Early Microvascular Recruitment Modulates Subsequent Insulin-Mediated Skeletal Muscle Glucose Metabolism During Lipid Infusion

OBJECTIVE

To test whether early, insulin-mediated microvascular recruitment in skeletal muscle predicts steady-state glucose metabolism in the setting of physiological elevation of free fatty acid concentrations.

RESEARCH DESIGN AND METHODS

We measured insulin’s microvascular and metabolic effects in 14 healthy young adults during a 2-h euglycemic insulin clamp. Plasma free fatty acid concentrations were raised (Intralipid and heparin infusion) for 3 h before the clamp and maintained at postprandial concentrations during the clamp. Microvascular blood volume (MBV) was measured by contrast-enhanced ultrasound (CEU) continuously from baseline through the first 30 min of the insulin clamp. Muscle glucose and insulin uptake were measured by the forearm balance method.

RESULTS

The glucose infusion rate (GIR) necessary to maintain euglycemia during the clamp varied by fivefold across subjects (2.5–12.5 mg/min/kg). The early MBV responses to insulin, as indicated by CEU video intensity, ranged widely, from a 39% decline to a 69% increase. During the clamp, steady state forearm muscle glucose uptake and GIR each correlated significantly with the change in forearm MBV (P < 0.01). To explore the basis for the wide range of vascular and metabolic insulin sensitivity observed, we also measured Vo_2max in a subset of eight subjects. Fitness (Vo_2max) correlated significantly with the GIR, the forearm glucose uptake, and the percentage change in MBV during the insulin clamp (P < 0.05 for each).

CONCLUSIONS

Early microvascular responses to insulin strongly associate with steady state skeletal muscle insulin-mediated glucose uptake. Physical fitness predicts both metabolic and vascular insulin responsiveness.Insulin recruits underperfused capillaries to increase skeletal muscle microvascular blood volume (MBV), as measured by contrast-enhanced ultrasound (CEU), within 20 min in both rats (1) and humans (2,3). This effect occurs with physiological insulin concentrations (2,4) and precedes both changes in total limb blood flow (1,5,6) and insulin’s metabolic action (1). In rodents, microvascular recruitment enhances the rate at which insulin is delivered to muscle interstitium (7), thereby facilitating insulin’s metabolic action, and exercise training has been shown to enhance insulin-induced microvascular recruitment and muscle glucose disposal in rodents (8).Raising plasma concentrations of free fatty acids (FFAs) induces insulin resistance within 2–4 h, can induce inflammation in muscle (9) and in circulating leukocytes (10), and produces endothelial dysfunction (10,11). Clinical studies have shown a marked impairment in insulin’s ability to recruit both muscle and skin microvasculature in chronically insulin-resistant obese subjects (12–14). FFA-induced insulin resistance impairs insulin-mediated microvascular recruitment in skin with elevation of FFA to physiological levels (∼1 mmol/L) (15) and in muscle microvasculature with higher FFA levels ∼3 mmol/L (16).Both acute exercise and training can affect the metabolic response to raising plasma FFA. Raising plasma FFA acutely through lipid and heparin infusion has less effect on insulin sensitivity in individuals who exercised intensively the preceding day (17). Exercise training also prevents FFA-induced hepatic and peripheral insulin resistance (18). It is not known whether training affects insulin-induced microvascular recruitment or the ability of FFA to inhibit recruitment in humans.Recently, we reported that human skeletal muscle insulin uptake (product of forearm blood flow and arteriovenous concentration) could be quantified and that it occurred through a saturable transport process at physiological concentrations of insulin (2). Whether FFA elevation would, by blocking insulin-induced increases in MBV, also limit muscle insulin uptake is not known.In this study, CEU was used to measure muscle microvascular perfusion and paired arterial and venous sampling to measure muscle insulin and glucose uptake in response to a physiologic insulin infusion in 14 healthy volunteers whose plasma FFA levels were maintained in a range encountered in human insulin-resistant states (∼1.0 mmol/L). To examine whether fitness was predictive of these responses, a subset of 8 volunteers underwent maximal exercise testing to quantify the relationship between Vo_2max and muscle metabolic and microvascular insulin sensitivity.