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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 antagonism attenuates insulin-mediated whole-body glucose disposal. Each rat received 2 h of insulin infusion in the absence or presence of either PD123319 infusion (50 μg/kg/min, started at time −5 or 30 min) or losartan injection (0.3 mg/kg i.v. at time −5 min). n = 8–16. *P < 0.02 (ANOVA).
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Figure 2: AT2R antagonism attenuates insulin-mediated whole-body glucose disposal. Each rat received 2 h of insulin infusion in the absence or presence of either PD123319 infusion (50 μg/kg/min, started at time −5 or 30 min) or losartan injection (0.3 mg/kg i.v. at time −5 min). n = 8–16. *P < 0.02 (ANOVA).

Mentions: We have previously demonstrated that basal AT1R and AT2R regulate muscle microvascular volume and glucose use (21). Because the microvasculature plays an important role in insulin delivery and substrate exchange between the plasma and interstitial compartments, we first examined whether changes in AT1R and AT2R activities altered insulin-mediated glucose disposal. As shown in Fig. 2, injection of losartan had no effect on insulin-mediated glucose disposal. On the other hand, PD123319 infusion, given either immediately before or 30 min after the initiation of insulin infusion, promptly attenuated insulin-stimulated whole-body glucose disposal, and this effect was maintained during the entire 120 or 90 min of PD123319 infusion (P < 0.02, ANOVA). At steady state, AT2R blockade decreased the whole-body glucose disposal rate by ~30% (P = 0.02 for both PD123319 groups). In saline-only rats, the microvascular parameters did not change significantly during the course of the study.


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 antagonism attenuates insulin-mediated whole-body glucose disposal. Each rat received 2 h of insulin infusion in the absence or presence of either PD123319 infusion (50 μg/kg/min, started at time −5 or 30 min) or losartan injection (0.3 mg/kg i.v. at time −5 min). n = 8–16. *P < 0.02 (ANOVA).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 2: AT2R antagonism attenuates insulin-mediated whole-body glucose disposal. Each rat received 2 h of insulin infusion in the absence or presence of either PD123319 infusion (50 μg/kg/min, started at time −5 or 30 min) or losartan injection (0.3 mg/kg i.v. at time −5 min). n = 8–16. *P < 0.02 (ANOVA).
Mentions: We have previously demonstrated that basal AT1R and AT2R regulate muscle microvascular volume and glucose use (21). Because the microvasculature plays an important role in insulin delivery and substrate exchange between the plasma and interstitial compartments, we first examined whether changes in AT1R and AT2R activities altered insulin-mediated glucose disposal. As shown in Fig. 2, injection of losartan had no effect on insulin-mediated glucose disposal. On the other hand, PD123319 infusion, given either immediately before or 30 min after the initiation of insulin infusion, promptly attenuated insulin-stimulated whole-body glucose disposal, and this effect was maintained during the entire 120 or 90 min of PD123319 infusion (P < 0.02, ANOVA). At steady state, AT2R blockade decreased the whole-body glucose disposal rate by ~30% (P = 0.02 for both PD123319 groups). In saline-only rats, the microvascular parameters did not change significantly during the course of the study.

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