Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes

Abstract

Aims/hypothesis Glucagon-like peptide-1 (GLP-1) analogues reduce the risk of macrovascular disease in diabetes; however, little is known about their microvascular effects. This research examined the microvascular actions of the GLP-1 analogues liraglutide and exenatide in individuals with and without type 2 diabetes (study 1). It also explored the involvement of the GLP-1 receptor (study 2) and the nitric oxide pathway in mediating the microvascular effects of the analogues. Methods Trial design: Studies 1 and 2 had a randomised, controlled, double-blind study design. Study 1 participants, intervention and methods: three participant groups were recruited: individuals with well-controlled type 2 diabetes, and obese and lean individuals without diabetes (21 participants per group). Liraglutide (0.06 mg), exenatide (0.5 μg) and saline (154 mmol/l NaCl; 0.9%) control were microinjected into separate sites in the dermis (forearm) in a randomised order, blinded to operator and participant. Skin microvascular perfusion was assessed by laser Doppler perfusion imaging. Outcomes were stabilised response (mean skin perfusion between 7.5 and 10 min post microinjection) and total response (AUC, normalised for baseline perfusion). Perfusion response to GLP-1 analogues was compared with saline within each group as well as between groups. Study 2 participants, intervention and methods: in healthy individuals ( N = 16), liraglutide (0.06 mg) and saline microinjected sites were pretreated with saline or the GLP-1 receptor blocker, exendin-(9,39), in a randomised order, blinded to participant and operator. Outcomes were as above (stabilised response and total perfusion response). Perfusion response to liraglutide was compared between the saline and the exendin-(9,39) pretreated sites. In vitro study: the effects of liraglutide and exenatide on nitrate levels and endothelial nitric oxide synthase phosphorylation (activation) were examined using human microvascular endothelial cells. Results Study 1 results: both analogues increased skin perfusion (stabilised response and total response) in all groups ( n = 21 per group, p < 0.001), with the microvascular responses similar across groups ( p ≥ 0.389). Study 2 results: liraglutide response (stabilised response and total response) was not influenced by pretreatment with exendin-(9,39) (70 nmol/l) ( N = 15, one dataset excluded) ( p ≥ 0.609). Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation ( p ≤ 0.020). Conclusions/interpretation Liraglutide and exenatide increased skin microvascular perfusion in individuals with and without well-controlled diabetes, potentially mediated, at least in part, by NO. Trial registration ...

Liraglutide treatment improves the coronary microcirculation in insulin resistant Zucker obese rats on a high salt diet

“…In support of these studies, it has also been established that LIRA increases NO-bioavailability in the vasculature in other disease states including arterial stenosis [33]. Further, Aung et al [34] recently showed that local delivery of LIRA increased skin microvascular perfusion in diabetic subjects and increased supernatant nitrate concentration and eNOS phosphorylation in human microvascular endothelial cell (HCMEC/D3 cell line) culture. Taken together, these findings suggest that it is reasonable to conclude that the improvement in coronary microvascular perfusion that we observed in LIRA treated obese Zucker rats is in part due to increased coronary NO production.…”

Adipose endothelial cells mastering adipose tissues metabolic fate

“…The metabolic benefits of the exenatide are correlated with the activation of VEGF-A-mediated angiogenesis and alleviate hypoxia in AT [ 78 ]. In line with animal studies, a recent clinical study reported that exenatide increased the vascularization of AT in obese diabetic patients to improve blood glucose levels and insulin sensitivity [ 79 , 80 ]. Therefore, activation GLP-1 R may facilitate AT vascularization, and then improve AT chronic hypoxia to alleviate obesity and obesity-related metabolic disturbance.…”

Encapsulation in Polymeric Nanoparticles Enhances the Enzymatic Stability and the Permeability of the GLP-1 Analog, Liraglutide, Across a Culture Model of Intestinal Permeability

“…GLP-1 analogs represent a unique class of antidiabetic peptide drugs with potential clinical benefits over existing therapies for T2DM treatment [32]. Lira, a lipophilic long-acting GLP-1 analog, is still subcutaneously administered.…”