Diabetes mellitus is a highly prevalent metabolic condition in ageing societies associated with high levels of morbidity, multiple therapies, and functional deterioration that challenges even the best of health care systems to deliver high-quality, individualized care. Most international clinical guidelines have ignored the often-unique issues of frailty, functional limitation, changes in mental health, and increasing dependency that characterize many aged patients with diabetes. A collaborative Expert Group of the IAGG and EDWPOP and an International Task Force have explored the key issues that affect diabetes in older people using a robust method comprising a Delphi process and an evidence-based review of the literature. Eight domains of interest were initially agreed and discussed: hypoglycemia, therapy, care home diabetes, influence of comorbidities, glucose targets, family/carer perspectives, diabetes education, and patient safety. A set of "consensus" statements was produced in each domain of interest. These form a foundation for future policy development in this area and should influence the clinical behavior and approach of all health professionals engaged in delivering diabetes care to older people.

In the present study, we show that in human endothelial cells the tetraspanin CD63/lamp3 distributes predominantly to the internal membranes of multivesicular-multilamellar late endosomes, which contain the unique lipid lysobisphosphatidic acid. Some CD63/lamp3 is also present in Weibel-Palade bodies, the characteristic secretory organelle of these cells. We find that CD63/lamp3 molecules can be transported from late endosomes to Weibel-Palade bodies and thus that CD63/lamp3 cycles between endocytic and biosynthetic compartments; however, movement of CD63/lamp3 is much slower than that of P-selectin, which is known to cycle between plasma membrane and Weibel-Palade bodies. When cells are treated with U18666A, a drug that mimics the Niemann-Pick type C syndrome, both proteins accumulate in late endosomes and fail to reach Weibel-Palade bodies efficiently, suggesting that P-selectin, like CD63/lamp3, cycles via late endosomes. Our data suggest that CD63/lamp3 partitions preferentially within late endosome internal membranes, thus causing its accumulation, and that this mechanism contributes to CD63/lamp3 retention in late endosomes; however, our data also indicate that the protein can eventually escape from these internal membranes and recycle toward Weibel-Palade bodies to be reused. Our observations thus uncover the existence of a selective trafficking route from late endosomes to Weibel-Palade bodies.

To cite this article: Vischer UM. von Willebrand factor, endothelial dysfunction, and cardiovascular disease. J Thromb Haemost 2006; 4: 1186-93.Summary. von Willebrand factor (VWF), a glycoprotein involved in arterial thrombus formation, is released into the circulation by secretion from endothelial cells. Plasma VWF levels are determined by genetic factors including ABO blood groups and VWF mutations, and by non-genetic factors including aging, impaired nitric oxide production, inflammation, free radical production and diabetes. Plasma VWF levels have been proposed as a risk factor for cardiovascular events. Although they are only weakly associated with the risk of coronary heart disease (CHD) in the general population, they are a more promising CHD risk factor in high-risk populations with previous cardiovascular events, diabetes or old age. However, is it still unclear whether VWF levels directly determine the rate and severity of arterial thrombus formation or whether they merely reflect alteration in other endothelial functions. The future status of VWF levels as a cardiovascular risk factor depends on additional studies on the genetic determinants of both VWF levels and cardiovascular outcomes. Further studies on VWF levels as a predictor of the risk of stroke (rather than CHD) in elderly or other high-risk population are also promising. Such studies could lead to the clinical use of plasma VWF levels to refine the estimation of the cardiovascular risk and of the expected benefit of antithrombotic agents.

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Please see also Cash J. D. DDAVP and factor VIII: a tale from Edinburgh. This issue, pp. 619±621. Mannucci P. M. Desmopressin (DDAVP) and factor VIII: the tale as viewed from Milan (and Malmo È ). This issue, pp. 622±624. Kaufmann J. E. et al. Desmopressin (DDAVP) induces NO production in human endothelial cells via V2 receptor-and cAMP-mediated signaling. This issue, pp. 821±828.Summary. The synthetic analog of vasopressin desmopressin (DDAVP) is widely used for the treatment of patients with von Willebrand disease (VWD), hemophilia A, several platelet disorders, and uremic bleeding. DDAVP induces an increase in plasma levels of von Willebrand factor (VWF), coagulation factor VIII (FVIII), and tissue plasminogen activator (t-PA). It also has a vasodilatory action. In spite of its extensive clinical use, its cellular mechanism of action remains incompletely understood. Its effect on VWF and t-PA as well as its vasodilatory effect are likely explained by a direct action on the endothelium, via activation of endothelial vasopressin V2R receptor and cAMP-mediated signaling. This leads to exocytosis from Weibel Palade bodies where both VWF and t-PA are stored, as well as to nitric oxide (NO) production via activation of endothelial NO synthase. The mechanism of action of DDAVP on FVIII plasma levels remains to be elucidated. The hemostatic effect of DDAVP likely involves additional cellular effects that remain to be discovered.

Summaryvon Willebrand factor (vWf) is released from endothelial cell storage granules after stimulation with thrombin, histamine and several other agents that induce an increase in cytosolic free calcium ([Ca2+]i). In vivo, epinephrine and the vasopressin analog DDAVP increase vWf plasma levels, although they are thought not to induce vWf release from endothelial cells in vitro. Since these agents act via a cAMP-dependent pathway in responsive cells, we examined the role of cAMP in vWf secretion from cultured human umbilical vein endothelial cells. vWf release increased by 50% in response to forskolin, which activates adenylate cyclase. The response to forskolin was much stronger when cAMP degradation was blocked with IBMX, an inhibitor of phosphodiesterases (+200%), whereas IBMX alone had no effect. vWf release could also be induced by the cAMP analogs dibutyryl-cAMP (+40%) and 8-bromo-cAMP (+25%); although their effect was weak, they clearly potentiated the response to thrombin. Epinephrine (together with IBMX) caused a small, dose-dependent increase in vWf release, maximal at 10-6 M (+50%), and also potentiated the response to thrombin. This effect is mediated by adenylate cyclase-coupled β-adrenergic receptors, since it is inhibited by propranolol and mimicked by isoproterenol. In contrast to thrombin, neither forskolin nor epinephrine caused an increase in [Ca2+]j as measured by fura-2 fluorescence. In addition, the effects of forskolin and thrombin were additive, suggesting that they act through distinct signaling pathways. We found a close correlation between cellular cAMP content and vWf release after stimulation with epinephrine and forskolin. These results demonstrate that cAMP-dependent signaling events are involved in the control of exocytosis from endothelial cells (an effect not mediated by an increase in [Ca2+]i) and provide an explanation for epinephrine-induced vWf release.

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