Activity restriction, impaired capillary function, and the development of insulin resistance in lean primates

Abstract

Insulin produces capillary recruitment in skeletal muscle through a nitric oxide (NO)-dependent mechanism. Capillary recruitment is blunted in obese and diabetic subjects and contributes to impaired glucose uptake. This study's objective was to define whether inactivity, in the absence of obesity, leads to impaired capillary recruitment and contributes to insulin resistance (IR). A comprehensive metabolic and vascular assessment was performed on 19 adult male rhesus macaques (Macaca mulatta) after sedation with ketamine and during maintenance anesthesia with isoflurane. Thirteen normal-activity (NA) and six activity-restricted (AR) primates underwent contrast-enhanced ultrasound to determine skeletal muscle capillary blood volume (CBV) during an intravenous glucose tolerance test (IVGTT) and during contractile exercise. NO bioactivity was assessed by flow-mediated vasodilation. Although there were no differences in weight, basal glucose, basal insulin, or truncal fat, AR primates were insulin resistant compared with NA primates during an IVGTT (2,225 ± 734 vs. 5,171 ± 3,431 μg·ml⁻¹·min⁻¹, P < 0.05). Peak CBV was lower in AR compared with NA primates during IVGTT (0.06 ± 0.01 vs. 0.12 ± 0.02 ml/g, P < 0.01) and exercise (0.10 ± 0.02 vs. 0.20 ± 0.02 ml/g, P < 0.01), resulting in a lower peak skeletal muscle blood flow in both circumstances. The insulin-mediated changes in CBV correlated inversely with the degree of IR and directly with activity. Flow-mediated dilation was lower in the AR primates (4.6 ± 1.0 vs. 9.8 ± 2.3%, P = 0.01). Thus, activity restriction produces impaired skeletal muscle capillary recruitment during a carbohydrate challenge and contributes to IR in the absence of obesity. Reduced NO bioactivity may be a pathological link between inactivity and impaired capillary function.

Figures

Fig. 1.

Assessment of 14,15-epoxyeicosatrienoic acids (14,15-EETs) and nitric oxide-mediated vasodilation. A: mean (± SE) values for 14,15-EET levels. B: baseline brachial artery dimension. C: postocclusive change in brachial artery dimension from baseline. D: %change in brachial artery dimension. *P < 0.05 vs. normal activity (NA) group. AR, activity restricted.

Fig. 2.

Forearm flexor perfusion at rest and during exercise. Mean (± SE) values for capillary blood volume (CBV), capillary blood flux rate, and microvascular blood flow from contrast-enhanced ultrasound performed at baseline and during contractile exercise for NA and AR primates. *P < 0.05 vs. NA group; †P < 0.05 vs. baseline.

Fig. 3.

Gastrocnemius baseline and peak perfusion after glucose challenge. Mean (± SE) values for CBV, capillary blood flux rate, and microvascular blood flow from contrast-enhanced ultrasound performed at baseline and peak hyperemia during intravenous glucose tolerance test (IVGTT). *P < 0.05 vs. NA group.

Fig. 4.

Contrast-enhanced ultrasound in a NA and an AR primate. Contrast-enhanced ultrasound time vs. CBV curves obtained during rest and peak hyperemia during an IVGTT for a NA subject (A) and an AR subject (B). Corresponding background-subtracted color-coded contrast-enhanced ultrasound images at increasing pulsing intervals (PI) are at right.

Fig. 5.

Correlation of CBV reserve and insulin resistance. Relation between CBV reserve and insulin area under the curve (AUC) during IVGTT (Spearman's test).

Fig. 6.

Correlation of activity with CBV reserve and microvascular insulin resistance. Relation between daily activity and either CBV reserve during IVGTT (Pearson's test; A) or microvascular insulin resistance index = (Δinsulin/peak CBV) during IVGTT (Spearman's test; B).