Endothelial dysfunction in type 2 diabetes
A. Natali
E. Ferrannini
The mechanisms responsible for the accelerated atherosclerosis observed in type 2 diabetes are not fully understood. One of the earliest events in the development of atherosclerosis is endothelial dysfunction, namely, a reduction in nitric oxide (NO) synthesis or its bioavailability within the peri-endothelial environment, where it is responsible for maintenance of vascular tissue integrity. The clinical evaluation of this pathway is hampered by the fact that in vivo NO cannot be directly measured; however, exploiting a novel, complex and elegant experimental setup, McVeigh and co-workers (Diabetologia 1992;35:771-776) were the first to document that NO bioavailability in type 2 diabetic patients is indeed reduced. In this edition of 'Then and now' that paper is reappraised not only for its originality, but also for the broad and extensive evaluation of the vascular functions explored, the complete clinical characterisation of patients enrolled and for the fact that all the major findings were subsequently replicated.
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The endothelium plays a central role in maintaining
vascular homeostasis through the release of vasodilating
and vasoconstricting substances. Seminal work by
Furchgott and Zawadzki in 1980 [1] revealed that the
endothelium is responsible for vascular relaxation
induced by acetylcholine, a muscarinic receptor agonist.
The clinical relevance of this pathway in human disease,
including hypertension and hypercholesterolaemia, was
reported in 1990 [2, 3]. Endothelial biology took centre
stage in 1998 when the Nobel Prize in Physiology or
Medicine was awarded to Robert F. Furchgott, Louis J.
Ignarro and Ferid Murad for their discoveries concerning
the role of NO as a signalling molecule controlling
vasodilation. The translational impact of this key
discovery has been suggested by in vitro studies that have
established a role of the endotheliumand NOin
protecting vessels from atherosclerosis [4]. With regard to
diabetes, early after the seminal paper by Furchgott and
Zawadzki [1], endothelial dysfunction was demonstrated
in experimental animal models of diabetes [5], while its
mechanisms were described by Bucala et al. [6].
The Diabetologia paper
The work by McVeigh and co-workers [7] was the first in vivo
demonstration of the presence of endothelial dysfunction in
type 2 diabetic patients. Specifically, they demonstrated that,
in type 2 diabetic patients, the ability of resistance vessels to
vasodilate in response to endothelium- or smooth muscle
celldependent stimuli was impaired (Fig. 1c, d, respectively),
while neither the vascular structure (Fig. 1a) nor unstimulated
(basal; Fig. 1b) endothelium-dependent blood flow appeared
to be compromised (as illustrated in the figures from the
original paper reproduced in Fig. 1). The authors also showed
that this vascular dysfunction is caused by reduced NO
release. To accomplish this, they used a technique that relies
upon the measurement of perfused forearm blood flow by
strain-gauge plethysmography in response to an intra-arterial
infusion of either acetylcholine (an endothelium-dependent
dilator) or nitroglycerine (a smooth-muscle-dependent
dilator). This method is still considered state-of-the art for the
study of endothelial function in resistance arteries. The
number of vascular tests, combined with the thorough clinical
characterisation of the patients, makes this study a very rich
source of information. In addition to the standard responses
to acetylcholine and nitrates, the investigators also evaluated
the response to ischaemia and the effect of blocking NO
synthesis with NG-monomethyl-L-arginine (L-NMMA)a
competitive inhibitor of NO-synthaseon both
acetylcholinestimulated and basal blood flow.
The main findings by McVeigh et al [7] have since
been replicated and have stood the test of time. In
particular, the impaired vasodilatory response to nitrates,
a somewhat neglected aspect of vascular dysfunction in
diabetes, has been confirmed by other investigators,
notably in the elegant study by Creager and co-workers
[8]. Similarly, the lack of significant associations
between the vascular dysfunction and the presence of
vascular complications or degree of metabolic control,
although quite surprising, has been reported by
subsequent studies [9, 10]
The finding that vascular dysfunction in type 2 diabetes is
caused by reduced NO release is highly original. Nevertheless,
the study by McVeigh et al [7] was subject to limitations that
warrant some discussion. For example, the post-ischaemic
vasodilatory response following only 5 min of ischaemia does
not accurately explore structural changes of the resistance
vessels, as claimed in the paper; rather, it provides another
index of endothelial function, since the vasodilation is largely
sustained by the blood flow acceleration caused by the drastic
reduction in peripheral resistance. The mean absolute blood
flow values achieved with the 5 min ischaemia (15 ml min1 dl1)
are far (...truncated)