In vivo molecular imaging of cardiac angiogenesis in persons with and without type 2 diabetes: A cross-sectional 68 Ga-RGD-PET study.

AIMS: To assess cardiac angiogenesis in type 2 diabetes by positron emission tomography (PET) tracer [68 Ga]Ga-NODAGA-E[(cRGDyK)]2 (68 Ga-RGD) imaging. METHODS: Cross-sectional study including 20 persons with type 2 diabetes and 10 non-diabetic controls (CONs). Primary prespecified outcome was difference in cardiac angiogenesis (cardiac 68 Ga-RGD mean target-to-background ratio [TBRmean ]) between type 2 diabetes and CONs. Secondary outcome was to investigate associations between cardiac angiogenesis and kidney function and other risk factors. RESULTS: Participants with type 2 diabetes had a mean ± SD age of 61 ± 9 years, 30% were women, median (IQR) diabetes duration of 11 (6-19) years and 3 (15%) had a history of cardiovascular disease. The CONs had comparable age and sex distribution to the participants with type 2 diabetes, and none had a history of coronary artery disease. Myocardial flow reserve was lower in type 2 diabetes (2.7 ± 0.6) compared with CONs (3.4 ± 1.2) ( p  = 0.03) and coronary artery calcium score was higher (562 [142-905] vs. 1 [0-150] p  = 0.04). Cardiac 68 Ga-RGD TBRmean was similar in participants with type 2 diabetes (0.89 ± 0.09) and CONs (0.89 ± 0.10) ( p  = 0.92). Cardiac 68 Ga-RGD TBRmean was not associated with estimated glomerular filtration rate, urine albumin creatinine ratio, cardiovascular disease, coronary artery calcium score or baroreflex sensitivity, neither in pooled analyses nor in type 2 diabetes. CONCLUSIONS: Cardiac angiogenesis, evaluated with 68 Ga-RGD PET, was similar in type 2 diabetes and CONs. Cardiac angiogenesis was not associated with kidney function or other risk markers in pooled analyses or in analyses restricted to type 2 diabetes.

Evaluation of the effects of ezetimibe on albuminuria and kidney fat in individuals with type 2 diabetes and chronic kidney disease.

AIM: To investigate the effects of ezetimibe on the urine albumin creatinine ratio (UACR) and kidney parenchyma fat content (kidney-PF) in individuals with type 2 diabetes (T2D) and early chronic kidney disease. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled study of ezetimibe 10 mg once daily for 16 weeks in individuals with T2D and a UACR of 30 mg/g or higher was conducted. Kidney-PF was assessed with magnetic resonance spectroscopy. Geometric mean changes from baseline were derived from linear regressions. RESULTS: A total of 49 participants were randomized to ezetimibe (n = 25) or placebo (n = 24). Overall, mean ± standard deviation age was 67 ± 7 years, body mass index was 31 ± 4 kg/m2 and the proportion of men was 84%. The mean estimated glomerular filtration rate was 76 ± 22 mL/min/1.73m2 and median (first-third quartile) UACR was 95 (41-297) mg/g. Median kidney-PF was 1.0% (0.3%-2.1%). Compared with placebo, ezetimibe did not significantly reduce UACR (mean [95% confidence interval] change: -3% [-28%-31%]) or kidney-PF (mean change: -38% [-66%-14%]). In participants with baseline kidney-PF above the median, ezetimibe reduced kidney-PF significantly (mean change: -60% [-84%--3%]) compared with placebo, while the reduction in UACR was not significant (mean change: -28% [-54%-15%]). CONCLUSIONS: Ezetimibe did not reduce the UACR or kidney-PF on top of modern T2D management. However, kidney-PF was reduced with ezetimibe in participants with high baseline kidney-PF.

Ceramides are decreased after liraglutide treatment in people with type 2 diabetes: a post hoc analysis of two randomized clinical trials.

BACKGROUND: Specific ceramides have been identified as risk markers for cardiovascular disease (CVD) years before onset of disease. Treatment with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide has been shown to induce beneficial changes in the lipid profile and reduce the risk of CVD. Reducing lipotoxic lipids with an antidiabetic drug therapy could be a path towards precision medicine approaches for the treatment of complications to diabetes. In this post-hoc study, an investigation was carried out on the effect of liraglutide on CVD-risk associated ceramides in two randomized clinical trials including participants with type 2 diabetes (T2D). METHODS: This study analyzed plasma samples from two independent randomized placebo-controlled clinical trials. The first trial, Antiproteinuric Effects of Liraglutide Treatment (LirAlbu12) followed a crossover design where 27 participants were treated for 12 weeks with either liraglutide (1.8 mg/d) or placebo, followed by a four-week washout period, and then another 12 weeks of the other treatment. The second clinical trial, Effect of Liraglutide on Vascular Inflammation in Type-2 Diabetes (LiraFlame26), lasted for 26 weeks and followed a parallel design, where 102 participants were randomized 1:1 to either liraglutide or placebo. Heresix prespecified plasma ceramides were measured using liquid chromatography mass spectrometry and assessed their changes using linear mixed models. Possible confounders were assessed with mediation analyses. RESULTS: In the LiraFlame26 trial, 26-week treatment with liraglutide resulted in a significant reduction of two ceramides associated with CVD risk, C16 Cer and C24:1 Cer (p < 0.05) compared to placebo. None of the remaining ceramides showed statistically significant changes in response to liraglutide treatment compared to placebo. Significant changes in ceramides were not found after 12-weeks of liraglutide treatment in the LirAlbu12 trial. Mediation analyses showed that weight loss did not affect ceramide reduction. CONCLUSIONS: It was demonstrated that treatment with liraglutide resulted in a reduction in C16 Cer and C24:1 Cer after 26 weeks of treatment. These findings suggest the GLP-1RA can be used to modulate ceramides in addition to its other properties. TRIAL REGISTRATION: Clinicaltrial.gov identifier: NCT02545738 and NCT03449654.

Visit-to-visit variability of clinical risk markers in relation to long-term complications in type 1 diabetes.

BACKGROUND: Clinical characteristics such as HbA1c , systolic blood pressure (SBP), albuminuria and estimated glomerular filtration rate (eGFR) are important when treating type 1 diabetes. We investigated the variability in these measures as risk markers for micro- and macrovascular complications. METHODS: This prospective study included 1062 individuals with type 1 diabetes. Visit-to-visit variability of HbA1c , SBP, albuminuria and eGFR was calculated as the SD of the residuals in individual linear regression models using all available measures in a specified period of 3 years (VV). Endpoints included were as follows: cardiovascular events (CVE) defined as myocardial infarction, non-fatal stroke, or coronary or peripheral arterial intervention; end-stage kidney disease (ESKD) defined as eGFR <15 ml/min/1.73 m2 , chronic dialysis or kidney transplantation; eGFR decline ≥30%; and mortality. Adjustment included age, sex, cholesterol, HbA1c , SBP, body mass index, smoking, albuminuria, eGFR, and mean, intercept, slope of respective exposure variables and regression models. RESULTS: SBP VV was significantly associated with CVE (adjusted hazard ratio per 50% increase, (CI 95%); p: 1.21 [1.05-1.39]; p = 0.008), ESKD (1.51 [1.16-1.96]; p = 0.002) and mortality (1.25 [1.09-1.44]; p = 0.002). HbA1c VV was significantly associated with mortality (1.51 [1.30-1.75]; p < 0.001); albuminuria VV with eGFR decline (1.14 [1.08-1.20]; p = 0.024) and ESKD (1.14 [1.02-1.27]; p < 0.001), but neither CVE nor mortality. Adjusted eGFR VV was not associated with endpoints. CONCLUSION: In type 1 diabetes, higher variability of basic clinical risk markers adds important risk stratification information for the development of micro- and macrovascular complications.

[Lancet Commission on Hypertension Group position statement on the global improvement of accuracy standards for devices that measure blood pressurePosicionamento do Grupo da Lancet Commission on Hypertension sobre a melhoria global dos padrões de acurácia para aparelhos que medem a pressão arterial]. / Declaración de posición del Grupo de la Comisión Lancet de Hipertensión con respecto a la mejora mundial de las normas de exactitud para los dispositivos de medición de la presión arterial.

The Lancet Commission on Hypertension identified that a key action to address the worldwide burden of high blood pressure (BP) was to improve the quality of BP measurements by using BP devices that have been validated for accuracy. Currently, there are over 3 000 commercially available BP devices, but many do not have published data on accuracy testing according to established scientific standards. This problem is enabled through weak or absent regulations that allow clearance of devices for commercial use without formal validation. In addition, new BP technologies have emerged (e.g. cuffless sensors) for which there is no scientific consensus regarding BP measurement accuracy standards. Altogether, these issues contribute to the widespread availability of clinic and home BP devices with limited or uncertain accuracy, leading to inappropriate hypertension diagnosis, management and drug treatment on a global scale. The most significant problems relating to the accuracy of BP devices can be resolved by the regulatory requirement for mandatory independent validation of BP devices according to the universally-accepted International Organization for Standardization Standard. This is a primary recommendation for which there is an urgent international need. Other key recommendations are development of validation standards specifically for new BP technologies and online lists of accurate devices that are accessible to consumers and health professionals. Recommendations are aligned with WHO policies on medical devices and universal healthcare. Adherence to recommendations would increase the global availability of accurate BP devices and result in better diagnosis and treatment of hypertension, thus decreasing the worldwide burden from high BP.

A Comissão Lancet sobre Hipertensão Arterial identificou que uma iniciativa central para enfrentar a carga mundial da hipertensão arterial seria a melhoria na qualidade da mensuração da pressão arterial pelo uso aparelhos de pressão arterial validados quanto à acurácia. Atualmente, existem mais de 3 000 aparelhos de pressão arterial disponíveis comercialmente; entretanto, muitos não têm dados publicados sobre testes de acurácia realizados de acordo com padrões científicos estabelecidos. Este problema resulta de regulamentação fraca ou inexistente, o que permite a aprovação para uso comercial de dispositivos sem validação formal. Além disso, surgiram novas tecnologias de mensuração da pressão arterial (por exemplo, sensores sem algemas) sem consenso científico quanto aos padrões de acurácia. No conjunto, essas questões contribuem para a oferta generalizada de dispositivos de pressão arterial clínica e domiciliar com acurácia limitada ou incerta, levando a diagnóstico, gerenciamento e tratamento inadequados da hipertensão em escala global. Os problemas mais significativos relacionados com a acurácia dos dispositivos de pressão arterial podem ser resolvidos por regulamentação que imponha a obrigatoriedade de validação independente dos aparelhos de pressão arterial, de acordo com a norma universalmente aceita pela Organização Internacional de Normalização. Esta é uma recomendação fundamental para a qual existe uma necessidade internacional urgente. Outras recomendações essenciais incluem o desenvolvimento de padrões de validação especificamente para novas tecnologias de mensuração da pressão arterial e listas on-line de aparelhos com acurácia adequada que sejam acessíveis aos consumidores e profissionais de saúde. As recomendações estão alinhadas com as políticas da Organização Mundial da Saúde (OMS) sobre dispositivos médicos e atenção universal à saúde. A adesão às recomendações aumentaria a oferta global de dispositivos de pressão arterial com acurácia adequada e resultaria em melhor diagnóstico e tratamento da hipertensão arterial, diminuindo assim a carga mundial dessa doença.

Uric acid is not associated with diabetic nephropathy and other complications in type 1 diabetes.

BACKGROUND: To examine the association between plasma uric acid (UA) and the presence of diabetic complications including diabetic nephropathy and cardiovascular risk factors in patients with type 1 diabetes. METHODS: This study, which is cross-sectional in design, included 676 Caucasian type 1 diabetes patients from the Steno Diabetes Center Copenhagen. Participants with UA within the three lowest sex-specific quartiles were compared with participants with levels in the highest quartile. Unadjusted and adjusted linear regression analyses were applied. Adjustment included sex, age, diabetes duration, body mass index, high-density lipoprotein cholesterol, smoking, haemoglobin A1c, 24-h pulse pressure, urinary albumin excretion rate (UAER), estimated glomerular filtration rate (eGFR) and treatment with renin-angiotensin-aldosterone system blockers. RESULTS: Of the 676 patients, 372 (55%) were male, mean ± SD age was 55 ± 13 years and eGFR was 82 ± 26 mL/min/1.73 m2. The median UA was 0.30 (interquartile range 0.23-0.37) mmol/L. UA in the upper sex-specific quartile was associated with lower eGFR, higher UAER and carotid-femoral pulse wave velocity and lower 24 h and daytime diastolic blood pressure (BP) in unadjusted analyses (P < 0.001). Moreover, UA in the upper sex-specific quartile was associated with higher nighttime systolic BP and the presence of cardiovascular disease in unadjusted analyses (P ≤ 0.01), but significance was lost after adjustment (P ≥ 0.17). UA was higher across the retinopathy groups [nil (n = 142), simplex (n = 277), proliferative (n = 229) and blind (n = 19)] in unadjusted analyses (P < 0.0001), but not after adjustment (P = 0.12). Patients with an accelerated decline in eGFR (≥3 mL/min/year) had significantly higher UA at baseline (P = 0.006) compared with slow decliners (<3 mL/min/year), but significance was lost after adjustment (P = 0.10). CONCLUSIONS: In type 1 diabetes patients, higher UA was associated with lower kidney function and other diabetic complications. The association between higher UA and lower eGFR and lower diastolic BP was independent of traditional risk factors.

Plasma high-sensitivity troponin T predicts end-stage renal disease and cardiovascular and all-cause mortality in patients with type 1 diabetes and diabetic nephropathy.

High-sensitivity troponin T (hsTnT) is a marker of cardiovascular disease (CVD) and in type 2 diabetes also a marker of renal events, but has not been evaluated in type 1 diabetics. We therefore reviewed a type 1 diabetes cohort of 442 without and 458 with diabetic nephropathy. Baseline samples were analyzed for hsTnT levels. Cox regression analyses assessed predictive value in relation to the development of end-stage renal disease (ESRD) in 99 patients, all-cause mortality in 178, and CVD events in 134 after up to 12 years of follow-up. To assess if hsTnT improved risk prediction beyond traditional clinical risk markers, we calculated c statistics and relative integrated discrimination improvement. HsTnT was significantly higher in patients with diabetic nephropathy compared to normoalbuminuria (median 8.9 vs 3.1 ng/L). For a doubling in hsTnT levels, and after adjustment for well-known risk factors, including NT-proBNP and hsCRP, the hazard ratio for ESRD at 1.26 was not significant in the diabetic nephropathy group, but there was a significant association with GFR decline after adjustment during follow-up (2.9 ml/min/1.73 m2 annual decline per doubling in hsTnT). The unadjusted and adjusted hazard ratios for mortality (1.64 and 1.32, respectively) were significant in patients with, but not for patients without, nephropathy. Adjusted hazard ratios for fatal and non-fatal CVD events were significant for the whole cohort (1.13), and those with nephropathy (1.14), but not significant for normoalbuminuria (1.06). Addition of hsTNT to traditional risk factors significantly increased the area under the curve by 0.01 in a receiver-operating characteristic curve for mortality. The relative integrated discrimination improvement was increased 15.7% for mortality, 6.3% for CVD, and 1.9% for ESRD (all significant). Thus, higher hsTnT is an independent predictor of renal decline and cardiovascular events in patients with type 1 diabetes and diabetic nephropathy.

Additive prognostic value of plasma N-terminal pro-brain natriuretic peptide and coronary artery calcification for cardiovascular events and mortality in asymptomatic patients with type 2 diabetes.

BACKGROUND: In patients with type 2 diabetes, cardiovascular disease (CVD) is the major cause of morbidity and mortality. We evaluated the combination of NT-proBNP and coronary artery calcium score (CAC) for prediction of combined fatal and non-fatal CVD and mortality in patients with type 2 diabetes and microalbuminuria (>30 mg/24-h), but without known coronary artery disease. Moreover, we assessed the predictive value of a predefined categorisation of patients into a high- and low-risk group at baseline. METHODS: Prospective study including 200 patients. All received intensive multifactorial treatment. Patients with baseline NT-proBNP > 45.2 ng/L and/or CAC ≥ 400 were stratified as high-risk patients (n = 133). Occurrence of fatal- and nonfatal CVD (n = 40) and mortality (n = 26), was traced after 6.1 years (median). RESULTS: High-risk patients had a higher risk of the composite CVD endpoint (adjusted hazard ratio [HR] 10.6 (95 % confidence interval [CI] 2.4-46.3); p = 0.002) and mortality (adjusted HR 5.3 (95 % CI 1.2-24.0); p = 0.032) compared to low-risk patients. In adjusted continuous analysis, both higher NT-proBNP and CAC were strong predictors of the composite CVD endpoint and mortality (p ≤ 0.0001). In fully adjusted models mutually including NT-proBNP and CAC, both risk factors remained associated with risk of CVD and mortality (p ≤ 0.022). There was no interaction between NT-proBNP and CAC for the examined endpoints (p ≥ 0.31). CONCLUSIONS: In patients with type 2 diabetes and microalbuminuria but without known coronary artery disease, NT-proBNP and CAC were strongly associated with fatal and nonfatal CVD, as well as with mortality. Their additive prognostic capability holds promise for identification of patients at high risk.

Cardiovascular risk stratification and blood pressure variability on ambulatory and home blood pressure measurement.

UNLABELLED: Variability is a phenomenon attributed to most biological processes and is a particular feature of blood pressure (BP) that concerns many physicians regarding the clinical meaning and the impact on their clinical practice. In this review, we assessed the role of different indices of BP variability in cardiovascular risk stratification. We reviewed the indices of BP variability derived from ambulatory BP monitoring (day-to-night ratio, morning surge of BP, and short-term BP variability) and home BP measurement (standardized conventional BP measurement and self-BP measurement), and summarized our recent results with the intention to provide a clear message for clinical practice. CONCLUSION: BP variability, either derived from ambulatory BP measurement or home BP measurement does not substantially refine cardiovascular risk prediction over and beyond the BP level. Practitioners should be aware that BP level remains the main modifiable risk factor derived from BP measurement and contributes to improving the control of hypertension and adverse health outcomes.

Gastrointestinal symptom burden in diabetic autonomic and peripheral neuropathy - A Danes cohort study.

OBJECTIVE: We investigated associations between gastrointestinal symptoms - evaluated as a combined weighted symptom score (CWSS) - Diabetic autonomic neuropathy (DAN), and distal symmetrical polyneuropathy (DSPN) in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Cross-sectional study in a tertiary outpatient clinic. CWSS was calculated based on questionnaires: gastroparesis composite symptom index (GCSI) and gastrointestinal symptom rating score (GSRS). DAN and DSPN were addressed using the composite autonomic symptom score 31 (COMPASS-31) questionnaire, cardiac autonomic reflex tests (CARTs), electrochemical skin conductance (ESC), vibration perception threshold (VPT), Michigan Neuropathy Screening Instrument (MNSI), pain- and thermal sensation. Analyses were adjusted for age, sex, diabetes duration, smoking, LDL-cholesterol, HbA1C and systolic blood pressure. Type 1 and type 2 diabetes were evaluated separately. RESULTS: We included 566 with type 1 diabetes and 377 with type 2 diabetes. Mean ± SD age was 58 ± 15 years and 565 (59.9 %) were women. A high CWSS was present in 143 (25 %) with type 1 and 142 (38 %) with type 2 diabetes. The odds of DAN by COMPASS-31 (p < 0.001) were higher in the high score group. For type 1 diabetes, odds of cardiac autonomic neuropathy were higher in the high CWSS group. The odds of DSPN by VPT and MNSI in type 1 diabetes, and by ESC, VPT and pain sensation in type 2 diabetes were higher in the high CWSS group. CONCLUSIONS: A high symptom score was associated with neuropathy by COMPASS-31 and vibration perception. Gastrointestinal symptom burden associated inconsistently with other neuropathy tests between diabetes types.

Contemporary prevalence of diabetic neuropathies in individuals with type 1 and type 2 diabetes in a Danish tertiary outpatient clinic.

BACKGROUND: Population-based prevalence estimates of distal symmetric polyneuropathy (DPN) and diabetic autonomic neuropathy (DAN) are scares. Here we present neuropathy estimates and describe their overlap in a large cohort of people with type 1 and type 2 diabetes. METHODS: In a large population of outpatient participants, DPN was assessed using vibration perception threshold, sural nerve function, touch, pain and thermal sensation. Definite DPN was defined by the Toronto Consensus Criteria. Painful DPN was defined by Douleur Neuropathique 4 Questions. DAN measures were: cardiovascular reflex tests, electrochemical skin conductance, and gastroparesis cardinal symptom index. RESULTS: We included 822 individuals with type 1 (mean age (±SD) 54 ± 16 years, median [IQR] diabetes duration 26 [15-40] years) and 899 with type 2 diabetes (mean age 67 ± 11 years, median diabetes duration 16 [11-22] years). Definite DPN was prevalent in 54 % and 68 %, and painful DPN was in 5 % and 15 % of type 1 and type 2 participants, respectively. The prevalence of DAN varied between 6 and 39 % for type 1 and 9-49 % for type 2 diabetes. DPN without other neuropathy was present in 45 % with T1D and 50 % with T2D. CONCLUSION: The prevalence of DPN and DAN was high. DPN and DAN co-existed in only 50 % of cases.

Increased Subclinical Coronary Artery Pathology in Type 2 Diabetes With Albuminuria.

Diabetes affects the kidneys, and the presence of albuminuria reflects widespread vascular damage and is a risk factor for cardiovascular disease (CVD). Still, the pathophysiological association between albuminuria and CVD remains incompletely understood. Recent advances in noninvasive imaging enable functional assessment of coronary artery pathology and present an opportunity to explore the association between albuminuria and CVD. In this cross-sectional study, we evaluated the presence of subclinical coronary artery pathology in people with type 2 diabetes, free of overt CVD. Using multimodal imaging, we assessed the coronary microcalcification activity (18F-sodium fluoride positron emission tomography/computed tomography [PET/CT], plaque inflammation [64Cu-DOTATATE PET/CT], and myocardial flow reserve [82Rb PET/CT]). The study population consisted of 90 participants, stratified by albuminuria; 60 had historic or current albuminuria (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g]), and 30 had normoalbuminuria (UACR <30 mg/g). We demonstrated that any albuminuria (historic or current) was associated with a more severe phenotype, in particular, higher levels of microcalcifications and impaired myocardial microvascular function; however, coronary inflammation activity was similar in people with and without albuminuria. Our findings establish a potential underlying mechanism connecting cardiovascular and kidney diseases and could indicate the initial stages of the cardiorenal syndrome.

New Diabetic Treatment by Alleviation of Autonomic Nervous System Dysfunction Measured as Periosteal Pressure Sensitivity at Sternum Improves Empowerment, Treatment Satisfaction, and Self-Reported Health of People with Type 2 Diabetes: A Randomized Trial.

Purpose: Autonomic nervous system dysfunction (ANSD), for which presently no treatment exists, has a negative impact on prognosis in people with type 2 diabetes (T2D). Periosteal pressure sensitivity (PPS) on sternum may be a measure of autonomic nervous system dysfunction (ANSD). We tested if a non-pharmacological PPS-feedback-guided treatment program based on non-noxious sensory nerve stimulation, known to reduce PPS, changed empowerment, treatment satisfaction, and quality of life in people with T2D, compared to usual treatment. Patients and Methods: Analysis of secondary endpoints in a single center, two-armed, parallel-group, observer-blinded, randomized controlled trial of individuals with T2D. Participants were randomized to non-pharmacological intervention as an add-on to treatment as usual. Endpoints were evaluated by five validated questionnaires: Diabetes specific Empowerment (DES-SF), Diabetes Treatment Satisfaction (DTSQ), quality of life (QOL) (WHO-5), clinical stress signs (CSS), and self-reported health (SF-36). Sample size calculation was based on the primary endpoint HbA1c. Results: We included 144 participants, 71 allocated to active intervention and 73 to the control group. Active intervention compared to control revealed improved diabetes-specific empowerment (p = 0.004), DTSQ (p = 0.001), and SF-36 self-reported health (p=0.003) and tended to improve quality of life (WHO-5) (p = 0.056). The findings were clinically relevant with a Cohen's effect size of 0.5 to 0.7. Conclusion: This non-pharmacological intervention, aiming to reduce PPS, and thus ANSD, improved diabetes-specific empowerment, treatment satisfaction, and self-reported health when compared to usual treatment. The proposed intervention may be a supplement to conventional treatment for T2D.

24-hour central aortic systolic pressure and 24-hour central pulse pressure are related to diabetic complications in type 1 diabetes - a cross-sectional study.

BACKGROUND: Non-invasive measurements of 24 hour ambulatory central aortic systolic pressure (24 h-CASP) and central pulse pressure (24 h-CPP) are now feasible. We evaluate the relationship between 24 h central blood pressure and diabetes-related complications in patients with type 1 diabetes. METHODS: The study was cross-sectional, including 715 subjects: 86 controls (C), 69 patients with short diabetes duration (< 10 years), normoalbuminuria (< 30 mg/24 h) without receiving antihypertensive treatment (SN), 211 with longstanding diabetes (≥ 10 years) and normoalbuminuria (LN), 163 with microalbuminuria (30-299 mg/24 h) (Mi) and 186 with macroalbuminuria (> 300 mg/24 h) (Ma).24 h-CASP and 24 h-CPP was measured using a tonometric wrist-watch-like device (BPro, HealthStats, Singapore) and derived using N-point moving average. RESULTS: In C, SN, LN, Mi and Ma mean ± SD 24 h-CASP was: 114 ± 17, 115 ± 13, 121 ± 13, 119 ± 16 and 121 ± 13 mmHg (p < 0.001); and 24 h-CPP: 38 ± 8, 38 ± 7, 44 ± 10, 46 ± 11 and 46 ± 11 mmHg, (p < 0.001).Following rigorous adjustment (24 h mean arterial pressure and conventional risk factors), 24 h-CASP and 24 h-CPP increased with diabetes, albuminuria degree, previous cardiovascular disease (CVD), retinopathy and autonomic dysfunction (p ≤ 0.031).Odds ratios per 1 standard deviation increase in 24 h-CASP, 24 h-CPP and 24 h systolic blood pressure (24 h-SBP) were for CVD: 3.19 (1.68-6.05), 1.43 (1.01-2.02) and 2.39 (1.32-4.33), retinopathy: 4.41 (2.03-9.57), 1.77 (1.17-2.68) and 3.72 (1.85-7.47) and autonomic dysfunction: 3.25 (1.65-6.41), 1.64 (1.12-2.39) and 2.89 (1.54-5.42). CONCLUSIONS: 24 h-CASP and 24 h-CPP was higher in patients vs. controls and increased with diabetic complications independently of covariates. Furthermore, 24 h-CASP was stronger associated to complications than 24 h-SBP.The prognostic significance of 24 h-CASP and 24 h-CPP needs to be determined in follow-up studies. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01171248.

Vitamin D deficiency and development of complications in individuals with type 1 and type 2 diabetes: A cohort study.

AIMS: To investigate vitamin D deficiency as a risk marker for complications in individuals with type 1 and type 2 diabetes. METHODS: A cohort study including 1448 adults with type 1 and 770 with type 2 diabetes. Individuals in the decile with lowest vitamin D level were classified as vitamin D deficient. Outcomes based on medical records and registers included mortality, major adverse cardiovascular event (MACE), heart failure, a composite kidney endpoint, albuminuria progression and sight-threatening eye disease. Risk in individuals with vitamin D deficiency was compared to the remaining using adjusted Cox proportional hazards models. RESULTS: Vitamin D deficiency was associated with higher risk of MACE (adjusted hazard ratio (HR): 2.6; 95 % confidence interval (CI): 1.3-5.2) in type 1, but not in type 2 diabetes. Risk of heart failure was higher in individuals with vitamin D deficiency in both cohorts (HR (95%CI): 16 (4.8-50) in type 1 and 2.4 (1.1-5.5) in type 2 diabetes). Vitamin D deficiency was not associated with development of microvascular complications or mortality. CONCLUSIONS: Vitamin D deficiency was a risk marker for MACE and heart failure in type 1 and for heart failure in type 2 diabetes, but not for microvascular complications or all-cause mortality.

Declining Incidence Rates of Distal Symmetric Polyneuropathy in People With Type 1 and Type 2 Diabetes in Denmark, With Indications of Distinct Patterns in Type 1 Diabetes.

OBJECTIVE: It is not known if incidence rates for diabetic distal symmetric polyneuropathy (DSPN) are decreasing, as they are for other diabetic complications. Here, we investigated incidence rates of DSPN in type 1 and type 2 diabetes in a large population-based study. RESEARCH DESIGN AND METHODS: In the period 1996 to 2018, 19,342 individuals were identified at a Danish tertiary diabetes center. Vibration perception threshold was assessed by biothesiometry and repeated throughout the study. Exclusion of prevalent DSPN cases or missing data left data on 9,473 individuals for analysis of DSPN using a cutoff of >25 V and on 2,783 individuals for analysis using an age-, sex-, and height-specific cutoff. Poisson regression analysis was used to model incidence rates of DSPN for both cutoff types and separately for diabetes types. Covariates were sex, age, diabetes duration, and calendar time. RESULTS: Incidence rates (95% CI) of DSPN decreased from 1996 to 2018 (e.g., from 4.78 [3.60-6.33]/100 person-years [PY] to 1.15 [0.91-1.47]/100 PY for 40-year-old men with type 1 diabetes and from 16.54 [11.80-23.18]/100 PY to 8.02 [6.63-9.69]/100 PY for 60-year-old men with type 2 diabetes, when using >25 V as the cutoff value). Analyses using age-, sex-, and height-specific cutoff values demonstrated similar incidence patterns by calendar time without sex differences. For type 1 diabetes, decreasing incidence rates were seen with older age. CONCLUSIONS: Incidence rates for DSPN are declining in type 1 and type 2 diabetes, possibly due to improved diabetes treatment. This causality remains to be explored. Distinct age-related patterns indicate that the pathophysiology of DSPN may differ between diabetes types.

The association between blood oxygen saturation and baroreflex sensitivity in adults with type 1 diabetes with and without albuminuria.

BACKGROUND: Low baroreflex sensitivity is an indicator of early cardiovascular autonomic neuropathy. We explored the association between baroreflex sensivity and blood oxygen saturation (SpO2) in type 1 diabetes and various degrees of microvascular disease. METHODS: In this Danish-Finnish cross-sectional multicentre study, baroreflex sensivity and SpO2 (pulse oximetry) were examined in persons with type 1 diabetes and normoalbuminuria (n = 98), microalbuminuria (n = 28), or macroalbuminuria (n = 43), and in non-diabetic controls (n = 54). Associations and differences between groups were analysed using regression models and adjustment included age, sex, smoking, HbA1c, blood haemoglobin, urine albumin creatinine ratio, body mass index, and estimated glomerular filtration rate. RESULTS: In type 1 diabetes, higher baroreflex sensitivity was associated with higher SpO2 before adjustment (% increase per one % increase in SpO2 = 20 % (95%CI: 11-30); p < 0.001) and the association remained significant after adjustment (p = 0.02). Baroreflex sensitivity was not different between non-diabetic controls and persons with type 1 diabetes and normoalbuminuria (p = 0.052). Compared with type 1 diabetes and normoalbuminuria, baroreflex sensitivity was lower in micro- (p < 0.001) and macroalbuminuria (p < 0.001). SpO2 was lower in persons with type 1 diabetes and normoalbuminuria compared with non-diabetic controls (p < 0.01). Within the participants with type 1 diabetes, SpO2 was not different in micro- or macroalbuminuria compared with normoalbuminuria (p-values > 0.05), but lower in macro-compared with microalbuminuria (p < 0.01). CONCLUSIONS: Lower baroreflex sensitivity was associated with lower SpO2 in type 1 diabetes. The present study support the hypothesis that hypoxia could be a therapeutic target in persons with type 1 diabetes.

Endotrophin as a risk marker of mortality and kidney complications in a type 1 diabetes cohort.

Hyperglycemia triggers pathological pathways leading to fibrosis, where extracellular matrix (ECM) components are accumulated. We investigated the potential of endotrophin, a pro-fibrotic molecule generated during collagen type VI formation, as a risk marker for complications to type 1 diabetes. Endotrophin was measured in serum and urine from 1,468 persons with type 1 diabetes. Outcomes included a composite kidney endpoint, first major adverse cardiovascular event (MACE), all-cause mortality, progression of albuminuria, incident heart failure, and sight-threatening diabetic eye disease. Cox proportional hazards models adjusted for conventional risk factors were applied. A doubling of serum endotrophin was independently associated with the kidney endpoint (n = 30/1,462; hazard ratio 3.39 [95% CI: 1.98-5.82]), all-cause mortality (n = 93/1,468; 1.44 [1.03-2.0]), and progression of albuminuria (n = 80/1,359; 1.82 [1.32-2.52]), but not with first MACE, heart failure, or sight-threatening diabetic eye disease after adjustment. Urinary endotrophin was not associated with any outcome after adjustment. Serum endotrophin was a risk marker for mortality and kidney complications in type 1 diabetes. Biomarkers of ECM remodeling, such as serum endotrophin, may identify persons with active pro-fibrotic processes at risk for complications in diabetes and where antifibrotic agents may reduce this risk.

Patients with type 1 diabetes and albuminuria have a reduced brain glycolytic capability that is correlated with brain atrophy.

Introduction: Patients with type 1 diabetes (T1D) demonstrate brain alterations, including white matter lesions and cerebral atrophy. In this case-control study, we investigated if a reason for this atrophy could be because of diabetes-related complications affecting cerebrovascular or cerebral glycolytic functions. Cerebral physiological dysfunction can lead to energy deficiencies and, consequently, neurodegeneration. Methods: We examined 33 patients with T1D [18 females, mean age: 50.8 years (range: 26-72)] and 19 matched healthy controls [7 females, mean age: 45.0 years (range: 24-64)]. Eleven (33%) of the patients had albuminuria. Total brain volume, brain parenchymal fraction, gray matter volume and white matter volume were measured by anatomical MRI. Cerebral vascular and glycolytic functions were investigated by measuring global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral lactate concentration in response to the inhalation of hypoxic air (12-14% fractional oxygen) using phase-contrast MRI and magnetic resonance spectroscopy (MRS) techniques. The inspiration of hypoxic air challenges both cerebrovascular and cerebral glycolytic physiology, and an impaired response will reveal a physiologic dysfunction. Results: Patients with T1D and albuminuria had lower total brain volume, brain parenchymal fraction, and gray matter volume than healthy controls and patients without albuminuria. The inhalation of hypoxic air increased CBF and lactate in all groups. Patients with albuminuria had a significantly (p = 0.032) lower lactate response compared to healthy controls. The CBF response was lower in patients with albuminuria compared to healthy controls, however not significantly (p = 0.24) different. CMRO2 was unaffected by the hypoxic challenge in all groups (p > 0.16). A low lactate response was associated with brain atrophy, characterized by reduced total brain volume (p = 0.003) and reduced gray matter volume (p = 0.013). Discussion: We observed a reduced response of the lactate concentration as an indication of impaired glycolytic activity, which correlated with brain atrophy. Inadequacies in upregulating cerebral glycolytic activity, perhaps from reduced glucose transporters in the brain or hypoxia-inducible factor 1 pathway dysfunction, could be a complication in diabetes contributing to the development of neurodegeneration and declining brain health.