122-OR: ADA Presidents' Select Abstract: Lower Plasma Levels of Truncated Apolipoprotein C-I Are Associated with Increased Risk of Diabetes—Multiethnic Study of Atherosclerosis

Apolipoprotein C-I (apoC-I) is a key regulator of triglyceride and HDL metabolism. Preclinical data also indicate a role of apoC-I in insulin resistance (IR) and hyperglycemia. In circulation, apoC-I appears as native (C-I) and truncated (C-I’) proteoform. Higher ratio of C-I’ to C-I (C-I’/C-I) is associated with more favorable cardiometabolic risk profiles. We now tested if C-I’/C-I is associated with longitudinal changes in fasting glucose (FG) and IR, and incident diabetes. ApoC-I proteoforms were measured by mass spectrometry immunoassay in plasma from 4,747 participants of the Multi-Ethnic Study of Atherosclerosis that were without diabetes at baseline. IR estimated by HOMA-IR was measured at baseline and at ~10-year follow-up. FG and incident diabetes (FG > 6.99 mmol/l or on diabetes medications) were evaluated for up to 16 years. Lower baseline C-I’/C-I was associated with greater longitudinal increases in FG and IR (by 2.7% [95%CI: 1.5, 3.9] and 4.3% [1.1, 7.3] per 1 SD decrease in C-I’/C-I), and increased risk of diabetes (n=768 events) after adjusting for baseline age, sex, race & ethnicity, income, education, BMI, systolic BP, FG, fasting insulin, antihypertensives and statins use, eGFR and plasma lipids (Hazard ratio: 1.19 [95% CI: 1.10, 1.28]). The association with diabetes was stronger in those with normal than impaired FG (1.20 [1.08, 1.33] vs. 1.09 [0.96, 1.23], p-interaction 0.023). Total apoC-I concentrations were not associated with changes in FG and IR in all models, and with incident diabetes upon adjusting for risk factors.

In conclusion, lower posttranslational apoC-I truncation was associated, independently of typical diabetes risk factors, with greater worsening of IR, greater increase in FG and higher risk of diabetes. The relationship of lower C-I’/C-I with diabetes risk appeared present prior to development of impaired FG. In contrast, total apoC-I concentrations were not related to worsening of glucose metabolism.