Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

Abstract

Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment. Am J Physiol Endocrinol Metab 304: E222-E228, 2013. First published November 27, 2012 doi:10.1152/ajpendo.00473.2012.-Glucagon-like peptide-1 (GLP-1) causes vasodilation and increases muscle glucose uptake independent of insulin. Recently, we have shown that GLP-1 recruits muscle microvasculature and increases muscle glucose use via a nitric oxide (NO)-dependent mechanism. Protein kinase A (PKA) is a major signaling intermediate downstream of GLP-1 receptors. To examine whether PKA mediates GLP-1's microvascular action in muscle, GLP-1 was infused to overnight-fasted male rats for 120 min in the presence or absence of H89, a PKA inhibitor. Hindleg muscle microvascular recruitment and glucose use were determined. GLP-1 infusion acutely increased muscle microvascular blood volume within 30 min without altering microvascular blood flow velocity or blood pressure. This effect persisted throughout the 120-min infusion period, leading to a significant increase in muscle microvascular blood flow. These changes were paralleled with an approximately twofold increase in plasma NO levels and hindleg glucose extraction. Systemic infusion of H89 completely blocked GLP-1-mediated muscle microvascular recruitment and increases in NO production and muscle glucose extraction. In cultured endothelial cells, GLP-1 acutely increased PKA activity and stimulated endothelial NO synthase phosphorylation at Ser 1177 and NO production. PKA inhibition abolished these effects. In ex vivo studies, perfusion of the distal saphenous artery with GLP-1 induced significant vasorelaxation that was also abolished by pretreatment of the vessels with PKA inhibitor H89. We conclude that GLP-1 recruits muscle microvasculature by expanding microvascular volume and increases glucose extraction in muscle via a PKA/NOdependent pathway in the vascular endothelium. This may contribute to postprandial glycemic control and complication prevention in diabetes.glucagon-like peptide 1; protein kinase A; microvascular recruitment; nitric oxide GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is a major incretin hormone and acts on its 64-kDa G protein-coupled receptor to increase cAMP production and mediates glucose-induced insulin secretion. Recent evidence suggests that GLP-1 is capable of increasing muscle glucose uptake independent of insulin (2). This was most convincingly demonstrated by an observation of increased myocardial uptake of glucose in Langendorff-perfused rat heart preparation (41). In conscious dogs, both GLP-1 and its active metabolite are able to increase myocardial glucose uptake without altering plasma insulin concentrations (32, 33).The mechanisms underlying GLP-1-stimulated glucose uptake in muscle are poorly understood. Endothelial cells (ECs) express abundant GLP-1 receptors (35), and GLP-1 has been shown to increase coronary blood flow and myocardial glucose uptake independent of insulin (34, 41). We have reported recently that GLP-1...

GLP-1 Receptor Agonist Exenatide Increases Capillary Perfusion Independent of Nitric Oxide in Healthy Overweight Men

“…These findings are consistent with several recent studies using native GLP-1 infusion in animals 4,8,12,13 and humans, 4,5 in which an increase in microvascular perfusion was demonstrated. We are the first to demonstrate that this vasoactive effect is also present with the use of a GLP-1RA in humans.…”

“…As such, infusion of the native GLP-1 was shown to increase muscle microvascular perfusion in several animal studies, whereas effects were abolished when NO-synthase was inhibited. 8,12 The observed discrepancy in NO-dependency remains to be elucidated. Feasibly, NO-dependence may differ between different types of vasculature.…”

Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats

“…These actions contribute up to 40% of insulin-mediated glucose disposal and are impaired in the insulin-resistant states (43). Our current observation, together with our prior reports that GLP-1 acutely recruits muscle microvasculature in both insulin-sensitive and -resistant states (10,13,15,40), strongly suggests that muscle microvasculature is a therapeutic target of GLP-1 and its analogs. However, although liraglutide can directly stimulate endothelial cell NO production (19) and exenatide can acutely increase capillary perfusion in humans (37), it does not appear that the increase in insulin-mediated microvascular recruitment in HFD-fed rats was secondary to an acute, direct action of liraglutide, as the last dose of liraglutide was given 24 h before insulin clamp and tissue harvest, and in rodents the half-life of liraglutide is only ϳ4 h (39).…”

“…Indeed, GLP-1 increases coronary blood flow and myocardial uptake of glucose in the Langendorff-perfused rat heart during low-flow ischemia (49) and myocardial glucose uptake in dogs with cardiomyopathy (31) and regulates muscle glucose uptake independent of its ability to enhance insulin secretion (3). Recently, we have shown that acute GLP-1 infusion increases muscle microvascular recruitment and glucose use independent of insulin secretion (10,40), likely via protein kinase A-mediated endothelial nitric oxide synthase (eNOS) activation (10,15). Importantly, GLP-1's microvascular action is preserved in both acute and chronic insulinresistant states (13).…”

Anagliptin increases insulin-induced skeletal muscle glucose uptake via an NO-dependent mechanism in mice

“…This activation of eNOS was completely abolished in the presence of the PKA inhibitor, H89. Dong et al reported that muscle microvascular recruitment induced by bolus infusion of GLP-1 was inhibited by the administration of H89 [39]. These findings suggest that anagliptin probably improves skeletal muscle capillary recruitment via the PKA pathway in mice.…”