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Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo.

Chai W, Wang W, Dong Z, Cao W, Liu Z - Diabetes (2011)

Bottom Line: Unopposed AT(2)R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT(1)R activity decreases both.AT(2)R blockade abolished insulin-mediated increases in muscle MBV and MBF and decreased insulin-stimulated glucose disposal by ~30%.In contrast, losartan plus insulin increased muscle MBV by two- to threefold without further increasing insulin-stimulated glucose disposal.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia, USA.

ABSTRACT

Objective: Angiotensin (ANG) II interacts with insulin-signaling pathways to regulate insulin sensitivity. The type 1 (AT(1)R) and type 2 (AT(2)R) receptors reciprocally regulate basal perfusion of muscle microvasculature. Unopposed AT(2)R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT(1)R activity decreases both. The current study examined whether ANG II receptors modulate muscle insulin delivery and sensitivity.

Research design and methods: Overnight-fasted rats were studied. In protocol 1, rats received a 2-h infusion of saline, insulin (3 mU/kg/min), insulin plus PD123319 (AT(2)R blocker), or insulin plus losartan (AT(1)R blocker, intravenously). Muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined. In protocol 2, rats received (125)I-insulin with or without PD123319, and muscle insulin uptake was determined.

Results: Insulin significantly increased muscle MBV and MBF. AT(2)R blockade abolished insulin-mediated increases in muscle MBV and MBF and decreased insulin-stimulated glucose disposal by ~30%. In contrast, losartan plus insulin increased muscle MBV by two- to threefold without further increasing insulin-stimulated glucose disposal. Plasma nitric oxide increased by >50% with insulin and insulin plus losartan but not with insulin plus PD123319. PD123319 markedly decreased muscle insulin uptake and insulin-stimulated Akt phosphorylation.

Conclusions: We conclude that both AT(1)Rs and AT(2)Rs regulate insulin's microvascular and metabolic action in muscle. Although AT(1)R activity restrains muscle metabolic responses to insulin via decreased microvascular recruitment and insulin delivery, AT(2)R activity is required for normal microvascular responses to insulin. Thus, pharmacologic manipulation aimed at increasing the AT(2)R-to-AT(1)R activity ratio may afford the potential to improve muscle insulin sensitivity and glucose metabolism.

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Related in: MedlinePlus

AT2R blockade decreases skeletal muscle 125I-insulin uptake. Five minutes after bolus injection of 125I-insulin (1.5 μCi i.v.), blood and skeletal muscle samples were collected, and intact 125I-insulin was determined after trichloroacetic acid precipitation. A: Fraction of plasma-intact 125I-insulin. B: Muscle 125I-insulin uptake. n = 4–6. Compared with saline, *P < 0.05.
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Figure 7: AT2R blockade decreases skeletal muscle 125I-insulin uptake. Five minutes after bolus injection of 125I-insulin (1.5 μCi i.v.), blood and skeletal muscle samples were collected, and intact 125I-insulin was determined after trichloroacetic acid precipitation. A: Fraction of plasma-intact 125I-insulin. B: Muscle 125I-insulin uptake. n = 4–6. Compared with saline, *P < 0.05.

Mentions: The above data clearly indicate that AT2R blockade attenuates insulin-mediated muscle microvascular recruitment, glucose disposal, and signaling. To this end, we examined whether modulating the ANG II receptor stimulation by endogenous ANG II would alter muscle insulin delivery and uptake (protocol 2). As shown in Fig. 7, infusion of PD123319 did not significantly alter 125I-insulin degradation in the plasma (Fig. 7A). However, it decreased muscle 125I-insulin content by nearly 50% (P < 0.05), confirming a decreased muscle insulin uptake in the presence of AT2R blockade.


Angiotensin II receptors modulate muscle microvascular and metabolic responses to insulin in vivo.

Chai W, Wang W, Dong Z, Cao W, Liu Z - Diabetes (2011)

AT2R blockade decreases skeletal muscle 125I-insulin uptake. Five minutes after bolus injection of 125I-insulin (1.5 μCi i.v.), blood and skeletal muscle samples were collected, and intact 125I-insulin was determined after trichloroacetic acid precipitation. A: Fraction of plasma-intact 125I-insulin. B: Muscle 125I-insulin uptake. n = 4–6. Compared with saline, *P < 0.05.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198098&req=5

Figure 7: AT2R blockade decreases skeletal muscle 125I-insulin uptake. Five minutes after bolus injection of 125I-insulin (1.5 μCi i.v.), blood and skeletal muscle samples were collected, and intact 125I-insulin was determined after trichloroacetic acid precipitation. A: Fraction of plasma-intact 125I-insulin. B: Muscle 125I-insulin uptake. n = 4–6. Compared with saline, *P < 0.05.
Mentions: The above data clearly indicate that AT2R blockade attenuates insulin-mediated muscle microvascular recruitment, glucose disposal, and signaling. To this end, we examined whether modulating the ANG II receptor stimulation by endogenous ANG II would alter muscle insulin delivery and uptake (protocol 2). As shown in Fig. 7, infusion of PD123319 did not significantly alter 125I-insulin degradation in the plasma (Fig. 7A). However, it decreased muscle 125I-insulin content by nearly 50% (P < 0.05), confirming a decreased muscle insulin uptake in the presence of AT2R blockade.

Bottom Line: Unopposed AT(2)R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT(1)R activity decreases both.AT(2)R blockade abolished insulin-mediated increases in muscle MBV and MBF and decreased insulin-stimulated glucose disposal by ~30%.In contrast, losartan plus insulin increased muscle MBV by two- to threefold without further increasing insulin-stimulated glucose disposal.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia, USA.

ABSTRACT

Objective: Angiotensin (ANG) II interacts with insulin-signaling pathways to regulate insulin sensitivity. The type 1 (AT(1)R) and type 2 (AT(2)R) receptors reciprocally regulate basal perfusion of muscle microvasculature. Unopposed AT(2)R activity increases muscle microvascular blood volume (MBV) and glucose extraction, whereas unopposed AT(1)R activity decreases both. The current study examined whether ANG II receptors modulate muscle insulin delivery and sensitivity.

Research design and methods: Overnight-fasted rats were studied. In protocol 1, rats received a 2-h infusion of saline, insulin (3 mU/kg/min), insulin plus PD123319 (AT(2)R blocker), or insulin plus losartan (AT(1)R blocker, intravenously). Muscle MBV, microvascular flow velocity, and microvascular blood flow (MBF) were determined. In protocol 2, rats received (125)I-insulin with or without PD123319, and muscle insulin uptake was determined.

Results: Insulin significantly increased muscle MBV and MBF. AT(2)R blockade abolished insulin-mediated increases in muscle MBV and MBF and decreased insulin-stimulated glucose disposal by ~30%. In contrast, losartan plus insulin increased muscle MBV by two- to threefold without further increasing insulin-stimulated glucose disposal. Plasma nitric oxide increased by >50% with insulin and insulin plus losartan but not with insulin plus PD123319. PD123319 markedly decreased muscle insulin uptake and insulin-stimulated Akt phosphorylation.

Conclusions: We conclude that both AT(1)Rs and AT(2)Rs regulate insulin's microvascular and metabolic action in muscle. Although AT(1)R activity restrains muscle metabolic responses to insulin via decreased microvascular recruitment and insulin delivery, AT(2)R activity is required for normal microvascular responses to insulin. Thus, pharmacologic manipulation aimed at increasing the AT(2)R-to-AT(1)R activity ratio may afford the potential to improve muscle insulin sensitivity and glucose metabolism.

Show MeSH
Related in: MedlinePlus