Extracellular matrix turnover proteins as risk markers in people with type 2 diabetes and microalbuminuria.

BACKGROUND: This post-hoc study investigated whether biomarkers reflecting extracellular matrix (ECM) turnover predicted cardiovascular disease (CVD), mortality, and progression of diabetic kidney disease (DKD) in individuals with type 2 diabetes (T2D) and microalbuminuria. METHODS: Serum levels of specific ECM turnover biomarkers were assessed in 192 participants with T2D and microalbuminuria from an observational study conducted at Steno Diabetes Center Copenhagen from 2007 to 2008. Endpoints included CVD events, mortality, and DKD progression, defined as decline in estimated glomerular filtration rate (eGFR) of >30 %. RESULTS: Participants had a mean age of 59 years, with 75 % males. Over a median follow-up of 4.9 to 6.3 years, the study recorded 38 CVD events, 24 deaths, and 40 DKD events. Elevated levels of a degradation fragment of collagen type I (C1M) were associated with an increased risk of >30 % eGFR decline, although this association was not independent of other risk factors. No significant associations were found between other ECM turnover biomarkers and DKD progression, mortality, or CVD risk. CONCLUSION: Elevated C1M levels were linked to DKD progression in individuals with T2D and microalbuminuria, but not independently of other risk factors. None of the ECM turnover biomarkers were associated with CVD or mortality.

Association of RASGRP1 polymorphism with vascular complications in Chinese diabetic patients with glycemic control and antihypertensive treatment.

BACKGROUND: Studies have shown that RASGRP1 was potently associated with the onset of type 2 diabetes mellitus (T2DM), and RASGRP1 rs7403531 was significantly correlated with islet function in T2DM patients. However, the effect of RASGRP1 polymorphism on blood glucose and blood pressure in T2DM patients after continuous treatment has yet to be fully elucidated. OBJECTIVE: This study aimed to explore the association between RASGRP1 genetic polymorphism and cardiovascular complications in T2DM patients, so as to provide more evidence for the individualized treatment of T2DM patients. METHODS: We retrospectively analyzed a large-scale multicenter drug clinical study cohort that based on a 2 × 2 factorial (glucose control axis and blood pressure lowering axis) randomized controlled design, with follow-up for 5 years. The major vascular endpoint events included cardiovascular death, non-fatal stroke, coronary heart disease, new-onset or worsening renal disease, and diabetic retinopathy. RASGRP1 rs12593201, rs56254815 and rs7403531 were finally selected as candidate single nucleotide polymorphisms. Mixed linear model and Cox hazard ratio (HR) model were used for data analysis with IBM SPSS (version 20.0 for windows; Chicago, IL). RESULTS: Our study enrolled 1357 patients with high-risk diabetes, with a mean follow-up duration of 4.8 years. RASGRP1 rs7403531 was associated with vascular events in hypoglycemic and antihypertensive therapy. Specifically, compared with CC carriers, patients with CT/TT genotype had fewer major microvascular events (HR = 0.41, 95% confidence interval (CI) 0.21-0.80, P = 0.009), and reduced the risk of major eye disease events (HR = 0.44, 95% CI 0.20-0.94, P = 0.03). For glucose lowering axis, CT/TT carriers had a lower risk of secondary nephropathy (HR = 0.48, 95% CI 0.25-0.92, P = 0.03) in patients with standard glycemic control. For blood pressure lowering axis, all cerebrovascular events (HR = 2.24, 95% CI 1.11-4.51, P = 0.025) and stroke events (HR = 2.07, 95% CI 1.03-4.15, P = 0.04) were increased in patients with CC genotype compared to those with CT/TT genotype in the placebo group, respectively. Furthermore, patients with CC genotype showed a reduced risk of major cerebrovascular events in antihypertensive group (HR = 0.36, 95% CI 0.15-0.86, P = 0.021). For RASGRP1 rs56254815, compared with the AA genotype carriers, the systolic blood pressure of AG/GG carriers in the antihypertensive group decreased by 1.5mmhg on average (P = 0.04). In the placebo group, the blood pressure of AG/GG carriers was 1.7mmHg higher than that of AA carriers (P = 0.02). CONCLUSION: We found that patients with G allele of RASGRP1 (rs56254815) showed a better antihypertensive therapy efficacy in T2DM patients. The rs7403531 T allele could reduce the risk of major microvascular events and major eye diseases in T2DM patients receiving either hypoglycemic or antihypertensive therapy. Our findings suggest that RASGRP1 genetic polymorphism might predict the cardiovascular complications in T2DM patients.

Association of the systemic immuno-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio with diabetic microvascular complications.

Background: The systemic immuno-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are widely used and have been shown to be predictive indicators of various diseases. Diabetic nephropathy (DN), retinopathy (DR), and peripheral neuropathy (DPN) are the most prominent and common microvascular complications, which have seriously negative impacts on patients, families, and society. Exploring the associations with these three indicators and diabetic microvascular complications are the main purpose. Methods: There were 1058 individuals with type 2 diabetes mellitus (T2DM) in this retrospective cross-sectional study. SII, NLR, and PLR were calculated. The diseases were diagnosed by endocrinologists. Logistic regression and subgroup analysis were applied to evaluate the association between SII, NLP, and PLR and diabetic microvascular complications. Results: SII, NLR, and PLR were significantly associated with the risk of DN [odds ratios (ORs): 1.52, 1.71, and 1.60, respectively] and DR [ORs: 1.57, 1.79, and 1.55, respectively] by multivariate logistic regression. When NLR ≥2.66, the OR was significantly higher for the risk of DPN (OR: 1.985, 95% confidence interval: 1.29-3.05). Subgroup analysis showed no significant positive associations across different demographics and comorbidities, including sex, age, hypertension, HbA1c (glycated hemoglobin), and dyslipidemia. Conclusion: This study found a positive relationship between NLR and DN, DR, and DPN. In contrast, SII and PLR were found to be only associated with DN and DR. Therefore, for the diagnosis of diabetic microvascular complications, SII, NLR and PLR are highly valuable.

Efficacy of 1-hour postload plasma glucose as a suitable measurement in predicting type 2 diabetes and diabetes-related complications: A post hoc analysis of the 30-year follow-up of the Da Qing IGT and Diabetes Study.

AIM: To evaluate whether 1-hour plasma glucose (1hPG) can be a comparable measurement to 2-hour plasma glucose (2hPG) in identifying individuals at high risk of developing diabetes. METHODS: A total of 1026 non-diabetic subjects in the Da Qing IGT and Diabetes Study were included and classified according to baseline postload 1hPG. The participants were followed up and assessed at 6-, 20- and 30year follow-up for outcomes including diabetes, all-cause and cardiovascular mortality, cardiovascular disease (CVD) events, and microvascular disease. We then conducted a proportional hazards analysis in this post hoc study to determine the risks of developing type 2 diabetes and its complications in a '1hPG-normal' group (1hPG <8.6 mmol/L) and a '1hPG-high' group (≥8.6 mmol/L). The predictive values of 1hPG and 2hPG were evaluated using a time-dependent receiver-operating characteristic (ROC) curve. RESULTS: Compared with the 1hPG-normal group, the 1hPG-high group had increased risk of diabetes (hazard ratio [HR] 4.45, 95% CI 3.43-5.79), all-cause mortality (HR 1.46, 95% CI 1.07-2.01), CVD mortality (HR 1.84, 95% CI 1.16-2.95), CVD events (HR 1.39, 95% CI 1.03-1.86) and microvascular disease (HR 1.70, 95% CI: 1.03-2.79) after adjusting for confounders. 1hPG exhibited a higher area under the ROC curve (AUC) for predicting diabetes than 2hPG during the long-term follow-up (AUC [1hPG vs. 2hPG]: 10 years: 0.86 vs. 0.84, p = 0.08; 20 years: 0.88 vs. 0.87, p = 0.04; 30 years: 0.85 vs. 0.82, p = 0.009). CONCLUSIONS: Elevated 1hPG level (≥8.6 mmol/L) was associated with increased risk of developing type 2 diabetes and its long-term complications, and could be considered as a suitable measurement for identifying individuals at high risk of type 2 diabetes.

Microvascular disease, modifiable risk factor profiles and incident arrhythmias in type 2 diabetes.

BACKGROUND: To assess the roles of diabetic microvascular disease and modifiable risk factors and their combination in the development of arrhythmias. METHODS: We included participants with type 2 diabetes (T2D) who were free of arrhythmias during recruitment in the UK Biobank study. The associations of microvascular disease states (defined by the presence of retinopathy, peripheral neuropathy or chronic kidney disease), four modifiable arrhythmic risk factors (body mass index, smoking, systolic blood pressure and glycosylated haemoglobin) and their joint associations with incident arrhythmias were examined. RESULTS: Among the 25 632 participants with T2D, 1705 (20.1%) of the 8482 with microvascular disease and 2017 (11.8%) of the 17 150 without microvascular disease developed arrhythmias during a median follow-up of 12.3 years. Having any of the three microvascular diseases was associated with a 48% increase in the hazard of developing arrhythmias. Incorporating microvascular disease states into a model alongside 11 traditional risk factors significantly enhanced arrhythmia prediction. Furthermore, individuals with microvascular disease who had optimal levels of zero to one, two, three or four arrhythmic risk factors showed an HR of 2.05 (95% CI 1.85, 2.27), 1.67 (95% CI 1.53, 1.83), 1.35 (95% CI 1.22, 1.50) and 0.91 (95% CI 0.73, 1.13), respectively, compared with those without microvascular disease. CONCLUSIONS: Although microvascular disease, a non-traditional risk factor, was associated with incident arrhythmias in individuals with T2D, having optimal levels of risk factors may mitigate this risk.

Quantitative model for assessment of lower-extremity perfusion in patients with diabetes.

BACKGROUND: Although diabetic and atherosclerotic vascular diseases have different pathophysiological mechanisms, the screening methods currently used for diabetic lower-extremity vascular diseases are mainly based on the evaluation methods used for atherosclerotic vascular diseases. Thus, assessment of microvascular perfusion is of great importance in early detection of lower-extremity ischemia in diabetes. PURPOSE: This cross-sectional study aimed to develop a quantitative model for evaluating lower-extremity perfusion. METHODS: We recruited 57 participants (14 healthy participants and 43 diabetes patients, of which 16 had lower-extremity arterial disease [LEAD]). All participants underwent technetium-99 m sestamibi (99mTc-MIBI) scintigraphy and ankle-brachial index (ABI) examination. We derived two key perfusion kinetics indices named activity perfusion index (API) and basal perfusion index (BPI). This study was registered in ClinicalTrials.gov (URL: https://www. CLINICALTRIALS: gov, NCT02752100). RESULTS: The estimated limb perfusion values in our lower-extremity perfusion assessment (LEPA) model showed excellent consistency with the actual measured data. Diabetes patients showed reduced lower-extremity perfusion in comparison with the control group (BPI: 106.21 ± 11.99 vs. 141.56 ± 17.38, p < 0.05; API: 12.34 ± 3.27 vs. 14.56 ± 3.12, p < 0.05). Using our model, the reductions in lower-extremity perfusion could be detected early in approximately 96.30% of diabetes patients. Patients with LEAD showed more severe reductions in lower-extremity perfusion than diabetes patients without LEAD (BPI: 47.85 ± 20.30 vs. 106.21 ± 11.99, p < 0.05; API: 7.06 ± 1.70 vs. 12.34 ± 3.27, p < 0.05). Discriminant analysis using API and BPI could successfully screen all diabetes patients with LEAD with a sensitivity of 100% and specificity of 80.77%. CONCLUSIONS: We established a LEPA model that could successfully assess lower-extremity microvascular perfusion in diabetes patients. This model has important application value for the recognition of early-stage LEAD in patients with diabetes.

Revascularizations and limb outcomes of hospitalized patients with diabetic peripheral arterial disease in the contemporary era.

BACKGROUND: Concomitant diabetes mellitus and peripheral artery disease (PAD) is a complex disease process. This retrospective analysis of the National Inpatient Sample sought to understand trends in limb outcomes of this unique and prevalent cohort of patients. METHODS: The National Inpatient Sample was queried between 2003 and 2017 for hospitalizations of patients with both type 2 diabetes mellitus and PAD. Trends in hospitalizations, limb outcomes, vascular interventions, and costs were analyzed. RESULTS: There were 10,303,673 hospitalizations of patients with concomitant diabetes mellitus and PAD that were identified between 2003 and 2017. The prevalence of hospitalizations associated with this disease process increased from 1644 to 3228 per 100,000 hospitalizations, a 96.4% increase. This included an increase of 288 to 587 per 100,000 hospitalizations of patients aged 18 to 49 years old, which was accompanied by a 10.8% increase in minor amputations. Nontraumatic lower extremity amputations decreased overall. Black and Hispanic ethnicity were associated with an increased risk for amputation, along with Medicaid insurance and lower income quartile. Inpatient endovascular revascularization has increased over time with an associated decrease in open revascularization procedures. Amputation-related hospital costs significantly increased from $6.6 billion in 2003 to $14.8 billion in 2017. CONCLUSIONS: An alarming increase of disease prevalence, negative in-hospital limb outcomes, and costs are seen in the current era in this analysis of patients with concurrent diabetes and PAD.

A multi-centre investigation of macrovascular and non-ocular microvascular complications in children and adolescents with diabetes mellitus in southern Ghana.

Objectives: To investigate the prevalence of macrovascular and non-ocular microvascular complications and the associated factors among children and adolescents with diabetes mellitus in selected hospitals in southern Ghana. Design: A cross-sectional study. Setting: The out-patient clinics of the Departments of Child Health, Medicine and Therapeutics, Family Medicine, Ophthalmology, and the National Diabetes Management and Research Centre, all at the Korle Bu Teaching Hospital, Accra, as well as from Cape-Coast Teaching Hospital in the Central Region of Ghana. Participants: Fifty-eight children and adolescents aged 4-19 years who had been diagnosed with diabetes mellitus. Main outcome measures: Macrovascular (peripheral artery disease and coronary heart disease) and non-ocular microvascular complications (neuropathy and nephropathy). Results: Data from 58 children and adolescents with diabetes were analysed. The mean age of participants was 14.6±2.6 years, and a female preponderance was observed (45, 77.6%). The prevalence of macrovascular and non-ocular microvascular complications was 27.6% and 8.6%, respectively. Long duration of diabetes diagnosis (p=0.044) and low triglycerides (p=0.009) were associated with microvascular complications, while high triglycerides (p=0.032), lower HDL cholesterol (p=0.046), and abnormal body mass index (p=0.020) were associated with macrovascular complications. Conclusions: Macrovascular and non-ocular microvascular complications are common among children and adolescents with diabetes in southern Ghana and are associated with a long duration of diabetes diagnosis, abnormal body mass index, low HDL cholesterol, and triglyceride levels. Therefore, the early institution of regular screening for diabetes-related complications to allow early detection and appropriate management is recommended. Funding: University of Ghana Research Fund.

Sjögren syndrome is a hidden contributor of macrovascular and microvascular complications in patients with type 2 diabetes.

OBJECTIVE: To investigate cardiovascular risk among diabetic patients with Sjögren syndrome. METHODS: This study was a nationwide population-based case-control study from 1997 to 2013, in which the association between autoimmune diseases and diabetes was investigated. The study population consisted of individuals with newly diagnosed type 2 diabetes with macrovascular or microvascular complications with at least two outpatient visits or one hospitalization as the outcome variables, and the exposure variables included traditional risk factors, medications, and autoimmune diseases. The odds ratio of cardiovascular events among each prevalent autoimmune disease and hydroxychloroquine's effect on cardiovascular risk were analyzed. RESULTS: The study included a total of 7026 individuals with diabetes with microvascular and macrovascular complications and the same number of patients in the control group. Sjögren syndrome was significantly higher in the diabetes complication group than in the non-complication group (0.8% vs 0.5%, P = 0.036). By using multivariate analysis, we found hypertension, hyperlipidemia, and Sjögren syndrome to be three independent risk factors for diabetes vascular complications (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.82-2.10; OR 1.53, 95% CI 1.42-1.64; and OR 1.67, 95% CI 1.06-2.65; respectively, all P < 0.05). Treatment with traditional statins and aspirin might be able to overcome the increased risk of developing cardiovascular events while comparing between diabetes patients with and without Sjögren syndrome. CONCLUSION: Sjögren syndrome is an unrecognized independent risk factor for cardiovascular events among diabetes patients, which indicates that patients with diabetes combined with Sjögren syndrome require closer follow up regarding cardiovascular complications in clinical settings. Treatment with hydroxychloroquine might not be enough to lower the cardiovascular risk significantly in diabetes patients with Sjögren syndrome.

Skin autofluorescence corresponds to microvascular reactivity in diabetes mellitus.

Advanced glycation accelerated by chronic hyperglycaemia contributes to the development of diabetic vascular complications throughout several mechanisms. One of these mechanisms is supposed to be impaired microvascular reactivity, that precedes significant vascular changes. The aim of this study was to find an association between advanced glycation, the soluble receptor for AGEs (sRAGE), and microvascular reactivity (MVR) in diabetes. Skin autofluorescence (SAF), which reflects advanced glycation, was assessed by AGE-Reader, MVR was measured by laser Doppler fluxmetry and evaluated together with sRAGE in 43 patients with diabetes (25 Type 1 and 18 Type 2) and 26 healthy controls of comparable age. SAF was significantly higher in patients with diabetes compared to controls (2.4 ± 0.5 vs. 2.0 ± 0.5 AU; p < 0.01). Patients with diabetes with SAF > 2.3 AU presented significantly worse MVR in both post-occlusive reactive hyperaemia (PORH) on the finger and forearm, and thermal hyperaemia (TH), compared to patients with SAF < 2.3 AU. SAF was age dependent in both diabetes (r = 0.41, p < 0.01) and controls (r = 0.45, p < 0.05). There was no association between SAF and diabetes control expressed by glycated haemoglobin. A significant relationship was observed between SAF and sRAGE in diabetes (r = 0.56, p < 0.001), but not in controls. A significant inverse association was found between SAF and MVR on the forearm in diabetes (PORH: r = -0.42, p < 0.01; TH: r = -0.46, p < 0.005). Both advanced glycation expressed by higher SAF or sRAGE and impaired MVR are involved in the pathogenesis of vascular complications in diabetes, and we confirm a strong interplay of these processes in this scenario.

Consultation rates in people with type 2 diabetes with and without vascular complications: a retrospective analysis of 141,328 adults in England.

OBJECTIVE: To assess trends in primary and specialist care consultation rates and average length of consultation by cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), or cardiometabolic multimorbidity exposure status. METHODS: Observational, retrospective cohort study used linked Clinical Practice Research Datalink primary care data from 01/01/2000 to 31/12/2018 to assess consultation rates in 141,328 adults with newly diagnosed T2DM, with or without CVD. Patients who entered the study with either a diagnosis of T2DM or CVD and later developed the second condition during the study are classified as the cardiometabolic multimorbidity group. Face to face primary and specialist care consultations, with either a nurse or general practitioner, were assessed over time in subjects with T2DM, CVD, or cardiometabolic multimorbidity. Changes in the average length of consultation in each group were investigated. RESULTS: 696,255 (mean 4.9 years [95% CI, 2.02-7.66]) person years of follow up time, there were 10,221,798 primary and specialist care consultations. The crude rate of primary and specialist care consultations in patients with cardiometabolic multimorbidity (N = 11,881) was 18.5 (95% CI, 18.47-18.55) per person years, 13.5 (13.50, 13.52) in patients with T2DM only (N = 83,094) and 13.2 (13.18, 13.21) in those with CVD (N = 57,974). Patients with cardiometabolic multimorbidity had 28% (IRR 1.28; 95% CI: 1.27, 1.31) more consultations than those with only T2DM. Patients with cardiometabolic multimorbidity had primary care consultation rates decrease by 50.1% compared to a 45.0% decrease in consultations for those with T2DM from 2000 to 2018. Specialist care consultation rates in both groups increased from 2003 to 2018 by 33.3% and 54.4% in patients with cardiometabolic multimorbidity and T2DM, respectively. For patients with T2DM the average consultation duration increased by 36.0%, in patients with CVD it increased by 74.3%, and in those with cardiometabolic multimorbidity it increased by 37.3%. CONCLUSIONS: Annual primary care consultation rates for individuals with T2DM, CVD, or cardiometabolic multimorbidity have fallen since 2000, while specialist care consultations and average consultation length have both increased. Individuals with cardiometabolic multimorbidity have significantly more consultations than individuals with T2DM or CVD alone. Service redesign of health care delivery needs to be considered for people with cardiometabolic multimorbidity to reduce the burden and health care costs.

Fetuin-A and risk of diabetes-related vascular complications: a prospective study.

BACKGROUND: Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops. METHODS: Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression. RESULTS: In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints). CONCLUSIONS: Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease.

Progression of Diabetic Complications in Subgroups of People with Long Term Diabetes Type 1 According to Clinical Course.

AIMS: Prevention and prediction of microvascular complications are important aims of medical care in people with type 1 diabetes. Since the course of the disease is heterogenous, we tried to identify subgroups with specific risk profiles for microvascular complications. METHODS: Retrospective analysis of a cohort of 285 people (22637 consultations) with >10 years of type 1 diabetes. Persons were grouped into slow (<15 years), fast (>15 years) and non progressors according to the average onset of microvascular complications. Generalized estimating equations for binary outcomes were applied and pseudo coefficients of determination were calculated. RESULTS: Progression to microvascular disease was associated with age (OR: 1.034 [1.001-1.068]; p=0.04), diabetes duration (OR: 1.057 [1.021-1.094]; p=0.002), HbA1c (OR: 1.035 [1.011-1.060]; p=0.005), BMI (OR: 0.928 [0.866-0.994]; p=0.034) and the social strata index (OR: 0.910 [0.830-0.998]; p=0.046). Generalized estimating equations predicted 31.02% and exclusion of HbA1c marginally reduced the value to 28.88%. The proportion of patients with LADA was higher in fast than slow progressors [13 (26.5%) vs. 14 (11.9%); p=0.019]. A generalized estimating equation comparing slow to fast progressors revealed no significant markers. CONCLUSION: In our analysis, we were able to confirm known risk factors for microvascular disease in people with type 1 diabetes. Overall, prediction of individual risk was difficult, the effect of individual markers minor and we could not find differences regarding slow or fast progression. We therefore emphasis the need for additional markers to predict individual risk for microvascular disease.

Early ABI Testing May Decrease Risk of Amputation for Patients With Lower Extremity Ulcers.

BACKGROUND: Patients with lower extremity wounds from diabetes mellitus or peripheral artery disease (PAD) have a risk of amputation as high as 25%. In patients with arterial disease, revascularization decreases the risk of amputation. We aimed to determine if the early assessment of arterial perfusion correlates with the risk of amputation. METHODS: We retrospectively reviewed patients referred to the vascular clinic over 18 months with Rutherford Grade 5 and 6 chronic limb-threatening ischemia to determine if patients had a pulse exam done at the time the wound was identified and when ankle brachial index (ABI) testing to evaluate perfusion was performed. Kaplan Meier analysis was used to determine if the timing of ABI testing affected the time to revascularization, wound healing, and risk of amputation. RESULTS: Ninety-three patients with lower extremity wounds were identified. Of these, 59 patients (63%) did not have a pulse exam performed by their primary care provider when the wound was identified. Patients were classified by when they underwent ankle brachial index testing to assess arterial perfusion. Twenty-four had early ABI (<30 days) testing, with the remaining 69 patients having late ABI testing. Patients in the early ABI group were more likely to have a pulse exam done by their PCP than those in the late group, 12 (50%) vs. 22 (32%), P = 0.03. Early ABI patients had a quicker time to vascular referral (13 days vs. 91 days, P < 0.001). Early ABI patients also had quicker times to wound healing than those in the late group (117 days vs. 287 days, P < 0.001). Finally, patients that underwent early ABI were less likely to require amputation (Fig. 1), although this did not reach statistical significance (P = 0.07). CONCLUSIONS: Early ABI testing expedites specialty referral and time to revascularization. It can decrease the time to wound healing. Larger cohort studies are needed to determine the overall effect of early ABI testing to decrease amputation rates.

Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients.

AIMS/INTRODUCTION: Cardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN. MATERIALS AND METHODS: Standardized CARTs (R-R response to paced breathing, Valsalva, postural changes) and digitized 12-lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R-R intervals (SDNN) and the root mean square of successive differences between normal-to-normal R-R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG-derived CAN and CARTs-defined CAN. RESULTS: Participants with CARTs-defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P < 0.001). The optimal cut-off points of ECG-derived CAN were <17.13 and <24.94 ms for SDNN and rMSSD, respectively. SDNN plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30-0.51) for the optimal cut-off point, showing fair agreement with CARTs-defined CAN. Combining SDNN and rMSSD optimal cut-off points does not provide additional predictive power for CAN. CONCLUSIONS: These analyses are the first to show the agreement between indices of heart rate variability derived from ECGs and the gold standard CARTs, thus supporting potential use as a measure of CAN in clinical research and clinical care.

Aberrant Functional Connectivity of the Posterior Cingulate Cortex in Type 2 Diabetes Without Cognitive Impairment and Microvascular Complications.

Objective: We aimed to investigate the alterations of brain functional connectivity (FC) in type 2 diabetes mellitus (T2DM) patients without clinical evidence of cognitive impairment and microvascular complications (woCIMC-T2DM) using resting-state functional MRI (rs-fMRI) and to determine whether its value was correlated with clinical indicators. Methods: A total of 27 T2DM and 26 healthy controls (HCs) were prospectively examined. Cognitive impairment was excluded using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) scales, and microvascular complications were excluded by fundus photography, microalbuminuria, and other indicators. The correlation maps, derived from rs-fMRI with posterior cingulate cortex (PCC) as the seed, were compared between T2DM patients and HCs. Pearson's correlation analysis was performed to determine the relationship between the FC of PCC and the clinical indicators. Results: Compared with HC, woCIMC-T2DM patients showed significantly decreased FCs with PCC (PCC-FCs) in the anterior cingulate cortex (ACC), right superior frontal gyrus, right medial frontal gyrus, and right angular gyrus. Meanwhile, increased PCC-FCs was observed in the right superior temporal gyrus and calcarine fissure (CAL). The FC of PCC-ACC was negatively correlated with glycosylated hemoglobin (HbA1c) and diabetes duration, and the FC of PCC-CAL was significantly positively correlated with HbA1c and diabetes duration. Conclusion: The FC, especially of the PCC with cognitive and visual brain regions, was altered before clinically measurable cognitive impairment and microvascular complications occurred in T2DM patients. In addition, the FC of the PCC with cognitive and visual brain regions was correlated with HbA1c and diabetes duration. This indicates that clinicians should pay attention not only to blood glucose control but also to brain function changes before the occurrence of adverse complications, which is of great significance for the prevention of cognitive dysfunction and visual impairment.

Basement membrane proteins in various arterial beds from individuals with and without type 2 diabetes mellitus: a proteome study.

BACKGROUND: Basement membrane (BM) accumulation is a hallmark of micro-vessel disease in diabetes mellitus (DM). We previously reported marked upregulation of BM components in internal thoracic arteries (ITAs) from type 2 DM (T2DM) patients by mass spectrometry. Here, we first sought to determine if BM accumulation is a common feature of different arteries in T2DM, and second, to identify other effects of T2DM on the arterial proteome. METHODS: Human arterial samples collected during heart and vascular surgery from well-characterized patients and stored in the Odense Artery Biobank were analysed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We included ascending thoracic aortas (ATA) (n = 10 (type 2 DM, T2DM) and n = 10 (non-DM)); laser capture micro-dissected plaque- and media compartments from carotid plaques (n = 10 (T2DM) and n = 9 (non-DM)); and media- and adventitia compartments from ITAs (n = 9 (T2DM) and n = 7 (non-DM)). RESULTS: We first extended our previous finding of BM accumulation in arteries from T2DM patients, as 7 of 12 pre-defined BM proteins were significantly upregulated in bulk ATAs consisting of > 90% media. Although less pronounced, BM components tended to be upregulated in the media of ITAs from T2DM patients, but not in the neighbouring adventitia. Overall, we did not detect effects on BM proteins in carotid plaques or in the plaque-associated media. Instead, complement factors, an RNA-binding protein and fibrinogens appeared to be regulated in these tissues from T2DM patients. CONCLUSION: Our results suggest that accumulation of BM proteins is a general phenomenon in the medial layer of non-atherosclerotic arteries in patients with T2DM. Moreover, we identify additional T2DM-associated effects on the arterial proteome, which requires validation in future studies.

Chronic venous disease and diabetic microangiopathy: pathophysiology and commonalities.

Chronic venous disease and diabetes mellitus are highly prevalent and debilitating conditions affecting millions of individuals globally. Although these conditions are typically considered as separate entities, they often co-exist which may be important in both understanding their pathophysiology and determining the best treatment strategy. Diabetes mellitus is twice as common in patients with chronic venous disease compared with the general population. Notably, a large proportion of patients with diabetes mellitus present with venous disorders, although this is often overlooked. The etiology of chronic venous disease is multifactorial, involving hemodynamic, genetic, and environmental factors which result in changes to the venous endothelium and structural wall as well as inflammation. Inflammation, endothelial dysfunction and hyperfiltration or leakage, are commonly observed in diabetes mellitus and cause various diabetic microvascular complications. Both diseases are also influenced by the increased expression of adhesion molecules, chemokines, and cytokines, and are characterized by the presence of vessel hypertension. Consequently, despite differences in etiology, the pathophysiology of both chronic venous disease and diabetic microangiopathy appears to be driven by endothelial dysfunction and inflammation. Treatment strategies should take the co-existence of chronic venous disease and diabetic microangiopathy into account. Compression therapy is recommended in inflammatory conditions that have an edema component as seen in both chronic venous disease and diabetes mellitus. Lifestyle changes like weight loss and exercise, will improve metabolic state and lower inflammation and should be promoted in these patients. Additionally, both patient populations may benefit from venoactive drugs.

Exosomes: Biomarkers and Therapeutic Targets of Diabetic Vascular Complications.

Diabetic vascular complications (DVC) including macrovascular and microvascular lesions, have a significant impact on public health, and lead to increased patient mortality. Disordered intercellular cascades play a vital role in diabetic systemic vasculopathy. Exosomes participate in the abnormal signal transduction of local vascular cells and mediate the transmission of metabolic disorder signal molecules in distant organs and cells through the blood circulation. They can store different signaling molecules in the membrane structure and release them into the blood, urine, and tears. In recent years, the carrier value and therapeutic effect of exosomes derived from stem cells have garnered attention. Exosomes are not only a promising biomarker but also a potential target and tool for the treatment of DVC. This review explored changes in the production process of exosomes in the diabetic microenvironment and exosomes' early warning role in DVC from different systems and their pathological processes. On the basis of these findings, we discussed the future direction of exosomes in the treatment of DVC, and the current limitations of exosomes in DVC research.