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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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Combined effects of insulin and AT1R blockade on skeletal-muscle microvascular parameters. Losartan (0.3 mg/kg i.v.) was given 5 min before the initiation of insulin clamp. A: Changes in muscle MBV. P < 0.001 (ANOVA). B: Changes in muscle MFV. P < 0.01 (ANOVA). C: Changes in muscle MBF. P < 0.01 (ANOVA). n = 7. Compared with 0 min, *P < 0.05 and **P < 0.01.
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Figure 5: Combined effects of insulin and AT1R blockade on skeletal-muscle microvascular parameters. Losartan (0.3 mg/kg i.v.) was given 5 min before the initiation of insulin clamp. A: Changes in muscle MBV. P < 0.001 (ANOVA). B: Changes in muscle MFV. P < 0.01 (ANOVA). C: Changes in muscle MBF. P < 0.01 (ANOVA). n = 7. Compared with 0 min, *P < 0.05 and **P < 0.01.

Mentions: We have shown that basal AT1R tone restricts skeletal muscle MBV, whereas basal AT2R activity increases muscle MBV (21). We next examined whether selective stimulation of the ANG II subtype receptors by endogenous ANG II regulate insulin-mediated microvascular recruitment. Figure 3 shows the microvascular responses to insulin infusion. Insulin infusion raised plasma insulin concentrations from 99 ± 15 pmol/L to 685 ± 151 pmol/L (n = 5, P < 0.02). As expected, insulin increased both MBV and MBF without altering MFV (Fig. 3). The addition of PD123319 to insulin infusion promptly inhibited this insulin-mediated increase in MBV and MBF and significantly increased the MFV (Fig. 4). When PD123319 was given before insulin infusion, insulin-induced increases in muscle MBV and MBF were completely prevented. On the other hand, infusion of PD123319 after insulin had already significantly recruited muscle microvasculature (i.e., 30 min after insulin infusion) abrogated the insulin effects. These changes did not seem to be secondary to changes in blood pressure or total blood flow because both MAP and FBF remained stable during the study (Table 1). Injection of losartan 5 min prior to the initiation of insulin promptly increased muscle MBV within 30 min, and the extent of the increase (2.4- to 3.2-fold) was quite similar to what we previously observed using losartan alone (21). The increase in MBV lasted for the entire 120 min. Muscle MFV did not change in the first 90 min but decreased at 120 min. As a result, muscle MBF increased promptly at 30 min, remained elevated at 60 min, and trended down afterward (Fig. 5). Though MAP did not change, FBF decreased by nearly 30% (P < 0.01) (Table 1).


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)

Combined effects of insulin and AT1R blockade on skeletal-muscle microvascular parameters. Losartan (0.3 mg/kg i.v.) was given 5 min before the initiation of insulin clamp. A: Changes in muscle MBV. P < 0.001 (ANOVA). B: Changes in muscle MFV. P < 0.01 (ANOVA). C: Changes in muscle MBF. P < 0.01 (ANOVA). n = 7. Compared with 0 min, *P < 0.05 and **P < 0.01.
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Figure 5: Combined effects of insulin and AT1R blockade on skeletal-muscle microvascular parameters. Losartan (0.3 mg/kg i.v.) was given 5 min before the initiation of insulin clamp. A: Changes in muscle MBV. P < 0.001 (ANOVA). B: Changes in muscle MFV. P < 0.01 (ANOVA). C: Changes in muscle MBF. P < 0.01 (ANOVA). n = 7. Compared with 0 min, *P < 0.05 and **P < 0.01.
Mentions: We have shown that basal AT1R tone restricts skeletal muscle MBV, whereas basal AT2R activity increases muscle MBV (21). We next examined whether selective stimulation of the ANG II subtype receptors by endogenous ANG II regulate insulin-mediated microvascular recruitment. Figure 3 shows the microvascular responses to insulin infusion. Insulin infusion raised plasma insulin concentrations from 99 ± 15 pmol/L to 685 ± 151 pmol/L (n = 5, P < 0.02). As expected, insulin increased both MBV and MBF without altering MFV (Fig. 3). The addition of PD123319 to insulin infusion promptly inhibited this insulin-mediated increase in MBV and MBF and significantly increased the MFV (Fig. 4). When PD123319 was given before insulin infusion, insulin-induced increases in muscle MBV and MBF were completely prevented. On the other hand, infusion of PD123319 after insulin had already significantly recruited muscle microvasculature (i.e., 30 min after insulin infusion) abrogated the insulin effects. These changes did not seem to be secondary to changes in blood pressure or total blood flow because both MAP and FBF remained stable during the study (Table 1). Injection of losartan 5 min prior to the initiation of insulin promptly increased muscle MBV within 30 min, and the extent of the increase (2.4- to 3.2-fold) was quite similar to what we previously observed using losartan alone (21). The increase in MBV lasted for the entire 120 min. Muscle MFV did not change in the first 90 min but decreased at 120 min. As a result, muscle MBF increased promptly at 30 min, remained elevated at 60 min, and trended down afterward (Fig. 5). Though MAP did not change, FBF decreased by nearly 30% (P < 0.01) (Table 1).

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