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Diabetes microangiopathy, a hallmark complication of diabetes, is characterised by structural and functional abnormalities within the intricate network of microvessels beyond well-known and documented target organs, i.e., the retina, kidney, and peripheral nerves. Indeed, an intact microvascular bed is crucial for preserving each organ’s specific functions and achieving physiological balance to meet their respective metabolic demands. Therefore, diabetes-related microvascular dysfunction leads to widespread multiorgan consequences in still-overlooked non-traditional target organs such as the brain, the lung, the bone tissue, the skin, the arterial wall, the heart, or the musculoskeletal system. All these organs are vulnerable to the physiopathological mechanisms that cause microvascular damage in diabetes (i.e., hyperglycaemia-induced oxidative stress, inflammation, and endothelial dysfunction) and collectively contribute to abnormalities in the microvessels’ structure and function, compromising blood flow and tissue perfusion. However, the microcirculatory networks differ between organs due to variations in haemodynamic, vascular architecture, and affected cells, resulting in a spectrum of clinical presentations. The aim of this review is to focus on the multifaceted nature of microvascular impairment in diabetes through available evidence of specific consequences in often overlooked organs. A better understanding of diabetes microangiopathy in non-target organs provides a broader perspective on the systemic nature of the disease, underscoring the importance of recognising the comprehensive range of complications beyond the classic target sites.

Cardiovascular diseases (CVDs) are the main cause of death among patients with type 2 diabetes mellitus (T2DM), particularly in low- and middle-income countries. To effectively prevent the development of CVDs in T2DM, considerable effort has been made to explore novel preventive approaches, individualized glycemic control and cardiovascular risk management (strict blood pressure and lipid control), together with recently developed glucose-lowering agents and lipid-lowering drugs. This review mainly addresses the important issues affecting the choice of antidiabetic agents and lipid, blood pressure and antiplatelet treatments considering the cardiovascular status of the patient. Finally, we also discuss the changes in therapy principles underlying CVDs in T2DM.

The initiation of this process involves endothelial dysfunction with the subendothelial deposition of modified lipoproteins, which are key for immune activation and the induction of vascular wall inflammation. [...]both lipoprotein metabolism and the inflammatory immune response play crucial roles in the initiation; perpetuation; and, eventually, resolution of the process [6]. [...]it has long been recognized that the metabolic and immune systems are among the most fundamental requirements for survival, and that this is why the respective pathways are closely related and evolutionarily preserved among species. [...]we may state that, in atherosclerosis, both the immune and metabolic pathways are fundamental parts of the etiopathogenetic process of atherosclerotic disease. Among those, we must consider an increased inflammatory innate immune response, including conditions related to aging, chronic kidney disease, obesity, hypertension, and type 2 diabetes. [...]all these factors, alone or in different proportions and combinations, are essential contributors nowadays that are closely linked to the appearance and progression of atherosclerosis globally.

Cardiovascular disease (CVD) remains the leading cause of mortality among people with type 1 diabetes (T1D), with cardiovascular mortality rates 2–5 times higher than in the general population. A concerning sex disparity exists within this high-risk population, as the cardioprotective advantage typically observed in women without diabetes appears attenuated or eliminated in individuals with T1D. This disparity is evident across the CVD spectrum, including coronary artery disease, stroke, heart failure, and cardiovascular mortality, with women consistently experiencing an excess burden of disease. These differences are particularly pronounced in women with early-onset T1D, leading to a substantial loss of life-years—approximately 18 years for women compared to 14 for men. Several factors may contribute to this sex disparity. First, the effect of hyperglycemia on CVD appears to have a sex-based differential impact and women with T1D often demonstrate more difficulties to achieve optimal glycemic control. Second, although women with T1D generally exhibit a more favorable CVD risk factor profile than men with T1D, the presence of hypertension, smoking or diabetic kidney disease seem to have a strong impact on CVD in women. Diabetes also appears to diminish sex-based differences in lipid metabolism, and a trend towards increased obesity rates among women with T1D has been observed. Lastly, female-specific factors, which are more prevalent in T1D, exacerbate cardiovascular risk. These include premature menopause, pregnancy-related disorders (such as preeclampsia), polycystic ovary syndrome, and autoimmune diseases, which disproportionately affect women. This narrative review examines the epidemiological evidence highlighting the aspects regarding the excess risk of CVD in women with T1D and evaluates sex disparities in both traditional and female-specific risk factors. Finally, we include a sex-based analysis from the Catalan Registry, which highlights the critical need for greater awareness and enhanced early detection and management of CVD risk factors in this population.

ObjectivesTo evaluate the prevalence and coprevalence of several chronic conditions in patients with type 2 diabetes in a Mediterranean region.DesignA cross-sectional study.SettingTwo hundred and eighty-six primary care teams of the Catalonian Health Institute (Catalonia, Spain).ParticipantsWe included patients aged ≥18 years with a diagnosis of type 2 diabetes by 31 December, 2016, who were registered in the Information System for the Development of Research in primary care (SIDIAP) database. We excluded patients with a diagnosis of type 1 diabetes, gestational diabetes mellitus and any other type of diabetes.Primary and secondary outcome measuresWe collected data on diabetes-related comorbidities (ie, chronic complications, associated cardiovascular risk factors and treatment complications). Diagnoses were based on the International Classification of Diseases, 10th Revision codes recorded in the database or, for some entities, on the cut-off points for a particular test result or a specific treatment indicated for that entity. The presence and stage of chronic kidney disease (CKD) were based on the glomerular filtration rate, the CKD Epidemiology Collaboration creatinine equation and the urine albumin-to-creatinine ratio.ResultsA total of 373 185 patients were analysed. 82% of patients exhibited ≥2 comorbidities and 31% exhibited ≥4 comorbidities. The most frequent comorbidities were hypertension (72%), hyperlipidaemia (60%), obesity (45%), CKD (33%), chronic renal failure (CRF)(28%) and cardiovascular disease (23%). The most frequently coprevalent pairs of chronic conditions were the combination of hypertension with hyperlipidaemia (45%), obesity (35%), CKD (28%), CRF (25%) or cardiovascular disease (19%), as well as the combination of hyperlipidaemia with obesity (28%), CKD (21%), CRF (18%) or cardiovascular disease (15%); other common pairs of comorbidities were obesity/CKD, obesity/CRF, hypertension/retinopathy, hypertension/albuminuria, hypertension/urinary tract infection, CVD/CRF and CVD/CKD, which were each present in more than 10% of patients.ConclusionPatients with type 2 diabetes have a high frequency of coprevalence of metabolic risk factors, cardiovascular disease and CKD and thus require an integrated management approach.

Aims/hypothesisMortality has declined in people with type 1 diabetes in recent decades. We examined how the pattern of decline differs by country, age and sex, and how mortality trends in type 1 diabetes relate to trends in general population mortality.MethodsWe assembled aggregate data on all-cause mortality during the period 2000–2016 in people with type 1 diabetes aged 0–79 years from Australia, Denmark, Latvia, Scotland, Spain (Catalonia) and the USA (Kaiser Permanente Northwest). Data were obtained from administrative sources, health insurance records and registries. All-cause mortality rates in people with type 1 diabetes, and standardised mortality ratios (SMRs) comparing type 1 diabetes with the non-diabetic population, were modelled using Poisson regression, with age and calendar time as quantitative variables, describing the effects using restricted cubic splines with six knots for age and calendar time. Mortality rates were standardised to the age distribution of the aggregate population with type 1 diabetes.ResultsAll six data sources showed a decline in age- and sex-standardised all-cause mortality rates in people with type 1 diabetes from 2000 to 2016 (or a subset thereof), with annual changes in mortality rates ranging from −2.1% (95% CI −2.8%, −1.3%) to −5.8% (95% CI −6.5%, −5.1%). All-cause mortality was higher for male individuals and for older individuals, but the rate of decline in mortality was generally unaffected by sex or age. SMR was higher in female individuals than male individuals, and appeared to peak at ages 40–70 years. SMR declined over time in Denmark, Scotland and Spain, while remaining stable in the other three data sources.Conclusions/interpretationAll-cause mortality in people with type 1 diabetes has declined in recent years in most included populations, but improvements in mortality relative to the non-diabetic population are less consistent.

The role of inflammation in heart failure (HF) has been extensively described, but it is uncertain whether inflammation exerts a different prognostic influence according to etiology. We aimed to examine the inflammatory state in chronic HF by measuring N-acetylglucosamine/galactosamine (GlycA) and sialic acid (GlycB), evolving proton nuclear magnetic resonance biomarkers of systemic inflammation, and explore their prognostic value in patients with chronic HF. The primary end point was a composite of all-cause death and HF readmission. A total of 429 patients were included. GlycB correlated with interleukin-1 receptor-like 1 in the whole cohort (r2 = 0.14, p = 0.011) and the subgroup of nonischemic etiology (r2 = 0.31, p <0.001). No association was found with New York Heart Association functional class or left ventricular ejection fraction. In patients with nonischemic HF (52.2%, n = 224), GlycA and GlycB exhibited significant association with the composite end point (hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.06 to 1.33, p = 0.004 and HR 2.13, 95% CI 1.43 to 3.13, p <0.001; respectively) and GlycB with HF readmission after multivariable adjustment (HR 2.25, 95% CI 1.54 to 3.30, p <0.001). GlycB levels were also associated with a greater risk of HF-related recurrent admissions (adjusted incidence rate ratio 1.33, 95% CI = 1.07 to 1.65, p = 0.009). None of the markers were associated with the clinical end points in patients with ischemic HF. In conclusion, GlycA and GlycB represent an evolving approach to inflammation status with prognostic value in long-term outcomes in patients with nonischemic HF.

Background Patients with diabetes mellitus (DM) have an increased risk of developing heart failure (HF). Further, DM is associated with poor prognosis in patients with HF. Our aim was to determine whether DM has any impact on the predictive value of a multi-biomarker panel in patients with HF. Methods We included 1069 consecutive ambulatory HF patients in the study: age 66.2 ± 12.8 years, 33.5 ± 13.3 left ventricular ejection fraction, 36% diabetic patients. We measured serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), ST2, galectin-3, high-sensitivity C reactive protein (hs-CRP), cystatin-C, soluble transferrin receptor (sTfR), and neprilysin and followed patients for 4.9 ± 2.8 years. Primary endpoints were all-cause and cardiovascular death. Results During follow-up, 534 patients died; 283 died of cardiovascular causes. Diabetic subjects had higher mortality (57.7 vs. 45.6%, p  < 0.001). NTproBNP ( p  = 0.07), hs-TnT ( p  < 0.001), galectin-3 ( p  < 0.001), and cystatin-C ( p  = 0.001) concentrations were higher in diabetic patients, whereas sTfR levels were lower ( p  = 0.005). There were no interactions between DM and NTproBNP, hs-TnT, galectin-3, hs-CRP, cystatin-C, sTfR, and neprilysin relative to risk prediction for all-cause or cardiovascular death. By contrast, ST2 significantly interacted with DM for all-cause ( p  = 0.02) and cardiovascular ( p  = 0.03) death. In diabetic patients, HRs for ST2 were 1.27 (95% CI 1.16–1.40, p  < 0.001) and 1.23 (95% CI 1.09–1.39, p  = 0.001) for all-cause and cardiovascular death, respectively. In nondiabetic patients, HRs for ST2 were 1.53 (95% CI 1.35–1.73, p  < 0.001) and 1.64 (95% CI 1.31–2.05, p  < 0.001) for all-cause and cardiovascular death, respectively. The multivariable Cox regression analysis showed that hs-TnT and ST2 were the only markers that were independently associated with both all-cause and cardiovascular mortality in patients with HF and diabetes. Moreover, in these patients, the combination of these two markers significantly increased discrimination as assessed by the area under the curve. Conclusions Biomarkers used in the general population to predict the clinical course of heart failure are also useful in patients with diabetes. In these patients, among all the biomarkers analysed only hs-TnT and ST2 were independently associated with both all-cause and cardiovascular mortality.

Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification, but the precise mechanisms are not fully elucidated. We aimed to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We examined the expression of CD36, pro-inflammatory cytokines, endoplasmic reticulum (ER) stress markers, and mineralization-regulating enzymes by RT-PCR in human VSMCs, cultured in a medium containing normal (5 mM) or high glucose (22 mM) for 72 h with or without oxidized low-density lipoprotein (oxLDL) (24 h). The uptake of 1,1′-dioctadecyl-3,3,3′,3-tetramethylindocarbocyanine perchlorate-fluorescently (DiI) labeled oxLDL was quantified by flow cytometry and fluorimetry and calcification assays were performed in VSMC cultured in osteogenic medium and stained by alizarin red. We observed induction in the expression of CD36, cytokines, calcification markers, and ER stress markers under high glucose that was exacerbated by oxLDL. These results were confirmed in carotid plaques from subjects with diabetes versus non-diabetic subjects. Accordingly, the uptake of DiI-labeled oxLDL was increased after exposure to high glucose. The silencing of CD36 reduced the induction of CD36 and the expression of calcification enzymes and mineralization of VSMC. Our results indicate that CD36 signaling is partially involved in hyperglycemia and oxLDL-induced vascular calcification in diabetes.

Patients with Type 1 Diabetes (T1DM) have a higher risk of cardiovascular disease. This study used carotid ultrasound to identify subclinical carotid plaques and Optical Coherence Tomography (OCT) to evaluate ophthalmological markers as predictors of carotid plaque presence in 242 adults with T1DM, employing machine learning models for early risk assessment. Individuals with carotid plaques ( N  = 67) did not show significant differences in retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) and inner plexiform layer (IPL) complex compared to those without ( N  = 175). However, subfoveal and temporal choroidal area thickness significantly decreased in individuals with plaques ( P  ≤ 0.01). Machine learning identified age, hypertension, dyslipidemia, smoking, and diabetic retinopathy as key predictors for plaque presence, while ophthalmological measures made a modest contribution. Choroidal thickness exhibited an inverse relationship with plaque risk. Despite robust accuracy and high specificity (82–85% and 92–98%, respectively), the models were overly conservative in predicting positive instances (balanced accuracy of 0.60 for the left eye and 0.71 for the right eye). If further validated, choroidal thickness could complement traditional risk factors as an early marker of CV risk in T1DM patients. Integrating this measure in specialized clinical settings could help identify individuals who may need additional cardiovascular assessments.