BackgroundGeneralized arterial alterations, such as endothelial dysfunction, medial matrix accumulations, and calcifications are associated with type 2 diabetes (T2D). These changes may render the vessel wall more susceptible to injury; however, the molecular characteristics of such diffuse pre-atherosclerotic changes in diabetes are only superficially known.MethodsTo identify the molecular alterations of the generalized arterial disease in T2D, DNA microarrays were applied to examine gene expression changes in normal-appearing, non-atherosclerotic arterial tissue from 10 diabetic and 11 age-matched non-diabetic men scheduled for a coronary by-pass operation. Gene expression changes were integrated with GO-Elite, GSEA, and Cytoscape to identify significant biological pathways and networks.ResultsGlobal pathway analysis revealed differential expression of gene-sets representing matrix metabolism, triglyceride synthesis, inflammation, insulin signaling, and apoptosis. The network analysis showed a significant cluster of dysregulated genes coding for both intra- and extra-cellular proteins associated with vascular cell functions together with genes related to insulin signaling and matrix remodeling.ConclusionsOur results identify pathways and networks involved in the diffuse vasculopathy present in non-atherosclerotic arterial tissue in patients with T2D and confirmed previously observed mRNA-alterations. These abnormalities may play a role for the arterial response to injury and putatively for the accelerated atherogenesis among patients with diabetes.

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). We suggested that plasma osteoprotegerin (OPG), a strong, independent predictor of cardiovascular disease, could discriminate between anti-diabetic treatments depending on their benefits regarding cardiovascular disease. The South Danish Diabetes Study, an investigator-driven, randomized, controlled clinical trial lasting 2 years, was used to test this hypothesis in patient groups with different medication strategies (insulin aspart or NPH insulin, added either metformin ⁄ placebo or rosiglitazone ⁄ placebo). A total of 371 individuals were eligible for the study. Basic variables were analysed along with measurement of plasma OPG and HbA 1c at the beginning and end of the study. Only rosiglitazone treatment caused a significant decrease in plasma OPG concentrations (p = 0.003), while no significant change was seen in the other treatment groups. The effect of rosiglitazone on plasma OPG remained significant in a univariate analysis adjusted for change in HbA 1c (p = 0.013). Of note, the change in plasma OPG significantly correlated with HbA 1c improvement in rosiglitazone-treated patients (R = 0.29, p = 0.0002), while this correlation was poor in those not receiving rosiglitazone (R = 0.06, p = 0.48). Treatment with rosiglitazone among patients with T2DM reduces the concentration of plasma OPG. This is not seen with metformin despite similar reductions in HbA 1c . Alteration in the OPG ⁄ RANKL pathway by glitazones may have implications for the understanding of both cardiovascular effects and bone side effects of the drug.Cardiovascular disease (CVD) is the leading cause of death in patients with type 2 diabetes mellitus (T2DM) [1,2]. Thus, a high number of diabetic patients suffer from heart disease, cerebrovascular disease or peripheral arterial disease [3][4][5]. Measures of glycaemic status correlate with and predict large vessel disease, and a meta-analysis has indicated that there may be beneficial effects of intensive glucose-lowering treatment on CVD events in diabetes, although this is debated [4,[6][7][8]. Reports have shown that peroxisome proliferatoractivated receptor (PPAR) c agonists (e.g. glitazones) in addition to their effects on insulin sensitivity improve some cardiovascular risk factors, e.g. blood pressure, coagulation factors and inflammation [9][10][11]. Moreover, experimental studies seem to indicate that activity of PPAR-c agonists is beneficial in relation to the atherogenic process. However, a recent meta-analysis has indicated that glitazones might be associated with an increased risk of myocardial infarction [12]. Recently, the final evaluation of the RECORD study revealed an increased risk of heart failure with the drug, but no increase in death from cardiac causes or all-cause mortality. Moreover, an increased risk of some fractures, mainly in women, was found when rosiglitazone was added to other glucose-lowering therapy in patients with T2DM compatible with other studi...

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Osteoprotegerin (OPG) is increased in arterial tissue from diabetic patients. OPG knock out mice develop vascular calcifications indicating that OPG is an inhibitor of the development of calcification. However, the observed calcifications may be secondary to osteoporosis in these animals. Furthermore, OPG neutralize the function of receptor activator of nuclear factor‐¿B ligand (RANKL).The project aim is to investigate direct functions of OPG and RANKL in vascular cells, including whether OPG is an inhibitor of the development of vascular calcification in vitro, without the interference of bone metabolism.OPG was knocked down in primary human vascular smooth muscle cells (HVSMCs) using siRNA. Microarray analysis was performed to investigate whether lack of OPG upregulates the expression of calcification‐associated genes. Pathway analysis (GenMAPP) showed no significant upregulation of the calcification‐associated gene group. Therefore, it was not possible to show that OPG is an inhibitor of calcification as suggested in animal studies.HVSMCs treated with OPG siRNA following stimulation with RANKL resulted in downregulation of the insulin signaling pathway (GenMAPP). The effect of RANKL on insulin signaling is a novel observation, which may provide an interesting putative link between the OPG‐RANKL balance and insulin signaling in diabetic patient.Research support: Novo Nordisk

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