👤 Janet K Snell-Bergeon

Atherosclerotic CVD is a major cause of death in individuals with type 1 diabetes mellitus (T1DM). However, conventional risk factors do not fully account for the increased risk. This study aimed to investigate whether serum proteins associate with diabetes status and the occurrence of CVD in T1DM. We used isotope dilution-MS/MS to quantify 28 serum proteins in 228 subjects participating in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used linear regression to analyze the association between serum protein levels and T1DM status using 47 healthy controls and 134 T1DM patients without CVD and Cox proportional hazards regression to assess their prediction for incident CVD by a case-cohort study using a subcohort of 145 T1DM subjects and a total of 47 CVD events. Of the 28 serum proteins studied, five of them-alpha-2-macroglobulin (A2M), apolipoprotein A-IV, apolipoprotein L1, insulin-like growth factor 2, and phospholipid transfer protein-were significantly associated with T1DM status, with A2M being 1.6-fold higher in T1DM. After adjusting for potential confounders, A2M independently predicted incident CVD, with a mean hazard ratio of 3.3 and 95% CI of 1.8-6.1. In our study, A2M showed the largest increase in serum levels when comparing patients with T1DM to control subjects. A2M also predicted incident CVD, suggesting that it could serve as both a marker and possibly a mediator of atherosclerosis in T1DM. These findings emphasize the importance of specific serum proteins in assessing and managing CVD risk in T1DM. Show less

Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D. We generated LDL receptor-deficient ( Diabetic Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux. Show less

Apolipoprotein C3 (APOC3) is a risk factor for incident coronary artery disease in people with type 1 diabetes (T1D). The pathways that link elevated APOC3 levels to an increased risk of incident cardiovascular disease in people with T1D are not understood. To explore potential mechanisms, we investigated the association of APOC3 with insulin resistance and coronary artery calcium (CAC). In a random subcohort of participants with T1D from Coronary Artery Calcification in Type 1 Diabetes (n = 134), serum APOC3, high-density lipoprotein (HDL)-associated APOC3, and retinol binding protein 4 (RBP4; a potential marker of insulin resistance) were measured by targeted mass spectrometry. We used linear regression to evaluate associations of serum APOC3 and HDL-APOC3 with APOB, non-HDL cholesterol, serum- and HDL-associated RBP4, and estimated insulin sensitivity and logistic regression to evaluate association with presence of CAC, adjusted for age, sex, and diabetes duration. Serum APOC3 correlated positively with APOB and non-HDL cholesterol and was associated with increased odds of CAC (odds ratio: 1.68, P = .024). Estimated insulin sensitivity was not associated with serum- or HDL-RBP4 but was negatively associated with serum APOC3 in men (ß estimate: -0.318, P = .0040) and decreased odds of CAC (odds ratio: 0.434, P = .0023). Serum APOC3 associates with increased insulin resistance and CAC in T1D. Show less

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 investigated 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 Apoc3 expression 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 the 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, inhibiting APOC3 might reduce CVD risk in T1DM patients. Show less

Individuals with type 1 diabetes have an increased incidence of coronary artery disease (CAD) and a higher risk of cardiovascular death compared with individuals of the same age in the general population. While chronic hyperglycaemia and insulin resistance partially explain excess CAD, little is known about the potential genetic determinants of accelerated coronary atherosclerosis in type 1 diabetes. The aim of the present study was to evaluate the association of apolipoprotein A-IV (APOA4) polymorphisms with coronary artery calcification (CAC) progression, a marker of subclinical atherosclerosis. Two previously well-studied functional APOA4 polymorphisms resulting in the substitution of the amino acid Thr for Ser at codon 347 and Gln for His at codon 360 were genotyped in 634 subjects with type 1 diabetes and 739 non-diabetic control subjects, the participants of the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. The His360 allele was associated with a significantly higher risk of CAC progression among patients with type 1 diabetes (33.7 vs 21.2%, p=0.014), but not in the control subjects (14.1 vs 11.1%, p=0.42). Logistic regression analysis confirmed that the presence of the APOA4 His360 allele predicts an increased risk of progression of coronary atherosclerosis in adults with type 1 diabetes of long duration (odds ratio = 3.3, p=0.003 after adjustment for covariates associated with CAD risk). CONCLUSIONS /INTERPRETATION: This is the first report suggesting an association between the APOA4 Gln360His polymorphism and risk of CAC progression in subjects with type 1 diabetes. Additional studies are needed to explore potential interactions between APOA4 genotypes and metabolic/oxidative stress components of the diabetic milieu leading to rapid progression of atherosclerosis. Show less