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

Abstract

Objective-The insulinotropic gut-derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide-dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans. Approach and Results-We included 10 healthy overweight men (age, 20-27 years; body mass index, 26-31 kg/m 2 ). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide-synthase inhibitor l-N G -monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant l-N G -monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=−5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=−0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged. Conclusions-Acute exenatide infusion increases capillary perfusion via nitric oxide-independent pathways in Materials and MethodsIn this mechanistic cross-over study, healthy overweight participants were subjected to continuous intravenous infusion of placebo (isotonic saline), GLP-1RA exenatide, l-NMMA or a combination of l-NMMA and exenatide. During these conditions, microvascular perfusion was assessed using intravital videomicroscopy and laser Doppler fluxmetry. A complete description of Materials and Methods are available in the Online-only Data Supplement. Results Patient CharacteristicsTen healthy overweight men were included in this analysis. Full characteristics of the subjects can be found in the Table. Capillary VideomicroscopyCompared with placebo, exenatide increased baseline capillary density with 8.0 (5.3-10.5) cap/mm 2 (P=0.016) and peak postarterial occlusion capillary density with 6.5 (4.8-7.8) cap/ mm 2 (P=0.016). This corresponds with an increase of 20.1% and 8.3%, respectively. When exenatide was coinfused with l-NMMA, no significant differences compared with exenatide infused alone were observed (Figure 1).Tests were performed during 2 study days. Day-to-day variation for baseline capillary density and postocclusive peak density were 4.7% and 1.7%, respectively. We conducted sensitivity analyses to assess potential interference of day-to-day variation by including unstimulated measurements (before any intervention) in the statistical model. These sensitivity analyses showed no different results compared with the original analyses. Laser Doppler FluxmetryDuring p...

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

“…15 We recently demonstrated that exenatide increased skin capillary perfusion in healthy men, using the same techniques and a similar study protocol as used in the current study. 16 It was therefore unexpected to find no effect of exenatide on skin capillary perfusion in patients with type 2 diabetes mellitus in the current study. Such a differential effect in microvascular activity is also known for insulin, which improves microvascular perfusion in healthy volunteers, but has no effect on microvascular function in patients with type 2 diabetes mellitus.…”

“…For example, we recently demonstrated that exenatide infusion decreased neurogenic activity in healthy overweight men. 16 In that study, the effect on neurogenic activity was negatively correlated with capillary density, leading us to speculate that an exenatide-induced reduction in dermal SNS activity reduces vascular tone and consequently increases capillary density.…”

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“…If GLP-1 RAs increase coronary blood flow, especially in patients with existing heart disease, this effect could reduce ischemia, infarct size, and risk of arrhythmias. A recent study in subjects with normal glucose tolerance demonstrated that GLP-1 infusion augments blood flow in small vessels in skeletal muscle and heart (35), and increased blood flow in small coronary vessels after myocardial ischemia has been shown to predict increased survival and reduced infarct size after MI (36). …”

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“…Interestingly, we observed a non‐significant decrease in TPR when exenatide was co‐infused with L‐NMMA. Although exenatide may induce NO‐independent vasodilation , it is unclear why this only occurred during L‐NMMA infusion in our study, and not also during exenatide infusion alone. Potentially, the vasodilator effects of exenatide can only be seen during a state of vasoconstriction in healthy subjects, as achieved by L‐NMMA infusion.…”