Physiologic Hyperinsulinemia Enhances Human Skeletal Muscle Perfusion by Capillary Recruitment

Abstract

Despite intensive study, the relation between insulin's action on blood flow and glucose metabolism remains unclear. Insulin-induced changes in microvascular perfusion, independent from effects on total blood flow, could be an important variable contributing to insulin's metabolic action. We hypothesized that modest, physiologic increments in plasma insulin concentration alter microvascular perfusion in human skeletal muscle and that these changes can be assessed using contrastenhanced ultrasound (CEU), a validated method for quantifying flow by measurement of microvascular blood volume (MBV) and microvascular flow velocity (MFV). In the first protocol, 10 healthy, fasting adults received insulin (0.05 mU ⅐ kg ؊1 ⅐ min ؊1 ) via a brachial artery for 4 h under euglycemic conditions. At baseline and after insulin infusion, MBV and MFV were measured by CEU during continuous intravenous infusion of albumin microbubbles with intermittent harmonic ultrasound imaging of the forearm deep flexor muscles. In the second protocol, 17 healthy, fasting adults received a 4-h infusion of either insulin (0.1 mU ⅐ kg ؊1 ⅐ min ؊1 , n ‫؍‬ 9) or saline (n ‫؍‬ 8) via a brachial artery. Microvascular volume was assessed in these subjects by an alternate CEU technique using an intra-arterial bolus injection of albumin microbubbles at baseline and after the 4-h infusion. With both protocols, muscle glucose uptake, plasma insulin concentration, and total blood flow to the forearm were measured at each stage. In protocol 2 subjects, tissue extraction of 1-methylxanthine (1-MX) was measured as an index of perfused capillary volume. Caffeine, which produces 1-MX as a metabolite, was administered to these subjects before the study to raise plasma 1-MX levels.In protocol 1 subjects, insulin increased muscle glucose uptake (180%, P < 0.05) and MBV (54%, P < 0.01) and decreased MFV (؊42%, P ‫؍‬ 0.07) in the absence of significant changes in total forearm blood flow. In protocol 2 subjects, insulin increased glucose uptake (220%, P < 0.01) and microvascular volume (45%, P < 0.05) with an associated moderate increase in total forearm blood flow (P < 0.05). Using forearm 1-MX extraction, we observed a trend, though not significant, toward increasing capillary volume in the insulin-treated subjects. In conclusion, modest physiologic increments in plasma insulin concentration increased microvascular blood volume, indicating altered microvascular perfusion consistent with a mechanism of capillary recruitment. The increases in microvascular (capillary) volume (despite unchanged total blood flow) indicate that the relation between insulin's vascular and metabolic actions cannot be fully understood using measurements of bulk blood flow alone.

Physiological hyperinsulinaemia increases intramuscular microvascular reactive hyperaemia and vasomotion in healthy volunteers

“…The present results are in agreement with previous studies that have demonstrated insulin-mediated effects on microvascular perfusion in human muscle using positron emission tomography or contrastenhanced ultrasound [6,7]. However, these methods do not measure muscle perfusion in real time and are therefore not able to measure vasomotion.…”

“…In addition, iontophorised insulin can directly increase skin microvascular perfusion, indicating a direct local microvascular effect of insulin [8]. Moreover, animal and human studies suggest that insulin-induced changes in basal microvascular perfusion occur before changes in total blood flow demonstrating an independency of both phenomena [5,7,27].…”

“…In humans, hyperinsulinaemia increased the distribution volume of glucose [6] and specifically increased capillary blood volume as measured with contrast-enhanced ultrasound [7]. In human skin, we have recently shown that insulin is capable of inducing functional recruitment of capillaries [8].…”

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

“…1 Values are means±SE for n=8 in each group *p<0.05 difference from saline; # p<0.05 difference from insulin contrast, there is growing evidence that insulin-mediated capillary recruitment may play a key role in muscle glucose uptake, particularly in animal models [18] and is impaired in animal models of muscle insulin resistance [12][13][14]41] and in obese humans [42,43]. Capillary recruitment is controlled independently of limb blood flow [17,18,21] and occurs in response to locally administered physiological insulin in human forearm in association with glucose uptake [44]. In the absence of an endothelial involvement, insulin may act directly on vascular smooth muscle cells of the terminal arterioles to mediate capillary recruitment.…”

“…However, in the present studies, the heart rate and blood pressure were normal and other recent studies have shown that insulin-mediated capillary recruitment occurred early, relative to muscle glucose uptake [18] and at physiological doses of insulin [17], indicating that a desensitising effect of the anaesthetic is unlikely. Moreover, studies in human forearm, where the subjects were instructed to remain still, have shown insulin-mediated capillary recruitment, again at physiological insulin levels [44].…”