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Objectives: Type-2 Diabetes mellitus (T2DM) increases both the patient risk of cardiovascular disease (CVD) and renal outcomes, such as chronic kidney disease (CKD). Recent clinical trials of the glucose-lowering drug-class of sodium-glucose co-transporter-2 inhibitors (SGLT2is) have shown benefits in preventing CVD events and progression of CKD, leading to an update of the Dutch T2DM treatment guideline for patients at risk. The aim of this study is to assess the health and economic impact of the guideline-recommended utilization of SGLT2is in the Netherlands. Methods: The patient population at risk was determined by multiplying Dutch T2DM prevalence rates with the total numbers of inhabitants of the Netherlands in 2020. Subsequently, two analyses, comparing a treatment setting before and after implementation of the new guideline for SGLT2is, were conducted. Clinical and adverse event rates in both settings as well as direct healthcare costs were sourced from the literature. Total costs were calculated by multiplying disease prevalence, event rates and costs associated to outcomes. One-time disutilities per event were included to estimate the health impact. The potential health and economic impact of implementing the updated guideline was calculated. Results: Using a 5-year time horizon, the guideline-suggested utilization of SGLT2is resulted in a health impact equal to 4835 quality adjusted life years gained (0.0031 per patient per year) and €461 million cost-savings. The costs of treatment with SGLT2is were €813 million. Hence the net budget impact was €352 million for the total Dutch T2DM population, which translated to €0,57 per patient per day. Conclusion: SGLT2is offer an option to reduce the number of CVD and CKD related events and associated healthcare costs and health losses in the Netherlands. Further research is needed to include the benefits of improved T2DM management options from a broader societal perspective.Highlights The glucose-lowering drug-class of sodium-glucose co-transporter-2 inhibitors (SGLT2is) has shown benefits in preventing cardiovascular events and progression of kidney disease in patients with type-2 diabetes leading to a revision of the respective Dutch treatment guideline. The 5-year budget impact of the adoption of SGLT2is in the new treatment guideline was equal to €352 million or €0.57 per patient per day, with a total of 4385 quality adjusted life years gained. The introduction of SGLT2is for Dutch type-2 diabetes patients has the potential to substantially reduce the number of cardiovascular as well as renal disease events and related healthcare costs while also delivering a health benefit.

Aims The COVID-19 pandemic impacted diabetes care by reducing diabetes outpatient visits and diabetes-related screening due to healthcare allocation. Yet the impact of COVID-19 on diabetes outpatients has not been extensively evaluated. This study aimed to assess the effect of the COVID-19 pandemic on all aspects of outpatient diabetes care, particularly diagnostics and intermediate outcomes. Methods This observational cohort study included 8,442 diabetes patients in the Dutch Pediatric and Adult Registry of Diabetes (DPARD) visiting diabetes outpatient clinics in 2019 and 2021. A mixed-effects regression analysis was used to examine differences in target achievement of HbA1c, BMI, blood pressure, LDL-cholesterol, eGFR, and the difference in mean HbA1c between 2019 and 2020 among n=1,426 outpatients who visited in both years. Analyses were adjusted for age, sex, and BMI Results A 22.7% (21.6 - 23.8%, pConclusions The COVID pandemic impacted Dutch diabetes outpatient care by reducing patient volume by 22.7%. Among patients who received outpatient care both before and during the pandemic period, HbA1c control and blood pressure control enhanced during the pandemic. Re-evaluation of current diabetes outpatient care organization is warranted to ensure optimal diabetes care in future times.

Diabetes mellitus is one of the largest global health concerns of recent times. Women with diabetes mellitus have a higher excess risk of all-cause mortality and more vascular events than men. Focusing on type 1 diabetes, this could be caused by gender inequalities in delivered diabetes care. This study aims to assess gender differences in type 1 diabetes outpatient care, particularly diagnostics and outcomes.This cross-sectional cohort study included all adult type 1 diabetes patients in the Dutch Pediatric and Adult Registry of Diabetes (DPARD) visiting diabetes outpatient clinics between 2016-2021. The frequency of process measurements, including physical examination and laboratory testing, was assessed among both sexes after adjustment for age and body mass index. Gender differences in eGFR ≥ 60, BMI-, and control in blood pressure and LDL-cholesterol were evaluated. Hospital variation in achieving HbA1c targets of 53 mmol/mol and median HbA1c were assessed. Cardiovascular risk scores were calculated in men and women using the Systematic Coronary Risk Evaluation (SCORE) European low-risk chart.Our study showed a 17% higher odds of reaching weight control and a 23% lower odds of achieving blood pressure targets in men than women. Gender-skewed cardiovascular mortality risk scores were found. Gender disparities in outcomes appear not to be caused by gender-biased attitudes in healthcare professionals since no gender differences were found in the performance of process measurements in type 1 diabetes care. In addition, hospitals appear to vary by extent of gender differences in achieving a target HbA1c of 53 mmol/mol.Gender equality exists in the diagnostic process of diabetes care. However, differences in weight control, blood pressure control, and cardiovascular mortality risk scores remain between both sexes, most likely due to multifactorial causes. Indications for interhospital variation in gender disparities in HbA1c control exist. Further focus on performance of process measurements between hospitals may identify areas for improvement of gender-skewed outcomes to further enhance Dutch diabetes care for both sexes.

Background Insulin has to be transported across the capillary endothelium to stimulate muscle glucose uptake. We investigated insulin uptake from the peripheral circulation in non-diabetic (ND) individuals and in type 2 diabetes (T2D) patients. Methods Single-center cross-sectional study involving 40 ND (age 65±11 years) and 30 T2D patients (age 67±8 years). Thirty-six participants were studied in the fasted state (22 ND subjects and 14 T2D patients termed NDF and T2DF) and 34 participants 1-h following a glucose challenge (18 ND subjects and 16 T2D patients indicated as NDG and T2DG). Main outcome measure was fractional extraction (FE) of insulin (FEins) and glucose using the forearm balance method. Results In NDF, FEins was 18 (10–26) % at lower insulin levels (63 51–80] pmol/l), while in NDG at higher insulin levels (776 [543–1176] pmol/l), FEins was 9 (4–16) % (p = 0.01 vs. NDF). In NDF only, a negative correlation was observed between FEins and arterial plasma insulin load (rho = − 0.575;p = 0.006) and fasting plasma glucose levels (rho = − 0.551;p = 0.01). In T2DF FEins was 6 (1–19) % and not different from FEins in T2DG (10 2–14) %), and was not associated to fasting glucose. FEins tended to be higher in NDF compared to T2DF (p = 0.07). Discussion We propose that in ND individuals, besides passive diffusion, an active high-affinity pathway with limited capacity around lower physiologic insulin levels exists for insulin transendothelial transport, contributing to glycemic control. In T2D patients, this mechanism of peripheral insulin uptake is diminished or even absent. Modulation of insulin extraction from the circulation may be a novel target to improve glucose metabolism in T2D.

Objective: In mice fed a high-fat diet, impairment of insulin signaling in endothelium is an early phenomenon that precedes decreased insulin sensitivity of skeletal muscle, adipose tissue, and liver. We assessed in humans whether short-term overfeeding affects insulin-induced microvascular recruitment in skeletal muscle and adipose tissue before changes occur in glucose uptake and lipolysis. Approach and Results: Fifteen healthy males underwent a hypercaloric and subsequent hypocaloric diet intervention. Before, during, and after the hypercaloric diet, and upon return to baseline weight, all participants underwent (1) a hyperinsulinemic-euglycemic clamp to determine insulin-induced glucose uptake and suppression of lipolysis (2) contrast-enhanced ultrasonography to measure insulin-induced microvascular recruitment in skeletal muscle and adipose tissue. In addition, we assessed insulin-induced vasodilation of isolated skeletal muscle resistance arteries by pressure myography after the hypercaloric diet in study participants and controls (n=5). The hypercaloric diet increased body weight (3.5 kg; P P P =0.041) and decreased the ratio between skeletal muscle and adipose tissue microvascular blood volume during hyperinsulinemia ( P =0.019). Insulin-induced vasodilation of isolated skeletal muscle arterioles was significantly lower in participants compared with controls ( P Conclusions: In lean men, short-term overfeeding reduces insulin-induced vasodilation of skeletal muscle resistance arteries and shifts the distribution of tissue perfusion during hyperinsulinemia from skeletal muscle to adipose tissue without affecting glucose uptake and lipolysis. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02628301.

Recent trials of two classes of glucose-lowering drugs (SGLT2 inhibitors and GLP1RAs) have shown consistent cardiovascular and renal benefits that appear independent of glycaemic control. These results have prompted the Dutch College of General Practitioners (NHG) together with the Dutch Society of Internal Medicine (NIV) to update the treatment algorithm in patients with type 2 diabetes mellitus (T2D) at very high CVD risk. The use of SGLT2 inhibitors or GLP1RAs is now recommended in 3 groups of people with T2D. 1. patients with established CVD; 2. Patients with chronic kidney disease and a moderately to high CVD risk according to KDIGO; 3. patients with heart failure with reduced ejection fraction (HFrEF). Treatment algorithms differ for drug-naïve and drug-treated patients with T2D. In both drug-naïve and drug-treated patients the use of a SGLT2 inhibitor respectively as monotherapy or add-on is recommended as first step. If HbA1c is above the individual target, metformin will be added in drug-naive patients whereas GLP1-RAs could be considered in drug-treated patients. GLP1-RAs should also be considered when SGLT2-inhibitors are contraindicated.

Hybrid closed loop (HCL) insulin pump systems and intermittently scanned continuous glucose monitoring (IS-CGM) are increasingly used by individuals with type 1 diabetes (T1D). The aim of the analysis was to compare the long-term cost-effectiveness of the MiniMed 670G HCL system versus IS-CGM plus multiple daily injections of insulin (MDI) or continuous subcutaneous insulin infusion (CSII) in adults with T1D in the Netherlands.The analysis was performed using the IQVIA CORE Diabetes Model with clinical input data sourced from observational studies. Simulated patients were assumed to have a baseline HbA1c of 7.8%. Use of the MiniMed 670G system was assumed to reduce HbA1c by 0.4% and confer a quality-of-life (QoL) benefit through reduced fear of hypoglycemia (FoH). The analysis was performed from a societal perspective over a lifetime time horizon; future costs and clinical outcomes pertaining to the Netherlands were used and discounted at 4% and 1.5% per annum, respectively.Use of the MiniMed 670G HCL system was projected to improve mean quality-adjusted life expectancy by 2.231 quality-adjusted life years (QALYs) versus IS-CGM. Total mean lifetime costs were EUR 13,683 higher with the MiniMed 670G system resulting in an ICER of EUR 6133 per QALY gained. Sensitivity analyses revealed findings to be sensitive to changes in assumptions around severe hypoglycemic event rates and the (QoL) benefit associated with reduced FoH.Over patient lifetimes, for adults with long-standing T1D in the Netherlands, use of the MiniMed 670G system is projected to be cost-effective versus IS-CGM plus MDI or CSII.

De NHG-Standaard Diabetes mellitus 2 is herzien. De herziene standaard bevat een nieuw medicamenteus stappenplan voor zeerhoogrisicopatienten. Het advies is om bij deze patienten eerder te starten met SGLT2-remmers en GLP1-receptoragonisten. Uit recent onderzoek blijkt namelijk dat deze bloedglucoseverlagende middelen voor een afname van de kans op hart- en vaatziekten zorgen.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors include a relatively new class of glucose-lowering drugs that reduce plasma glucose concentrations by inhibiting proximal tubular reabsorption of glucose in the kidney, while increasing its excretion in urine. Recent large randomised controlled trials have demonstrated that many of these agents reduce the occurrence of major adverse cardiovascular events, hospitalisation for heart failure, cardiovascular death and/or chronic kidney disease progression in patients with and without type 2 diabetes mellitus (DM2). Given their unique insulin-independent mode of action and favourable efficacy and adverse-event profile, SGLT2 inhibitors are promising and they offer an interesting therapeutic approach for the cardiologist to incorporate into routine practice. However, despite accumulating data supporting this class of therapy, cardiologists infrequently prescribe SGLT2 inhibitors, potentially due to a lack of familiarity with their use and the reticence to change DM medication. Here, we provide an up-to-date practical guide highlighting important elements of treatment initiation based on real-world evidence and expert opinion. We describe how to change DM medication, including insulin dosing when appropriate, and how to anticipate any adverse events based on real-world experience in patients with DM2 in the Meander Medical Centre in Amersfoort, the Netherlands. This includes a simple algorithm showing how to initiate SGLT2 inhibitor treatment safely, while considering the consequence of the glucosuric effects of these inhibitors for the individual patient. Supplementary Information The online version of this article (10.1007/s12471-021-01580-9) contains supplementary material, which is available to authorized users.

Objective assess how many patients with low ambulatory diastolic blood pressure (DBP) are not identified when relying on office DBP alone, and thus have ‘masked diastolic hypotension’. Design cross-sectional, retrospective cohort study. Setting academic hospital. Subjects 848 patients treated for hypertension who received ambulatory blood pressure monitoring (ABPM). Methods cut-off value between on- and off-target systolic blood pressure (SBP): 140 mmHg. Cut-off for low office and/or ambulatory DBP: DBP ≤ 70 mmHg. ‘Masked diastolic hypotension’ was defined as office DBP > 70 mmHg and mean ambulatory DBP ≤ 70 mmHg. Results mean age of the sample was 60 ± 13 years, 50% was female, 37% had diabetes, 42% preexisting cardiovascular disease (CVD), mean office blood pressure (BP) was 134/79 mmHg. In all patients (n = 848), low office DBP was present in n = 84(10%), while n = 183(22%) had low ambulatory DBP. In all patients with normal-to-high office DBP (n = 764), n = 122(16%) had ‘masked diastolic hypotension’. In this group, ambulatory DBP was 14–19 mmHg lower than office DBP. Patients with low ambulatory DBP were older, had more (cardiovascular) comorbidities, and used more (antihypertensive) drugs. Antihypertensive drugs were lowered or discontinued in 30% of all patients with ‘masked diastolic hypotension’ due to side effects. Conclusions ‘masked diastolic hypotension’ is common among patients treated for hypertension, particularly in older patients with CVD (e.g. coronary artery disease, diabetes), patient groups in which the European Society of Cardiology/Hypertension guideline advises to prevent low DBP. Although it remains to be examined at which BP levels the harms of low DBP outweigh the benefits of lowering SBP, our observations are aimed to increase awareness among physicians.

Aims The global epidemic of diabetes mellitus continues to expand, including its large impact on national health care. Measuring diabetes outcomes and their causes of variation highlights areas for improvement in care and efficiency gains; large registries carry this potential. By means of a systematic review, we aimed to give an overview of national registries worldwide by quantifying their data and assessing their influence on diabetes care. Methods The literature on MEDLINE up to March 31, 2020, was searched, using keywords diabetes mellitus, national, registry, registration, and/or database. National disease-specific registries from corresponding articles were included. Database characteristics and clinical variables were obtained. All registries were compared to the ICHOM standard set of outcomes. Results We identified 12 national clinical diabetes registries, comprising a total of 7,181,356 diabetic patients worldwide. Nearly all registries recorded weight, HbA1c, lipid profile, and insulin treatment; the recording of other variables varied to a great extent. Overall, registries corresponded fairly well with the ICHOM set. Most registries proved to monitor and improve the quality of diabetes care using guidelines as a benchmark. The effects on national healthcare policy were more variable and often less clear. Conclusions National diabetes registries confer clear insights into diagnostics, complications, and treatment. The extent to which registries influenced national healthcare policy was less clear. A globally implemented standard outcome set has the potential to improve concordance between national registries, enhance the comparison and exchange of diabetes outcomes, and allocate resources and interventions where most needed.

Background and Aims: Metabolic-associated fatty liver disease (MAFLD) is driven by high caloric intake and sed-entary lifestyle. Migration towards high income countries may induce these driving factors; yet, the influence of such on the prevalence of MAFLD is clearly understudied. Here, we investigated the Fatty Liver Index (FLI), a proxy of steatosis in MAFLD, after migration of Ghanaian sub-jects. Methods: Cross-sectional data of 5282 rural, urban and migrant participants from the Research on Obesity and Diabetes among African Migrants (also known as RODAM) study were analyzed with logistic regression for geographi-cal differences in FLI and associations with type 2 diabetes mellitus (T2DM), waist-to-hip ratio, and 10-year predicted risk of atherosclerotic cardiovascular disease (ASCVD). Results: Both FLI and the proportion with an FLI indica-tive of MAFLD steatosis (FLI ≥60) were higher in migrants compared with non-migrants. Prevalence of elevated FLI (FLI ≥60) in non-migrant males was 4.2% compared to 28.9% in migrants. For females, a similar gradient was ob-served, from 13.6% to 36.6% respectively. Compared to rural residents, the odds for a FLI ≥60 were higher in migrants living in urban Europe (odds ratio [OR] 9.02, 95% confidence interval [CI]: 5.02–16.20 for men, and 4.00, 95% CI: 3.00–5.34 for women). Compared to controls, the ORs for FLI ≥60 were 2.43 (95% CI: 1.73–3.41) for male T2DM cases and 2.02 (95% CI: 1.52–2.69) for female T2DM cases. One-unit higher FLI was associated with an elevated (≥7.5%) 10-year ASCVD risk (OR: 1.051, 95% CI: 1.041–1.062 for men, and 1.020, 95% CI: 1.015–1.026 for women). Conclusions: FLI as a proxy for MAFLD increased stepwise in Ghanaians from rural areas, through urban ar-eas, to Europe. Our results clearly warrant awareness for MAFLD in migrant population as well as confirmation with imaging modalities.

Background The Hestia criteria can be used to select pulmonary embolism (PE) patients for outpatient treatment. The subjective Hestia criterion “medical/social reason for admission” allows the treating physician to consider any patient-specific circumstances in the final management decision. It is unknown how often and why this criterion is scored. Methods This is a patient-level post hoc analysis of the combined Hestia and Vesta studies. The main outcomes were the frequency of all scored Hestia items in hospitalized patients and the explicit reason for scoring the subjective criterion. Hemodynamic parameters and computed tomography-assessed right ventricular (RV)/left ventricular (LV) ratio of those only awarded with the subjective criterion were compared with patients treated at home. Results From the 1,166 patients screened, data were available for all 600 who were hospitalized. Most were hospitalized to receive oxygen therapy (45%); 227 (38%) were only awarded with the subjective criterion, of whom 51 because of “intermediate to intermediate-high risk PE.” Compared with patients with intermediate risk PE (RV/LV ratio > 1.0) treated at home (179/566, 32%), hospitalized patients with only the subjective criterion had a higher mean RV/LV ratio (mean difference +0.30, 95% confidence interval [CI] 0.19–0.41) and a higher heart rate (+18/min, 95% CI 10–25). No relevant differences were observed for other hemodynamic parameters. Conclusion The most frequent reason for hospital admission was oxygen therapy. In the decision to award the subjective criterion as sole argument for admission, the severity of the RV overload and resulting hemodynamic response of the patient was taken into account rather than just abnormal RV/LV ratio.

Thus far, the association between residual vein occlusion and immediate compression therapy and postthrombotic syndrome is undetermined. Therefore, we investigated whether compression therapy immediately after diagnosis of deep vein thrombosis affects the occurrence of residual vein obstruction (RVO), and whether the presence of RVO is associated with postthrombotic syndrome and recurrent venous thromboembolism. In a prespecified substudy within the IDEAL (individualized duration of elastic compression therapy against long-term duration of therapy for prevention of postthrombotic syndrome) deep vein thrombosis (DVT) study, 592 adult patients from 10 academic and nonacademic centers across The Netherlands, with objectively confirmed proximal DVT of the leg, received no compression or acute compression within 24 hours of diagnosis of DVT with either multilayer bandaging or compression hosiery (pressure, 35 mm Hg). Presence of RVO and recurrent venous thromboembolism was confirmed with compression ultrasonography and incidence of postthrombotic syndromeas a Villalta score of at least 5 at 6 and 24 months. The average time from diagnosis until assessment of RVO was 5.3 (standard deviation, 1.9) months. A significantly lower percentage of patients who did receive compression therapy immediately after DVT had RVO (46.3% vs 66.7%; odds ratio, 0.46; 95% confidence interval, 0.27-0.80; P = .005). Postthrombotic syndrome was less prevalent in patients without RVO (46.0% vs 54.0%; odds ratio, 0.65; 95% confidence interval, 0.46-0.92; P = .013). Recurrent venous thrombosis showed no significant association with RVO. Immediate compression should therefore be offered to all patients with acute DVT of the leg, irrespective of severity of complaints. This study was registered at ClinicalTrials.gov (NCT01429714) and the Dutch Trial registry in November 2010 (NTR2597).

Background: Therapy with elastic compression stockings has been the cornerstone for prevention of post-thrombotic syndrome for decades in patients after acute deep venous thrombosis. It is uncertain who benefits most from therapy, and what the optimum duration of therapy should be. We therefore aimed to assess the safety and efficacy of individualised duration of compression therapy versus the standard duration of 24 months following an initial treatment period of 6 months. Methods: We did a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial at 12 hospitals in the Netherlands and two in Italy. We randomly assigned patients (1:1) with acute proximal deep vein thrombosis of the leg and without pre-existent venous insufficiency (Clinical Etiological Anatomical and Pathophysiological score

Aims: In type 2 diabetes impaired insulin-induced muscle perfusion is thought to contribute to reduced whole-body glucose uptake. In this study, we examined the effects of iloprost, a stable prostacyclin analogue, on insulin-induced muscle capillary recruitment and whole-body glucose uptake. Materials and Methods: In a randomized cross-over design, 12 type 2 diabetes patients (age, 55 [46-69] years; BMI, 33.1 [31.0-39] kg/m2) underwent two hyperinsulinaemic-euglycaemic clamps, one with and one without simultaneous low-dose iloprost infusion. Contrast-enhanced ultrasonography of the vastus lateralis muscle was performed before and during the clamp. Muscle capillary recruitment was calculated as percentage change in microvascular blood volume (MBV) before and during the clamp. Results: Insulin infusion reduced skeletal muscle MBV by ~50% compared to the fasting state (fasting, 1.77·10−4 [1.54·10−5–2.44·10−3] arbitrary units (AU); hyperinsulinaemia, 6.69·10−5 [2.68·10−6–5.72·10−4] AU; P = 0.050). Infusion of iloprost prevented this insulin-induced skeletal muscle capillary derecruitment, from (−49.5 [−89.5 to 55.3] %) to (8.0 [−68.8 to 306.6] %), for conditions without and with iloprost, respectively. The rate of glucose disappearance (Rd) did not change significantly during iloprost infusion (17.3 [10.0-40.8] μmol/kg/min) compared with insulin infusion alone (17.6 [9.9-68.7] μmol/kg/min). Conclusions: Our data suggest that acute improvement in insulin-stimulated muscle perfusion is not an attractive therapeutic approach to bypass cellular resistance to glucose uptake in type 2 diabetes. Whether long-term improvements in insulin-induced muscle perfusion may prove beneficial for glucose disposal remains to be determined.

Aims: We aimed to re-assess the previously shown but recently disputed association between HbA1c and severe hypoglycemia. Methods: 52 Patients with T1D and IAH participated in an earlier reported randomized, crossover trial with two 16-week intervention periods comparing continuous glucose monitoring (CGM) with self-monitoring of blood glucose (SMBG). In this previous study, time spent in normoglycemia (the primary outcome), was improved by 9.6% (p

The aim of this study was to evaluate whether psychological distress modifies the effect of continuous glucose monitoring (CGM) in patients with type 1 diabetes (T1D) and impaired awareness of hypoglycemia. Fifty-two patients with T1D and impaired awareness of hypoglycemia participated in an earlier reported randomized crossover trial with two 16-week intervention periods comparing CGM with self-monitoring of blood glucose (SMBG). During the CGM phase, time spent in euglycemia (4-10 mmol/L), the primary outcome, was 9.6% higher compared with the SMBG phase (P < 0.0001). Psychological distress was operationalized as low emotional well-being (World Health Organization Well-being Index 5 [WHO-5] < 50) high diabetes-related distress (Problem Areas in Diabetes 5 [PAID-5] ≥ 8) and/or high fear of hypoglycemia (Hypoglycemia Fear Survey [HFS] Worry > mean HFS Worry score +1 standard deviation). Modifying effects were assessed by analyzing psychological distress score × intervention - interaction effects. Results showed that both the low emotional well-being group and normal emotional well-being group had equal glycemic outcomes during the CGM phase. High diabetes distress and elevated fear of hypoglycemia did not result in significant interaction effects for glycemic outcomes. This study demonstrated that CGM is equally effective in terms of glycemic improvements in high versus low distressed patients with T1D and impaired awareness of hypoglycemia.

Aim To further our understanding of individual use and experience of continuous glucose monitoring (CGM) in adults with Type 1 diabetes and impaired awareness of hypoglycaemia, we conducted a qualitative study supplementary to a randomized controlled trial, using semi-structured interviews. Methods Twenty-three participants of the IN CONTROL trial were interviewed within 4 weeks after the last study visit. The interview centred around experiences of CGM, taking into account the person's expectations prior to the trial. The interview was semi-structured, using open-ended questions and, if needed, prompts were offered to elicit further responses. Using thematic analysis, the interview transcripts were coded independently by three members of the research team. The consolidated criteria for reporting qualitative research (COREQ) were followed. Results Overall, CGM was experienced as helpful in gaining more insight into glucose variability, and temporarily improved sense of control, reduced distress and made participants less dependent on others. However, some participants experienced confrontation with CGM output as intrusive, while some reported frustration due to failing technique and difficulty trusting the device. Participants reported active and passive self-management behaviours mirroring individual differences in attitudes and coping styles. Conclusions In adults with Type 1 diabetes at risk of recurrent hypoglycaemia due to impaired awareness of hypoglycaemia, CGM use enhances a sense of control and safety for most, but not all. Future studies should further explore differential use of CGM in this population in the context of active and passive self-management styles. This article is protected by copyright. All rights reserved.

Preclinical studies have suggested that polyphenols extracted from red wine (RWPs) favourably affect insulin sensitivity, but there is controversy over whether RWPs exert similar effects in humans. The aim of the present study was to determine whether RWPs improve insulin sensitivity in obese volunteers. Obese (body mass index >30 kg/m2) volunteers were randomly allocated to RWPs 600 mg/d (n = 14) or matched placebo (n = 15) in a double-blind parallel-arm study for 8 weeks. The participants were investigated at baseline and at the end of the study. Insulin sensitivity was determined using a hyperinsulinaemic-euglycaemic clamp (M-value), a mixed-meal test (Matsuda index), and homeostatic model assessment of insulin resistance (HOMA-IR). RWPs elicited no significant changes in M-value (RWP group: median [interquartile range; IQR] baseline 3.0 [2.4; 3.6]; end of study 3.3 [2.4; 4.8] vs placebo group: median [IQR] baseline 3.4 [2.8; 4.4]; end of study 2.9 [2.8; 5.9] mg/kg/min; P =.65), in Matsuda index (RWP group: median [IQR] baseline 3.3 [2.2; 4.8]; end of study 3.6 [2.4; 4.8] vs placebo group: median [IQR] baseline 4.0 [3.0; 6.0]; end of study 4.0 [3.0; 5.2]; P =.88), or in HOMA-IR. This study showed that 8 weeks of RWP supplementation did not improve insulin sensitivity in 29 obese volunteers. Our findings were not consistent with the hypothesis that RWPs ameliorate insulin resistance in human obesity.

After food ingestion, macronutrients are transported to and stored in the skeletal muscle and adipose tissue. They can be subsequently used as an energy source in times of energy deprivation. Uptake of these nutrients in myocytes and adipocytes depends largely on adequate tissue perfusion. Interestingly, insulin is able to dilate skeletal muscle arterioles, which facilitates the delivery of macronutrients and insulin itself to muscle tissue. Insulin-stimulated skeletal muscle perfusion is impaired in several insulin-resistant states and is believed to contribute to impaired skeletal muscle glucose uptake and consequently impaired whole-body glucose disposal. Insulin-resistant individuals also exhibit blunted postprandial adipose tissue perfusion. However, the relevance of this impairment to metabolic dysregulation is less clear. In this review, we provide an overview of adipose tissue perfusion in healthy and insulin-resistant individuals, its regulation among others by insulin, and the possible influences of impaired adipose tissue perfusion on whole-body insulin sensitivity. Finally, we propose a novel hypothesis that acute overfeeding impacts distribution of macronutrients by reducing skeletal muscle perfusion, while adipose tissue perfusion remains intact. Visual Overview— An online visual overview is available for this article.

Background/Objectives:Epidemiological, in vitro and animal studies suggest that grape polyphenols, such as those present in wine, have favorable effects on the metabolic syndrome. However, controversy remains whether treatment with grape polyphenols is effective in humans. Here, we aimed to systemically review the effects of grape polyphenols on metabolic syndrome components in humans.Subjects/Methods:We systematically searched Medline, EMBASE and the Cochrane database for all clinical trials assessing the effects of grape polyphenols on insulin sensitivity, glycemia, blood pressure or lipid levels. We screened all titles and reviewed abstracts of potentially relevant studies. Full papers were assessed for eligibility and quality-rated according to the Jadad scale by two independent assessors.Results:Thirty-nine studies met the eligibility criteria. In individuals without component criteria of the metabolic syndrome, only low- and medium-quality studies were found with primarily neutral results. In individuals with the metabolic syndrome or related conditions, one of two high-quality studies suggested improvement in insulin sensitivity. Glycemia was improved in 2 of 11 lower-quality studies and 2 of 4 high-quality studies. Seven of 22 studies demonstrated a significant decrease in blood pressure, but only one was of high quality. Two of four high-quality studies pointed towards effects on total cholesterol while other lipidemic parameters were not affected.Conclusions:No compelling data exist that grape polyphenols can positively influence glycemia, blood pressure or lipid levels in individuals with or without the metabolic syndrome. Limited evidence suggests that grape polyphenols may improve insulin sensitivity.European Journal of Clinical Nutrition advance online publication, 1 February 2017; doi:10.1038/ejcn.2016.227.

Background: Dutch cardiovascular risk management guidelines state almost every older adult (≥70 years) is eligible for a lipid lowering drug (LLD). However, life expectancy, frailty or comorbidities may influence this treatment decision. Objective: investigate how many older adults, according to age, frailty (Drubbel-frailty index) and comorbidities were prescribed LLDs. Methods: data of 244,328 adults ≥70 years from electronic health records of 415 Dutch general practices from 2011-15 were used. Number of LLD prescriptions in patients with (n = 55,309) and without (n = 189,019) cardiovascular disease (CVD) was evaluated according to age, frailty and comorbidities. Results: about 69% of adults ≥70 years with CVD and 36% without CVD were prescribed a LLD. LLD prescriptions decreased with age; with CVD: 78% aged 70-74 years and 29% aged ≥90 years were prescribed a LLD, without CVD: 37% aged 70-74 years and 12% aged ≥90 years. In patients with CVD and within each age group, percentage of LLD prescriptions was 20% point(pp) higher in frail compared with non-frail. In patients without CVD, percentage of LLD prescriptions in frail patients was 11pp higher in adults aged 70-74 years and 40pp higher in adults aged ≥90 years compared to non-frail. Similar trends were seen in the analyses with number of comorbidities. Conclusion: in an older population, LLD prescriptions decreased with age but - contrary to our expectations - LLD prescriptions increased with higher frailty levels.

IntroductionHodgkin’s lymphoma (HL) has become the prototype of a curable disease. However, many young survivors suffer from late adverse effects of treatment. Both chemotherapy (CT) and radiotherapy (RT) may induce primary ovarian insufficiency (POI), which has been associated with reduced bone mineral density (BMD), neurocognitive dysfunction and possibly cardiovascular disease (CVD). While the general assumption is that POI increases CVD risk, other hypotheses postulate reverse causality, suggesting that cardiovascular risk factors determine menopausal age or that biological ageing underlies both POI and CVD risk. None of these hypotheses are supported by convincing evidence. Furthermore, most studies on POI-associated conditions have been conducted in women with early natural or surgery-induced menopause with short follow-up times. In this study, we will examine the long-term effects of CT-induced and/or RT-induced POI on BMD, cardiovascular status, neurocognitive function and quality of life in female HL survivors.Methods and analysisThis study will be performed within an existing Dutch cohort of HL survivors. Eligible women were treated for HL at ages 15–39 years in three large hospitals since 1965 and survived for ≥8 years after their diagnosis. Women visiting a survivorship care outpatient clinic will be invited for a neurocognitive, cardiovascular and BMD assessment, and asked to complete several questionnaires and to provide a blood sample. Using multivariable regression analyses, we will compare the outcomes of HL survivors who developed POI with those who did not. Cardiovascular status will also be compared with women with natural POI.Ethics and disseminationThis study has been approved by the Institutional Review Board of the Netherlands Cancer Institute and has been registered at ‘Toetsingonline’ from the Dutch Central Committee on Research involving Human Subjects (file no. NL44714.031.13). Results will be disseminated through peer-reviewed publications and will be incorporated in follow-up guidelines for HL survivors.

Insulin-mediated microvascular recruitment (IMVR) regulates delivery of insulin and glucose to insulin-sensitive tissues. We have previously proposed that perivascular adipose tissue (PVAT) controls glucose metabolism and vascular function through outside-to-inside communication and through vessel-to-vessel, or “vasocrine” signaling. Here, we studied this hypothesis in mice by examining effects of removal of local intramuscular PVAT on muscle blood flow and glucose metabolism. Using the hyperinsulinemic, euglycemic clamp (HEC) in combination with positron emission tomography, we found that local PVAT removal transiently reduces muscle glucose uptake by ±50 percent. Contrast-enhanced ultrasonography and intravital microscopy of the gracilis artery (GA) during the HEC showed that PVAT removal abolishes insulin-induced increases in GA diameter and abrogated insulin-stimulated muscle blood volume (microvascular recruitment or IMVR). The effect of PVAT on IMVR was mediated by distinct microvessels or anastomoses, which we showed using lightsheet microscopy of mice expressing mCherry in endothelial cells. Proteomics analysis revealed that PVAT removal significantly alters expression of 109 of 1719 detected proteins in muscle. Observed changes in protein expression included reduction of a mitochondrial protein cluster and of vesicle-associated membrane protein 5 (Vamp5), involved in Glut4 trafficking. In conclusion, we have found that PVAT within muscle regulates muscle perfusion, glucose uptake and muscle protein expression, communicating with the distal microcirculation via microvascular anastomoses. These data highlight the importance of PVAT in vascular and metabolic physiology, and are relevant for type 2 diabetes and associated muscle dysfunction. Disclosure A.H. Turaihi: None. E.H. Serne: None. C. Molthoff: None. M.T. Goumans: None. C.J. Jimenez: None. J.S. Yudkin: None. Y.M. Smulders: None. V.W. van Hinsbergh: None. E.C. Eringa: None.

Objective: Cognitive impairments in type 1 diabetes may result from hyperglycemia-associated cerebral microangiopathy. In this study we aimed to identify cerebral microangiopathy and skin microvascular dysfunction - as surrogate marker for generalized microvascular function - as predictors of cognitive decline over time. Research Design and Methods: Twenty-five type 1 diabetes patients and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow-up (mean duration of 3.8±0.8 years). At baseline, 1.5 T cerebral magnetic resonance imaging was used to detect white matter lesions (WML) and cerebral microbleeds. In addition, skin capillary perfusion was assessed by means of capillary microscopy. Multiple linear regression analysis was performed to examine if cerebral microangiopathy and capillary perfusion were associated with changes in cognitive performance. Results: In type 1 diabetes patients, but not in healthy controls, the presence of WML (ß=-0.419;p=0.037) as well as lower skin capillary perfusion (baseline: ß=0.753;p Conclusions: In type 1 diabetes patients, presence of WML and lower skin capillary perfusion predict poorer general cognitive ability over time. The relationship between WML and cognitive decline was significantly reduced when adjusting for capillary perfusion, suggesting that generalized microvascular dysfunction at least partly underlies WML-associated cognitive decline. Disclosure A.L. Emanuel: None. E. van Duinkerken: None. M.P. Wattjes: Consultant; Self; Biogen. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Roche Pharma, Sanofi Genzyme. M. Klein: None. F. Barkhof: None. F.J. Snoek: None. E.C. Eringa: None. R. Ijzerman: Research Support; Self; AstraZeneca. E.H. Serne: None.

Introduction: Insulin signaling in adipose tissue has been shown to regulate insulin's effects in muscle. In muscle, perivascular adipose tissue (PVAT) and vascular insulin signaling regulate muscle perfusion. Insulin receptor substrate (IRS) 2 has been shown to control adipose tissue function and glucose metabolism, and here we tested the hypothesis that IRS2 mediates insulin's actions on the vessel wall as well as the vasoactive properties of PVAT. Methods: We studied PVAT and muscle resistance arteries (RA) from littermate IRS2+/+ and IRS2-/- mice and vasoreactivity by pressure myography, vascular insulin signaling, adipokine expression, and release and PVAT morphology. As insulin induced constriction of IRS2+/+ RA in our mouse model, we also exposed RA's of C57/Bl6 mice to PVAT from IRS2+/+ and IRS2-/- littermates to evaluate vasodilator properties of PVAT. Results: IRS2-/- RA exhibited normal vasomotor function, yet a decreased maximal diameter compared to IRS2+/+ RA. IRS2+/+ vessels unexpectedly constricted endothelin-dependently in response to insulin, and this effect was absent in IRS2-/- RA due to reduced ERK1/2activation. For evaluation of PVAT function, we also used C57/Bl6 vessels with a neutral basal effect of insulin. In these experiments insulin (10.0 nM) increased diameter in the presence of IRS2+/+ PVAT (17 ± 4.8, p = 0.014), yet induced a 10 ± 7.6% decrease in diameter in the presence of IRS2-/- PVAT. Adipocytes in IRS2-/- PVAT (1314 ± 161 μm2) were larger (p = 0.0013) than of IRS2+/+ PVAT (915 ± 63 μm2). Adiponectin, IL-6, PAI-1 secretion were similar between IRS2+/+ and IRS2-/- PVAT, as were expression of pro-inflammatory genes (TNF-α, CCL2) and adipokines (adiponectin, leptin, endothelin-1). Insulin-induced AKT phosphorylation in RA was similar in the presence of IRS2-/- and IRS2+/+ PVAT. Conclusion: In muscle, IRS2 regulates both insulin's vasoconstrictor effects, mediating ERK1/2-ET-1 activation, and its vasodilator effects, by mediating the vasodilator effect of PVAT. The regulatory role of IRS2 in PVAT is independent from adiponectin secretion.

BACKGROUND: Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population.METHODS: We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903.FINDINGS: Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8-67·3) versus 55·4% (53·1-57·7; mean difference 9·6%, 95% CI 8·0-11·2; p10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1-6·9; pINTERPRETATION: CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population.FUNDING: Eli Lilly and Sanofi.

Decreased tissue perfusion increases the risk of developing insulin resistance and cardiovascular disease in obesity, and decreased levels of globular adiponectin (gAdn) have been proposed to contribute to this risk. We hypothesized that gAdn controls insulin's vasoactive effects through AMP-activated protein kinase (AMPK), specifically its α2 subunit, and studied the mechanisms involved. In healthy volunteers, we found that decreased plasma gAdn levels in obese subjects associate with insulin resistance and reduced capillary perfusion during hyperinsulinemia. In cultured human microvascular endothelial cells (HMEC), gAdn increased AMPK activity. In isolated muscle resistance arteries gAdn uncovered insulin-induced vasodilation by selectively inhibiting insulin-induced activation of ERK1/2, and the AMPK inhibitor compound C as well as genetic deletion of AMPKα2 blunted insulin-induced vasodilation. In HMEC deletion of AMPKα2 abolished insulin-induced Ser(1177) phosphorylation of eNOS. In mice we confirmed that AMPKα2 deficiency decreases insulin sensitivity, and this was accompanied by decreased muscle microvascular blood volume during hyperinsulinemia in vivo. This impairment was accompanied by a decrease in arterial Ser(1177) phosphorylation of eNOS, which closely related to AMPK activity. In conclusion, globular adiponectin controls muscle perfusion during hyperinsulinemia through AMPKα2, which determines the balance between NO and ET-1 activity in muscle resistance arteries. Our findings provide a novel mechanism linking reduced gAdn-AMPK signaling to insulin resistance and impaired organ perfusion.

OBJECTIVE: In addition to insulin's metabolic actions, insulin can dilate arterioles which increase blood flow to metabolically active tissues. This effect is blunted in insulin-resistant subjects. Insulin's effect on SVR, determined by resistance arterioles, has, however, rarely been examined directly. We determined the effects of both hyperinsulinemia and a mixed meal on SVR and its relationship with insulin sensitivity.METHODS: Thirty-seven lean and obese women underwent a hyperinsulinemic-euglycemic clamp, and 24 obese volunteers underwent a mixed-meal test. SVR was assessed using CPP before and during hyperinsulinemia as well as before and 60 and 120 minutes after a meal.RESULTS: SVR decreased significantly during hyperinsulinemia (-13%; p < 0.001) and after the meal (-11%; p < 0.001). Insulin decreased SVR more strongly in insulin-sensitive individuals (standardized β: -0.44; p = 0.01). In addition, SVR at 60 minutes after meal ingestion was inversely related to the Matsuda index (β: -0.39; p = 0.04) and the change in postprandial SVR was directly related to postprandial glycemia (β: 0.53; p < 0.01).CONCLUSIONS: Hyperinsulinemia and meal ingestion decrease SVR, which is directly associated with metabolic insulin resistance. This suggests that resistance to insulin-induced vasodilatation contributes to regulation of vascular resistance.

Objective— The insulinotropic gut–derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide–dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans. Approach and Results— We included 10 healthy overweight men (age, 20–27 years; body mass index, 26–31 kg/m 2 ). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide–synthase inhibitor l - N G -monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P =0.016). Concomitant l - N G -monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements ( R =−5.6%; P =0.092), which was strongly and inversely associated with capillary perfusion ( R =−0.928; P =0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged. Conclusions— Acute exenatide infusion increases capillary perfusion via nitric oxide–independent pathways in healthy overweight men, suggesting direct actions of this GLP-1RA on microvascular perfusion or interaction with vasoactive factors.

Essentials The value of compression therapy in acute phase of deep vein thrombosis is still unclear. Patients with deep vein thrombosis received acute compression hosiery, bandaging, or none. Acute compression reduces irreversible skin signs related to post thrombotic syndrome. Compression hosiery may be the preferred choice for the acute phase. Summary: Background The effectiveness of compression therapy in the acute phase of deep vein thrombosis (DVT) is not yet determined. Objectives To investigate the impact of compression therapy in the acute phase of DVT on determinants of the Villalta score, health-related quality of life (HRQOL), and costs. Patients/Methods Eight hundred and sixty-five patients with proximal DVT (substudy of the IDEAL DVT study) received, immediately after DVT diagnosis, either no compression, multilayer bandaging, or hosiery. In the acute phase and 3 months after diagnosis, HRQOL was determined by use of the EQ-5D, SF6D, and VEINES-QoL intrinsic method (VEINES-QoLint). At 3 months, signs and symptoms were assessed for the total and separate items of the Villalta score, and healthcare costs were calculated. Results The compression groups had lower overall objective Villalta scores than the no-compression group (1.47 [standard deviation (SD) 1.570] and 1.59 [SD 1.64] versus 2.21 [SD 2.15]). The differences were mainly attributable to irreversible skin signs (induration, hyperpigmentation, and venectasia) and pain on calf compression. Subjective and total Villalta scores were similar across groups. Differences in HRQOL were only observed at 1 month; HRQOL was better for hosiery (EQ-5D 0.86 [SD 0.18]; VEINES-QoLint 0.66 [SD 0.18]) than for multilayer compression bandaging (EQ-5D 0.81 [SD 0.23; VEINES-QoLint 0.62 [SD 0.19]). Mean healthcare costs per patient were €417.08 (€354.10 to €489.30) for bandaging, €114.25 (€92.50 to €198.43) for hosiery, and €105.86 (€34.63 to €199.30) for no compression. Conclusions Initial compression reduces irreversible skin signs, edema, and pain on calf compression. Multilayer bandaging is slightly more effective than hosiery, but has substantially higher costs, without a gain in HRQOL. From a patient and economic perspective, compression hosiery would be preferred when initial compression is applied. Trial registration: IDEAL DVT study ClinicalTrials.gov number, NCT01429714.

Sleep and sleep disorders are related to cardiovascular disease, and microvascular function is an early cardiovascular disease marker. Therefore, the relationship of sleep (measured in sleep quality and duration) with microvascular function was examined in healthy adults. Sleep quality was assessed with the validated Sleep Wake Experience List (SWEL) questionnaire. Duration of sleep was self-reported in an additional question. Microvascular function was measured using nailfold capillaroscopy. Linear regression analyses were used to examine the relationship between sleep and microvascular function. Potential confounders included physical activity, smoking, blood pressure, body mass index and several biochemical parameters. Analyses were performed in 259 participants (116 men). For women reporting insufficient (

OBJECTIVE This study investigated whether the relationship between neuropathy and microvascular dysfunction in patients with type 2 diabetes is independent of diabetes-related factors. For this purpose, we compared skin microvascular function in patients with type 2 diabetes with that of patients with cryptogenic axonal polyneuropathy (CAP), a polyneuropathy of unknown etiology. RESEARCH DESIGN AND METHODS Cross-sectional information was collected from 16 healthy controls (HCs), 16 patients with CAP, 15 patients with type 2 diabetes with polyneuropathy (DPN), and 11 patients with type 2 diabetes without polyneuropathy. Axonal degeneration was assessed with skin biopsy and nerve conduction studies. Microvascular skin vasodilation was measured using laser Doppler fluxmetry combined with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS Patients with CAP and DPN demonstrated a similar decrease in intraepidermal nerve fiber density and sural sensory nerve action potential compared with HCs. The vasodilator response to ACh was similar among patients with CAP (relative mean difference based on log values 13.3%; 95% CI −35.0 to 97.7%; P = 0.652) but was lower in the patients with diabetes with neuropathy (157.5%; 42.0–366.7%; P = 0.003) and without neuropathy (174.2%; 44.2–421.3%; P = 0.003) compared with HCs. No significant differences were found between the groups of patients with diabetes (P = 0.845). The vasodilator response to SNP was not significantly different among the groups (P = 0.082). CONCLUSIONS In this study, endothelium-dependent vasodilation was reduced in patients with type 2 diabetes regardless of the presence of polyneuropathy, whereas microvascular vasodilation was normal in patients with CAP. These data suggest that in type 2 diabetes, neuropathy does not contribute to impaired microvascular endothelium-dependent vasodilation and vice versa. In addition, this study suggests that impaired microvascular vasodilation does not contribute to CAP.

It has been demonstrated that insulin’s vascular actions contribute to regulation of insulin sensitivity. Insulin’s effects on muscle perfusion regulate postprandial delivery of nutrients and hormones to insulin-sensitive tissues. We here describe a technique for combining intravital microscopy (IVM) and contrast-enhanced ultrasonography (CEUS) of the adductor compartment of the mouse hindlimb to simultaneously visualize muscle resistance arteries and perfusion of the microcirculation in vivo. Simultaneously assessing insulin’s effect at multiple levels of the vascular tree is important to study relationships between insulin’s multiple vasoactive effects and muscle perfusion. Experiments in this study were performed in mice. First, the tail vein cannula is inserted for the infusion of anesthesia, vasoactive compounds and ultrasound contrast agent (lipid-encapsulated microbubbles). Second, a small incision is made in the groin area to expose the arterial tree of the adductor muscle compartment. The ultrasound probe is then positioned at the contralateral upper hindlimb to view the muscles in cross-section. To assess baseline parameters, the arterial diameter is assessed and microbubbles are subsequently infused at a constant rate to estimate muscle blood flow and microvascular blood volume (MBV). When applied before and during a hyperinsulinemic-euglycemic clamp, combined IVM and CEUS allow assessment of insulin-induced changes of arterial diameter, microvascular muscle perfusion and whole-body insulin sensitivity. Moreover, the temporal relationship between responses of the microcirculation and the resistance arteries to insulin can be quantified. It is also possible to follow-up the mice longitudinally in time, making it a valuable tool to study changes in vascular and whole-body insulin sensitivity.

BackgroundAnkylosing spondylitis (AS) is associated with an increased cardiovascular risk that might be due to the chronic underlying inflammatory process. We investigated whether subclinical atherosclerosis of the carotid artery in patients with AS was reduced after anti-inflammatory treatment with tumour necrosis factor (TNF) inhibitors in a prospective observational cohort study.Methods67 out of 81 AS patients who used TNF inhibitors and underwent ultrasonography at baseline returned for follow-up after 4.9 years. Of all patients, 12 (15%) discontinued the use of TNF inhibitors. Assessments of medication use, AS-related factors and cardiovascular risk factors were measured at baseline and repeated at follow-up. B-mode carotid ultrasonography was used to investigate arterial wall parameters, including carotid intima-media thickness (cIMT) and Young's elastic modulus (YEM).ResultsAfter a median 4.9 years of follow-up, cIMT did not change significantly (paired t test +0.011 mm, p=0.561) in those who continued the use of TNF inhibitors, while cIMT increased substantially (+0.057 mm, p=0.069) in those who did not continue their use of TNF inhibitors. The effect of TNF inhibitors was mainly mediated by a subsequent decrease in AS disease activity. Vascular elasticity (as measured with YEM) did not change significantly in patients who discontinued TNF inhibitors or those who continued TNF inhibitors.ConclusionsThe use of TNF inhibitors might stabilise or slow down the progression of subclinical atherosclerosis in AS patients, reflecting a decreased cardiovascular risk in these patients.

Objective The mechanisms underlying obesity-related hypertension are incompletely understood. Microvascular dysfunction might play a role by increasing peripheral vascular resistance (PVR). Metabolic and microvascular effects of insulin are impaired in obesity, but how these impairments contribute to disturbed blood pressure homeostasis is unclear. Specifically, it is unknown whether local microvascular vasoactive effects of insulin play a role in determining systemic vascular resistance. The aim of this study was to investigate the association between PVR and local microvascular effects of insulin. Design and Methods Thirty-seven healthy, overweight subjects (age 25-55 years, BMI 25-30 kg/m2) were cross-sectionally studied. Local insulin-mediated vasodilation was measured using skin laser Doppler fluxmetry combined with transcutaneous iontophoresis of insulin. For comparison, local vasodilatory effects of acetylcholine and sodium nitroprusside were measured. PVR was calculated from mean arterial pressure and cardiac output, assessed by pulse-dye densitometry. Results PVR was inversely correlated with insulin-mediated vasodilation (r = −0.50; P < 0.01). This finding was maintained after adjustment for age, sex, blood pressure, and smoking. PVR was not associated with local microvascular effects of acetylcholine. Conclusions Our study in overweight subjects suggests that insulin's role in the microvasculature may contribute to blood pressure control.