The association between diabetes status, HbA1c, diabetes duration, microvascular disease, and bone quality of the distal radius and tibia as measured with high-resolution peripheral quantitative computed tomography-The Maastricht Study.

In this small cross-sectional study of predominantly well-treated participants with relatively short-term type 2 diabetes duration, HbA1c > 7% (53 mmol/mol) was associated with lower cortical density and thickness and higher cortical porosity at the distal radius, lower trabecular thickness at the distal tibia, and higher trabecular number at both sites. INTRODUCTION: To examine the association between diabetes status and volumetric bone mineral density (vBMD), bone microarchitecture and strength of the distal radius and tibia as assessed with HR-pQCT. Additionally-in participants with type 2 diabetes (T2DM), to examine the association between HbA1c, diabetes duration, and microvascular disease (MVD) and bone parameters. METHODS: Cross-sectional data from 410 (radius) and 198 (tibia) participants of The Maastricht Study (mean age 58 year, 51% female). Diabetes status (normal glucose metabolism, prediabetes, or T2DM) was based on an oral glucose tolerance test and medication history. RESULTS: After full adjustment, prediabetes and T2DM were not associated with vBMD, bone microarchitecture, and strength of the radius and tibia, except for lower trabecular number (Tb.N) of the tibia (- 4%) in prediabetes and smaller cross-sectional area of the tibia (- 7%) in T2DM. In T2DM, HbA1c > 7% was associated with lower cortical vBMD (- 5%), cortical thickness (- 16%), higher cortical porosity (+ 20%) and Tb.N (+ 9%) of the radius, and higher Tb.N (+ 9%) and lower trabecular thickness (- 13%) of the tibia. Diabetes duration > 5 years was associated with higher Tb.N (+ 6%) of the radius. The presence of MVD was not associated with any bone parameters. CONCLUSIONS: In this study with predominantly well-treated T2DM participants with relatively short-term diabetes duration, inadequate blood glucose control was negatively associated with cortical bone measures of the radius. In contrast, trabecular number was increased at both sites. Studies of larger sample size are warranted for more detailed investigations of bone density and bone quality in patients with T2DM.

Semi-automatic assessment of skin capillary density: proof of principle and validation.

BACKGROUND: Skin capillary density and recruitment have been proven to be relevant measures of microvascular function. Unfortunately, the assessment of skin capillary density from movie files is very time-consuming, since this is done manually. This impedes the use of this technique in large-scale studies. We aimed to develop a (semi-) automated assessment of skin capillary density. METHODS: CapiAna (Capillary Analysis) is a newly developed semi-automatic image analysis application. The technique involves four steps: 1) movement correction, 2) selection of the frame range and positioning of the region of interest (ROI), 3) automatic detection of capillaries, and 4) manual correction of detected capillaries. To gain insight into the performance of the technique, skin capillary density was measured in twenty participants (ten women; mean age 56.2 [42-72] years). To investigate the agreement between CapiAna and the classic manual counting procedure, we used weighted Deming regression and Bland-Altman analyses. In addition, intra- and inter-observer coefficients of variation (CVs), and differences in analysis time were assessed. RESULTS: We found a good agreement between CapiAna and the classic manual method, with a Pearson's correlation coefficient (r) of 0.95 (P<0.001) and a Deming regression coefficient of 1.01 (95%CI: 0.91; 1.10). In addition, we found no significant differences between the two methods, with an intercept of the Deming regression of 1.75 (-6.04; 9.54), while the Bland-Altman analysis showed a mean difference (bias) of 2.0 (-13.5; 18.4) capillaries/mm(2). The intra- and inter-observer CVs of CapiAna were 2.5% and 5.6% respectively, while for the classic manual counting procedure these were 3.2% and 7.2%, respectively. Finally, the analysis time for CapiAna ranged between 25 and 35min versus 80 and 95min for the manual counting procedure. CONCLUSION: We have developed a semi-automatic image analysis application (CapiAna) for the assessment of skin capillary density, which agrees well with the classic manual counting procedure, is time-saving, and has a better reproducibility as compared to the classic manual counting procedure. As a result, the use of skin capillaroscopy is feasible in large-scale studies, which importantly extends the possibilities to perform microcirculation research in humans.

Fasting and post-oral-glucose-load levels of methylglyoxal are associated with microvascular, but not macrovascular, disease in individuals with and without (pre)diabetes: The Maastricht Study.

AIMS: Reactive dicarbonyl compounds, such as methylglyoxal (MGO), rise during an oral glucose tolerance test (OGTT), particularly in (pre)diabetes. Fasting MGO levels are associated with chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with poorly controlled type 2 diabetes mellitus (T2DM). Yet, whether fasting or post-OGTT plasma MGO levels are associated with vascular disease in people with (pre)diabetes is unknown. METHODS: Subjects with normal glucose metabolism (n=1796; age: 57.9±8.2 years; 43.3% men), prediabetes (n=478; age: 61.6±7.6 years; 54.0% men) and T2DM (n=669; age: 63.0±7.5 years; 67.0% men) from the Maastricht Study underwent OGTTs. Plasma MGO levels were measured at baseline and 2h after OGTT by mass spectrometry. Prior CVD was established via questionnaire. CKD was reflected by estimated glomerular filtration rate (eGFR) and albuminuria; retinopathy was assessed using retinal photographs. Data were analyzed using logistic regression adjusted for gender, age, smoking, systolic blood pressure, total-to-HDL cholesterol ratio, triglycerides, HbA1c, BMI and medication use. Odd ratios (ORs) were expressed per standard deviation of LN-transformed MGO. RESULTS: Fasting and post-OGTT MGO levels were associated with higher ORs for albuminuria ≥30mg/24h [fasting: 1.12 (95% CI: 0.97-1.29); post-OGTT: 1.19 (1.01-1.41)], eGFR<60mL/min/1.73 m2 [fasting: 1.58 (95% CI: 1.38-1.82), post-OGTT: 1.57 (1.34-1.83)] and retinopathy [fasting: 1.59 (95% CI: 1.01-2.53), post-OGTT: 1.38 (0.77-2.48)]. No associations with prior CVD were found. CONCLUSION: Fasting and post-OGTT MGO levels were associated with microvascular disease, but not prior CVD. Thus, therapeutic strategies directed at lowering MGO levels may prevent microvascular disease.

Changes in fibrinolytic activity after angiotensin II receptor blockade in therapy-resistant hypertensive patients.

BACKGROUND: In hypertensive patients, the activated renin-angiotensin system induces a prothrombotic state resulting from imbalance between coagulation and fibrinolysis. Although blood pressure cannot be regulated in therapy-resistant hypertensive patients, they may still be responsive to medication that attenuates the renin-angiotensin system. OBJECTIVE: our objective was to study possible attenuating properties of angiotensin II type 1 receptor blockers (AT1RBs) on the prothrombotic state in therapy-resistant hypertensive patients, focusing on parameters of fibrinolysis and coagulation. METHODS: Fourteen therapy-resistant hypertensive patients received AT1RB eprosartan infusion (45 and 150 microg kg(-1)) (study group), and 33 therapy-resistant hypertensive patients received saline (0.9%) infusion (control group) prior to renal angiography. Baseline values of parameters of coagulation and fibrinolysis were set at 1.00, and relative changes were calculated. RESULTS: Plasminogen activator inhibitor type 1 (PAI-1) antigen showed non-significant decreases in both the study group (arterial 1.00-0.45, venous 1.00-0.42) and control group (arterial 1.00-0.84, venous 1.00-0.88). PAI-1 activity significantly decreased in the study group (arterial 1.00-0.72, venous 1.00-0.71) and control group (arterial 1.00-0.83, venous 1.00-0.94). In the study group, tissue-type plasminogen activator (t-PA) antigen decreased significantly (arterial 1.00-0.62, venous 1.00-0.67), whereas t-PA activity significantly increased (arterial 1.00-6.15, venous 1.00-2.66). In the control group, t-PA antigen remained unchanged. No changes were observed in blood pressure during and after infusion of eprosartan. CONCLUSION: Therapy-resistant hypertensive patients show beneficial changes in fibrinolytic activity after infusion of a non-pressor dose of AT1RB.

Effect of antioxidant vitamin supplementation on endothelial function in type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

Controversy exists among trials assessing whether prolonged antioxidant vitamin supplementation improves endothelial function in type 2 diabetes mellitus (T2DM) subjects. The aim of this study was to systematically review and quantify the effect of antioxidant vitamin supplementation on endothelial function in T2DM subjects. MEDLINE, Cochrane, Scopus and Web of Science were searched up to February 2013 for randomized controlled trials assessing the effect of antioxidant vitamin E and/or C supplementation on endothelial function in T2DM subjects. Ten randomized controlled trials comparing antioxidant vitamin-supplemented and control groups (overall n = 296) met the inclusion criteria. Post-intervention standardized mean difference (SMD) in endothelial function did not reach statistical significance between groups (0.35; 95% confidence interval = -0.17, 0.88; P = 0.18). In subgroup analysis, post-intervention endothelial function was significantly improved by antioxidant vitamin supplementation in T2DM subgroups with body mass index (BMI) ≤ 29.45 kg m(-2) (SMD = 1.02; P < 0.05), but not in T2DM subgroups with BMI > 29.45 kg m(-2) (SMD = -0.07; P = 0.70). In meta-regression, an inverse association was found between BMI and post-intervention SMD in endothelial function (B = -0.024, P = 0.02). Prolonged antioxidant vitamin E and/or C supplementation could be effective to improve endothelial function in non-obese T2DM subjects.

Microvascular dysfunction as a link between obesity, insulin resistance and hypertension.

Impaired microvascular dilatation from any cause and impaired insulin-mediated capillary recruitment in particular result in suboptimal delivery of glucose and insulin to skeletal muscle, and subsequently impairment of glucose disposal (insulin resistance). In addition, microvascular dysfunction, through functional and/or structural arteriolar and capillary drop-out, and arteriolar constriction, increases peripheral resistance and thus blood pressure. Microvascular dysfunction may thus constitute a pathway that links insulin resistance and hypertension. Overweight and obesity may be an important cause of microvascular dysfunction. Mechanisms linking overweight and obesity to microvascular dysfunction include changes in the secretion of adipokines leading to increased levels of free fatty acids and inflammatory mediators, and decreased levels of adiponectin all of which may impair endothelial insulin signaling. Microvascular dysfunction may thus constitute a new treatment target in the prevention of type 2 diabetes mellitus and hypertension.

Selective endothelin B receptor blockade does not influence BNP-induced natriuresis in man.

Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) both exhibit natriuretic activity within the human kidney. Furthermore, they both act partly through activation of the endothelial nitric oxide pathway. Since ET-1 may cause vasodilation and natriuresis via stimulation of the ET-B receptor, the aim of the present study was to investigate whether renal ET-B receptors participate in the renal actions of BNP. In this placebo-controlled, crossover study, we infused BNP (4 pmol/kg/min) or placebo (i.v.) for 1 h, with or without co-infusion of the ET-B receptor antagonist BQ-788 (50 nmol/min) for 15 min on 4 separate days, in 10 healthy subjects (mean age 54+/-6 years.). During infusion, we measured effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) using PAH/inulin clearance. Cardiac output was measured before and after infusion, using echocardiography. Blood pressure and heart rate (HR) were monitored as well. Urine and plasma samples were taken every hour to measure diuresis, natriuresis, cyclic 3',5' guanosine monophosphate, and ET-1 levels. BNP with or without ET-B receptor blockade increased natriuresis and diuresis. In addition, BNP alone increased GFR and filtered load, without changing ERPF. BQ-788 infusion did not affect renal hemodynamics or natriuresis. Neither BNP nor BQ-788 altered cardiac output, blood pressure, and heart rate. In conclusion, the present study shows that selective ET-B receptor blockade has no effect on the BNP-induced natriuresis and glomerular filtration rate.

The effect of polyneuropathy on foot microcirculation in Type II diabetes.

AIMS/HYPOTHESIS: The aim of this study was to investigate the influence of peripheral polyneuropathy (PNP) on skin microcirculation and foot swelling rate in the feet of patients with Type II (non-insulin-dependent) diabetes mellitus. METHODS: 38 Type II diabetic patients, 24 with PNP (PNP+), 14 without PNP (PNP-), and 16 healthy control subjects were studied, first supine and subsequently sitting with the foot dependent for 50 mn. RESULTS: In patients with PNP, foot skin temperature was higher, (p<0.04) and capillary blood cell velocity (CBV, nailfold capillary microscopy), was lower compared to patients without PNP (222 vs 313 micro m/s respectively, p<0.03). Compared to the control subjects, the percentage reduction in skin blood flux, (LDF, laser-Doppler fluxmetry), after 10 min was higher in the PNP- and PNP+ patients (3% vs 18% and 26% respectively, p<0.02). These disturbances were most pronounced in PNP+ patients with a history of a foot ulcer. Foot swelling rate (mercury strain gauge plethysmography) in the first 10 min of dependency, was lower in patients with PNP+ compared to the control subjects (0.00165 vs 0.00286 ml.100 ml(-1)s respectively, p<0.01). In addition, we found a negative correlation (r=-0.41; p<0.01) between Valk-score (severity of PNP) and FSR. CONCLUSION/INTERPRETATION: Type II diabetes PNP is associated with multiple abnormalities in the (skin) microcirculation of the foot, characterised by reduced capillary blood flow, an enhanced reduction in skin blood flux and impaired fluid filtration after sitting up. The most severe abnormalities were observed in patients with a history of foot ulceration.