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

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.

FIG. 1.

Animal study protocols.

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.

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.

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.

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.

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.