Increased apolipoprotein C 3 drives cardiovascular risk in type 1 diabetes

4 1 6 5 jci.org Volume 129 Number 10 October 2019 Introduction Atherosclerotic cardiovascular disease (CVD) is a major cause of morbidity and mortality in subjects with type 1 diabetes mellitus (T1DM) (1). Although some results suggest that CVD risk associated with diabetes is declining in parallel with the reduced rate of CVD in the general population (2), the overall CVD risk remains higher in T1DM patients, especially in premenopausal women, in subjects with suboptimally controlled blood glucose levels, and in subjects with features of insulin resistance and metabolic syndrome (3). The Diabetes Control and Complications Trial (DCCT), a prospective study with a mean follow-up of 6.5 years for microvascular and macrovascular disease in patients with T1DM, and its observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study arm, demonstrated that improved glycemic control by intensive insulin therapy is associated with longterm reductions in mortality and cardiovascular events (4–6). Moreover, improved plasma lipids and lipoproteins appeared to mediate a substantial proportion of the protective effect of more stringent glucose control through intense insulin therapy over time (7). Lowering LDL cholesterol (LDL-C) with statins is the best strategy documented to date for decreasing CVD risk in T1DM, but substantial residual risk remains. The increased risk is often attributed to hyperglycemia, fluctuating glucose levels, or glucosemediated metabolic memory (8, 9). However, several lines of evidence suggest that glucose does not directly account for the increased CVD risk in patients with diabetes, or at least is not the only risk factor (7, 10, 11). It is likely that relative insulin deficiency or insulin resistance could explain at least some of the residual CVD risk associated with T1DM. Accordingly, insulin has been shown to suppress gene expression of apolipoprotein C3 (APOC3) (12, 13), an abundant apolipoprotein that increases triglyceride-rich lipoproteins (TRLs) and their remnants in the circulation by blocking their catabolism and clearance (14). Studies in humans have convincingly demonstrated that APOC3 loss-of-function mutations lower TRL levels and offer cardioprotection (15–20). APOC3 was long believed to elevate plasma TRL levels by inhibiting lipoprotein lipase (14, 21), but a human antisense oligonucleotide (ASO) therapeutic against APOC3 markedly reduced triglyceride (TG) levels in lipoprotein lipase–deficient humans with severe hypertriglyceridemia (22). Recent studies in mice and humans indicate that APOC3 regulates Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency, rather than hyperglycemia, elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we examined the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic expression of Apoc3 in diabetic mice, resulting in lower levels of TRLs, without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibition of APOC3 might reduce CVD risk in patients with T1DM. Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes