Objective: Osteoprotegerin (OPG) is a newly identified inhibitor of bone resorption. Recent studies indicate that OPG also acts as an important regulatory molecule in the vasculature. Plasma levels of OPG seem to be elevated in subjects with diabetes as well as in non-diabetic subjects with cardiovascular disease. The aim of the present study was to examine the association between plasma OPG levels and microvascular complications and glycemic control in patients with type 2 diabetes. Design and methods: Four groups of 20 subjects in each, individually matched for age and gender, were included in the study: (i) subjects with normal glucose tolerance (NGT); (ii) subjects with impaired glucose tolerance (IGT); (iii) type 2 diabetic patients without retinopathy; and (iv) type 2 diabetic patients with diabetic maculopathy (DMa). Plasma concentration of OPG was measured in duplicate by a sandwich ELISA method. Furthermore, fundus photography, flourescein angiography, and measurements of urinary albumin excretion rate (RIA) were performed. Results: Plasma OPG was significantly higher in diabetic (iii þ iv) than in NGT (i) subjects (3.04^0.15 vs 2.54^0.16 ng/l, P , 0.05). Plasma OPG was significantly higher in the DMa (iv) group than in the NGT (i) group (3.25^0.23 vs 2.54^0.16 ng/l, P ¼ 0.01). Moreover, plasma OPG was significantly higher (3.61^0.36 ng/l) in the group of diabetic subjects with both microalbuminuria and DMa (n ¼ 7) than in the NGT (i) (2.54^0.16 ng/l, P , 0.01), IGT (ii) (2.82^0.21 ng/l, P , 0.05), and no retinopathy (iii) groups (2.83^0.20 ng/l, P , 0.05). Conclusions: We found increased levels of OPG in plasma from diabetic patients with microvascular complications. This finding indicates that OPG may be involved in the development of vascular dysfunction in diabetes.

Aims/hypothesis We followed type 2 diabetic patients over a long period to evaluate the predictive value of ambulatory pulse pressure (PP) and decreased nocturnal BP reduction (non-dipping) for nephropathy progression. Methods Type 2 diabetic patients (n=112) were followed for an average of 9.5 (range 0.5-14.5) years. At baseline, all patients underwent 24 h ambulatory BP measurement. Urinary albumin excretion rate was evaluated by three urinary albumin:creatinine ratio measurements at baseline and follow-up. Results At baseline, patients who subsequently progressed to a more advanced nephropathy stage (n=35) had reduced diastolic night/day BP variation and higher 24 h systolic BP and PP values; they also had more advanced nephropathy and were more likely to smoke than those with no progression of nephropathy (n=77). In a Cox regression analysis, independent predictors of nephropathy progression were 24 h PP (p<0.01), diastolic night:day BP ratio (p=0.02) and smoking (p=0.02). The adjusted hazards ratio (95% CI) for each mmHg increment in 24 h PP was 1.04 (1.01-1.07), whereas the adjusted hazards ratio (95% CI) for each 1% increase in diastolic night:day BP ratio was 1.06 (1.01-1.11). Only one of 33 patients (3.0%) with both a diastolic night:day BP ratio and a 24 h PP below the median progressed, whereas 17 of 32 patients (53.1%) with both a diastolic night:day BP ratio and a 24 h PP equal to or above the median progressed to a more advanced nephropathy stage (p<0.001). Conclusions/interpretation Ambulatory PP, impaired nocturnal BP decline and smoking are strong, independent predictors of nephropathy progression in type 2 diabetic patients.

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Increased PP is associated with endothelial activation and albuminuria in Type 2 diabetic patients. Thus, endothelial dysfunction may represent a pathophysiological link between an elevated PP and microvascular complications in these subjects. Prospective studies are needed to further elucidate these associations.

Acute hyperglycaemia does not seem to increase plasma levels of OPG in non-diabetic subjects, whereas hyperinsulinaemia may suppress plasma levels of OPG. This finding indicates that the elevated plasma levels of OPG observed in diabetic subjects with poor metabolic control cannot be ascribed to hyperglycaemia per se.

Intensive therapy aiming at near normalization of glucose levels effectively delays the onset and slows the progression of complications in insulin-dependent diabetes mellitus (IDDM) and is recommended in most patients. However, in a recent report, intensive insulin treatment was found to be associated with deleterious effects on nocturnal blood pressure (BP), the proposed mechanisms being subclinical nocturnal hypoglycemia or hyperinsulinemia. The aim of the present study was to evaluate the association between glycemic control, insulin dose, and 24-h ambulatory BP (AMBP) in a group of well-characterized IDDM patients. Twenty-four-h AMBP was measured in 123 normoalbuminuric [urinary albumin excretion (UAE) < 20 microg/min] IDDM patients using an oscillometric technique (SpaceLabs 90207) with readings at 20-min intervals. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. Tobacco use and level of physical activity was assessed by questionnaire. HbA1c was determined by high-pressure liquid chromatography (nondiabetic range, 4.4-6.4%), and patients were stratified into quartiles according to HbA1c levels. Mean HbA1c values in the four groups were 7.0% (n = 31), 8.0% (n = 31), 8.6% (n = 31), and 9.7% (n = 30). The groups were comparable regarding age, gender, diabetes duration, body mass index, UAE, smoking status, and physical activity. AMBP levels were almost identical in the HbA1c quartiles with night values of (increasing HbA1c order): 110/63, 112/66, 112/66, and 113/65 mm Hg (P = 0.69/P = 0.32). There was no association between tight glucose control and higher nocturnal BP or a more blunted circadian BP variation. On the contrary, a weak positive correlation between night to day ratios of mean arterial BP and HbA1c values was found (r = 0.26, P = 0.005), i.e. blunted circadian BP variation is most frequent in patients with high HbA1c values. Neither did we find doses of insulin to be associated with night BP (r = 0.04, P = 0.68). Tight blood glucose control is not associated with deleterious effects on 24-h AMBP in normoalbuminuric IDDM patients. Intensive therapy can be implemented without concerns of inducing high nocturnal BP and accelerating diabetic complications.

Arterial wall viscosity (AWV) of central arteries, as well as distensibility, is important to properly buffer systolic ejection pressure. AWV is measured either by the area within the hysteresis of distension-pressure (DD-P) loop, defined as the viscous energy (AWVZVe) or the ratio of Ve/Ve+energy stored during systole (ZAWV%). We record DD-P loop via echotracking; averaged over 30 cardiac cycles, AWV and AWV% are calculated via MatLab software. Here we perform a post analysis of the DD-P loop in 12 groups of rats (nZ5-8): normo-or hypertensive, with and without arterial remodeling, at different operating blood pressures (BP), using different compounds. AWV decreases and DD-P loop is flattened with increased BP; moreover it is differently altered if pulse pressure (PP) is altered and remains low at any operating BP in models with vascular wall remodeling. However in all conditions the ratio AWV% is poorly modified. Our results suggest that the AWV as the Ve (hysteresis loop area) is the most relevant in defining the viscous properties of the artery; they indicate that mean operating BP, PP and structural distensibility independently participate in modifying the shape of the loop which is largely dependent on the delay between peak systolic pressure and peak systolic diameter, apparent in the higher BP of the loop. This suggests that isobaric distensibility cannot be compared in the lower and upper part of the loop but only at a similar mean BP. Further studies will aim to confirm these suggestions and determine how to improve loop hysteresis evaluation P8.13Cardiovascular diseases are often studied at a pre-clinical stage using dedicated mouse models. However, (non-)invasive measurements in the murine cardiovascular system are difficult to obtain, limited to a restricted number of aortic locations, and need to be justified from an ethical perspective. In this work we present a 1-D model of the systemic circulation in mice. Murine arterial tree dimensions have been acquired and averaged from the segmentation of Micro-Computed Tomography (m-CT) scans of 3 wild-type C57Bl/6 mice (12-15 weeks old). The resulting geometry consists of 85 arterial segments, including all major aortic branches as well as the tail and the cerebral tree. The remaining input to the model has been obtained from a wide range of literature data. An empirical relationship has been fitted to estimate the local arterial wall distensibility in all segments. Peripheral vessels are terminated with three-element windkessel models to account for the resistance and compliance of the distal vasculature. The integrated form of the momentum and continuity equations is solved numerically to yield pressures and flows throughout the arterial network. The model predicts pressure and velocity waveforms in good qualitative and semi-quantitative agreement with invasive pressure measurements as well as high-frequency ultrasound Pulsed-Wave Doppler aortic velocity and M-mode aortic distensibility measurements. In conclusion, a well-tuned and appropriately validate...