Endothelial dysfunction in type 2 diabetes

Diabetologia, Jan 2012

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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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. - 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)


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A. Natali, E. Ferrannini. Endothelial dysfunction in type 2 diabetes, Diabetologia, 2012, pp. 1559-1563, Volume 55, Issue 6, DOI: 10.1007/s00125-011-2445-5