Fitness Abrogates the Ability of Free Fatty Acids (FFA) to Inhibit Insulin's Microvascular Action

Abstract

Insulin acutely (within 20 min) increases microvascular blood volume (MBV) within human forearm muscle as measured by contrast enhanced ultrasound (CEU). This serves to increase insulin delivery to muscle and facilitates insulin's metabolic action. This vascular effect of insulin is impaired by the insulin resistance that accompanies either chronic obesity or acute (within 2-4hr) increases in the circulating levels of FFA. Interestingly, and as yet unexplained, raising plasma FFA via infusion of Intralipid has less effect on insulin sensitivity in individuals who are highly trained. It is not known whether training affects the ability of FFA to inhibit insulin-induced microvascular recruitment. PURPOSE: The current study was undertaken to address whether the level of fitness (VO2 max) or adiposity (% body fat) predicted MBV and/or glucose infusion rate (GIR) during a euglycemic insulin clamp. METHODS: A group (n =11) of young (18-35), lean (BMI≤25), healthy subjects received Intralipid 20% + heparin for 5 hrs (3hr prior to and throughout a 2hr, 1mU/kg/min insulin clamp). MBV as measured by CEU was obtained continuously during the first 30 min of the clamp. Fitness level was assessed by conducting an exercise test (Bruce protocol) to obtain VO2 max in a subset (n=8) on a separate day. RESULTS: We found that VO2 max was a strong predictor of MBV (r = 0.74 p <0.05) the GIR likewise strongly correlated with MBV(r = 0.75, p= 0.01) supporting the hypothesis that insulin's vascular action is a significant contributor to its metabolic effects. We also observed the expected inverse relationship between VO2 max and % body fat (r = -0.79, p= 0.02). CONCLUSION: Fitness limits the ability of elevated FFA to block both insulin's vasodilatory and metabolic effects. The increased microvascular surface area in response to insulin seen in those with higher VO2 max can facilitate exchange of insulin and glucose with muscle interstitium thereby contributing to the higher GIR. In addition the lower body fat %, therefore greater % lean body mass, may also contribute to the higher GIR. Taken together these findings suggest that a more fit person is less likely to develop either vascular or metabolic insulin resistance in response to elevated circulation FFA. The mechanism for the protective effect of fitness is unclear. Supported by NIH Grant RO1 DK073759