Impact of Free Fatty Acids on Vascular Insulin Responses Across the Arterial Tree: A Randomized Crossover Study

Abstract

Context: Vascular insulin resistance is commonly observed in obesity and diabetes; yet, insulin action across the vascular tree and the relationship between insulin responses at different vascular locations remains incompletely defined.

Objective: To elucidate the impact of elevated free fatty acids (FFAs) on insulin action across the arterial tree and define the relationship among insulin actions in the different arterial segments.

Methods: This randomized crossover study assigned healthy lean adults to 2 separate admissions with euglycemic insulin clamp superimposed for the final 120 minutes of 5-hour lipid or matched-volume saline infusion. Vascular measures including peripheral and central arterial blood pressure, brachial artery flow-mediated dilation (FMD), carotid femoral pulse wave velocity (cfPWV), augmentation index (AIx), pulse wave separation analysis, subendocardial viability ratio (SEVR), and skeletal and cardiac muscle microvascular perfusion were determined before and after insulin clamp. Insulin-mediated whole body glucose disposal was calculated.

Results: Insulin enhanced FMD, AIx, reflection magnitude, and cardiac and skeletal muscle microvascular perfusion. Elevation of plasma FFA concentrations to the levels seen in the postabsorptive state in people with insulin resistance suppressed SEVR, blunted insulin-induced increases in FMD and cardiac and skeletal muscle microvascular blood volume, and lowered insulin's ability to reduce AIx and reflection magnitude. In multivariate regression, insulin-mediated muscle microvascular perfusion was independently associated with insulin-mediated FMD and cfPWV.

Conclusion: Clinically relevant elevation of plasma FFA concentrations induces pan-arterial insulin resistance, the vascular insulin resistance outcomes are interconnected, and insulin-mediated muscle microvascular perfusion associates with cardiovascular disease predictors. Our data provide biologic plausibility whereby a causative relationship between FFAs and cardiovascular disease could exist, and suggest that further attention to interventions that block FFA-mediated vascular insulin resistance may be warranted.

Keywords: arterial stiffness; endothelium; flow-mediated dilation; free fatty acids; insulin; microvasculature.

Figure 1.

CONSORT flow diagram.

Figure 2.

(A) Study protocol for admissions. BD, blood draw; GLP-1, glucagon like peptide-1; NO, nitric oxide; FFA, free fatty acids. (B) Mean glucose infusion rate during euglycemic insulin clamp with standard error of mean (bars) during euglycemic insulin clamp. (C) Mean FFA concentrations with standard error of mean during euglycemic insulin clamp. Open circles = saline admission, black squares = lipid admission. *P < .0001, 2-way ANOVA analysis comparing final 40 minutes of euglycemic insulin clamp between admissions. #P < .0001, paired t-test comparing time 0 and time 120 minutes.

Figure 3.

(A) FMD. (B) Cardiac MBV. (C) Cardiac MFV. (D) Skeletal muscle MBV. (E) Skeletal muscle MFV. Open circles = 0 minutes (pre-insulin clamp). Open triangles = 120 minutes (postinsulin clamp). (F) Scatter plot showing the relationship between insulin-mediated FMD and insulin-mediated skeletal muscle MBV. Open circles = saline admission, black squares = lipid admission. Solid line = best fit line, dotted line = 95% CI of best fit line. FMD, flow-mediated dilation; MBV, microvascular blood volume, MFV, microvascular flow velocity.

Figure 4.

Clinically relevant elevation of plasma FFA concentrations induces pan-arterial insulin resistance and measures of nitric oxide–dependent endothelial function are closely related. AIx, augmentation index; cfPWV, carotid femoral pulse wave velocity; FMD, flow-mediated dilation; MBV, microvascular blood volume; SEVR, subendocardial viability ratio.