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.