The treatment of type 2 diabetes (T2D) focuses on glycemic control to reduce microvascular and macrovascular complications. Unfortunately, while pivotal studies using conventional therapies have demonstrated that intensive glycemic control positively impacts microvascular complications, effects on cardiovascular benefit are less robust (1). There is therefore intense interest in newer antidiabetes agents, such as glucagon-like peptide 1 receptor (GLP-1R) agonists, which lower blood glucose and modify cardiovascular risk factors (lipids, adiposity, blood pressure) without increasing hypoglycemic risk (2). Whether GLP-1R agonists improve endothelial dysfunction is less clear, but this potential effect is important as endothelial dysfunction increases the risk for cardiovascular events in T2D (3).

While acute GLP-1(7-36) infusion consistently improves forearm vasodilation (a measurement of endothelial function) (47), effects with GLP-1R agonists are inconsistent. In a 16-week study of 20 patients with T2D, exenatide improved brachial artery flow-mediated dilation compared with glimepiride (8). In contrast, exenatide therapy for 3 months did not increase vasoreactivity by digital plethysmography compared with metformin in 50 obese, glucose-intolerant patients (9). Similarly, in a separate study involving 49 T2D participants, liraglutide did not improve forearm blood flow measured by venous occlusion plethysmography in response to graded infusions of acetylcholine or sodium nitroprusside relative to placebo or glimepiride (10). The effect of dipeptidyl peptidase-4 (DPP-4) inhibition on endothelial function is also inconsistent, with some indicating beneficial (11,12), neutral (13,14), or even detrimental (15) effects. Possible explanations for differing results between GLP-1(7-36), GLP-1R agonists, and DPP-4 inhibitors include 1) differences in study design (T2D vs. patients without diabetes, measurement during fasting vs. feeding, lack of active control for glycemic and metabolic changes) or 2) the vascular bed studied (large “macrocirculation” conduit arteries vs. small “microcirculation” vessels).

Therefore, Koska et al. (16) examined the postprandial effect of GLP-1R agonists and demonstrated that a single preprandial dose of exenatide improved endothelial function following a high-fat meal or oral glucose tolerance test in patients with impaired glucose tolerance or new-onset T2D. Whether these effects persist over time in patients with a longer duration of T2D was unclear, however. In this issue of Diabetes, Koska et al. (17) report the results of mechanistic studies examining the effect of short-term exenatide on postprandial endothelial function in patients with long-standing T2D. They also characterize the molecular mechanisms responsible for vasodilatory effects of exenatide in vitro in human aortic endothelial cells and ex vivo in human subcutaneous adipose tissue arterioles.

In this crossover study involving 36 participants with T2D, exenatide treatment for 11 days lowered fasting blood glucose, body weight, blood pressure, and total cholesterol compared with placebo. The cumulative 8-h reactive hyperemia index (RHI)—a measure of endothelial function—increased with exenatide following two sequential meals, independent of changes in HbA1c, body weight, glucose, triglyceride, or insulin. In a second mechanistic study, acute coinfusion of the GLP-1R antagonist exenatide-9 abolished exenatide-induced increases in RHI. In the in vitro experiments, exenatide increased AMPKα phosphorylation and endothelial nitric oxide (NO) synthase (eNOS) phosphorylation and increased eNOS activity and NO production. Finally, in the ex vivo vasoreactivity studies, exendin-4 and GLP-1 increased vasodilatation in isolated subcutaneous arterioles. As hyperglycemia and products of lipolysis promote endothelial dysfunction, the authors measured the effects of high glucose and lipolysis on arteriolar vasodilatation. Exendin-4 dilated arterioles in a dose- and NO-dependent manner and also improved endothelial function during both hyperglycemia and lipolysis. These effects were reproduced with AMPKα agonism, which activates eNOS, and were inhibited with AMPKα blockade. The authors therefore conclude that exenatide stimulates AMPK-related vasodilatory pathways and NO bioactivity via direct GLP-1R–mediated mechanisms.

The study by Koska et al. (17) demonstrates that exenatide exerts a protective endothelial function effect in the postprandial period following short-term therapy in patients with T2D (diabetes duration >5 years). A potential limitation of this study was the lack of an active comparator to control for changes in glycemia, lipids, insulin, and adiposity, which are factors known to influence endothelial function. In addition, as the presence of GLP-1R expression in endothelial cells has not yet been elucidated, it would have been informative to identify a functional GLP-1R in the current experimental model. Pyke et al. (18) recently reported GLP-1R immunopositivity in vascular smooth muscle cells but not in endothelial cells of the primate kidney or heart. Recognizing that accurate localization of the GLP-1R is methodologically challenging and prone to pitfalls (19,20), extensive clarification of the presence or absence of GLP-1R expression in human endothelial cells is still required. While exenatide-9 did block the vasodilatory effects of exenatide, suggesting a direct GLP-1R–mediated mechanism, exenatide-9 is a nonselective antagonist of the GLP-1R, with weak partial agonist properties (21). As a result, the direct effects of GLP-1R agonism on endothelial function remain incompletely understood.

Nevertheless, these carefully performed studies by Koska and colleagues (16,17) support a direct role for exenatide on the endothelial function in humans and are consistent with prior studies for GLP-1(7-36) but are in contrast to many studies using GLP-1R agonists and DPP-4 inhibitors. How, then, do we interpret these differences, and how can we reconcile whether or not GLP-1R agonists directly modify endothelial function? Additional studies using active comparators to correct for changes in hormonal and metabolic factors would complement and strengthen the present findings and help to better define endothelial versus nonendothelial effects of GLP-1R agonists on vascular function (Fig. 1). Also confirmation of a functional canonical GLP-1R in endothelial cells is needed to determine whether effects of exenatide on endothelial function are GLP-1R mediated. In the absence of a canonical GLP-1R in endothelial cells, the existence of a second, as-yet unidentified, noncanonical GLP-1R, sensitive to both exenatide and exenatide-9, could also explain these observations and should be explored. Finally, future studies are needed to better define the role of GLP-1R signaling in vascular smooth muscle cells which may impact endothelial function indirectly.

Figure 1

GLP-1R agonists and endothelial function. Potential signaling pathways in endothelial and nonendothelial cells and tissues responsible for the effects of GLP-1R agonists on improving endothelial function are shown. Hashed lines represent potential pathways; solid lines represent known pathways. ROS, reactive oxygen species.

Figure 1

GLP-1R agonists and endothelial function. Potential signaling pathways in endothelial and nonendothelial cells and tissues responsible for the effects of GLP-1R agonists on improving endothelial function are shown. Hashed lines represent potential pathways; solid lines represent known pathways. ROS, reactive oxygen species.

In conclusion, endothelial dysfunction is a unifying pathobiological process that links diabetic macrovascular and microvascular complications. The studies by Koska and colleagues (16,17) are important as they have better defined how GLP-1R agonists impact endothelial function in humans. Moreover, novel physiological insights derived from these elegant experiments supporting the presence of direct vascular effects with GLP-1R agonists may ultimately help to better interpret the pending results of large cardiovascular and microvascular outcome studies using these agents.

See accompanying article, p. 2624.

Funding. J.L. is supported by an Eliot Phillipson Clinician Scientist Fellowship Award, Department of Medicine, University of Toronto. D.C. is supported by a Canadian Diabetes Association-KRESCENT Program Joint New Investigator Award and receives operating support from the Canadian Institutes of Health Research, Kidney Foundation of Canada, and JDRF.

Duality of Interest. J.L. has received speaker's honoraria from Novo Nordisk. D.C. has received consulting fees from Boehringer Ingelheim, Eli Lilly, Astellas, Merck, and AstraZeneca and operational funds from Boehringer Ingelheim, Merck, and AstraZeneca. No other potential conflicts of interest relevant to this article were reported.

1.
Giorgino
F
,
Leonardini
A
,
Laviola
L
.
Cardiovascular disease and glycemic control in type 2 diabetes: now that the dust is settling from large clinical trials
.
Ann N Y Acad Sci
2013
;
1281
:
36
50
[PubMed]
2.
Lovshin
JA
,
Drucker
DJ
.
Incretin-based therapies for type 2 diabetes mellitus
.
Nat Rev Endocrinol
2009
;
5
:
262
269
[PubMed]
3.
van Sloten
TT
,
Henry
RM
,
Dekker
JM
, et al
.
Endothelial dysfunction plays a key role in increasing cardiovascular risk in type 2 diabetes: the Hoorn study
.
Hypertension
2014
;
64
:
1299
1305
[PubMed]
4.
Basu
A
,
Charkoudian
N
,
Schrage
W
,
Rizza
RA
,
Basu
R
,
Joyner
MJ
.
Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride
.
Am J Physiol Endocrinol Metab
2007
;
293
:
E1289
E1295
[PubMed]
5.
Ceriello
A
,
Esposito
K
,
Testa
R
,
Bonfigli
AR
,
Marra
M
,
Giugliano
D
.
The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an “endothelial resistance” to glucagon-like peptide 1 in diabetes
.
Diabetes Care
2011
;
34
:
697
702
[PubMed]
6.
Nyström
T
,
Gutniak
MK
,
Zhang
Q
, et al
.
Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease
.
Am J Physiol Endocrinol Metab
2004
;
287
:
E1209
E1215
[PubMed]
7.
Tesauro
M
,
Schinzari
F
,
Adamo
A
, et al
.
Effects of GLP-1 on forearm vasodilator function and glucose disposal during hyperinsulinemia in the metabolic syndrome
.
Diabetes Care
2013
;
36
:
683
689
[PubMed]
8.
Irace
C
,
De Luca
S
,
Shehaj
E
, et al
.
Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an observational research
.
Diab Vasc Dis Res
2013
;
10
:
72
77
[PubMed]
9.
Kelly
AS
,
Bergenstal
RM
,
Gonzalez-Campoy
JM
,
Katz
H
,
Bank
AJ
.
Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial
.
Cardiovasc Diabetol
2012
;
11
:
64
[PubMed]
10.
Nandy
D
,
Johnson
C
,
Basu
R
, et al
.
The effect of liraglutide on endothelial function in patients with type 2 diabetes
.
Diab Vasc Dis Res
2014
;
11
:
419
430
[PubMed]
11.
Matsubara
J
,
Sugiyama
S
,
Akiyama
E
, et al
.
Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes
.
Circ J
2013
;
77
:
1337
1344
12.
Kubota
Y
,
Miyamoto
M
,
Takagi
G
, et al
.
The dipeptidyl peptidase-4 inhibitor sitagliptin improves vascular endothelial function in type 2 diabetes
.
J Korean Med Sci
2012
;
27
:
1364
1370
[PubMed]
13.
Nakamura
K
,
Oe
H
,
Kihara
H
, et al
.
DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes: EDGE study
.
Cardiovasc Diabetol
2014
;
13
:
110
[PubMed]
14.
Hage
C
,
Brismar
K
,
Lundman
P
,
Norhammar
A
,
Rydén
L
,
Mellbin
L
.
The DPP-4 inhibitor sitagliptin and endothelial function in patients with acute coronary syndromes and newly detected glucose perturbations: a report from the BEGAMI study
.
Diab Vasc Dis Res
2014
;
11
:
290
293
[PubMed]
15.
Ayaori
M
,
Iwakami
N
,
Uto-Kondo
H
, et al
.
Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients
.
J Am Heart Assoc
2013
;
2
:
e003277
[PubMed]
16.
Koska
J
,
Schwartz
EA
,
Mullin
MP
,
Schwenke
DC
,
Reaven
PD
.
Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes
.
Diabetes Care
2010
;
33
:
1028
1030
[PubMed]
17.
Koska
J
,
Sands
M
,
Burciu
C
, et al
.
Exenatide protects against glucose- and lipid-induced endothelial dysfunction: evidence for direct vasodilation effect of GLP-1 receptor agonists in humans
.
Diabetes
2015
;
64
:
2624
2635
18.
Pyke
C
,
Heller
RS
,
Kirk
RK
, et al
.
GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody
.
Endocrinology
2014
;
155
:
1280
1290
[PubMed]
19.
Pyke
C
,
Knudsen
LB
.
The glucagon-like peptide-1 receptor—or not?
Endocrinology
2013
;
154
:
4
8
[PubMed]
20.
Drucker
DJ
.
Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls
.
Diabetes
2013
;
62
:
3316
3323
[PubMed]
21.
Campbell
JE
,
Drucker
DJ
.
Pharmacology, physiology, and mechanisms of incretin hormone action
.
Cell Metab
2013
;
17
:
819
837
[PubMed]