PCSK9 plasma concentration is associated with epicardial adipose tissue volume and metabolic control in patients with type 1 diabetes.

Patients with type 1 diabetes (T1D) have a greater risk of cardiovascular disease. Proconvertase subtilisin-kexin 9 (PCSK9) is involved in the atherosclerosis process. This study aimed to determine the relationship between PCSK9 levels and epicardial adipose tissue (EAT) volume and cardiometabolic variables in patients with T1D. This was an observational cross-sectional study including 73 patients with T1D. Clinical, biochemical and imaging data were collected. We divided the patients into two groups according to their glycemic control and the EAT index (iEAT) percentile. We performed a correlation analysis between the collected variables and PCSK9 levels; subsequently, we performed a multiple regression analysis with the significant parameters. The mean age was 47.6 ± 8.5 years, 58.9% were men, and the BMI was 26.9 ± 4.6 kg/m2. A total of 31.5%, 49.3% and 34.2% of patients had hypertension, dyslipidemia and smoking habit, respectively. The PCSK9 concentration was 0.37 ± 0.12 mg/L, which was greater in patients with worse glycemic control (HbA1c > 7.5%), dyslipidemia and high EAT volume (iEAT > 75th percentile). The PCSK9 concentration was positively correlated with age (r = 0.259; p = 0.027), HbA1c (r = 0.300; p = 0.011), insulin dose (r = 0.275; p = 0.020), VLDL-C level (r = 0.331; p = 0.004), TG level (r = 0.328; p = 0.005), and iEAT (r = 0.438; p < 0.001). Multiple regression analysis revealed that 25% of the PCSK9 variability was explained by iEAT and HbA1c (p < 0.05). The PCSK9 concentration is associated with metabolic syndrome parameters, poor glycemic control and increased EAT volume in patients with T1D.

Cardiovascular Disease in Type 1 Diabetes Mellitus: Epidemiology and Management of Cardiovascular Risk.

Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes mellitus (T1DM) patients, and cardiovascular risk (CVR) remains high even in T1DM patients with good metabolic control. The underlying mechanisms remain poorly understood and known risk factors seem to operate differently in T1DM and type 2 diabetes mellitus (T2DM) patients. However, evidence of cardiovascular risk assessment and management in T1DM patients often is extrapolated from studies on T2DM patients or the general population. In this review, we examine the existing literature about the prevalence of clinical and subclinical CVD, as well as current knowledge about potential risk factors involved in the development and progression of atherosclerosis in T1DM patients. We also discuss current approaches to the stratification and therapeutic management of CVR in T1DM patients. Chronic hyperglycemia plays an important role, but it is likely that other potential factors are involved in increased atherosclerosis and CVD in T1DM patients. Evidence on the estimation of 10-year and lifetime risk of CVD, as well as the efficiency and age at which current cardiovascular medications should be initiated in young T1DM patients, is very limited and clearly insufficient to establish evidence-based therapeutic approaches to CVD management.

Publisher Correction: Soluble LRP1 is an independent biomarker of epicardial fat volume in patients with type 1 diabetes mellitus.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Associations between epicardial adipose tissue, subclinical atherosclerosis and high-density lipoprotein composition in type 1 diabetes.

BACKGROUND: The pathophysiology of cardiovascular complications in people with type 1 diabetes (T1DM) remains unclear. An increase in epicardial adipose tissue (EAT) and alterations in the composition of high-density lipoprotein (HDL) are associated with coronary artery disease, but information on its relationship in T1DM is very limited. Our aim was to determine the association between EAT volume, subclinical atherosclerosis, and HDL composition in type 1 diabetes. METHODS: Seventy-two long-term patients with T1DM without clinical atherosclerosis were analyzed. EAT volume and subclinical atherosclerosis were measured using cardiac computed tomography angiography. EAT was adjusted according to body surface to obtain an EAT index (iEAT). HDL composition was determined. RESULTS: The mean iEAT was 40.47 ± 22.18 cc/m2. The bivariate analysis showed positive associations of the iEAT with gender, age, hypertension, dyslipidemia, smoking, body mass index, waist circumference, insulin dose, and triglyceride (P < 0.05). The iEAT correlated positively with small HDL, increased content of apolipoprotein (apo)A-II and apoC-III, and decreased content of apoE and free cholesterol. Multiple linear regression showed that age, apoA-II content in HDL, and waist circumference were independently associated with the iEAT. Fifty percent of the patients presented subclinical atherosclerotic lesions. These patients had a higher iEAT, and their HDL contained less cholesterol and more apoA-II and lipoprotein-associated phospholipase A2 than patients without subclinical atherosclerosis. CONCLUSION: Alterations in the composition of HDL in TIDM are associated with increased iEAT and the presence of subclinical atherosclerosis. We propose that these abnormalities of HDL composition could be useful to identify T1DM patients at highest cardiovascular risk.

Soluble LRP1 is an independent biomarker of epicardial fat volume in patients with type 1 diabetes mellitus.

Epicardial adipose tissue (EAT) is a metabolically active tissue intimately associated with metabolic syndrome and cardiovascular disease. Quantification of EAT volume is an interesting clinical tool for the evaluation of cardiometabolic disease. Nevertheless, current methodology presents serious disadvantages. The soluble form of the receptor LRP1 (sLRP1) is a non-invasive biomarker of EAT in general population. Here, we analysed the potential of circulating sLRP1 as biomarker of EAT volume in patients with type 1 diabetes mellitus (T1DM). The study included a well-characterized cohort of T1DM patients without clinical cardiovascular disease (N = 73). EAT volume was assessed by a multidetector computed tomography (MDCT). sLRP1 and panel of inflammatory and endocrine mediators were measured using commercially available ELISA. EAT volume showed a direct association with circulating sLRP1 (ß = 0.398, P = 0.001) in univariate linear regression analysis. This association was higher than that observed for other potential inflammatory and endocrine biomarkers. Using multivariate linear regression analyses, we demonstrated that the association between EAT volume and circulating sLRP1 was independent of potential confounding factors, including age, sex, body mass index, CRP, HbA1c and LDL-C (P < 0.050 for all multivariate linear regression models). In conclusion, sLRP1 is an independent biomarker of EAT in T1DM patients.

Hypertriglyceridemic waist in type 1 diabetes patients: prevalence and related factors.

BACKGROUND: The hypertriglyceridemic waist has been linked to a higher number of cardiovascular risk factors and a greater probability of developing diabetes and cardiovascular disease. Around 50% of individuals with type 1 diabetes (T1D) are overweight or obese and triglyceridemia is associated with the onset of micro- and macrovascular complications. METHODS: A cross-sectional study was conducted in men with T1D to assess the association between the prevalence of hypertriglyceridemic waist and cardiovascular risk factors and hypogonadism. Triglyceride levels + abdominal circumference taken together were stratified into quartiles to identify the hypertriglyceridemic waist phenotype. RESULTS: One hundred and eighty-one male patients were included. An increased prevalence of hypogonadism and hypertension in parallel to increased triglyceride + waist circumference quartile was observed. Patients in the highest quartile had higher insulin resistance measured by estimated glucose disposal rate (eGDR 7.8±2.1 mg/kg-1.min-1 in 1st quartile vs. 5.8±1.8 mg/kg-1.min-1 in 4th quartile, P=0.000), insulin requirements, hip circumference, percentage of fat mass, glycosilated hemoglobin and total and LDL cholesterol as well as lower levels of total testosterone (27.24±9.3 nmol/L in 1st quartile vs. 17.4±8 nmol/L in 4th quartile, P=0.000) and HDL cholesterol. An inverse relationship was found between triglycerides + waist circumference and total testosterone levels (R=-0.367, P<0.0001). CONCLUSIONS: The hypertriglyceridemic waist in men with T1D is associated with an atherogenic lipid profile, hypertension, worse metabolic diabetes control, increased insulin resistance and a higher prevalence of hypogonadism.

Testosterone undecanoate improves lipid profile in patients with type 1 diabetes and hypogonadotrophic hypogonadism.

Testosterone deficiency (Td) has been associated with the metabolic syndrome. Few studies have evaluated this condition in type 1 diabetes (T1D). The primary aim of this study was to evaluate the effectiveness of testosterone undecanoate (TU) on insulin sensitivity, glycemic control, anthropometric parameters, blood pressure and lipid profile in patients with Td and T1D. We performed a randomized placebo-controlled multicenter study. INCLUSION CRITERIA: a) age ≥ 18 years; b) autoimmune diabetes; c) Td (total testosterone <10 nmol/L or calculated free testosterone <225 pmol/L and low/normal LH; d) ability to sign informed consent; e) comply with the study protocol. EXCLUSION CRITERIA: a) pituitary tumor, empty sella, hyperprolactinemia, panhypopituitarism or secondary hypogonadism; b) contraindications for treatment with testosterone undecanoate (TU); c) patients who did not agree to sign their informed consent. Six patients were randomly assigned to testosterone undecanoate (TU) treatment and 7 to placebo with the following dosing schedule: baseline, 6 weeks and 16 weeks. Blood test, anthropometric parameters, blood pressure and insulin sensitivity were determined at baseline, 6, 16 and 22 weeks. No differences were observed regarding insulin sensitivity, HbA1c or basal glucose, anthropometric parameters or blood pressure. At 22 weeks, the decrease in total cholesterol was 37.4 ± 27.5 mg/dL in the TU group compared with an increase of 13.2 ± 17.8 mg/dL in the placebo group (P<0.005), and LDL cholesterol concentration decreased 30.2 ± 22.1 mg/dL, compared with an increase of 10.5 ± 13.4 mg/dL in the placebo group (P=0.004). We conclude that treatment with TU in patients with T1D and Td improves lipid profile, with no effects on metabolic control or anthropometric parameters.

Control glucémico y complicaciones crónicas a 20 años del comienzo de la diabetes tipo 1. Resultados de una unidad especializada / Blood glucose control and complications at 20 years from onset of type 1 diabetes. Results from a specialist unit

OBJETIVOS: Conocer en un grupo de pacientes con diabetes tipo 1 (DM1) de larga evolución la prevalencia de complicaciones tardías y su relación con el control glucémico desde el diagnóstico, así como la prevalencia y control de los factores de riesgo cardiovascular (FRCV). MATERIAL Y MÉTODOS: Pacientes con comienzo de DM1 entre 1985 y 1994, seguidos en nuestro centro. Se recogieron datos antropométricos, de control glucémico, complicaciones crónicas y FRCV al comienzo y anualmente, mediante revisión de la historia clínica. Se realizó además una visita con examen físico y extracción de muestra de sangre. RESULTADOS: Participaron 77 pacientes (46 varones, edad 47 ± 8,5 años, tiempo de evolución 22,4 ± 2,2 años). Dieciséis pacientes (20,4%) desarrollaron retinopatía, 8 (10,4%) nefropatía, 12 (15,6%) polineuropatía y 3 (3,9%) macroangiopatía. Presentaban hipertensión arterial, dislipidemia y obesidad un 28,6, un 46,8 y un 20,8%, respectivamente. El 22,1% de ellos eran sedentarios y el 35,1%, fumadores. La hemoglobina glucosilada (HbA1c) media durante todo el período de seguimiento fue 7,2 ± 0,8%, en los primeros 5 años 6,4 ± 1,2% y en la visita del estudio 7,6 ± 1,1%. El 70% de los pacientes se mantuvieron dentro de objetivos en los primeros 5 años, el 45% en los 5 años siguientes y alrededor del 25% a partir de los 10 años de evolución. Los pacientes sin complicaciones tenían mejor control glucémico global (HbA1c7,0 ± 0,7% vs. 7,6 ± 0,9%; p = 0,003) y en los primeros 5 años (HbA1c 6,1 ± 0,9 vs. 7,0 ± 1,4%; p = 0,001). CONCLUSIÓN: La prevalencia de complicaciones a los 20 años en pacientes con DM1 bien controlados desde el diagnóstico es baja y está relacionada con el control glucémico global durante el seguimiento y los primeros años de la enfermedad. La prevalencia de fumadores es elevada. OBJECTIVES: To determine the prevalence of chronic complications in a group of patients with long duration type 1 diabetes (DM1), and their relationship with glycemic control since diagnosis of disease, as well as control and prevalence of cardiovascular risk factors (CVRF)

OBJECTIVES: To determine the prevalence of chronic complications in a group of patients with long duration type 1 diabetes (DM1), and their relationship with glycemic control since diagnosis of disease, as well as control and prevalence of cardiovascular risk factors (CVRF). MATERIAL AND METHODS: The study included patients diagnosed in our center between 1985 and 1994 and followed-up until the present. Anthropometric data, glycemic control, chronic complications, and CVRF were collected from medical records at baseline and annually. A visit was made that included a physical examination and complete blood analysis. RESULTS: A total of 77 patients were studied (46 males, and mean age 47 ± 8.5 years, duration of follow-up, 22.4 ± 2.2 years). Sixteen patients (20.4%) developed retinopathy, 8 (10.4%) nephropathy, 12 (15.6%) polyneuropathy, and 3 (3.9%) macroangiopathy. Hypertension, dyslipidemia and obesity were found in 28.6%, 46.8% and 20.8%, respectively, and 22.1% were sedentary, and 35.1% were smokers. Mean glycosylated hemoglobin (HbA1c) during the entire follow-up was 7.2 ± 0.8%. In the first five years it was 6.4 ± 1.2% and at the study visit, it was 7.6 ± 1.1%. More than two-thirds (70%) of patients remained on target in the first five years, with 45% in the next five years, and about 25% from years 10 to 22. Patients with no complications showed better glycemic control during the entire follow-up (HbA1c 7.0 ± 0.7% vs. 7.6 ± 0.9%; P=.003), and also in the first five years (HbA1c 6.1 ± 0.9 vs. 7.0 ± 1.4%; P=.001). CONCLUSION: Prevalence of complications after 20 years of follow-up in well controlled DM1 since diagnosis is low, and is related to the overall glycemic control during follow-up and in the early years of the disease. The prevalence of smoking is high

Age, insulin requirements, waist circumference, and triglycerides predict hypogonadotropic hypogonadism in patients with type 1 diabetes.

INTRODUCTION: The prevalence of hypogonadotropic hypogonadism (HH) in patients with type 2 diabetes mellitus is higher than in the general population and leads to detrimental effects on metabolic control, lipid profile, and body composition. Few studies have examined its role in type 1 diabetes mellitus. AIM: To determine the prevalence of HH in patients with type 1 diabetes and associated risk factors. MAIN OUTCOME MEASURES: Clinical and biochemical parameters were gathered on initial evaluation. An HH score creating different experimental models was devised to calculate the risk of HH for an individual with type 1 diabetes. METHODS: Cross-sectional study of 181 male patients with type 1 diabetes consecutively admitted to the Diabetes outpatient clinics of three urban hospitals. All participants were Caucasians aged ≥ 18 years with type 1 diabetes duration of more than 6 months. RESULTS: One hundred and eighty-one male patients with a mean age of 44.2 ± 13.2 years and a type 1 diabetes duration of 18.9 ± 12.7 years were included. Fifteen patients had HH, representing a prevalence of 8.3% (95% confidence interval [CI]: 4.3-12.3%). Age (odds ratio [OR] 1.066 [95% CI: 1.002-1.134]), waist circumference (OR 1.112 [95% CI: 1028-1203]), and insulin requirements ([IU/Kg] ×10 [OR 1.486 {95% CI: 1052-2.098}]) were independently associated with the presence of HH. The model that best predicted HH generated this formula: HH-score = (1.060 × age) + (1.084 × waist circumference) + (14.00 × insulin requirements) + triglycerides, where age was expressed in years, waist circumference in cm, insulin requirements in IU/kg/d, and triglycerides in mg/dL. An HH score > 242.4 showed 100% sensitivity and 53.2% specificity for HH diagnosis; positive and negative predictive values were 17.0 % and 100%, respectively. CONCLUSIONS: One in 10 men with type 1 diabetes presents HH. This condition is associated with age, waist circumference, and insulin requirements. A simple formula based on clinical parameters can rule out its presence.

Thyroglobulin as early prognostic marker to predict remission at 18-24 months in differentiated thyroid carcinoma.

INTRODUCTION: Thyroglobulin (Tg), the most common marker to determine remission of differentiated thyroid carcinoma (DTC), can take 18 months or longer to be undetectable. We hypothesized that Tg stimulated after surgery and immediately before radioiodine treatment (baseline-stimulated Tg) could be a good predictor of remission at 18-24 months. The aim of this study was to evaluate the role of baseline-stimulated Tg as early prognostic marker of DTC. PATIENTS AND METHODS: Retrospective study of 133 patients with DTC from 1998 to 2010 (age at diagnosis 47·4 ± 16·8, follow-up 5·09 ± 3·2 years). Initial subset analysis was performed after excluding patients with positive TgAb, who were later included in the second. Baseline-stimulated Tg was divided into tertiles. Multivariate logistic regression analysis included baseline Tg and other known prognostic markers and receiver operating characteristic (ROC) curve to identify the best cut-off level of baseline Tg were performed. RESULTS: Baseline-stimulated Tg in the highest tertile was the only predictive variable of persistence of disease at 18-24 months in the initial analysis (OR 45·3, P < 0·01). In the second analysis, the predictive variables were baseline-stimulated Tg (OR 39·6, P < 0·001), presence of TgAb (OR 23·4, P < 0·005) and uptake outside of the thyroid bed post-treatment whole body scan (WBS; OR 5·3, P < 0·05) were predictive of persistence of disease. The ROC curve showed that baseline-stimulated Tg below 8·55 µg/l identified 95% of disease-free patients at 18-24 months after initial treatment. CONCLUSIONS: Baseline-stimulated Tg is a good predictor of remission of disease at 18-24 months after initial treatment and could be a useful marker to stratify risk immediately after surgery.

Family history in the diagnosis of monogenic diabetes "leads and misleads".

Always granting that de novo mutations are possible, family history and biological characteristics are nonetheless crucial for the diagnosis of monogenic diabetes. We report here the case of two patients with monogenic diabetes in which the initial family history misled the diagnostic work-up and did not support the diagnosis. Family history details changed substantially after the molecular diagnosis was established.

Infradiagnóstico de complicaciones crónicas de la diabetes mellitus: utilidad de una revisión sistemática en una sola visita / Infradiagnosed complications of chronic diabetes mellitus: the value of systematic review in a single visit

Antecedentes: El diagnóstico precoz de las complicaciones crónicas de la diabetes mellitus permite reducir la progresión de las mismas y, por tanto, mejorar la calidad de vida y disminuir la mortalidad cardiovascular

Introduction: Early diagnosis of diabetes mellitus complications reduces their progression and therefore improves quality of life and decreases cardiovascular mortality. Objectives To evaluate the efficiency of a unit for detection of chronic complications of diabetes, and to analyze the incidence and prevalence of complications in a sample of patients from our area of interest and concern

Infradiagnosed complications of chronic diabetes mellitus: the value of systematic review in a single visit.

INTRODUCTION: Early diagnosis of diabetes mellitus complications reduces their progression and therefore improves quality of life and decreases cardiovascular mortality. OBJECTIVES: To evaluate the efficiency of a unit for detection of chronic complications of diabetes, and to analyze the incidence and prevalence of complications in a sample of patients from our area of interest and concern. METHODS: A cross-sectional study performing routine screening of all diabetes complications in patients aged 18-80 years diagnosed with type 1 or type 2 diabetes mellitus at least 6 months before. Anthropometric variables were measured and data on drug treatment and the most recent lipid profile were collected. RESULTS: 460 patients were included in the study. The prevalence and incidence rates of chronic complications of diabetes were 57% and 35.4% respectively. Glycosylated hemoglobin values ≤ 7% were found in 42% of patients, blood pressure levels below 130/80 mmHg in 20% of patients, and LDL cholesterol levels less than 2.59 mmol/L in 46% of patients. Patients with new complications were older and had higher BMI and hip circumference values, as well as higher systolic blood pressure levels and greater use of antihypertensive drugs. CONCLUSION: A unit for routine screening of chronic complications of diabetes would allow for detection of macroangiopathy and microangiopathy in a single annual visit, increasing visit compliance, and for implementation of measures to prevent its progression.

Immediate and delayed postoperative morbidity in functional and non-functioning pituitary adenomas.

Neurosurgery is the most widely used definite treatment for pituitary tumors, while medical treatments are a good option to improve symptoms, which tend to recur when drugs are stopped. The aim of this study was to assess postsurgical morbidity of secreting pituitary adenomas (adrenocorticotropin hormone -ACTH- and growth hormone -GH- secreting) and non-functioning (NF) adenomas, operated between January 2002 and May 2009. We retrospectively reviewed the data of 94 patients who were operated by the same neurosurgeons and compared the immediate (1st month) and delayed (1st year) complications between the three groups of adenomas. Forty had immediate post-operative complications (42% of NF, 37% of GH-secreting and 48% of ACTH-secreting adenomas). The most frequent complications were transient diabetes insipidus (23%), cerebrospinal fluid leaks (7%), sinusitis and meningitis (2%). Patients with Cushing's disease showed a tendency to have more transient diabetes insipidus and sinusitis compared to NF adenomas (P = 0.071). Ten patients had delayed complications during the first post-operative year (7% of NF, 11% of GH-secreting and 15% of ACTH-secreting), with a greater incidence of arthromyalgias and acute carpal tunnel syndrome in ACTH-secreting adenomas, compared with the other groups (P < 0.05). We conclude, that although ACTH-secreting adenomas are mostly microadenomas (78%) and affect younger patients, they are associated with a greater number of immediate and delayed complications during the first postoperative year (mainly invalidating arthromyalgias and acute carpal tunnel syndrome) compared with larger GH-secreting and NF adenomas, probably related to acute glucocorticoid deprivation after successful surgery.

Maturity onset diabetes of the young and pregnancy.

Three and a half decades after the clinical description of "Maturity Onset Diabetes of the Young" (MODY), and despite its low prevalence, important knowledge has been gathered concerning its genetic basis, molecular pathways, clinical phenotypes and pharmacogenetic issues. This knowledge has proved to be important not only for the attention of subjects carrying a mutation but also for the insight provided in Type 2 diabetes mellitus. In recent years, a shift from the term "MODY" to "monogenic diabetes" has taken place, the latter term being a better and more comprehensive descriptor. We stick to the "old" term because information on other types of monogenic diabetes and pregnancy is scarce. In this review we perform an overview of the entity, the prevalence rates reported in women with gestational diabetes mellitus and the specific impact of each type on pregnancy outcome.