Interactions of the Osteokines, Glucose/Insulin System and Vascular Risk Networks in Patients With Newly Diagnosed Type 2 Diabetes (VNDS 15).

BACKGROUND AND AIM: Bone as an endocrine organ regulates metabolic processes independently of mineral metabolism through the production/release of proteins collectively named 'osteokines'. Relevant connections were reported between the insulin/glucose system, calcification of the atherosclerotic plaque, and several osteokines. We aimed to test the hypothesis that the osteokine network could be involved in beta-cell function, insulin sensitivity, and vascular damage in a cohort of people with newly diagnosed type 2 diabetes (T2D). SUBJECTS AND METHODS: In 794 drug-naive, GADA-negative, newly-diagnosed T2D patients (mean ± SD age: 59 ± 9.8 years; BMI: 29.3 ± 5.3 kg/m2; HbA1c: 6.6 ± 1.3%) we assessed: plasma concentration of osteocalcin (OCN), osteopontin (OPN), RANKL, and its putative decoy receptor osteoprotegerin (OPG); insulin sensitivity (SI) by hyperinsulinemic euglycemic clamp; beta cell function (BCF), estimated by OGTT minimal modelling and expressed as derivative (DC) and proportional (PC) control. Echo-doppler of carotid and lower limb arteries were also performed in 708 and 701 subjects, respectively. RESULTS: OCN, RANKL and OPG were significantly associated with PC (p < 0.02); OCN was positively related to DC (p = 0.018). OPG was associated with lower IS (p < 0.001). Finally, the higher RANKL levels, the greater was the severity of atherosclerosis in common carotid artery (p < 0.001). Increased OPG and OPN concentrations were related to subclinical atherosclerosis in peripheral arteries of lower limbs (p = 0.023 and p = 0.047, respectively). CONCLUSION: These data suggest that, in patients with newly diagnosed T2D, the osteokine network crosstalks with the glucose/insulin system and may play a role in modulating the atherosclerotic process.

Fully automated epicardial adipose tissue volume quantification with deep learning and relationship with CAC score and micro/macrovascular complications in people living with type 2 diabetes: the multicenter EPIDIAB study.

BACKGROUND: The aim of this study (EPIDIAB) was to assess the relationship between epicardial adipose tissue (EAT) and the micro and macrovascular complications (MVC) of type 2 diabetes (T2D). METHODS: EPIDIAB is a post hoc analysis from the AngioSafe T2D study, which is a multicentric study aimed at determining the safety of antihyperglycemic drugs on retina and including patients with T2D screened for diabetic retinopathy (DR) (n = 7200) and deeply phenotyped for MVC. Patients included who had undergone cardiac CT for CAC (Coronary Artery Calcium) scoring after inclusion (n = 1253) were tested with a validated deep learning segmentation pipeline for EAT volume quantification. RESULTS: Median age of the study population was 61 [54;67], with a majority of men (57%) a median duration of the disease 11 years [5;18] and a mean HbA1c of7.8 ± 1.4%. EAT was significantly associated with all traditional CV risk factors. EAT volume significantly increased with chronic kidney disease (CKD vs no CKD: 87.8 [63.5;118.6] vs 82.7 mL [58.8;110.8], p = 0.008), coronary artery disease (CAD vs no CAD: 112.2 [82.7;133.3] vs 83.8 mL [59.4;112.1], p = 0.0004, peripheral arterial disease (PAD vs no PAD: 107 [76.2;141] vs 84.6 mL[59.2; 114], p = 0.0005 and elevated CAC score (> 100 vs < 100 AU: 96.8 mL [69.1;130] vs 77.9 mL [53.8;107.7], p < 0.0001). By contrast, EAT volume was neither associated with DR, nor with peripheral neuropathy. We further evidenced a subgroup of patients with high EAT volume and a null CAC score. Interestingly, this group were more likely to be composed of young women with a high BMI, a lower duration of T2D, a lower prevalence of microvascular complications, and a higher inflammatory profile. CONCLUSIONS: Fully-automated EAT volume quantification could provide useful information about the risk of both renal and macrovascular complications in T2D patients.

Fenofibrate to prevent amputation and reduce vascular complications in patients with diabetes: FENO-PREVENT.

BACKGROUND: The potential preventive effect of fenofibrate on lower extremity amputation (LEA) and peripheral arterial disease (PAD) in patients with type 2 diabetes (T2D) is not fully elucidated. METHODS: We selected adult patients ≥ 20 years of age with T2D from the Korean National Health Insurance Service Database (2009-2012). The fenofibrate users were matched in a 1:4 ratio with non-users using propensity scores (PS). The outcome variables were a composite of LEA and PAD and the individual components. The risks of outcomes were implemented as hazard ratio (HR) with 95% confidence intervals (CI). For safety issues, the risks of acute kidney injury, rhabdomyolysis and resulting hospitalization were analyzed. RESULTS: A total of 114,920 patients was included in the analysis with a median follow-up duration of 7.6 years (22,984 and 91,936 patients for the fenofibrate user and non-user groups, respectively). After PS matching, both groups were well balanced. The fenofibrate group was associated with significantly lower risks of composite outcome of LEA and PAD (HR 0.81; 95% CI 0.70-0.94), LEA (HR 0.76; 95% CI 0.60-0.96), and PAD (HR 0.81; 95% CI 0.68-0.96). The risk of acute kidney injury, rhabdomyolysis, or hospitalization for these events showed no significant difference between the two groups. Subgroup analyses revealed consistent benefits across age groups, genders, and baseline lipid profiles. CONCLUSIONS: This nationwide population-based retrospective observational study suggests that fenofibrate can prevent LEA and PAD in patients with T2D who are on statin therapy.

MicroRNAs in diabetic macroangiopathy.

Diabetic macroangiopathy is a leading cause of diabetes-related mortality worldwide. Both genetic and environmental factors, through a multitude of underlying molecular mechanisms, contribute to the pathogenesis of diabetic macroangiopathy. MicroRNAs (miRNAs), a class of non-coding RNAs known for their functional diversity and expression specificity, are increasingly recognized for their roles in the initiation and progression of diabetes and diabetic macroangiopathy. In this review, we will describe the biogenesis of miRNAs, and summarize their functions in diabetic macroangiopathy, including atherosclerosis, peripheral artery disease, coronary artery disease, and cerebrovascular disease, which are anticipated to provide new insights into future perspectives of miRNAs in basic, translational and clinical research, ultimately advancing the diagnosis, prevention, and treatment of diabetic macroangiopathy.

Glycaemic control and microvascular complications among paediatric type 2 diabetes mellitus patients in Hong Kong at 2 years after diagnosis.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is becoming increasingly common among children and adolescents worldwide, including those in Hong Kong. This study analysed the characteristics and prevalence of microvascular complications among paediatric T2DM patients in Hong Kong at diagnosis and 2 years after diagnosis. METHODS: All patients aged <18 years who had been diagnosed with DM at public hospitals in Hong Kong were recruited into the Hong Kong Childhood Diabetes Registry. Data collected at diagnosis and 2 years after diagnosis were retrospectively retrieved from the Registry for patients diagnosed from 2014 to 2018. RESULTS: Median haemoglobin A1c (HbA1c) levels were 7.5% (n=203) at diagnosis and 6.5% (n=135) 2 years after diagnosis; 59.3% of patients achieved optimal glycaemic control (HbA1c level <7%) at 2 years. A higher HbA1c level at diagnosis was associated with worse glycaemic control at 2 years (correlation coefficient=0.39; P<0.001). The presence of dyslipidaemia (adjusted odds ratio [aOR]=3.19; P=0.033) and fatty liver (aOR=2.50; P=0.021) at 2 years were associated with suboptimal glycaemic control. Diabetic neuropathy and retinopathy were rare in our cohort, but 18.6% of patients developed microalbuminuria (MA) within 2 years after diagnosis. Patients with MA had a higher HbA1c level at 2 years (median: 7.2% vs 6.4%; P=0.037). Hypertension was a risk factor for MA at 2 years, independent of glycaemic control (aOR=4.61; P=0.008). CONCLUSION: These results highlight the importance of early diagnosis and holistic management (including co-morbidity management) for paediatric T2DM patients.

Serum biomarkers for predicting microvascular complications of diabetes mellitus.

INTRODUCTION: Diabetic microvascular complications such as retinopathy, nephropathy, and neuropathy are primary causes of blindness, terminal renal failure, and neuropathic disorders in type 2 diabetes mellitus patients. Identifying reliable biomarkers promptly is pivotal for early detection and intervention in these severe complications. AREAS COVERED: This review offers a thorough examination of the latest research concerning serum biomarkers for the prediction and assessment of diabetic microvascular complications. It encompasses biomarkers associated with glycation, oxidative stress, inflammation, endothelial dysfunction, basement membrane thickening, angiogenesis, and thrombosis. The review also highlights the potential of emerging biomarkers, such as microRNAs and long non-coding RNAs. EXPERT OPINION: Serum biomarkers are emerging as valuable tools for the early assessment and therapeutic guidance of diabetic microvascular complications. The biomarkers identified not only reflect the underlying pathophysiology but also align with the extent of the disease. However, further validation across diverse populations and improvement of the practicality of these biomarkers in routine clinical practice are necessary. Pursuing these objectives is essential to advance early diagnosis, risk assessment, and individualized treatment regimens for those affected by diabetes.

Prognostic value of novel atherogenic indices in patients with acute myocardial infarction with and without type 2 diabetes.

AIMS: Atherogenic indices: Triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, Atherogenic Index of Plasma (AIP), Atherogenic Coefficient (AC), Castelli's Risk Index I and II (CRI-I, CRI-II) are used in clinical studies as surrogates of major adverse cardiac and cerebrovascular events (MACCE). Risk prediction of MACCE in patients with acute myocardial infarction (AMI) has vital role in clinical practice. We aimed to assess prognostic value of these indices following AMI. METHODS: We analyzed patients with AMI with and without T2DM and the prognostic values of atherogenic indices for in-hospital death and MACCE within 12 months after AMI. RESULTS: Of 2461 patients, 152 in-hospital deaths (6.2 %) were reported (74 patients [7.4 %] with T2DM and 78 [5.3 %] without T2DM; p = 0.042). MACCE occurred in 22.7 % of patients (29.7 % with T2DM and 17.9 % without T2DM; p < 0.001). TG/HDL-C and AIP were higher in T2DM patients compared to those without T2DM (p < 0.001). Long-term MACCE was more prevalent in patients with T2DM (p < 0.001). The AUC-ROC for predicting in-hospital death based on TG/HDL-C and AIP was 0.57 (p = 0.002). CONCLUSIONS: None of the atherogenic indices was an independent risk factor for in-hospital death or MACCE at 12-month follow-up in patients with AMI. AIP was an independent risk factor for death at 12-month follow-up.

Age at onset of type 2 diabetes and prevalence of vascular disease and heart failure: Systematic review and dose-response meta-analysis.

AIM: To investigate the relationship between age at diagnosis of type 2 diabetes and the risk of macrovascular disease, heart failure, and microvascular disease. METHODS: In August 2022, PubMed/EMBASE were searched for articles reporting (i) coronary artery disease, cerebrovascular disease, peripheral vascular disease, amputation; (ii) heart failure; and (iii) retinopathy, neuropathy, nephropathy (albuminuria, chronic kidney disease [CKD], end-stage renal disease) by age at diagnosis of type 2 diabetes. Random effects, non-linear dose-response meta-analysis was undertaken for each outcome to assess the association with age at diagnosis (40 years = reference), using both crude and maximally adjusted odds ratios separately, with and without adjustment for current age (age at sampling). RESULTS: We identified 42 articles (230,003 to 3,465,590 participants; 1035 to 391,140 events). Age at diagnosis was positively associated with the risk of macrovascular diseases, heart failure, and CKD, independent of current age, and negatively associated with retinopathy. For other microvascular outcomes, when adjusting for current age, a "reverse U" relationship was observed (peak risk = 55-60 years). DISCUSSION: Retinopathy was negatively associated with age at diagnosis, highlighting the importance of retinopathy screening in early-onset type 2 diabetes. The implications of other associations were unclear due to the heterogeneity in methodologies and findings.

Prediction of Micro- and Macrovascular Complications in Type 2 Diabetes Mellitus using Heart Rate Variability.

OBJECTIVE: To explore the utility of heart rate variability (HRV), a noninvasive marker of cardiac autonomic activity, as a prescreening tool for the prediction of micro- and macrovascular complications in type 2 diabetes mellitus (T2DM). METHODS: Consenting type 2 diabetic patients of both genders between 30 and 70 years, without known micro- and macrovascular complications of diabetes, were enrolled. Patients with medications affecting the HRV were excluded. Prior to other screening tests, 15 minutes of resting electrocardiogram (ECG) (1 kHz) was recorded in enrolled patients, followed by an exercise stress test and assessment for nephropathy, retinopathy, and peripheral neuropathy. The patients with positive stress tests were referred for coronary angiography to confirm coronary artery disease. Based on screening test results, patients were grouped as Group I-T2DM without complications (n = 31) and Group II-T2DM with micro/macrovascular complications (n = 29), (total = 60). RESULTS: Group comparison and test for association were employed, and p-value of <0.05 was considered significant. Significantly reduced HRV (decreased standard deviation of NN interval) between groups and a strong association of HRV indices with complications of diabetes were observed. Logistic regression to classify complicated vs noncomplicated group was used, and an accuracy of 0.78 with 85% sensitivity, 74% specificity with area under the curve (AUC) of 0.83 was observed. CONCLUSION: Significantly reduced HRV, stronger association with complications, and 85% sensitivity, 74% specificity, and 78% accuracy of classification make HRV indices a promising prescreening tool to predict micro- and macrovascular complications in type 2 diabetes.

Correlation of cerebral small vessel disease burden with outcome after lower extremity amputation.

AIMS: This study assessed whether changes associated with cerebral small vessel disease (CSVD) evaluated from head computed tomography (CT) images captured for non-related clinical purposes predict overall survival (OS), leg salvage (LS), and amputation-free survival (AFS) after lower extremity amputation (LEA). METHODS: We retrospectively included a cohort of 240 patients who had undergone a lower extremity amputation in Tampere University Hospital between the years 2007 and 2020 and had a head CT scan (within one year before amputation). A neuroradiologist graded the white matter lesions (WMLs) and reported infarcts, and the latter's effects on OS, LS, and AFS were evaluated. RESULTS: Altogether, 162 (67.5 %) and 91 (38.1 %) patients had WMLs and infarcts, respectively. Mild/moderate (HR 1.985, CI 95 % 1.317-2.992) and severe (HR 2.259, CI 95 % 1.501-3.399) WMLs and infarcts (HR 1.413, CI 95 % 1.029-1.940) were associated with inferior OS. After a minor amputation, mild/moderate (HR 2.012, CI 95 % 1.054-3.843) and severe (HR 3.879, CI 95 % 2.096-7.180) WMLs were similarly associated with inferior AFS. CONCLUSIONS: Overall, WML and infarcts detected on head CT scans were associated with impaired OS after LEA and AFS after minor LEA. Evaluation of CSVD could provide useful prognostic information for clinicians.

Sheffield One-Stop Service: A potential model to improve the screening uptake of diabetic peripheral neuropathy and other microvascular complications of diabetes.

The world is experiencing an enormous rise in the prevalence of diabetes, which is associated with massive healthcare costs that threaten to overwhelm many healthcare systems. Most of the diabetes expenditure is attributed to the management of chronic diabetes complications, including diabetic peripheral neuropathy (DPN)/diabetic foot complications, chronic kidney disease, sight-threatening retinopathy and cardiovascular diseases. Of these complications, the most overlooked is DPN. Most consultations around the world do not even involve taking off shoes and socks to carry out a foot examination, and even when carried out, the peripheral neurological examination using the 10-g monofilament diagnoses DPN when it is already at an advanced stage. Thus, all too often diabetes complications are diagnosed late, resulting in devastating outcomes, particularly in low- to middle-income countries. There is, therefore, an urgent need to instigate new strategies to improve microvascular screening uptake using a holistic protocol for annual diabetes health checks outside the busy diabetes clinic. One such approach, the Sheffield One-Stop Microvascular Screening Service, which involves modern point of care devices to diagnose DPN, has been shown to be feasible and effective, resulting in high uptake and early management of diabetes complications. This article outlines the advantages of this One-Stop Microvascular Screening Service and a plan to trial an adapted version of this service to a resource-limited country, the Philippines. If successful, this model has the potential for implementation in other countries around the world.

Assessment of arterial stiffness in paediatric patients with type 1 diabetes mellitus.

AIMS: To investigate early indicators of cardiovascular disease (CVD) in children and adolescents with type 1 diabetes mellitus (T1DM), focusing on pulse wave velocity (PWV) and its associations with various anthropometric and glycemic parameters. PATIENTS AND METHODS: A total of 124 children and adolescents with T1D (mean age 10.75 ± 3.57 years) were included in this cross-sectional study. Anthropometric data, including height, weight, body mass index (BMI), glycemic parameters, such as HbA1c and time in range (TIR) were assessed. PWV was assessed by oscillometric method using the Mobil-O-Graph PWA device. Univariate and multivariate linear regression were used to explore the association of PWV z-score with anthropometric, demographic, and glycaemic variables. RESULTS: Significant negative association between PWV and age and height (ß = -0.336, 95 % CI -0.44 to -0.25, p < 0.001 and ß = -0.491, 95 % CI -0.62 to -0.36, p < 0.001, respectively), while gender showed a significant positive association with PWV, with females displaying higher PWV values compared to males (ß = 0.366, 95 % CI 0.17 to 0.56, p < 0.001). TIR was positively associated with PWV (ß = 0.092, 95 % CI 0.01 to 0.16, p = 0.017 only for patients having TIR ≤ 50 %. Finally, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were positively associated with PWV (ß = 0.086, 95 % CI 0.02 to 0.14, p = 0.007 and ß = 0.152, 95 % CI 0.07 to 0.23, p < 0.001, respectively). CONCLUSION: Youth with T1DM who spend <50 % of time in range exhibit uniquely increased signs of arterial stiffness, indicating that poor glycemic control may contribute to early vascular damage. Differences related to age, gender and height should be considered.

Association between lung function and risk of microvascular diseases in patients with diabetes: A prospective cohort and Mendelian randomization study.

BACKGROUND AND AIMS: To investigate causal relationships of lung function with risks microvascular diseases among participants with diabetes, type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM), respectively, in prospective and Mendelian randomization (MR) study. METHODS AND RESULTS: 14,617 participants with diabetes and without microvascular diseases at baseline from the UK Biobank were included in the prospective analysis. Of these, 13,421 had T2DM and 1196 had T1DM. The linear MR analyses were conducted in the UK Biobank with 6838 cases of microvascular diseases and 10,755 controls. Lung function measurements included forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The study outcome was microvascular diseases, a composite outcome including chronic kidney diseases, retinopathy and peripheral neuropathy. During a median follow-up of 12.1 years, 2668 new-onset microvascular diseases were recorded. FVC (%predicted) was inversely associated with the risk of new-onset microvascular diseases in participants with diabetes (Per SD increment, adjusted HR = 0.86; 95%CI:0.83-0.89), T2DM (Per SD increment, adjusted HR = 0.86; 95%CI:0.82-0.90) and T1DM (Per SD increment, adjusted HR = 0.87; 95%CI: 0.79-0.97), respectively. Similar results were found for FEV1 (%predicted). In MR analyses, genetically predicted FVC (adjusted RR = 0.55, 95%CI:0.39-0.77) and FEV1 (adjusted RR = 0.48, 95%CI:0.28-0.83) were both inversely associated with microvascular diseases in participants with T1DM. No significant association was found in those with T2DM. Similar findings were found for each component of microvascular diseases. CONCLUSION: There was a causal inverse association between lung function and risks of microvascular diseases in participants with T1DM, but not in those with T2DM.

Nocturnal hypoxemic burden and micro- and macrovascular disease in patients with type 2 diabetes.

BACKGROUND: Micro- and macrovascular diseases are common in patients with type 2 diabetes mellitus (T2D) and may be partly caused by nocturnal hypoxemia. The study aimed to characterize the composition of nocturnal hypoxemic burden and to assess its association with micro- and macrovascular disease in patients with T2D. METHODS: This cross-sectional analysis includes overnight oximetry from 1247 patients with T2D enrolled in the DIACORE (DIAbetes COhoRtE) study. Night-time spent below a peripheral oxygen saturation of 90% (T90) as well as T90 associated with non-specific drifts in oxygen saturation (T90non - specific), T90 associated with acute oxygen desaturation (T90desaturation) and desaturation depths were assessed. Binary logistic regression analyses adjusted for known risk factors (age, sex, smoking status, waist-hip ratio, duration of T2D, HbA1c, pulse pressure, low-density lipoprotein, use of statins, and use of renin-angiotensin-aldosterone system inhibitors) were used to assess the associations of such parameters of hypoxemic burden with chronic kidney disease (CKD) as a manifestation of microvascular disease and a composite of cardiovascular diseases (CVD) reflecting macrovascular disease. RESULTS: Patients with long T90 were significantly more often affected by CKD and CVD than patients with a lower hypoxemic burden (CKD 38% vs. 28%, p < 0.001; CVD 30% vs. 21%, p < 0.001). Continuous T90desaturation and desaturation depth were associated with CKD (adjusted OR 1.01 per unit, 95% CI [1.00; 1.01], p = 0.008 and OR 1.30, 95% CI [1.06; 1.61], p = 0.013, respectively) independently of other known risk factors for CKD. For CVD there was a thresholdeffect, and only severly and very severly increased T90non-specific was associated with CVD ([Q3;Q4] versus [Q1;Q2], adjusted OR 1.51, 95% CI [1.12; 2.05], p = 0.008) independently of other known risk factors for CVD. CONCLUSION: While hypoxemic burden due to oxygen desaturations and the magnitude of desaturation depth were significantly associated with CKD, only severe hypoxemic burden due to non-specific drifts was associated with CVD. Specific types of hypoxemic burden may be related to micro- and macrovascular disease.

Combined associations of visceral adipose tissue and adherence to a Mediterranean lifestyle with T2D and diabetic microvascular complications among individuals with prediabetes.

BACKGROUND: It's unclear if excess visceral adipose tissue (VAT) mass in individuals with prediabetes can be countered by adherence to a Mediterranean lifestyle (MEDLIFE). We aimed to examine VAT mass, MEDLIFE adherence, and their impact on type 2 diabetes (T2D) and diabetic microvascular complications (DMC) in individuals with prediabetes. METHODS: 11,267 individuals with prediabetes from the UK Biobank cohort were included. VAT mass was predicted using a non-linear model, and adherence to the MEDLIFE was evaluated using the 25-item MEDLIFE index, encompassing categories such as "Mediterranean food consumption," "Mediterranean dietary habits," and "Physical activity, rest, social habits, and conviviality." Both VAT and MEDLIFE were categorized into quartiles, resulting in 16 combinations. Incident cases of T2D and related DMC were identified through clinical records. Cox proportional-hazards regression models were employed to examine associations, adjusting for potential confounding factors. RESULTS: Over a median follow-up of 13.77 years, we observed 1408 incident cases of T2D and 714 cases of any DMC. High adherence to the MEDLIFE, compared to the lowest quartile, reduced a 16% risk of incident T2D (HR: 0.84, 95% CI: 0.71-0.98) and 31% for incident DMC (0.69, 0.56-0.86). Conversely, compared to the lowest quartile of VAT, the highest quartile increased the risk of T2D (5.95, 4.72-7.49) and incident any DMC (1.79, 1.36-2.35). We observed an inverse dose-response relationship between MEDLIFE and T2D/DMC, and a dose-response relationship between VAT and all outcomes (P for trend < 0.05). Restricted cubic spline analysis confirmed a nearly linear dose-response pattern across all associations. Compared to individuals with the lowest MEDLIFE quartile and highest VAT quartile, those with the lowest T2D risk had the lowest VAT and highest MEDLIFE (0.12, 0.08-0.19). High MEDLIFE was linked to reduced T2D risk across all VAT categories, except in those with the highest VAT quartile. Similar trends were seen for DMC. CONCLUSION: High adherence to MEDLIFE reduced T2D and MDC risk in individuals with prediabetes, while high VAT mass increases it, but MEDLIFE adherence may offset VAT's risk partly. The Mediterranean lifestyle's adaptability to diverse populations suggests promise for preventing T2D.

Plasma copeptin and markers of arterial disorder in patients with type 2 diabetes, a cross-sectional study.

OBJECTIVES: There is currently limited understanding of the relationship between copeptin, the midregional portion of proadrenomedullin (MRproADM) and the midregional fragment of the N-terminal of proatrial natriuretic peptide (MRproANP), and arterial disorders. Toe brachial index (TBI) and aortic pulse wave velocity (aPWV) are established parameters for detecting arterial disorders. This study evaluated whether copeptin, MRproADM, and MRproANP were associated with TBI and aPWV in patients with type 2 diabetes with no history of cardiovascular disease (CVD). METHODS: In the CARDIPP study, a cross-sectional analysis of 519 patients with type 2 diabetes aged 55-65 years with no history of CVD at baseline, had complete data on copeptin, MRproADM, MRproANP, TBI, and aPWV was performed. Linear regression analysis was used to investigate the associations between conventional CVD risk factors, copeptin, MRproADM, MRproANP, TBI, and aPWV. RESULTS: Copeptin was associated with TBI (ß-0.0020, CI-0.0035- (-0.0005), p = 0.010) and aPWV (ß 0.023, CI 0.002-0.044, p = 0.035). These associations were independent of age, sex, diabetes duration, mean 24-hour ambulatory systolic blood pressure, glycated hemoglobin A1c, total cholesterol, estimated glomerular filtration rate, body mass index, and active smoking. CONCLUSIONS: Plasma copeptin may be a helpful surrogate for identifying individuals at higher risk for arterial disorders. TRIAL REGISTRATION:  ClinicalTrials.gov identifier NCT010497377.

Controlling Nutritional Status (CONUT) score is a novel marker of type 2 diabetes mellitus and diabetic microvascular complications.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) and its microvascular complications are characterized by chronic inflammation. The Controlling Nutritional Status (CONUT) score is a tool used to assess nutritional status and is often associated indirectly with inflammatory processes. We aimed to compare the CONUT scores of T2DM patients with those of healthy volunteers and to compare T2DM patients with and without microvascular complications. METHODS: Patients diagnosed with T2DM and healthy volunteers (as controls) were included in the study. The CONUT score is calculated using the following formula: serum albumin score + total cholesterol score + total lymphocyte count score. CONUT scores of T2DM patients and healthy controls, as well as those of diabetics with and without microvascular complications, were compared. RESULTS: The CONUT scores of the T2DM and control groups were (1 [0-7]) and (0 [0-2]), respectively (p < 0.001). The sensitivity and specificity of the CONUT score (<1.5 threshold) in detecting T2DM were 43% and 90%, respectively (AUC: 0.67, p < 0.001, 95% CI: 0.64-0.71). Moreover, the CONUT score was an independent risk factor for T2DM (OR: 0.34, p < 0.001, 95% CI: 0.22-0.52). The CONUT score of T2DM patients with microvascular complications (2 [0-7]) was significantly higher than that of T2DM patients without microvascular complications (0 [0-4]) and control subjects (0 [0-2]) (p < 0.001). A CONUT score higher than 1.5 had 83% sensitivity and 92% specificity in detecting T2DM with microvascular complications (AUC: 0.91, p < 0.001, 95% CI: 0.89-0.93). CONCLUSION: The CONUT score could be useful in detecting diabetic microvascular complications in clinical practice, as it is an inexpensive and easy-to-assess marker.

Noninvasive Liver Fibrosis Indices as Indicators of Microvascular and Macrovascular Complications in Type 2 Diabetes.

Objective: Nonalcoholic fatty liver disease (NAFLD) is more prevalent in patients with obesity, diabetes, and metabolic syndrome, which are risk factors for nonalcoholic steatohepatitis and liver fibrosis. NAFLD is related to cardiovascular outcomes in diabetes. We aimed to investigate the relationship between diabetic complications and NAFLD fibrosis score (NFS) and Fibrosis-4 score (FIB-4). Methods: Three hundred patients with type 2 diabetes mellitus (T2DM) were retrospectively evaluated according to NAFLD diagnosis on ultrasound in outpatient clinic. Risk of advanced fibrosis was estimated using FIB-4 and NFS. Diabetic complications of the patients were noted. Results: Presence of diabetic retinopathy is related to FIB-4 (P = 0.001) and NFS (P < 0.001) scores. NFS score (P = 0.037), not FIB-4 (P = 0.517), is related to diabetic nephropathy. Among macrovascular complications, only coronary artery disease is related to NFS and FIB-4 scores (P = 0.037 and P = 0.004, respectively). Although we cannot establish any association between fasting blood glucose, glycosylated hemoglobin (HbA1c) values and noninvasive liver fibrosis scores (P > 0.05), diabetes duration, and age positively correlated with the FIB-4 score (P = 0.033, P = 0.001). In logistic regression analysis, NFS > 0.676 values are associated with increased rates of diabetic retinopathy, independent of age, sex, HbA1c, and duration diabetes (odds ratio: 1.155, P = 0.030). FIB-4 has no relation with microvascular complications according to logistic regression analysis (P > 0.05 for all). Neither FIB-4 nor NFS has an effect on the presence of macrovascular complications (P > 0.05 for all). Conclusion: Our findings suggest that increase in NFS score is associated with the presence of diabetic retinopathy, independent of confounding factors. Further studies are needed on the applicability of noninvasive fibrosis scores in monitoring the presence of diabetic microvascular and macrovascular complications.

Diabetes-Related Macrovascular Complications Are Associated With an Increased Risk of Diabetic Microvascular Complications: A Prospective Study of 1518 Patients With Type 1 Diabetes and 20 802 Patients With Type 2 Diabetes in the UK Biobank.

BACKGROUND: Diabetic vascular complications share common pathophysiological mechanisms, but the relationship between diabetes-related macrovascular complications (MacroVCs) and incident diabetic microvascular complications remains unclear. We aimed to investigate the impact of MacroVCs on the risk of microvascular complications. METHODS AND RESULTS: There were 1518 participants with type 1 diabetes (T1D) and 20 802 participants with type 2 diabetes from the UK Biobank included in this longitudinal cohort study. MacroVCs were defined by the presence of macrovascular diseases diagnosed after diabetes at recruitment, including coronary heart disease, peripheral artery disease, stroke, and ≥2 MacroVCs. The primary outcome was incident microvascular complications, a composite of diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy. During a median (interquartile range) follow-up of 11.61 (5.84-13.12) years and 12.2 (9.50-13.18) years, 596 (39.3%) and 4113 (19.8%) participants developed a primary outcome in T1D and type 2 diabetes, respectively. After full adjustment for conventional risk factors, Cox regression models showed significant associations between individual as well as cumulative MacroVCs and the primary outcome, except for coronary heart disease in T1D (T1D: diabetes coronary heart disease: 1.25 [0.98-1.60]; diabetes peripheral artery disease: 3.00 [1.86-4.84]; diabetes stroke: 1.71 [1.08-2.72]; ≥2: 2.57 [1.66-3.99]; type 2 diabetes: diabetes coronary heart disease: 1.59 [1.38-1.82]; diabetes peripheral artery disease: 1.60 [1.01-2.54]; diabetes stroke: 1.50 [1.13-1.99]; ≥2: 2.66 [1.92-3.68]). Subgroup analysis showed that strict glycemic (glycated hemoglobin <6.5%) and blood pressure (<140/90 mm Hg) control attenuated the association. CONCLUSIONS: Individual and cumulative MacroVCs confer significant risk of incident microvascular complications in patients with T1D and type 2 diabetes. Our results may facilitate cost-effective high-risk population identification and development of precise prevention strategies.

Cross-sectional association of continuous glucose monitoring-derived metrics with cerebral small vessel disease in older adults with type 2 diabetes.

AIM: To examine cross-sectional associations between continuous glucose monitoring (CGM)-derived metrics and cerebral small vessel disease (SVD) in older adults with type 2 diabetes. MATERIALS AND METHODS: In total, 80 patients with type 2 diabetes aged ≥70 years were analysed. Participants underwent CGM for 14 days. From the CGM data, we derived mean sensor glucose, percentage glucose coefficient of variation, mean amplitude of glucose excursion, time in range (TIR, 70-180 mg/dl), time above range (TAR) and time below range metrics, glycaemia risk index and high/low blood glucose index. The presence of cerebral SVD, including lacunes, microbleeds, enlarged perivascular spaces and white matter hyperintensities, was assessed, and the total number of these findings comprised the total cerebral SVD score (0-4). Ordinal logistic regression analyses were performed to examine the association of CGM-derived metrics with the total SVD score. RESULTS: The median SVD score was 1 (interquartile range 0-2). Higher hyperglycaemic metrics, including mean sensor glucose, TAR >180 mg/dl, TAR >250 mg/dl, and high blood glucose index and glycaemia risk index, were associated with a higher total SVD score. In contrast, a higher TIR (per 10% increase) was associated with a lower total SVD score (odds ratio 0.73, 95% confidence interval 0.56-0.95). Glycated haemoglobin, percentage glucose coefficient of variation, mean amplitude of glucose excursions, time below range and low blood glucose index were not associated with total cerebral SVD scores. CONCLUSIONS: The hyperglycaemia metrics and TIR, derived from CGM, were associated with cerebral SVD in older adults with type 2 diabetes.