The Lipidomic Profile Is Associated with the Dietary Pattern in Subjects with and without Diabetes Mellitus from a Mediterranean Area.

Lipid functions can be influenced by genetics, age, disease states, and lifestyle factors, particularly dietary patterns, which are crucial in diabetes management. Lipidomics is an expanding field involving the comprehensive exploration of lipids from biological samples. In this cross-sectional study, 396 participants from a Mediterranean region, including individuals with type 1 diabetes (T1D), type 2 diabetes (T2D), and non-diabetic individuals, underwent lipidomic profiling and dietary assessment. Participants completed validated food frequency questionnaires, and lipid analysis was conducted using ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC/MS). Multiple linear regression models were used to determine the association between lipid features and dietary patterns. Across all subjects, acylcarnitines (AcCa) and triglycerides (TG) displayed negative associations with the alternate Healthy Eating Index (aHEI), indicating a link between lipidomic profiles and dietary habits. Various lipid species (LS) showed positive and negative associations with dietary carbohydrates, fats, and proteins. Notably, in the interaction analysis between diabetes and the aHEI, we found some lysophosphatidylcholines (LPC) that showed a similar direction with respect to aHEI in non-diabetic individuals and T2D subjects, while an opposite direction was observed in T1D subjects. The study highlights the significant association between lipidomic profiles and dietary habits in people with and without diabetes, particularly emphasizing the role of healthy dietary choices, as reflected by the aHEI, in modulating lipid concentrations. These findings underscore the importance of dietary interventions to improve metabolic health outcomes, especially in the context of diabetes management.

Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus.

BACKGROUND: In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state. METHODS: An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D. RESULTS: A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D. CONCLUSIONS: Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes.

Low adherence to the Mediterranean diet is associated with increased prevalence and number of atherosclerotic plaques in the ILERVAS cohort.

BACKGROUND AND AIMS: Current research on the association between dietary patterns and subclinical atherosclerotic disease (SAD) is still limited, and published results are inconsistent and often consist of small population sizes. We aimed to evaluate the association between the Mediterranean diet (MDiet) and SAD in a large cohort of Mediterranean individuals. METHODS: This was a cross-sectional study that included 8116 subjects from the ILERVAS cohort. The presence of atherosclerotic plaques (AP) was assessed by ultrasound examination. Adherence to the MDiet was assessed using the 14-item Mediterranean Diet Adherence Score (MEDAS). Inclusion criteria were subjects with at least one cardiovascular risk factor. Exclusion criteria were a clinical history of diabetes, chronic kidney disease, or a prior cardiovascular event. Bivariable and multivariable models were performed. RESULTS: Compared with subjects without SAD, participants with SAD were older and had a higher frequency of smoking habit, hypertension, dyslipidemia, HbA1c and waist circumference. The adjusted multivariable analysis showed that a higher MEDAS was associated with a lower risk of AP (incidence rate ratios [IRR] 0.97, 95% CI [0.96-0.98]; p<0.001). Furthermore, moderate or high adherence to the MDiet was associated with a lower number of AP compared with a low MDiet adherence (IRR 0.90, 95% CI [0.87-0.94]; p<0.001). In both models, female sex was associated with a lower risk of AP. CONCLUSIONS: Our findings point to a potentially protective role of MDiet for SAD in a Mediterranean population with low-to-moderate cardiovascular risk. Further research is needed to establish a causal relationship between both variables.

Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes.

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14.

Atherosclerosis, a process in which macrophages play a key role, is accelerated in diabetes. Elevated concentrations of serum-oxidized low-density lipoproteins (oxLDL) represent a common feature of both conditions. The main goal of this study was to determine the contribution of oxLDL to the inflammatory response of macrophages exposed to diabetic-mimicking conditions. THP1 cells and peripheral blood monocytes purified from non-diabetic healthy donors were cultured under normal (5 mM) or high glucose (HG) (15 mM) with oxLDL. Then, foam cell formation, expression of CD80, HLADR, CD23, CD206, and CD163, as well as toll-like receptor 4 (TLR4) and co-receptors CD36 and CD14 (both at the cell surface and soluble (sCD14)), and inflammatory mediators' production were measured by flow cytometry, RT-qPCR, or ELISA. Additionally, serum sCD14 was determined in subjects with subclinical atherosclerosis with and without diabetes by ELISA. Our results showed that oxLDL-mediated intracellular lipid accumulation via CD36 increased under HG and that HG + oxLDL enhanced TNF, IL1B, and IL8, and decreased IL10. Moreover, TLR4 was upregulated in macrophages under HG and monocytes of subjects with diabetes and atherosclerosis. Interestingly, HG-oxLDL upregulated CD14 gene expression, although its total cellular protein abundance remained unaltered. sCD14 shedding via PRAS40/Akt-dependent mechanisms, with pro-inflammatory activity, was significantly increased in cultured macrophages and plasma from subjects with diabetes and subclinical atherosclerosis or hypercholesterolemia. Our data support an enhanced synergistic pro-inflammatory effect induced by HG and oxLDL in cultured human macrophages, possibly explained by increased sCD14 shedding.

Caffeine and the Risk of Diabetic Retinopathy in Type 2 Diabetes Mellitus: Findings from Clinical and Experimental Studies.

The aim of this study was to assess the potential benefits of caffeine intake in protecting against the development of diabetic retinopathy (DR) in subjects with type 2 diabetes (T2D). Furthermore, we tested the effect of topical administration of caffeine on the early stages of DR in an experimental model of DR. In the cross-sectional study, a total of 144 subjects with DR and 147 individuals without DR were assessed. DR was assessed by an experienced ophthalmologist. A validated food frequency questionnaire (FFQ) was administered. In the experimental model, a total of 20 mice were included. One drop (5 µL) of caffeine (5 mg/mL) (n = 10) or vehicle (5 µL PBS, pH 7.4) (n = 10) was randomly administered directly onto the superior corneal surface twice daily for two weeks in each eye. Glial activation and retinal vascular permeability were assessed using standard methods. In the cross-sectional study in humans, the adjusted-multivariable model showed that a moderate and high (Q2 and Q4) caffeine intake had a protective effect of DR (odds ratio (95% confidence interval) = 0.35 (0.16-0.78); p = 0.011 and 0.35 (0.16-0.77); p = 0.010, respectively). In the experimental model, the administration of caffeine did not improve either reactive gliosis or retinal vascular permeability. Our results suggest a dose-dependent protective effect of caffeine in the development of DR, while the potential benefits of antioxidants in coffee and tea should also be considered. Further research is needed to establish the benefits and mechanisms of caffeinated beverages in the development of DR.

Circulating metabolomic and lipidomic changes in subjects with new-onset type 1 diabetes after optimization of glycemic control.

AIMS: To uncover novel candidate metabolomic and lipidomic biomarkers in newly-diagnosed type 1 diabetes (T1DM) after achieving optimal glucose control. METHODS: Comprehensive lipidomic and metabolomic analysis was performed in serum of 12 adults with T1DM at onset and after achieving optimal glycemic control (HbA1c < 7 %) (after 2-6 months). RESULTS: After intensive therapy, subjects (mean age 25.2 years, 58.3 % men) showed decreases in blood glucose (p < 0.001), HbA1c [11.5 % (9.2-13.4) to 6.2 % (5.2 - 6.7); p < 0.001] and changes in 51 identified lipids. Among these changes, we found that triglycerides (TG) containing medium chain fatty acids (TG45:0, TG47:1), sphingomyelins (SM) (SM(d18:2/20:0), SM42:4)), and phosphatidylcholines (PC) (PC(O-26:2), PC(O-30:0), PC(O-32:0), PC(O-42:6), PC(O-44:5), PC(O-38:3), PC(O-33:0), PC(O-46:8), PC(O-44:6), PC(O-40:3), PC(O-42:4), PC(O-46:7), PC(O-46:6), PC(O-44:5), PC(O-42:3), PC(O-44:4)) decreased; whereas PC(35:1), PC(37:1) and TG containing longer chain fatty acids (TG(52:1), TG(55:7), TG(51:2), TG(53:3), TG52:2), TG(53:2), TG(57:3), TG(61:3), TG(61:2) increased. Further, dihydro O-acylceramide (18:1/18:0/16:0), diacylglycerophosphoethanolamine (PE(34:1)), diacylglycerophosphoinositol (PI(38:6), and dihydrosphingomyelins (dihydroSM(36:0), dihydroSM(40:0), dihydroSM(41:0), dihydroSM(42:0)) increased. Uric acid, mannitol, and mannitol-1-acetate levels also increased. CONCLUSIONS: Our data uncovered potential favorable changes in the metabolism of glycerophospholipids, glycerolipids, and sphingolipids in new-onset T1DM after achieving optimal glycemic control. Further research on their potential role in developing diabetes-related complications is needed.

Circulating Small Noncoding RNA Profiling as a Potential Biomarker of Atherosclerotic Plaque Composition in Type 1 Diabetes.

OBJECTIVE: Cardiovascular disease (CVD) accounts for most deaths in patients with type 1 diabetes (T1D); however, the determinants of plaque composition are unknown. miRNAs regulate gene expression, participate in the development of atherosclerosis, and represent promising CVD biomarkers. This study analyzed the circulating miRNA expression profile in T1D with either carotid calcified (CCP) or fibrous plaque (CFP). RESEARCH DESIGN AND METHODS: Circulating small noncoding RNAs were sequenced and quantified using next-generation sequencing and bioinformatic analysis in an exploratory set of 26 subjects with T1D with CCP and in 25 with CFP. Then, in a validation set of 40 subjects with CCP, 40 with CFP, and 24 control subjects with T1D, selected miRNA expression was measured by digital droplet PCR. Putative gene targets enriched for pathways implicated in atherosclerosis/vascular calcification/diabetes were analyzed. The patients' main clinical characteristics were also recorded. RESULTS: miR-503-5p, let-7d-5p, miR-106b-3p, and miR-93-5p were significantly upregulated, while miR-10a-5p was downregulated in patients with CCP compared with CFP (all fold change >±1.5; P < 0.05). All candidate miRNAs showed a significant correlation with LDL-cholesterol, direct for the upregulated and inverse for the downregulated miRNA, in CCP. Many target genes of upregulated miRNAs in CCP participate in osteogenic differentiation, apoptosis, inflammation, cholesterol metabolism, and extracellular matrix organization. CONCLUSIONS: These findings characterize miRNAs and their signature in the regulatory network of carotid plaque phenotype in T1D, providing new insights into plaque pathophysiology and possibly novel biomarkers of plaque composition.

The novel inflammatory biomarker GlycA and triglyceride-rich lipoproteins are associated with the presence of subclinical myocardial dysfunction in subjects with type 1 diabetes mellitus.

BACKGROUND: Subjects with Type 1 diabetes mellitus (T1DM) have an increased incidence of heart failure (HF). Several pathophysiological mechanisms have been involved in its development. The aim of this study was to analyze the potential contribution of the advanced lipoprotein profile and plasma glycosylation (GlycA) to the presence of subclinical myocardial dysfunction in subjects with T1DM. METHODS: We included subjects from a Danish cohort of T1DM subjects (Thousand & 1 study) with either diastolic and/or systolic subclinical myocardial dysfunction, and a control group without myocardial dysfunction, matched by age, sex and HbA1c. All underwent a transthoracic echocardiogram and an advanced lipoprotein profile obtained by using the NMR-based Liposcale® test. GlycA NMR signal was also analyzed. Systolic dysfunction was defined as left ventricular ejection fraction ≤ 45% and diastolic dysfunction was considered as E/e'≥12 or E/e' 8-12 + volume of the left atrium > 34 ml/m2. To identify a metabolic profile associated with the presence of subclinical myocardial dysfunction, a multivariate supervised model of classification based on least squares regression (PLS-DA regression) was performed. RESULTS: One-hundred forty-six subjects had diastolic dysfunction and 18 systolic dysfunction. Compared to the control group, patients with myocardial dysfunction had longer duration of diabetes (p = 0.005), and higher BMI (p = 0.013), serum NTproBNP concentration (p = 0.001), systolic blood pressure (p < 0.001), albuminuria (p < 0.001), and incidence of advanced retinopathy (p < 0.001). The supervised classification model identified a specific pattern associated with myocardial dysfunction, with a capacity to discriminate patients with myocardial dysfunction from controls. PLS-DA showed that triglyceride-rich lipoproteins (TGRLs), such as VLDL (total VLDL particles, large VLDL subclass and VLDL-TG content) and IDL (IDL cholesterol content), as well as the plasma concentration of GlycA, were associated with the presence of subclinical myocardial dysfunction. CONCLUSION: Proatherogenic TGRLs and the proinflammatory biomarker Glyc A are strongly associated to myocardial dysfunction in T1DM. These findings suggest a pivotal role of TGRLs and systemic inflammation in the development of subclinical myocardial dysfunction in T1DM.

Diabetic retinopathy predicts cardiovascular disease independently of subclinical atherosclerosis in individuals with type 2 diabetes: A prospective cohort study.

Background: Diabetic retinopathy (DR) and preclinical atherosclerosis are associated with higher cardiovascular risk. However, no studies have investigated the predictive role of DR and preclinical atherosclerosis jointly on cardiovascular events in subjects with type 2 diabetes (T2D). We aimed to assess the contribution of DR and subclinical atherosclerosis on the risk of adverse cardiovascular events in subjects with T2D without previous cardiovascular disease (CVD). Methods: We included two prospective cohorts of subjects with T2D from the same geographical area. Assessment of subclinical atherosclerosis was performed by carotid ultrasound. An ophthalmologist classified DR according to standard criteria. Cardiovascular outcomes considered for analysis were the following: ischemic heart disease, stroke, heart failure, peripheral artery disease, revascularization procedures, and cardiovascular mortality. Bivariable and multivariable predictive models were performed. Results: From a total of 374 subjects with T2D 44 developed cardiovascular events during the 7.1 years of follow-up. Diabetes duration, total cholesterol, and glycated hemoglobin (HbA1c) at baseline were higher in subjects who developed cardiovascular outcomes (p < 0.001, p = 0.026, and p = 0.040, respectively). Compared with subjects without events, those developing cardiovascular events had higher prevalence of retinopathy (65.9% vs. 38.8%, p = 0.001; respectively) and more than mild retinopathy (43.2% vs. 31.8%, p = 0.002; respectively). Furthermore, all-cause mortality was higher in subjects with MACE than those without events (13.6% vs. 3.3%, p = 0.009; respectively). The multivariable analyses showed that HbA1c and the presence of DR at baseline were predictive of cardiovascular outcomes (p = 0.045 and p = 0.023, respectively). However, the burden of subclinical atherosclerosis was not (p = 0.783 and p = 0.071, respectively). Conclusion: DR is a strong predictor of cardiovascular events in T2D individuals at primary CVD prevention, even after accounting for the presence of preclinical carotid atherosclerosis. These results may help to individualize CVD prevention strategies in T2D.

Association of α-klotho with subclinical carotid atherosclerosis in subjects with type 1 diabetes mellitus.

BACKGROUND: Compelling evidence suggests that the fibroblast growth factor 23 (FGF23) / α-klotho axis is impaired in subjects with diabetes mellitus. We examined the relationship between parameters related to calcium/phosphate homeostasis, including FGF23 and α-klotho, and subclinical carotid atherosclerosis burden in type 1 diabetes mellitus (T1D) subjects. METHODS: This cross-sectional study involved 226 subjects with T1D and 147 age-, sex- and plaque-matched, non-diabetic (non-T1D) subjects, both with normal renal function. Carotid ultrasound was performed to determine the presence and burden of atheromatous plaques. Concentrations of the intact form of FGF23 and α-klotho were assessed by ELISA. Calcium, phosphate, parathyroid hormone, and vitamin D levels were also determined. Negative binomial regression models were used to examine relationship between parameters studied and subclinical carotid atherosclerosis. RESULTS: Only FGF23 was increased in T1D compared with non-diabetic subjects (> 2-fold; p < 0.05). α-klotho was higher in subjects with subclinical carotid atherosclerosis (1.4-fold, p < 0.05). Regression analysis revealed that the log α-klotho concentration was positively associated with the presence of subclinical carotid atherosclerosis both in T1D subjects (incidence rate ratio [IRR]: 1.41; 95% confidence interval [CI], 1.06-1.89; p < 0.05) and in non-T1D subjects (IRR: 1.65; 95% CI, 1.02-2.75; p < 0.05). The models also showed that age, smoking and albuminuria-to-creatinine ratio were positively associated with subclinical carotid atherosclerosis in T1D subjects. Interestingly, sex-related protection against plaque was also revealed in T1D women. CONCLUSION: Higher α-klotho was associated with subclinical carotid atherosclerotic in the absence of kidney dysfunction. This finding also points to a new pathophysiological pathway involved in the development and progression of this complication.

Predictive Value of the Advanced Lipoprotein Profile and Glycated Proteins on Diabetic Retinopathy.

This study aimed to assess whether the advanced characteristics of serum lipoprotein subclasses could better predict the risk of developing diabetic retinopathy (DR) and its severity compared to other established risk factors in subjects with type 1 (T1D) and type 2 (T2D) diabetes. This observational, cross-sectional substudy analyzed DR-related data from 309 T1D and 264 T2D subjects. The advanced lipoprotein and glycoprotein profile was determined by nuclear magnetic resonance (NMR) spectroscopy (Liposcale test). NMR analysis of lipoproteins revealed that T1D subjects with DR showed standard non-HDL particles, despite higher IDL lipid concentrations. Notably, IDL lipids were elevated in T1D subjects with worsened DR. VLDL and LDL were smaller, whereas HDL triglycerides were increased in DR compared with non-DR. On the other hand, the T2D subjects with DR showed altered characteristics in the LDL fraction, mainly revealed by a significant decrease in smaller LDL and a reduction in LDL-C. Moreover, the glycoprotein profile did not reveal significant changes among DR groups, regardless of the type of diabetes. However, lipoprotein characteristics and glycoproteins unveiled by NMR analysis did not improve the predictive value of conventional lipids or other traditional, well-established biomarkers of DR in our cohorts.

Diabetic retinopathy as a predictor of cardiovascular morbidity and mortality in subjects with type 2 diabetes.

This study aimed to evaluate the predictive value of diabetic retinopathy (DR) and its stages with the incidence of major cardiovascular events and all-cause mortality in type 2 diabetes mellitus (T2DM) persons in our large primary healthcare database from Catalonia (Spain). A retrospective cohort study with pseudo-anonymized routinely collected health data from SIDIAP was conducted from 2008 to 2016. We calculated incidence rates of major cardiovascular events [coronary heart disease (CHD), stroke, or both-macrovascular events] and all-cause mortality for subjects with and without DR and for different stages of DR. The proportional hazards regression analysis was done to assess the probability of occurrence between DR and the study events. About 22,402 T2DM subjects with DR were identified in the database and 196,983 subjects without DR. During the follow-up period among the subjects with DR, we observed the highest incidence of all-cause mortally. In the second place were the macrovascular events among the subjects with DR. In the multivariable analysis, fully adjusted for DR, sex, age, body mass index (BMI), tobacco, duration of T2DM, an antiplatelet or antihypertensive drug, and HbA1c, we observed that subjects with any stage of DR had higher risks for all of the study events, except for stroke. We observed the highest probability of all-cause death events (adjusted hazard ratios, AHRs: 1.34, 95% CI: 1.28; 1.41). In conclusion, our results show that DR is related to CHD, macrovascular events, and all-cause mortality among persons with T2DM.

GlycA and GlycB as Inflammatory Markers in Chronic Heart Failure.

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.

Validation of dynamic risk stratification and impact of BRAF in risk assessment of thyroid cancer, a nation-wide multicenter study.

Introduction: The dynamic risk stratification (DRS) is a relatively new system in thyroid cancer that considers the response to primary treatment to improve the initial risk of recurrence. We wanted to validate DRS system in a nationwide multicenter study and explore if the incorporation of BRAFV600E into DRS helps to better categorize and predict outcomes. Materials and methods: Retrospective study of 685 patients from seven centers between 1991 and 2016, with a mean age of 48 years and a median follow-up time of 45 months (range 23-77). The overall BRAFV600E prevalence was 53.4%. We classified patients into four categories based on DRS ('excellent', 'indeterminate', 'biochemical incomplete', and 'structural incomplete' response). Cox regression was used to calculate adjusted hazard ratios (AHR) and proportions of variance explained (PVEs). Results: We found 21.6% recurrences and 2.3% cancer-related deaths. The proportion of patients that developed recurrence in excellent, indeterminate, biochemical incomplete and structural incomplete response to therapy was 1.8%, 54%, 91.7% and 96.2% respectively. Considering the outcome at the end of the follow up, patients showed no evidence of disease (NED) in 98.2, 52, 33.3 and 25.6% respectively. Patients in the structural incomplete category were the only who died (17.7%). Because they have similar outcomes in terms of NED and survival, we integrated the indeterminate and biochemical incomplete response into one unique category creating the 3-tiered DRS system. The PVEs of the AJCC/TNM staging, ATA risk classification, 4-tiered DRS, and 3-tiered DRS to predict recurrence at five years were 21%, 25%, 57% and 59% respectively. BRAFV600E was significantly associated with biochemical incomplete response (71.1 vs 28.9%) (HR 2.43; 95% CI, 1.21 to 5.23; p=0.016), but not with structural incomplete response or distant metastases. BRAF status slightly changes the AHR values of the DRS categories but is not useful for different risk grouping. Conclusions: This is the first multicenter study to validate the 4-tiered DRS system. Our results also show that the 3-tiered DRS system, by integrating indeterminate and biochemical incomplete response into one unique category, may simplify response to therapy keeping the system accurate. BRAF status does not provide any additional benefit to DRS.

Advanced lipoprotein profile in individuals with normal and impaired glucose metabolism.

INTRODUCTION AND OBJECTIVES: Several types of lipoproteins beyond low-density lipoproteins (LDL) are causally related to cardiovascular disease. We aimed to analyze an advanced lipoprotein profile in individuals with normal and impaired glucose metabolism from different cohorts of a Mediterranean region. METHODS: Cross-sectional study in 929 participants (463 normoglycemia, 250 prediabetes, and 216 type 2 diabetes mellitus) with normal renal function, free from cardiovascular disease, and without lipid-lowering treatment. Conventional and advanced (nuclear magnetic resonance [NMR] spectroscopy) lipoprotein profiles were analyzed. RESULTS: Compared with men, normoglycemic women showed lower serum triglyceride and LDL cholesterol concentrations, lower total LDL particles (P) as well as their subclasses and their cholesterol and triglyceride content, higher high-density lipoproteins (HDL)-P and all HDL-related variables (P≤ .05 for all comparisons). Compared with normoglycemic participants, diabetic participants showed higher large and small very LDL-P concentrations (P <.05) and lower total HDL-P and medium HDL-P concentrations (P <.05). Waist circumference and Fatty Liver Index were positively associated with a proatherogenic profile. CONCLUSIONS: Women had a better advanced lipoprotein profile than did men. Adiposity indexes related to insulin-resistance were positively associated with a proatherogenic lipid profile. NMR revealed altered lipoprotein particles other than LDL in participants with diabetes, frequently associated with an increased cardiovascular risk. Our findings support the usefulness of extended lipoprotein analysis by NMR spectroscopy to uncover new therapeutic targets to prevent cardiovascular events in at-risk participants.

Advanced Quantitative Lipoprotein Characteristics Do Not Relate to Healthy Dietary Patterns in Adults from a Mediterranean Area.

We aimed to assess the potential relationship between dietary patterns (i.e., Mediterranean diet and healthy eating) and the advanced lipoprotein profile (ALP) in a representative cohort of the Mediterranean population. Thus, ALP data from 1142 participants, including 222 with type 1 (19.4%) and 252 type 2 diabetes (22.1%), and 668 subjects without diabetes were used to study cross-sectional associations between quantitative characteristics of lipoproteins and adherence to the Mediterranean diet. The alternate Mediterranean diet score (aMED) and the alternate healthy eating index (aHEI) were calculated. The ALP was determined by nuclear magnetic resonance (NMR) spectrometry. Bivariable and multivariable analyses were performed. Participants in the third tertile of the aMED showed higher levels of low-density lipoprotein triglycerides (LDL-TG) (mean (SD) 17.5 (5.0); p = 0.037), large high-density lipoprotein particles (HDL-P) (0.3 (0.1); p = 0.037), and medium low-density lipoprotein particles (LDL-P) (434.0 (143.0); p = 0.037). In comparison with participants in the second and first tertiles of the aHEI, participants in the third tertile had higher levels of LDL-TG (17.7 (5.0); p = 0.010), and large HDL-P (0.3 (0.1); p = 0.002), IDL-C (11.8 (5.0); p = 0.001), intermediate-density lipoprotein triglycerides (IDL-TG) (13.2 (4.2); p < 0.001), LDL-TG (17.7(5.0); p = 0.010), high-density lipoprotein triglycerides (HDL-TG) (14.5 (4.4); p = 0.029,) large HDL-P (0.3 (0.1); p = 0.002) and very-low-density lipoprotein particles (VLDL-P) size (42.1 (0.2); p = 0.011). The adjusted-multivariable analysis for potential confounding variables did not show any association between the lipoproteins and dietary patterns (i.e., aMED and aHEI). In conclusion, none of the quantitative characteristics of lipoproteins were concomitantly associated with the extent of adherence to the Mediterranean diet measured using the aMED or aHEI scores in the studied population. Our findings also revealed that people with the highest adherence were older, had a higher body mass index (BMI) and more frequently had dyslipidemia, hypertension, or diabetes than those with the lowest adherence to the Mediterranean diet (MDiet). Thus, further research may be needed to assess the potential role of the dietary pattern on the ALP.

Outstanding improvement of the advanced lipoprotein profile in subjects with new-onset type 1 diabetes mellitus after achieving optimal glycemic control.

AIMS: The impact of glycemic optimization on lipoprotein subfraction parameters in apparently normolipidemic subjects with new-onset type 1 diabetes mellitus (T1D) was examined. METHODS: We evaluated the serum lipid and advanced lipoprotein profiles in twenty subjects at onset of T1D and twenty non-diabetic controls by laboratory methods and 1H NMR spectroscopy shortly after diabetes diagnosis (baseline), and after achieving optimal glycemic control (HbA1c ≤ 7.0%). RESULTS: Advanced lipoprotein analysis revealed a significant reduction from baseline in serum concentrations of triglycerides (TG), cholesterol (C), and apolipoprotein (Apo)B-containing lipoproteins of treated subjects (VLDL-TG: -21%, IDL-TG: -30%, LDL-TG: -34%, LDL-TG: -36%, P < 0.05; VLDL-C: -23%, IDL-C: -44%, LDL-C: -16%; p < 0.05). Decreased VLDL and LDL lipids were mainly attributed to concomitant reductions in the concentration of medium-sized VLDL (-36%) and medium-sized LDL (-31%) and, to a lesser extent, to large-sized LDL (-14%). Notably, proatherogenic IDL characteristics and related surrogates of atherogenicity were resolved upon achievement of optimal glycemic status. Moreover, the concentration of HDL-TG was also reduced (-18%) at follow-up. CONCLUSIONS: Our data showed that the achievement of optimal glycemic control after T1D onset corrected hidden derangements in ApoB-containing lipoproteins (particularly IDL) and HDL-TG that are related to higher cardiovascular risk in poorly controlled T1D.

Circulating CD5L is associated with cardiovascular events and all-cause mortality in individuals with chronic kidney disease.

This study assessed the association of CD5L and soluble CD36 (sCD36) with the risk of a cardiovascular event (CVE), including CV death and all-cause mortality in CKD. We evaluated the association of CD5L and sCD36 with a predefined composite CV endpoint (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, congestive heart failure, arrhythmia, peripheral arterial disease [PAD] or amputation by PAD, aortic aneurysm, or death from CV causes) and all-cause mortality using Cox proportional hazards regression, adjusted for CV risk factors. The analysis included 1,516 participants free from pre-existing CV disease followed up for 4 years. The median age was 62 years, 38.8% were female, and 26.8% had diabetes. There were 98 (6.5%) CVEs and 72 (4.8%) deaths, of which 26 (36.1%) were of CV origin. Higher baseline CD5L concentration was associated with increased risk of CVE (HR, 95% CI, 1.17, 1.0-1.36), and all-cause mortality (1.22, 1.01-1.48) after adjusting for age, sex, diabetes, systolic blood pressure, dyslipidemia, waist circumference, smoking, and CKD stage. sCD36 showed no association with adverse CV outcomes or mortality. Our study showed for the first time that higher concentrations of CD5L are associated with future CVE and all-cause mortality in individuals with CKD.

1H-magnetic resonance spectroscopy lipoprotein profile in patients with chronic heart failure versus matched controls.

INTRODUCTION AND OBJECTIVES: Advanced lipoprotein phenotyping is a better predictor of atherosclerotic cardiovascular risk than cholesterol concentration alone. Lipoprotein profiling in heart failure (HF) is incompletely characterized. We aimed to describe the lipoprotein profile in patients with chronic HF compared with a matched control population. METHODS: This cross-sectional study was performed from May 2006 to April 2014 and included ambulatory patients with chronic HF. Lipid concentrations and the size of main lipoprotein fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein) and the particle concentration of their 3 subfractions (large, medium and small) were assessed using 1H magnetic resonance spectroscopy. RESULTS: The 429 included patients with chronic HF were compared with 428 matched controls. Patients with chronic HF had lower total cholesterol and lower mean LDL (1115 vs 1352 nmol/L; P<.001) and HDL (25.7 vs 27.9µmol/L; P <.001) particle concentrations, with this last difference being mediated by a significantly lower concentration of the small subfraction of HDL (15.2 vs 18.6µmol/L; P <.001). Mean very low-density lipoprotein, LDL, and HDL particle size was significantly higher in patients with HF vs controls. All HDL-related differences from controls persisted after adjustment for New York Heart Association functional class or body mass index. We found strong negative correlations of known cardiac biomarkers (N-terminal pro-brain natriuretic peptide and interleukin-1 receptor-like 1) with total and small LDL and HDL fractions and HDL particle size. CONCLUSIONS: Patients with chronic HF significantly differ in their lipoprotein profile compared with unaffected controls. Further research is needed to better understand the pathogenic relevance of this difference.