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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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AT2R blockade decreases insulin-stimulated NO production and skeletal muscle Akt phosphorylation. A: Changes in plasma NO levels. n = 5–6. P = 0.005 (ANOVA). Compared with saline, *P < 0.01; compared with insulin, #P < 0.05. B: Changes in muscle Akt phosphorylation. n = 7–9. P < 0.001 (ANOVA). Compared with saline, *P < 0.01; compared with insulin, #P < 0.04. C: Changes in muscle eNOS phosphorylation. n = 4. P > 0.05 (ANOVA). For gel images in B and C, they were from different parts of the same gels with same exposure.
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Figure 6: AT2R blockade decreases insulin-stimulated NO production and skeletal muscle Akt phosphorylation. A: Changes in plasma NO levels. n = 5–6. P = 0.005 (ANOVA). Compared with saline, *P < 0.01; compared with insulin, #P < 0.05. B: Changes in muscle Akt phosphorylation. n = 7–9. P < 0.001 (ANOVA). Compared with saline, *P < 0.01; compared with insulin, #P < 0.04. C: Changes in muscle eNOS phosphorylation. n = 4. P > 0.05 (ANOVA). For gel images in B and C, they were from different parts of the same gels with same exposure.

Mentions: The rapid attenuation of insulin-stimulated whole-body glucose disposal and muscle microvascular recruitment by PD123319 prompted us to further examine the impact of ANG II receptor stimulation by endogenous ANG II on the insulin effects on the vasculature (NO production) and muscle (Akt phosphorylation). Both insulin and losartan increase microvascular recruitment via a NO-dependent pathway (6,21). As shown in Fig. 6A, 2 h of insulin infusion increased plasma NO levels by nearly twofold (P < 0.01). Concurrent PD123319 infusion decreased insulin-mediated increases in plasma NO levels by 37% (P < 0.04) to levels that were not significantly different from the saline controls. On the other hand, losartan injection had no significant impact on insulin-stimulated NO production. Figure 6B shows insulin-stimulated Akt phosphorylation in the skeletal muscle. Similar to the pattern of plasma NO levels, insulin significantly increased muscle Akt phosphorylation, and this effect was suppressed back to the saline control level when PD123319 infusion was superimposed on insulin infusion. Again, losartan had no effect on insulin-stimulated Akt phosphorylation in muscle. Muscle endothelial NO synthase (eNOS) phosphorylation did not differ among all four groups (Fig. 6C).


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 insulin-stimulated NO production and skeletal muscle Akt phosphorylation. A: Changes in plasma NO levels. n = 5–6. P = 0.005 (ANOVA). Compared with saline, *P < 0.01; compared with insulin, #P < 0.05. B: Changes in muscle Akt phosphorylation. n = 7–9. P < 0.001 (ANOVA). Compared with saline, *P < 0.01; compared with insulin, #P < 0.04. C: Changes in muscle eNOS phosphorylation. n = 4. P > 0.05 (ANOVA). For gel images in B and C, they were from different parts of the same gels with same exposure.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: AT2R blockade decreases insulin-stimulated NO production and skeletal muscle Akt phosphorylation. A: Changes in plasma NO levels. n = 5–6. P = 0.005 (ANOVA). Compared with saline, *P < 0.01; compared with insulin, #P < 0.05. B: Changes in muscle Akt phosphorylation. n = 7–9. P < 0.001 (ANOVA). Compared with saline, *P < 0.01; compared with insulin, #P < 0.04. C: Changes in muscle eNOS phosphorylation. n = 4. P > 0.05 (ANOVA). For gel images in B and C, they were from different parts of the same gels with same exposure.
Mentions: The rapid attenuation of insulin-stimulated whole-body glucose disposal and muscle microvascular recruitment by PD123319 prompted us to further examine the impact of ANG II receptor stimulation by endogenous ANG II on the insulin effects on the vasculature (NO production) and muscle (Akt phosphorylation). Both insulin and losartan increase microvascular recruitment via a NO-dependent pathway (6,21). As shown in Fig. 6A, 2 h of insulin infusion increased plasma NO levels by nearly twofold (P < 0.01). Concurrent PD123319 infusion decreased insulin-mediated increases in plasma NO levels by 37% (P < 0.04) to levels that were not significantly different from the saline controls. On the other hand, losartan injection had no significant impact on insulin-stimulated NO production. Figure 6B shows insulin-stimulated Akt phosphorylation in the skeletal muscle. Similar to the pattern of plasma NO levels, insulin significantly increased muscle Akt phosphorylation, and this effect was suppressed back to the saline control level when PD123319 infusion was superimposed on insulin infusion. Again, losartan had no effect on insulin-stimulated Akt phosphorylation in muscle. Muscle endothelial NO synthase (eNOS) phosphorylation did not differ among all four groups (Fig. 6C).

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