Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes
Jenny E. Kanter, … , Jay W. Heinecke, Karin E. Bornfeldt
Jenny E. Kanter, … , Jay W. Heinecke, Karin E. Bornfeldt
Published July 11, 2019
Citation Information: J Clin Invest. 2019;129(10):4165-4179. https://doi.org/10.1172/JCI127308.
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Research Article Metabolism

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes

Abstract

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.

Authors

Jenny E. Kanter, Baohai Shao, Farah Kramer, Shelley Barnhart, Masami Shimizu-Albergine, Tomas Vaisar, Mark J. Graham, Rosanne M. Crooke, Clarence R. Manuel, Rebecca A. Haeusler, Daniel Mar, Karol Bomsztyk, John E. Hokanson, Gregory L. Kinney, Janet K. Snell-Bergeon, Jay W. Heinecke, Karin E. Bornfeldt

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Figure 2

Diabetes increases APOC3 levels relative to plasma TG levels through a lack of sufficient insulin.

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Diabetes increases APOC3 levels relative to plasma TG levels through a l...
(A) Female Ldlr–/– GpTg mice were rendered diabetic using LCMV. Saline was used as a control in nondiabetic littermates. At the onset of diabetes, the mice were switched to a low-fat, semipurified diet and maintained on the diet for 4 weeks. Plasma TGs were compared with plasma APOC3 levels measured by ELISA using data from 3 separate cohorts of mice (n = 42–43). Ranges and averages of TG levels and blood glucose (mg/dL) in diabetic and nondiabetic mice are listed below the graph. (B–E) Diabetes was induced by STZ treatment in male Ldlr–/– GpTg mice. Following induction of diabetes, half of the diabetic cohort received the SGLT2 inhibitor dapagliflozin in their drinking water for 4 weeks. n = 6–8. (B) Blood glucose levels at the end of the study. (C) Plasma cholesterol levels. (D) Plasma TGs. (E) Plasma APOC3 levels. Diabetes was induced using LCMV in Ldlr–/– GpTg mice. (F–I) Following development of diabetes, half of the diabetic cohort was subjected to intense insulin therapy with the goal of normalizing blood glucose, whereas the other half was maintained on traditional insulin therapy. n = 5–6. (F) Blood glucose at the end of the study. (G) Plasma cholesterol. (H) Plasma TGs. (I) Plasma APOC3. ND, nondiabetic mice; D, diabetic mice. D + int. ins., diabetes plus intense insulin therapy. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed, unpaired Student’s t test (A) or 1-way ANOVA followed by Tukey’s multiple comparisons tests (B–I).