👤 Marissa Lightbourne

Despite the growing burden of youth-onset type 2 diabetes (Y-T2D), the long-term risk for fatal/non-fatal cardiovascular disease (CVD) in Y-T2D compared to peers is unknown. The International Childhood Cardiovascular Cohort (i3C) combined-risk z-score is a novel tool for predicting 35-year risk of adult CVD events. In Y-T2D compared to peers (Lean and overweight/obesity [OW/OB]), we estimated predicted CVD events and evaluated the relationship of the i3C z-score with risk-enhancing factors. In a pooled cohort cross-sectional analysis of 1547 adolescents and young adults (AYA) aged 10-25 years [627 Lean, 803 OW/OB, 117 Y-T2D], i3C combined-risk z-scores and estimated hazard ratios (HR) were obtained from the published i3C equation using risk z-scores of systolic blood pressure, body mass index (BMI), smoking history, total cholesterol, and triglycerides. ANCOVA regression models were used: 1) to compare i3C z-scores and HR in AYA with Y-T2D, OW/OB and Lean peers, and 2) to measure associations between i3C estimated HR and risk-enhancing factors including apolipoprotein B (ApoB), total low density lipoprotein particle number (LDL-P), and high sensitivity C reactive protein (hsCRP). Models were adjusted for diagnosis group, race, study center and multiple comparisons with Bonferroni. Y-T2D had the highest i3C z-score (Y-T2D: 1.23 [1.10, 1.36] vs. OW/OB: 0.84 [0.80, 0.88] vs. Lean: -0.11 [-0.15, -0.06], mean[95%CI]) and estimated HR for predicted CVD events (Y-T2D: 4.25 [3.65-4.86] vs. OW/OB: 3.04 [2.85-3.22] vs. Lean: 0.95 [0.74-1.17], HR [95% CI]). Risk-enhancing factors increased the HR for predicted CVD risk by 0.3 for each 10 mg/dL increase in ApoB, 0.1 for each 100 nmol/L increase in LDL-P, and 0.16 for each 2 mg/L increase in hsCRP, all P < 0.001. Y-T2D had an estimated 4.5- and 1.4-times higher risk for predicted CVD events compared to Lean and OW/OB peers, respectively. Lipoprotein and inflammatory risk-enhancing factors may help stratify and guide primary prevention strategies in high-risk AYA. Show less

Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood. Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin. Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma. Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 ( Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients. Show less