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

Aung MM, Slade K, Freeman LAR, Kos K, Whatmore JL, Shore AC, Gooding KM

Diabetologia16 Jun 2019Cited by 21 (Europe PMC)

PMID31203378PMCIDPMC6677680DOI10.1007/s00125-019-4918-xPepBankPUB-31203378

Summary

Aims/hypothesisGlucagon-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.MethodsTrial 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.ResultsStudy 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/interpretationLiraglutide and exenatide increased skin microvascular perfusion in individuals with and without well-controlled diabetes, potentially mediated, at least in part, by NO.Trial registrationClinicalTrials.gov NCT01677104.FundingThis work was supported by Diabetes UK (grant numbers: 09/0003955 and 12/0004600 [RW and JM Collins Legacy, Funded Studentship]).

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study10

9 results from studies that gave the peptide. 5 results from people.

01HumanRandomized controlled trialEfficacy outcome
Exenatide increased stabilised skin perfusion versus saline in participants with diabetes and obese or lean participants without diabetes.
In plain wordsExenatide increased stable skin blood flow versus saline in participants with diabetes and participants without diabetes.
Peptide
Exenatide (exendin-4)
Outcome
IncreaseStabilised skin perfusion response
Study
n = 63
Comparator
Saline
Outcome group
Vascular function · Cardiovascular
Studied dose
0.5 μg · intradermalAs given in this study (human).
Source sentences
Summary
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).
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-3120337806
02HumanRandomized controlled trialEfficacy outcome
Exenatide increased total skin perfusion versus saline in participants with diabetes and obese or lean participants without diabetes.
In plain wordsExenatide increased total skin blood flow versus saline in participants with diabetes and participants without diabetes.
Peptide
Exenatide (exendin-4)
Outcome
IncreaseTotal skin perfusion response
Study
n = 63
Comparator
Saline
Outcome group
Vascular function · Cardiovascular
Studied dose
0.5 μg · intradermalAs given in this study (human).
Source sentences
Summary
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).
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-3120337807
03HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes and in obese and lean adults without diabetes, intradermal liraglutide increased forearm skin perfusion versus saline in all groups.
In plain wordsIn people with and without type 2 diabetes, liraglutide injected into the skin raised blood flow in the skin more than saline did.
Peptide
Liraglutide
Outcome
IncreaseSkin microvascular perfusion (stabilised and total response)
Study
n = 21
Comparator
Saline
Outcome group
Vascular function · Cardiovascular
Studied dose
0.06 mg · intradermal microinjectionAs given in this study (human).
Source sentences
Summary
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).
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-3120337801
04HumanRandomized controlled trialEfficacy outcome
The skin perfusion response to liraglutide was similar in adults with type 2 diabetes and in obese and lean adults without diabetes.
In plain wordsThe skin blood flow response to liraglutide was similar in people with diabetes, obese people and lean people without diabetes.
Peptide
Liraglutide
Outcome
No significant changeSkin perfusion response across participant groups
Study
n = 21
Comparator
Other participant groups
Outcome group
Vascular function · Cardiovascular
Studied dose
0.06 mg · intradermal microinjectionAs given in this study (human).
Source sentences
Summary
with the microvascular responses similar across groups (p ≥ 0.389).
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
Show in the study text Report a problemFND-3120337802
05HumanRandomized controlled trialMechanism
In healthy adults, pretreatment with the GLP-1 receptor blocker exendin-(9,39) did not change the skin perfusion response to liraglutide.
In plain wordsIn healthy adults, blocking the GLP-1 receptor did not change the skin blood flow response to liraglutide.
Peptide
Liraglutide
Outcome
No significant changeLiraglutide perfusion response after GLP-1 receptor blockade with exendin-(9,39)
Study
n = 15
Comparator
Saline pretreatment
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
0.06 mg · intradermal microinjectionAs given in this study (human).
Source sentences
Summary
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).
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3120337803
06LabIn vitro (cells)Mechanism
In human microvascular endothelial cells, liraglutide increased nitrate production.
In plain wordsIn cells, liraglutide increased the production of nitrate, a marker of nitric oxide.
Peptide
Liraglutide
Outcome
IncreaseNitrate production in human microvascular endothelial cells
Study
humann: not reported in source
Human microvascular endothelial cells
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation (p ≤ 0.020).
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3120337804
07LabIn vitro (cells)Mechanism
In human microvascular endothelial cells, liraglutide increased endothelial nitric oxide synthase (eNOS) phosphorylation.
In plain wordsIn cells, liraglutide increased the activation of eNOS, an enzyme that makes nitric oxide.
Peptide
Liraglutide
Outcome
IncreaseeNOS phosphorylation in human microvascular endothelial cells
Study
humann: not reported in source
Human microvascular endothelial cells
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation (p ≤ 0.020).
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3120337805
08LabIn vitro (cells)Mechanism
In human microvascular endothelial cells, exenatide increased nitrate production.
In plain wordsIn cells, exenatide increased nitrate production.
Peptide
Exenatide (exendin-4)
Outcome
IncreaseNitrate production
Study
humann: not reported in source
Human microvascular endothelial cells
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation (p ≤ 0.020).
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3120337809
09LabIn vitro (cells)Mechanism
In human microvascular endothelial cells, exenatide increased endothelial nitric oxide synthase phosphorylation.
In plain wordsIn cells, exenatide increased activation of the enzyme endothelial nitric oxide synthase.
Peptide
Exenatide (exendin-4)
Outcome
IncreaseeNOS phosphorylation
Study
humann: not reported in source
Human microvascular endothelial cells
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation (p ≤ 0.020).
1 context sentence(design, population, supporting numbers)
Summary · context
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.
Show in the study text Report a problemFND-3120337810

Studies that did not test the peptide alone1

In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Exenatide (exendin-4).

10HumanNot a test of Exenatide (exendin-4) aloneObservational studyEfficacy outcome
In study 1, skin perfusion responses to the GLP-1 analogues liraglutide and exenatide were similar across participants with type 2 diabetes and obese or lean participants without diabetes.
In plain wordsSkin blood flow responses to the GLP-1 drugs liraglutide and exenatide were similar in people with diabetes and in people without diabetes.
Peptide
Exenatide (exendin-4)
Outcome
No significant changeMicrovascular response across participant groups
Study
n = 63
Comparator
Participants with diabetes and obese or lean participants without diabetes
Outcome group
Vascular function · Cardiovascular
Source sentences
Summary
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).
2 context sentences(design, population, supporting numbers)
Summary · context
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).
Summary · context
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.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-3120337808

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · source ClinicalTrials.gov (opens in a new tab)

CompletedNot applicableNCT01677104

The Microvascular Function of GLP-1 and Its Analogues

Katarina Kosn = 63Aug 2012 to Jul 2014

Type 2 Diabetes · Obesity

Trial page ClinicalTrials.govUpdated 13 Apr 2017

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Versions 4 to 8Current
28 Oct 2026, 02:03 UTC
The same notice was added 5 times, first on 22 Oct 2026, 02:26 UTC. The status did not change between them.
Study results updated
Version 3
21 Oct 2026, 18:59 UTC
Study data updated · source update from Europe PMC
Version 2
12 Oct 2026, 12:10 UTC
Study results updated
Version 1
9 Oct 2026, 03:05 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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