM risk, with P=1.40x10^-10 and P=1.80x10^-18. Compared to hE3 mice, hE4 had fasting hyperglycemia and hyperinsulinemia, GTT and ITT curves were shifted upwards, and the glucose infusion rate during clamp was decreased. Skeletal muscle glucose disposal was blunted, and this was explained by decreased muscle insulin delivery. hE4 mice had normal muscle capillary recruitment in response to insulin, and alternatively APOE4 potently antagonized insulin transcytosis by cultured EC. The blunting of insulin transcytosis in culture was mediated by ApoE receptor 2 (ApoER2), and EC ApoER2 excision in hE4 mice fully corrected muscle insulin delivery and glucose disposal, and systemic glucose homeostasis. In EC ApoER2 interactome studies APOE4 caused recruitment of the scaffolding protein JNK interacting protein 1 (JIP1), and JNK1 or JIP1 knockdown prevented APOE4 blunting of EC insulin transcytosis. In parallel, in hE4 mice both the JNK inhibitor SP600125 and EC JIP1 deletion normalized glucose control.
Conclusions: APOE4 is a risk allele for T2DM. Mechanistically, the APOE4-EC ApoER2 tandem attenuates EC insulin transcytosis through JIP1 and JNK activation, resulting in decreased muscle insulin delivery and glucose disposal, leading to systemic insulin resistance and glucose intolerance. Targeting these processes may afford protection from T2DM and its impact on CVD in 15 to 20% of the population.