1755-P: Insulin-Mediated Glucose Disposal and Muscle Microvascular Recruitment Are Mutual Predictors in Humans

We examined the effects of inhibiting nitric oxide synthase with Nω-nitro-l-arginine-methyl ester (l-NAME) on total hindlimb blood flow, muscle microvascular recruitment, and hindlimb glucose uptake during euglycemic hyperinsulinemia in vivo in the rat. We used two independent methods to measure microvascular perfusion. In one group of animals, microvascular recruitment was measured using the metabolism of exogenously infused 1-methylxanthine (1-MX), and in a second group contrast-enhanced ultrasound (CEU) was used. Limb glucose uptake was measured by arterial-venous concentration differences after 2 h of insulin infusion. Saline alone did not alter femoral artery flow, glucose uptake, or 1-MX metabolism. Insulin (10 mU·min-1·kg-1) significantly increased hindlimb total blood flow (0.69 ± 0.02 to 1.22 ± 0.11 ml/min, P < 0.05), glucose uptake (0.27 ± 0.05 to 0.95 ± 0.08 μmol/min, P < 0.05), 1-MX uptake (5.0 ± 0.5 to 8.5 ± 1.0 nmol/min, P < 0.05), and skeletal muscle microvascular volume measured by CEU (10.0 ± 1.6 to 15.0 ± 1.2 video intensity units, P < 0.05). Addition of l-NAME to insulin completely blocked the effect of insulin on both total limb flow and microvascular recruitment (measured using either 1-MX or CEU) and blunted glucose uptake by 40% ( P < 0.05). We conclude that insulin specifically recruits flow to the microvasculture in skeletal muscle via a nitric oxide-dependent pathway and that this may be important to insulin's overall action to regulate glucose disposal.

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Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00205.2016 ◽

2016 ◽

Vol 311 (3) ◽

pp. E640-E648 ◽

Cited By ~ 13

Author(s):

Weidong Chai ◽

Zhuo Fu ◽

Kevin W. Aylor ◽

Eugene J. Barrett ◽

Zhenqi Liu

Keyword(s):

Insulin Resistance ◽

Endothelial Function ◽

High Fat Diet ◽

Capillary Density ◽

Glucose Disposal ◽

Endothelial Cell Proliferation ◽

High Fat ◽

Euglycemic Hyperinsulinemic Clamp ◽

Receptor Agonists ◽

Microvascular Recruitment

Muscle microvasculature critically regulates endothelial exchange surface area to facilitate transendothelial delivery of insulin, nutrients, and oxygen to myocytes. Insulin resistance blunts insulin-mediated microvascular recruitment and decreases muscle capillary density; both contribute to lower microvascular blood volume. Glucagon-like peptide 1 (GLP-1) and its analogs are able to dilate blood vessels and stimulate endothelial cell proliferation. In this study, we aim to determine the effects of sustained stimulation of the GLP-1 receptors on insulin-mediated capillary recruitment and metabolic insulin responses, small arterial endothelial function, and muscle capillary density. Rats were fed a high-fat diet (HFD) for 4 wk with or without simultaneous administration of liraglutide and subjected to a euglycemic hyperinsulinemic clamp for 120 min after an overnight fast. Insulin-mediated muscle microvascular recruitment and muscle oxygenation were determined before and during insulin infusion. Muscle capillary density was determined and distal saphenous artery used for determination of endothelial function and insulin-mediated vasodilation. HFD induced muscle microvascular insulin resistance and small arterial vessel endothelial dysfunction and decreased muscle capillary density. Simultaneous treatment of HFD-fed rats with liraglutide prevented all of these changes and improved insulin-stimulated glucose disposal. These were associated with a significantly increased AMPK phosphorylation and the expressions of VEGF and its receptors. We conclude that GLP-1 receptor agonists may exert their salutary glycemic effect via improving microvascular insulin sensitivity and muscle capillary density during the development of insulin resistance, and early use of GLP-1 receptor agonists may attenuate metabolic insulin resistance as well as prevent cardiovascular complications of diabetes.

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GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00283.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. E355-E362 ◽

Cited By ~ 33

Author(s):

Kim A. Sjøberg ◽

Jens J. Holst ◽

Stephen Rattigan ◽

Erik A. Richter ◽

Bente Kiens

Keyword(s):

Glucose Uptake ◽

Vascular Function ◽

Vastus Lateralis ◽

Positive Control ◽

Glucose Disposal ◽

Vastus Lateralis Muscle ◽

Gut Hormone ◽

Balance Technique ◽

Glucagon Like Peptide 1 ◽

Microvascular Recruitment

The insulinotropic gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have effects on vascular function and glucose disposal. However, whether GLP-1 is able to increase microvascular recruitment (MVR) in humans has not been investigated. GLP-1 was infused in the femoral artery in overnight-fasted, healthy young men. Microvascular recruitment was measured with real-time contrast-enhanced ultrasound and leg glucose uptake by the leg balance technique with and without inhibition of the insulinotropic response of GLP-1 by coinfusion of octreotide. As a positive control, MVR and leg glucose uptake were measured during a hyperinsulinemic-euglycemic clamp. Infusion of GLP-1 caused a rapid increase ( P < 0.05) of 20 ± 12% (mean ± SE) in MVR in the vastus lateralis muscle of the infused leg after 5 min, and MVR further increased to 60 ± 8% above preinfusion levels by 60 min infusion. The effect was slightly slower but similar in magnitude in the noninfused contralateral leg, in which GLP-1 concentration was within the physiological range. Octreotide infusion did not prevent the GLP-1-induced increase in MVR. GLP-1 infusion did not increase leg glucose uptake with or without octreotide coinfusion. GLP-1 infusion in rats increased MVR by 28% ( P < 0.05) but did not increase muscle glucose uptake. During the hyperinsulinemic clamp, MVR increased ∼40%, and leg glucose uptake increased 35-fold. It is concluded that GLP-1 in physiological concentrations causes a rapid insulin-independent increase in muscle MVR but does not affect muscle glucose uptake.

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Losartan increases muscle insulin delivery and rescues insulin's metabolic action during lipid infusion via microvascular recruitment

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00537.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. E538-E545 ◽

Cited By ~ 24

Author(s):

Nasui Wang ◽

Weidong Chai ◽

Lina Zhao ◽

Lijian Tao ◽

Wenhong Cao ◽

...

Keyword(s):

Insulin Resistance ◽

Angiotensin Ii ◽

Insulin Delivery ◽

Microvascular Perfusion ◽

Whole Body ◽

Glucose Disposal ◽

Lipid Infusion ◽

Metabolic Action ◽

Microvascular Recruitment ◽

Insulin Uptake

Insulin delivery and transendothelial insulin transport are two discrete steps that limit muscle insulin action. Angiotensin II type 1 receptor (AT1R) blockade recruits microvasculature and increases glucose use in muscle. Increased muscle microvascular perfusion is associated with increased muscle delivery and action of insulin. To examine the effect of acute AT1R blockade on muscle insulin uptake and action, rats were studied after an overnight fast to examine the effects of losartan on muscle insulin uptake ( protocol 1), microvascular perfusion ( protocol 2), and insulin's microvascular and metabolic actions in the state of insulin resistance ( protocol 3). Endothelial cell insulin uptake was assessed, using 125I-insulin as tracer. Systemic lipid infusion was used to induce insulin resistance. Losartan significantly increased muscle insulin uptake (∼60%, P < 0.03), which was associated with a two- to threefold increase in muscle microvascular blood volume (MBV; P = 0.002) and flow (MBF; P = 0.002). Losartan ± angiotensin II had no effect on insulin internalization in cultured endothelial cells. Lipid infusion abolished insulin-mediated increases in muscle MBV and MBF and lowered insulin-stimulated whole body glucose disposal ( P = 0.0001), which were reversed by losartan administration. Inhibition of nitric oxide synthase abolished losartan-induced muscle insulin uptake and reversal of lipid-induced metabolic insulin resistance. We conclude that AT1R blockade increases muscle insulin uptake mainly via microvascular recruitment and rescues insulin's metabolic action in the insulin-resistant state. This may contribute to the clinical findings of decreased cardiovascular events and new onset of diabetes in patients receiving AT1R blockers.

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Abstract 308: Losartan Increases Muscle Insulin Delivery via Microvascular Recruitment and Rescues Insulin’s Metabolic Action during Lipid Infusion

Hypertension ◽

10.1161/hyp.60.suppl_1.a308 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Nasui Wang ◽

Weidong Chai ◽

Lina Zhao ◽

Zhenqi Liu

Keyword(s):

Insulin Resistance ◽

Angiotensin Ii ◽

Insulin Delivery ◽

Microvascular Perfusion ◽

Whole Body ◽

Glucose Disposal ◽

Lipid Infusion ◽

Metabolic Action ◽

Microvascular Recruitment ◽

Insulin Uptake

Rationale: Insulin delivery and transendothelial insulin transport are two discrete steps that limit muscle insulin action. Angiotensin II type 1 receptor (AT 1 R) blockade recruits microvasculature and increases glucose use in muscle. Increased muscle microvascular perfusion is associated with increased muscle delivery and action of insulin. Objective: To examine the effect of acute AT 1 R blockade on muscle insulin uptake and action in rats. Methods and Results: Rats were studied after an overnight fast to examine the effects of losartan on muscle insulin uptake (protocol 1), microvascular perfusion (protocol 2), and insulin’s microvascular and metabolic actions in the state of insulin resistance (protocol 3). Endothelial cell insulin uptake was assessed using 125 I-insulin as tracer. Systemic lipid infusion was used to induce insulin resistance. Losartan significantly increased muscle insulin uptake (∼60%, p<0.03), which was associated with 2-3-fold increase in muscle microvascular blood volume (MBV, p=0.002) and flow (MBF, p=0.002). Losartan ± angiotensin II had no effect on insulin internalization in cultured endothelial cells. Lipid infusion abolished insulin-mediated increases in muscle MBV and MBF, and lowered insulin-stimulated whole body glucose disposal (p=0.0001) which were reversed by losartan administration. Inhibition of nitric oxide synthase abolished losartan-induced muscle insulin uptake and reversal of lipid-induced metabolic insulin resistance. Conclusion: AT 1 R blockade increases muscle insulin uptake mainly via microvascular recruitment and rescues insulin’s metabolic action in the insulin resistant state. This may contribute to the clinical findings of decreased cardiovascular events and new onset of diabetes in patients receiving AT 1 R blockers.

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Local NOS inhibition impairs vascular and metabolic actions of insulin in rat hindleg muscle in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00289.2013 ◽

2013 ◽

Vol 305 (6) ◽

pp. E745-E750 ◽

Cited By ~ 22

Author(s):

Eloise A. Bradley ◽

Stephen M. Richards ◽

Michelle A. Keske ◽

Stephen Rattigan

Keyword(s):

Blood Flow ◽

Glucose Uptake ◽

Femoral Artery ◽

Metabolic Effects ◽

Microvascular Blood Flow ◽

Glucose Disposal ◽

Artery Blood Flow ◽

Femoral Artery Blood Flow ◽

Microvascular Recruitment

Insulin stimulates microvascular recruitment in skeletal muscle, and this vascular action augments muscle glucose disposal by ∼40%. The aim of the current study was to determine the contribution of local nitric oxide synthase (NOS) to the vascular actions of insulin in muscle. Hooded Wistar rats were infused with the NOS inhibitor Nω-nitro-l-arginine methylester (l-NAME, 10 μM) retrogradely via the epigastric artery in one leg during a systemic hyperinsulinemic-euglycemic clamp (3 mU·min−1·kg−1 × 60 min) or saline infusion. Femoral artery blood flow, microvascular blood flow (assessed from 1-methylxanthine metabolism), and muscle glucose uptake (2-deoxyglucose uptake) were measured in both legs. Local l-NAME infusion did not have any systemic actions on blood pressure or heart rate. Local l-NAME blocked insulin-stimulated changes in femoral artery blood flow (84%, P < 0.05) and microvascular recruitment (98%, P < 0.05), and partially blocked insulin-mediated glucose uptake in muscle (reduced by 34%, P < 0.05). l-NAME alone did not have any metabolic effects in the hindleg. We conclude that insulin-mediated microvascular recruitment is dependent on local activation of NOS in muscle and that this action is important for insulin's metabolic actions.

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