Relationship of Plasma Apolipoprotein C-I Truncation with Risk of Diabetes in the Multi-Ethnic Study of Atherosclerosis and the Actos Now for the Prevention of Diabetes (ACT NOW) study

Objective: Higher truncated-to-native apolipoprotein (apo) C-I proteoform ratios (C-I’/C-I) are associated with favorable cardiometabolic risk profiles, but its relationship with longitudinal changes in insulin resistance and incident diabetes is unknown. Research Design and Methods: Plasma apoC-I proteoforms were measured by mass spectrometry immunoassay at baseline in 4,742 non-diabetic MESA and 524 prediabetes ACT NOW participants. The primary outcome was incident diabetes (fasting glucose [FG] ≥7.0 mmol/l or hypoglycemic medications use in MESA; FG ≥7.0 mmol/l or 2-hour OGTT glucose ≥ 11.1 mmol/l in ACT NOW). Secondary outcomes were changes in FG and HOMA-IR in MESA, and OGTT-glucose area under the curve (AUCglucose) and Matsuda insulin sensitivity index (ISI) in ACT NOW. Results: In MESA, higher C-I’/C-I was associated with lower risk of diabetes (n=564 events, HR: 0.87 [95%CI: 0.79, 0.95] per SD, p=0.0036, median follow-up 9 years), and smaller increases (follow-up adjusted for baseline) in FG (-0.5%, p<0.0001) and HOMA-IR (-2.9%, p=0.011) after adjusting for baseline clinical and demographic covariates, including plasma triglycerides and HDL-C. Total apoC-I concentrations were not associated with changes in FG, HOMA-IR and incident diabetes. In ACT NOW, higher C-I’/C-I was associated with smaller increases in AUCglucose (-1.8%, p=0.0052), greater increases in ISI (7.2%, p=0.0095), and lower risk of diabetes (n=59 events, 0.66 [0.48, 0.91], p=0.004, median follow-up 2.5 years) after adjusting for treatment group and diabetes risk factors, including plasma lipids. Conclusion: Our results indicate that apoC-I truncation may contribute to changes in glucose levels and insulin resistance, and risk of diabetes.