Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism

Weidong Chai, Zhenhua Dong, Nasui Wang, Wenhui Wang, Lijian Tao, Wenhong Cao, Zhenqi Liu, Weidong Chai, Zhenhua Dong, Nasui Wang, Wenhui Wang, Lijian Tao, Wenhong Cao, Zhenqi Liu

Abstract

Glucagon-like peptide 1 (GLP-1) increases tissue glucose uptake and causes vasodilation independent of insulin. We examined the effect of GLP-1 on muscle microvasculature and glucose uptake. After confirming that GLP-1 potently stimulates nitric oxide (NO) synthase (NOS) phosphorylation in endothelial cells, overnight-fasted adult male rats received continuous GLP-1 infusion (30 pmol/kg/min) for 2 h plus or minus NOS inhibition. Muscle microvascular blood volume (MBV), microvascular blood flow velocity (MFV), and microvascular blood flow (MBF) were determined. Additional rats received GLP-1 or saline for 30 min and muscle insulin clearance/uptake was determined. GLP-1 infusion acutely increased muscle MBV (P < 0.04) within 30 min without altering MFV or femoral blood flow. This effect persisted throughout the 120-min infusion period, leading to a greater than twofold increase in muscle MBF (P < 0.02). These changes were paralleled with increases in plasma NO levels, muscle interstitial oxygen saturation, hind leg glucose extraction, and muscle insulin clearance/uptake. NOS inhibition blocked GLP-1-mediated increases in muscle MBV, glucose disposal, NO production, and muscle insulin clearance/uptake. In conclusion, GLP-1 acutely recruits microvasculature and increases basal glucose uptake in muscle via a NO-dependent mechanism. Thus, GLP-1 may afford potential to improve muscle insulin action by expanding microvascular endothelial surface area.

Figures

FIG. 1.
FIG. 1.
Animal study protocols.
FIG. 2.
FIG. 2.
Effects of GLP-1 on Akt, eNOS, and PKA in cultured ECs. Representative gels and quantifications of Akt (Ser473) (A), eNOS (Ser1177) (B and C), eNOS (Ser635) (D), and PKA (E) phosphorylation. n = 4–9 each. Compared with basal, *P < 0.05, **P < 0.01. Insulin (100 nmol/L) was used as positive control.
FIG. 3.
FIG. 3.
Effects of GLP-1 on muscle microvascular recruitment. GLP-1 was infused continuously at 30 pmol/kg/min in the absence or presence of l-NAME, which was infused systemically starting 30 min before the initiation of GLP-1 infusion. A: Changes in MBV. B: Changes in MFV. C: Changes in MBF. Compared with 0 min, *P < 0.05, #P < 0.01. n = 4–8 each.
FIG. 4.
FIG. 4.
Effects of GLP-1 on plasma NO and insulin levels, muscle oxygenation, and eNOS phosphorylation. GLP-1 was infused continuously at 30 pmol/kg/min. A: Changes in plasma NO levels during GLP-1 infusion. #P < 0.01 vs. 0 min; P < 0.04 between the two groups (ANOVA). B: Changes in plasma NO levels during l-NAME + GLP-1 infusion. Compared with −30 min, #P < 0.01. C: Changes in muscle eNOS (Ser1177) phosphorylation. P = 0.8. D: Changes in muscle oxygen saturation over time. #P < 0.05 vs. 0 min; P < 0.02 between the two groups (ANOVA). E: Plasma insulin concentrations. P = 0.437 (ANOVA). F: Arterial glucose concentrations. *P < 0.01 vs. 0 min. n = 5–9 each.
FIG. 5.
FIG. 5.
Effects of GLP-1 on muscle glucose extraction. A: Saline control. P > 0.05 (ANOVA); n = 5. B: GLP-1 group. Compared with basal, *P < 0.05, n = 6; P = 0.008 (ANOVA). C: l-NAME + GLP-1 group. P > 0.05 (ANOVA); n = 5. GLP-1 was infused continuously at 30 pmol/kg/min. l-NAME was infused systemically starting 30 min before the initiation of GLP-1 infusion.
FIG. 6.
FIG. 6.
Effects of GLP-1 on muscle insulin clearance and uptake. A: Fraction of intact 125I-insulin in blood and muscle; blood (white bar), muscle (gray bar). Compared with blood, #P < 0.01. B: Muscle 125I-insulin clearance. Compared with saline, *P = 0.02 (ANOVA). C: Muscle 125I-insulin uptake. Compared with saline, #P < 0.01 (ANOVA). n = 5–9 each.

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