Acipimox in Type 1 Diabetes: fatty acids as a potential, but challenging, therapeutic target

Objective: To examine the effect of acute, isolated non-esterified fatty acid lowering, on insulin action, arterial stiffness and cardiac autonomic function in type I diabetes.

Methods: Randomized, double-blind, crossover trial of acipimox versus placebo in participants with and without type 1 diabetes (n=9 and 8, respectively).

Results: Participants with type 1 diabetes were more insulin resistant than controls and exhibited increased arterial stiffness (pulse wave velocity and augmentation index), autonomic dysregulation (heart rate variability), cardiac diastolic dysfunction (E:A ratio), and increased cardiac contractility (fractional shortening) with preserved cardiac output. Acipimox treatment was confounded by a pronounced early rebound effect. However, independent of acipimox, within-subject higher pretest fatty acid levels corresponded to greater insulin resistance, higher mean tachycardic heart rates at rest, and possibly increased cardiac output.

Conclusions: These findings confirm and expand upon previous observations that individuals with type 1 diabetes are more insulin resistant and exhibit cardiovascular changes consistent with increased sympathetic tone. The correlation of poor peripheral glucose utilization and cardiovascular changes with elevated fatty acid levels suggests that lowering fatty acid levels may improve insulin sensitivity and decrease sympathetic tone. In the future, a more durable or targeted method of fatty acid lowering could represent a novel cardioprotective target of intervention in people with type 1 diabetes.