Abstractb-Cell failure coupled with insulin resistance is a key factor in the development of type 2 diabetes. Changes in circulating levels of adipokines, factors released from adipose tissue, form a significant link between excessive adiposity in obesity and both aforementioned factors. In this review, we consider the published evidence for the role of individual adipokines on the function, proliferation, death and failure of b-cells, focusing on those reported to have the most significant effects (leptin, adiponectin, tumour necrosis factor a, resistin, visfatin, dipeptidyl peptidase IV and apelin). It is apparent that some adipokines have beneficial effects whereas others have detrimental properties; the overall contribution to b-cell failure of changed concentrations of adipokines in the blood of obese pre-diabetic subjects will be highly dependent on the balance between these effects and the interactions between the adipokines, which act on the b-cell via a number of intersecting intracellular signalling pathways. We emphasise the importance, and comparative dearth, of studies into the combined effects of adipokines on b-cells.

The most frequent ultimate cause of death is myocardial arrest. In many cases this is due to myocardial hypoxia, generally arising from failure of the coronary macro- and microcirculation to deliver enough oxygenated red cells to the cardiomyocytes. The principle reason for this is occlusive thrombosis, either by isolated circulating thrombi, or by rupture of upstream plaque. However, an additionally serious pathology causing potentially fatal stress to the heart is extra-cardiac disease, such as pulmonary hypertension. A primary cause of the latter is pulmonary embolus, considered to be a venous thromboembolism. Whilst the thrombotic scenario has for decades been the dominating paradigm in cardiovascular disease, these issues have, until recently, been infrequently considered in cancer. However, there is now a developing view that cancer is also a thrombotic disease, and notably a disease predominantly of the venous circulation, manifesting as deep vein thrombosis and pulmonary embolism. Indeed, for many, a venous thromboembolism is one of the first symptoms of a developing cancer. Furthermore, many of the standard chemotherapies in cancer are prothrombotic. Accordingly, thromboprophylaxis in cancer with heparins or oral anticoagulation (such as Warfarin), especially in high risk groups (such as those who are immobile and on high dose chemotherapy), may be an important therapy. The objective of this communication is to summarise current views on the epidemiology and pathophysiology of arterial and venous thrombosis in cancer.

The role of the adipocyte-derived factor visfatin in metabolism remains controversial, although some pancreatic b-cellspecific effects have been reported. This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic b-cells. b-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. One-hour static insulin secretion was measured by ELISA. Phospho-specific ELISA and western blotting were used to detect insulin receptor activation. Real-time SYBR Green PCR array technology was used to measure the expression of 84 diabetes-related genes in both treatment and control cells. Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1b (32-fold increase), HNF4a (16-fold increase) and nuclear factor kB (40-fold increase). Significant down-regulation was seen in angiotensin-converting enzyme (K3 . 73-fold) and UCP2 (K1 . 3-fold). Visfatin also caused a significant 46% increase in insulin secretion compared to control (P!0 . 003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of b-cell function-associated genes in mouse b-cells.

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