Weight change and sulfonylurea therapy are related to 3 year change in microvascular function in people with type 2 diabetes

Aims/hypothesis: Although cardiovascular disease is the biggest cause of death in people with diabetes, microvascular complications have a significant impact on quality of life and financial burden of the disease. Little is known about the progression of microvascular dysfunction in the early stages of type 2 diabetes before the occurrence of clinically apparent complications. We aimed to explore the determinants of endothelial-dependent and -independent microvascular function progression over a 3 year period, in people with and without both diabetes and few clinical microvascular complications. Methods: Demographics were collected in 154 participants with type 2 diabetes and in a further 99 participants without type 2 diabetes. Skin microvascular endothelium-dependent response to iontophoresis of acetylcholine and endothelium-independent responses to sodium nitroprusside were measured using laser Doppler fluximetry. All assessments were repeated 3 years later. Results: People with type 2 diabetes had impaired endothelial-dependent microvascular response compared with those without (AUC 93.9 [95% CI 88.1, 99.4] vs 111.9 [102.3, 121.4] arbitrary units [AU] × min, p < 0.001, for those with vs without diabetes, respectively). Similarly, endothelial-independent responses were attenuated in those with diabetes (63.2 [59.2, 67.2] vs 75.1 [67.8, 82.4] AU × min, respectively, p = 0.002). Mean microvascular function declined over 3 years in both groups to a similar degree (pinteraction 0.74 for response to acetylcholine and 0.69 for response to sodium nitroprusside). In those with diabetes, use of sulfonylurea was associated with greater decline (p = 0.022 after adjustment for co-prescriptions, change in HbA1c and weight), whereas improving glycaemic control was associated with less decline of endothelial-dependent microvascular function (p = 0.03). Otherwise, the determinants of microvascular decline were similar in those with and without diabetes. The principal determinant of change in microvascular function in the whole population was weight change over 3 years, such that those that lost ≥5% weight had very little decline in either endothelial-dependent or -independent function compared with those that were weight stable, whereas those who gained weight had a greater decline in function (change in endothelial-dependent function was 1.2 [95% CI -13.2, 15.7] AU × min in those who lost weight; -15.8 [-10.5, -21.0] AU × min in those with stable weight; and -37.8 [-19.4, -56.2] AU × min in those with weight gain; ptrend < 0.001). This association of weight change with change in endothelial function was driven by people with diabetes; in people without diabetes, the relationship was nonsignificant. Conclusions/interpretation: Over 3 years, physiological change in weight was the greatest predictor of change in microvascular function.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was supported by the Innovative Medicines Initiative (the SUMMIT consortium, IMI-2008/115006).published version, accepted version (12 month embargo

Reservoir-Excess Pressure Parameters Independently Predict Cardiovascular Events in Individuals With Type 2 Diabetes

The parameters derived from reservoir-excess pressure analysis (RPA) have prognostic utility in several populations. However, evidence in type 2 diabetes (T2DM) remains scarce. We determined if these parameters were associated with T2DM, and whether they would predict cardiovascular events in individuals with T2DM.We studied 306people with T2DM and cardiovascular disease (CVD)(DMCVD:70.4±7.8yrs), 348people with T2DM but without CVD (DM:67.7±8.4yrs) and 178peoplewithout T2DM or CVD (CTRL:67.2±8.9yrs). RPA-derived parameters including reservoir pressure integral (INTPR), peak reservoir pressure (MAXPR), excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC) were obtained by radial artery tonometry. INTPR was lower in DMCVD and DM than CTRL. MAXPR was lower, and INTXSP was greater in DMCVD than DM and CTRL. SRC was lower in a stepwise manner among groups(DMCVD&lt;DM&lt;CTRL).DRC was greater in DMCVD than CTRL. In the sub group of individuals with T2DM (n=642), 14 deaths (6 cardiovascular and 9non-cardiovascular causes) and 108cardiovascular events occurred during a 3-yr follow-up period. Logistic regression analysis revealed that INTPR [odds ratio 0.59(95%CI:0.45-0.79)] and DRC [odds ratio 1.60(95%CI:1.25-2.06)] were independent predictors of cardiovascular events during follow-up after adjusting for conventional risk factors(both p&lt;0.001). Further adjustments for potential confounders had no influence on associations. These findings demonstrate that altered RPA-derived parameters are associated with T2DM. Furthermore, baseline values of INTPR and DRC independently predict cardiovascular events in individuals with T2DM, indicating the potential clinical utility of these parameters for risk stratification in T2DM

A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function

Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically "favorable adiposity" phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.</p

Use of Vascular Assessments and Novel Biomarkers to Predict Cardiovascular Events in Type 2 Diabetes:The SUMMIT VIP Study

Cardiovascular disease (CVD) risk prediction represents an increasing clinical challenge in the treatment of diabetes. We used a panel of vascular imaging, functional assessments, and biomarkers reflecting different disease mechanisms to identify clinically useful markers of risk for cardiovascular (CV) events in subjects with type 2 diabetes (T2D) with or without manifest CVD

Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes

This is the author’s version of a work that was accepted for publication in Free Radical Biology and Medicine. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Radical Biology and Medicine Vol 60, 2013, doi: 10.1016/j.freeradbiomed.2013.01.024.Diets rich in green, leafy vegetables have been shown to lower blood pressure (BP) and reduce the risk of cardiovascular disease. Green, leafy vegetables and beetroot are particularly rich in inorganic nitrate. Dietary nitrate supplementation, via sequential reduction to nitrite and NO, has previously been shown to lower BP and improve endothelial function in healthy humans. We sought to determine if supplementing dietary nitrate with beetroot juice, a rich source of nitrate, will lower BP and improve endothelial function and insulin sensitivity in individuals with type 2 diabetes (T2DM). Twenty-seven patients, age 67.2±4.9 years (18 male), were recruited for a double-blind, randomized, placebo-controlled crossover trial. Participants were randomized to begin, in either order, a 2-week period of supplementation with 250ml beetroot juice daily (active) or 250ml nitrate-depleted beetroot juice (placebo). At the conclusion of each intervention period 24-h ambulatory blood pressure monitoring, tests of macro- and microvascular endothelial function, and a hyperinsulinemic isoglycemic clamp were performed. After 2 weeks administration of beetroot juice mean ambulatory systolic BP was unchanged: 134.6±8.4mmHg versus 135.1±7.8mmHg (mean±SD), placebo vs active-mean difference of -0.5mmHg (placebo-active), p=0.737 (95% CI -3.9 to 2.8). There were no changes in macrovascular or microvascular endothelial function or insulin sensitivity. Supplementation of the diet with 7.5mmol of nitrate per day for 2 weeks caused an increase in plasma nitrite and nitrate concentration, but did not lower BP, improve endothelial function, or improve insulin sensitivity in individuals with T2DM

Acute and Chronic Impact of Dynamic Exercise on Arterial Stiffness in Older Hypertensives

Arterial stiffness increases with ageing and hypertension. Regular physical activity has been recommended as an important management component of hypertension. The purpose of this study was to examine the acute impact of maximal dynamic exercise and the effect of 20 weeks of aerobic exercise on arterial stiffness of the carotid and brachial arteries in older hypertensives. Nine previously sedentary and treated older hypertensives (2 men and 7 women, age 68.2 ± 5.4 yrs) performed maximal treadmill exercise to volitional fatigue while arterial stiffness indices (arterial distensibility and β stiffness index) were measured prior to, immediately (about 10 min) following, and 24 h following maximal exercise. These measurements were repeated following 20 weeks of moderate intensity aerobic exercise training. Maximal exercise had no impact on arterial stiffness indices immediately and 24 h following exercise intervention. Following 20 weeks of training, arterial stiffness indices remained unchanged at rest and following maximal exercise. These data show that, in older hypertensives, 1) acute maximal dynamic exercise had no impact on arterial stiffness of the carotid and brachial arteries, and 2) 20 weeks of moderate intensity aerobic exercise training failed to modify arterial stiffness

Development and Validation of a Path Length Calculation for Carotid-Femoral Pulse Wave Velocity Measurement: A TASCFORCE, SUMMIT, and Caerphilly Collaborative Venture.

Current distance measurement techniques for pulse wave velocity (PWV) calculation are susceptible to intercenter variability. The aim of this study was to derive and validate a formula for this distance measurement. Based on carotid femoral distance in 1183 whole-body magnetic resonance angiograms, a formula was derived for calculating distance. This was compared with distance measurements in 128 whole-body magnetic resonance angiograms from a second study. The effects of recalculation of PWV using the new formula on association with risk factors, disease discrimination, and prediction of major adverse cardiovascular events were examined within 1242 participants from the multicenter SUMMIT study (Surrogate Markers of Micro- and Macrovascular Hard End-Points for Innovative Diabetes Tools) and 825 participants from the Caerphilly Prospective Study. The distance formula yielded a mean error of 7.8 mm (limits of agreement =-41.1 to 56.7 mm; P<0.001) compared with the second whole-body magnetic resonance angiogram group. Compared with an external distance measurement, the distance formula did not change associations between PWV and age, blood pressure, or creatinine (P<0.01) but did remove significant associations between PWV and body mass index (BMI). After accounting for differences in age, sex, and mean arterial pressure, intercenter differences in PWV persisted using the external distance measurement (F=4.6; P=0.004), whereas there was a loss of between center difference using the distance formula (F=1.4; P=0.24). PWV odds ratios for cardiovascular mortality remained the same using both the external distance measurement (1.14; 95% confidence interval, 1.06-1.24; P=0.001) and the distance formula (1.17; 95% confidence interval, 1.08-1.28; P<0.001). A population-derived automatic distance calculation for PWV obtained from routinely collected clinical information is accurate and removes intercenter measurement variability without impacting the diagnostic utility of carotid-femoral PWV

Gakushuin Natural Radiocarbon Measurements VII

This material was digitized as part of a cooperative project between Radiocarbon and the University of Arizona Libraries.The Radiocarbon archives are made available by Radiocarbon and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform February 202

Arterial wall shear rate response to reactive hyperaemia is markedly different between young and older humans

Key points: The vasodilatory response to reactive hyperaemia is impaired with advancing age, but it is unclear whether this is because of an altered wall shear rate (WSR) stimulus or an altered flow-mediated dilatation (FMD) response. Using new technology that allows detailed WSR measurement, we assessed the WSR-FMD response in healthy older people. Our data show that older people have a markedly altered and diminished WSR response to reactive hyperaemia compared to young people, but reduced WSR alone does not fully explain reduced FMD. In young people, WSR appears to be coupled to FMD but, by age ∼65 years, the arterial vasodilatory response has begun to uncouple from the WSR stimulus. These findings point to the importance and utility of comprehensively characterizing the WSR-FMD response when using reactive hyperaemia to assess vascular function, as well as giving new insight into the age-related alteration in vascular function. Abstract: The vasodilatory response to reactive hyperaemia is impaired with age, but it is unknown whether this is because of an altered wall shear rate (WSR) stimulus or an altered flow-mediated dilatation (FMD) response to the WSR stimulus. Inherent difficulties in measuring blood flow velocity close to the arterial wall have prevented detailed assessment of the WSR-FMD response. Using an enhanced multigate spectral Doppler ultrasound system (ultrasound advanced open platform), we aimed to produce new data on the WSR-FMD relationship in healthy older adults. Sixty healthy people, comprising 28 young (27.5 ± 5.5 years) and 32 older (64.9 ± 3.7 years) individuals, underwent FMD assessment. Raw data were post-processed using custom-designed software to obtain WSR and diameter parameters. The data revealed that older people have a much altered and diminished WSR response to reactive hyperaemia compared to younger people [e.g. WSR peak: 622 (571-673) vs. 443 (396-491) 1/s in young and older respectively; P < 0.05]. However, reduced WSR alone does not appear to fully explain the reduced FMD response in older people because associations between WSR and FMD were few and weak. This was in contrast to young adults, where associations were strong. We conclude that WSR during FMD is much altered and diminished in older people, and there appears to be an 'uncoupling' of WSR from FMD in older people that may reflect a loss of precision in the reactive hyperaemia stimulus-response relationship. These findings also point to the importance and utility of comprehensively characterizing the WSR-FMD response when using reactive hyperaemia to assess vascular function.This article is available to RD&E staff via NHS OpenAthens. Click on the Publisher URL, and log in with NHS OpenAthens if prompted.European Union's Seventh Framework Programme. Grant Number: FP7/2007‐2013 Italian Ministry of University and Research Innovative Medicines Initiative. Grant Number: IMI/115006 NIHR. Grant Number: IMI/115006published version, accepted version (12 month embargo), submitted versio