The vasodilatory actions of insulin on resistance and terminal arterioles and their impact on muscle glucose uptake

Clerk, Lucy H.; Vincent, Michelle A.; Lindner, Jonathan R.; Clark, Michael G.; Rattigan, Stephen; Barrett, Eugene J.

doi:10.1002/dmrr.414

Cited by 94 publications

(68 citation statements)

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“…Only vasodilators that act to recruit nutritive capillaries can potentiate insulin action to increase glucose uptake. It remains to be further investigated whether flow can independently increase glucose uptake once capillary recruitment is maximal as predicted elsewhere [32].…”

Section: Discussionmentioning

confidence: 94%

Local methacholine but not bradykinin potentiates insulin-mediated glucose uptake in muscle in vivo by augmenting capillary recruitment

et al. 2004

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Aims/hypothesis. Insulin has nitric-oxide-dependent vasodilatory effects in muscle, including capillary recruitment, that enhance access for itself and glucose. However, nitric-oxide-dependent vasodilators other than methacholine do not enhance insulin action. Our hypothesis is that methacholine, unlike bradykinin, enhances insulin-mediated glucose uptake in muscle by augmenting capillary recruitment. Methods. Local infusion of either methacholine or bradykinin into one leg of the anaesthetised rat was made during physiological insulin (3 mU·kg −1 ·min −1 ) infusion under euglycaemic conditions and without affecting systemic blood pressure. Whole-body glucose infusion was determined, as was femoral blood flow, 2-deoxyglucose uptake into calf muscles and the metabolism of infused 1-methylxanthine, a measure of capillary recruitment for each leg. Results. Methacholine alone (0.3 µmol·l -1 ) increased femoral arterial blood flow, increased capillary recruitment but had no effect on 2-deoxyglucose uptake of the test leg relative to the contra-lateral control leg. Insulin alone (systemically) required a glucose infusion rate of 8.7 mg·kg −1 ·min −1 to maintain euglycaemia, increased 2-deoxyglucose uptake and capillary recruitment, but was without effect on femoral blood flow in either leg. Local methacholine with systemic insulin infusion increased femoral blood flow, 2-deoxyglucose uptake and capillary recruitment in the test leg only. Bradykinin (0.07 µmol·l -1 ), alone or with insulin, administered in a manner that increased femoral blood flow similarly to methacholine, did not affect 2-deoxyglucose uptake or capillary recruitment. Conclusions/interpretation. Methacholine but not bradykinin enhances insulin-mediated muscle glucose uptake in vivo. We conclude that methacholine acts at specific sites in the vasculature of muscle to stimulate capillary recruitment and thereby enhance insulin access.Keywords Global vasodilatation in muscle · Insulin and glucose delivery to muscle · Muscle blood flow · Specific regional vasodilatation in muscle.

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Section: Discussionmentioning

confidence: 94%

Local methacholine but not bradykinin potentiates insulin-mediated glucose uptake in muscle in vivo by augmenting capillary recruitment

et al. 2004

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“…However, divergent results across studies using differing insulin doses, duration of insulin exposure, and methods of assessing blood flow raised considerable controversy regarding the temporal sequence and physiological significance of the effect of insulin on total blood flow (20 -24). More recent studies (25)(26)(27)(28) have focused on the regulation of tissue perfusion at the microvascular level by capillary recruitment. Expanding the microvascular bed by recruiting previously underperfused capillaries would predictably increase the exchange surface available, even in the absence of changes in total limb blood flow.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia Rapidly Increases Human Muscle Microvascular Perfusion but Fails to Increase Muscle Insulin Clearance

2007

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OBJECTIVE-Transport of insulin from the central circulation into muscle is rate limiting for the stimulation of glucose metabolism. By recruiting muscle microvasculature, insulin may promote its own movement into muscle interstitium. We tested whether in humans, as in the rat, insulin exerts an early action to recruit microvasculature within skeletal muscle. We further hypothesized that expansion of the microvascular volume of muscle would enhance muscle insulin clearance.RESEARCH DESIGN AND METHODS-Microvascular volume, total blood flow, and muscle insulin and glucose uptake (forearm balance method) were measured in 14 lean, healthy volunteers before and during a 2-h hyperinsulinemic-euglycemic clamp (1 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Microvascular volume was measured using contrast-enhanced ultrasound.RESULTS-Forearm muscle microvascular volume increased within 20 min of insulin infusion (P Ͻ 0.01), whereas an effect to increase total forearm flow was not observed until 100 min. Forearm insulin uptake increased with physiological hyperinsulinemia (15 Ϯ 3 and 87 Ϯ 13 fmol ⅐ min Ϫ1 ⅐ 100 ml Ϫ1 basal vs. last 40 min of clamp, P Ͻ 0.001). However, the extraction fraction and clearance of insulin declined (P ϭ 0.02, for each), indicating saturability of muscle insulin uptake at physiological hyperinsulinemia.CONCLUSIONS-Skeletal muscle contributes to peripheral insulin clearance both in the basal state and with physiological hyperinsulinemia. Insulin promptly expands human muscle microvascular volume but only slowly increases blood flow. Despite increased microvascular volume available for insulin uptake, muscle insulin clearance decreases significantly. These findings are consistent with the presence of a saturable transport mechanism facilitating the transendothelial transport of insulin into human muscle.

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“…However, it should be acknowledged that opposing views exist in the literature as to whether the vasodilator effects of (physiological levels of) insulin contribute to the effect of insulin on tissue glucose uptake (17). The emerging view is that insulin may increase capillary recruitment and increase tissue perfusion, without necessarily increasing total blood flow (43). This view could be the explanation for the correlation between the change in foot volume and the metabolic but not vascular action of insulin, as found by post hoc analysis.…”

Section: Characterization Of Subject With Tzd-induced Edemamentioning

confidence: 99%

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

et al. 2006

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OBJECTIVE -The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention.RESEARCH DESIGN AND METHODS -In a randomized, double-blind, placebocontrolled, cross-over study in 18 obese, nondiabetic subjects with features of the metabolic syndrome, we investigated the effects of a 12-week treatment with 4 mg rosiglitazone twice a day on glucose disposal, hemodynamics (including forearm vasoconstrictor response to nitric oxide [NO]), synthase inhibition by N-monomethyl-L-arginine-acetate (L-NMMA), vascular permeability (transcapillary escape rate of albumin), and plasma volume during a hyperinsulinemiceuglycemic clamp (120 min, 120 mU/m 2 per min).RESULTS -As expected, rosiglitazone increased the glucose infusion rate during clamping. However, neither vascular permeability nor forearm blood flow response to hyperinsulinemia or L-NMMA was affected by rosiglitazone. Compared with placebo, rosiglitazone decreased diastolic blood pressure by 5 mmHg (95% CI 2.35-6.87, P ϭ 0.0005) and increased plasma volume by 255 ml/1.73 m 2 (80 -430, P ϭ 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume (R 2 ϭ 0.53, P ϭ 0.001).CONCLUSIONS -Rosiglitazone improved insulin sensitivity but had no effect on NOdependent vasodilatation in the forearm or vascular permeability in obese, insulin-resistant, nondiabetic subjects. As such, TZD-related fluid retention was not caused by improvement of the vascular actions of insulin. Nonetheless, rosiglitazone-induced improvement in insulin sensitivity appears to be correlated to edema formation. Diabetes Care 29:581-587, 2006T hiazolidinedione (TZD) derivatives improve insulin sensitivity and hence are valuable in the treatment of type 2 diabetes (1). Important adverse effects are fluid retention and peripheral edema formation. The precise mechanism(s) of these adverse effects are unclear and probably are multifactorial (2).Although multiple factors are involved, the existence of an initial trigger or main mechanism could be of clinical importance. In theory, the initial trigger of fluid retention may originate either from kidney, heart, or peripheral circulation. As TZD treatment is associated with a reduction in blood pressure (3-6), a primary renal mechanism seems unlikely. A primary cardiac origin also seems improbable, because long-term studies with rosiglitazone have not revealed any negative effect on myocardial structure or function (7).The combination of blood pressure reduction, fluid retention, and edema formation is compatible with changes in the peripheral circulation resulting in capillary leakage. This may be induced by certain actions of TZDs, such as improved insulin-mediated vasodilatation, direct vasoa...

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The vasodilatory actions of insulin on resistance and terminal arterioles and their impact on muscle glucose uptake

Cited by 94 publications

References 68 publications

Local methacholine but not bradykinin potentiates insulin-mediated glucose uptake in muscle in vivo by augmenting capillary recruitment

Local methacholine but not bradykinin potentiates insulin-mediated glucose uptake in muscle in vivo by augmenting capillary recruitment

Hyperinsulinemia Rapidly Increases Human Muscle Microvascular Perfusion but Fails to Increase Muscle Insulin Clearance

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

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