220-OR: Reduced Apolipoprotein C-I Truncation Is Associated with Worsening of Insulin Resistance and Risk of Diabetes in Persons with Impaired Glucose Tolerance

Apolipoprotein C-I (apoC-I) is key regulator of triglyceride and HDL metabolism. It appears as native and truncated posttranslational proteoforms. Higher truncated-to-native apoC-I proteoforms ratio (C-I’/C-I) is associated with favorable cardiometabolic risk profile. Whether apoC-I proteoform composition is associated with declines in insulin sensitivity and secretion, and incident diabetes is unknown. Plasma apoC-I proteoforms (by mass spectrometry immunoassay) were measured at baseline in 524 participants of the ACT NOW, a placebo-controlled study of pioglitazone in impaired glucose tolerance. Baseline and follow-up indices of insulin sensitivity (ISI, by Matsuda’s equation) and secretion (∆I/∆G calculated as AUC_insulin/AUC_glucose) were derived from glucose and insulin concentrations during an OGTT. At baseline, C-I’/C-I correlated with both ISI and ∆I/∆G (r=0.26; r=-0.17, both p<0.0001). Prospectively, higher baseline C-I’/C-I was associated with higher ISI (by 9.4% [95% CI: 4.1, 13.9] per 1 SD; follow-up adjusted for baseline, time of follow-up and treatment group), lower ∆I/∆G (-4.9% [-7.7, -1.0]) and reduced diabetes risk (n=59 events, HR 0.75 [95%CI: 0.57-0.98]). The C-I’/C-I associations with insulin sensitivity and diabetes were independent of diabetes risk factors (e.g., BMI) and plasma lipids (HR 0.72 [0.54-0.96]). The C-I’/C-I association with diabetes was attenuated after adjusting for change (follow-up adjusting for baseline) in ISI (HR 0.82 [0.61-1.11]) but not in ∆I/∆G (HR 0.67 [0.49-0.93]).

In conclusion, lower apoC-I truncation was associated, independently of typical diabetes risk factors, with decline in insulin sensitivity and increased risk of diabetes in individuals with impaired glucose tolerance. The association with incident diabetes appears to reflect favorable effects of apoC-I truncation on insulin sensitivity but not on insulin secretion.