Early microvascular recruitment modulates subsequent insulin-mediated skeletal muscle glucose metabolism during lipid infusion

Abstract

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 V(O(2max)) in a subset of eight subjects. Fitness (V(O(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.

Figure 1

A: The correlation between the GIR and FGU, each measured during the last 40 min of the euglycemic insulin clamp. B: The correlation between FGU measured during the last 40 min of the insulin clamp and the percentage change of MBV measured during the first 30 min of insulin infusion. C: The correlation of GIR measured during the last 40 min of the insulin clamp with the percentage change in MBV during the initial 30 min of insulin infusion. FAV, forearm volume.

Figure 2

A: The mean ± SEM of FGU observed in the five individuals who either had no increase in MBV or had an actual decline (lowest tertile) versus that in the five individuals who had the greatest percent increase in MBV (highest tertile). B: The mean ± SEM changes in FIU between baseline and the last 40 min of the insulin clamp in the same two groups. The P values were determined by unpaired t tests. FAV, forearm volume.

Figure 3

A: The correlation between whole-body GIR and FGU, each measured during the last 40 min of the insulin clamp, in eight individuals in whom fitness was assessed by Vo_2max. B: The correlation between the Vo_2max and FGU in the same individuals. C: The correlation between Vo_2max and the percentage change in MBV seen during the first 30 min of insulin infusion in the same individuals. D: The correlation between FGU measured during the last 40 min of the insulin clamp and the percentage change of MBV measured during the first 30 min of the insulin infusion in the same individuals. FAV, forearm volume.