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We aimed to determine, in patients with type 1 diabetes (T1DM), the impact of excluding hyperglycemia as a criterion from the International Diabetes Federation (IDF) definition of the metabolic syndrome (MetS), both on its prevalence and on its association with micro and macrovascular complications and markers of subclinical inflammation.A cross-sectional design, including 280 patients with T1DM. We defined MetS by three different models: (i) the standard IDF criteria, (ii) a modification consisting of excluding of hyperglycemia as a criterion (modified IDF criteria) and (iii) a modification consisting in changing the hyperglycemia by insulin resistance (MetS + IR model) defined by the estimated glucose disposal rate. Microvascular complications and cardioautonomic neuropathy were assessed. We measured an inflammatory panel including high sensitivity C reactive protein, erythrocyte sedimentation rate, homocysteine, and fibrinogen concentrations.After excluding hyperglycemia, the prevalence of MetS was 6.4% (95%CI: 4.1 to 9.9) compared with 20.7% (95%CI: 16.3 to 25.8) using standard IDF criteria. After adjusting for duration of diabetes, all three MetS definitions increased the odds for having microvascular complications [OR: 6.012 (2.208-16.307) for modified definition; OR: 5.176 (2.555-10.486) for standard definition and [OR: 3.374 (1.649-8.456) for MetS+IR model]. However, the both modified IDF models for MetS showed better predictive performance than standard criteria for suffering from neuropathy, nephropathy, cardiovascular disease and were associated with markers of subclinical inflammation.The prevalence of MetS significantly varies as a function whether or not hyperglycemia is included as a diagnostic criterion. The subset of patients fulfilling the modified MetS definitions may reflect better the concept of metabolic syndrome in T1DM. These modified definitions were accompanied by a poorer metabolic control and lipid profile, showing the worse inflammatory biomarker profiles and higher odds for micro- and macrovascular complications. In patients with T1DM, the inclusion of insulin resistance instead of hyperglycemia as a criterion of MetS may be of interest in routine clinical practice.

Introduction Cardiovascular autonomic neuropathy (CAN) associates an abnormal circadian pattern in blood pressure (BP) regulation that might be aggravated by the coexistence of arterial stiffness. We aimed to evaluate the effect of arterial stiffness in the circadian rhythm of BP in patients with type 1 diabetes and CAN. Methods Cross-sectional study including 56 consecutive patients with type 1 diabetes and CAN, with ( n = 28) or without ( n = 24) arterial stiffness as defined by an ankle-brachial index above 1.2. CAN was diagnosed by BP and heart rate responses to active standing and cardiovascular autonomic reflex tests. Absence of nocturnal decrease in BP–“ non-dipping” pattern– was defined by a daytime to nighttime decrease in mean BP smaller than 10%. Results The study’s subjects mean age was 40 ± 11 years-old, their mean duration of diabetes was 22 ± 10 years, and their mean A1c was 7.9 ± 1.5%. A “ non-dipping” pattern was observed in 28 patients (54%) regardless of the presence or absence of arterial stiffness. Age, waist circumference, body mass index, and A1c, were introduced as independent variables into a multiple regression analysis. The stepwise model ( R2: 0.113, p = 0.016) retained only A1c levels (β: ‒ 0.333, 95% confidence interval [CI]: −3.10 to −0.33) as significant predictor of the percentage of nighttime decrease in mean BP. Conclusions A non-dipping pattern in BP is very common in patients with type 1 diabetes presenting with subclinical CAN and is associated with a poorer metabolic control. On the contrary, coexistence of arterial stiffness is not associated with abnormalities in circadian BP regulation.

Women with functional hyperandrogenism show both increased markers of oxidative stress and a mild iron overload. Combined oral contraceptives (COC) may worsen redox status in the general population. Since iron depletion ameliorates oxidative stress in other iron overload states, we aimed to address the changes in the redox status of these women as a consequence of COC therapy and of bloodletting, conducting a randomized, controlled, parallel, open-label clinical trial in 33 adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. After three months of treatment with a COC, participants were randomized (1:1) to three scheduled bloodlettings or observation for another nine months. After taking a COC, participants showed a mild decrease in their plasma electrochemical antioxidant capacity, considering fast-acting antioxidants [MD: −1.51 (−2.43 to −0.60) μC, p = 0.002], and slow-acting antioxidants [MD: −1.90 (−2.66 to −1.14) μC, p < 0.001]. Women submitted to bloodletting showed a decrease in their non-enzymatic antioxidant capacity levels (NEAC) throughout the trial, whereas those individuals in the control arm showed a mild increase in these levels at the end of the study (Wilks’ λ: 0.802, F: 3.572, p = 0.041). Decreasing ferritin and plasma hemoglobin during the trial were associated with worse NEAC levels. COC may impair redox status in women with functional hyperandrogenism. Decreasing iron stores by scheduled bloodletting does not override this impairment.

Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3–4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4–6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P P

Copeptin is a stable peptide derived from cleavage of the precursor of arginine-vasopressin (AVP), [1,2] that can be easily measured by using a simple rapid assay. Copeptin has been related with an increased incidence of stroke and cardiovascular mortality in individuals with diabetes, mainly type 2 [3,4]. It is also a risk predictor for end-stage renal disease, coronary heart disease, and all-cause mortality in people with type 1 diabetes (T1DM) [5]. However, we have recently reported that copeptin does not appear to be a reliable marker for the screening of asymptomatic peripheral arterial disease in a population of patients with T1DM [6]. We here explore the putative relationships between serum copeptin level and carotid intima-media thickness (cIMT) in asymptomatic T1DM-patients comprehensively investigated for subclinical carotid atherosclerosis.

Aim: To clarify whether autoantibodies against glutamic acid decarboxylase (GAD-ab) are associated with cardiac autonomic neuropathy (CAN). Methods: 319 consecutive patients with type 1 diabetes (DM1) were included. We assessed CAN by responses of heart rate variability to deep breathing (E/I index), Valsalva maneuver, standing (30:15 ratio), low-frequency activity (LFa), and high-frequency activity (HFa). We assayed GAD-ab by immunoprecipitation radioligand. Results: Mean age was of 40 ± 14 years, with 20 ± 12 years as mean duration of diabetes. Mean A1c was 7.2 ± 1.0%. We confirmed CAN in 66 patients resulting in a 21% (95% CI 17-25) prevalence of asymptomatic CAN. GAD-ab were present in 199 individuals (62%), with no significant differences as a function of the presence of CAN or not [44 (70%) vs. 144 (66%), respectively; P = 0.544]. GAD-ab titles were similar between both groups (431 ± 695 U/mL in CAN subjects vs. 390 ± 662 U/mL in subjects without CAN, P = 0.688). Considering all patients as a whole, GAD-ab titles only correlated with duration of DM1 (r = -0.346, P < 0.001). HFa correlated with age (r = -0.523, P < 0.001), duration of DM1 (r = -0.374, P < 0.001), and A1c (r = -0.261, P < 0.001), but not with GAD-ab. Similarly, LFa correlated with age (r = -0.473, P < 0.001), duration of DM1 (r = -0.223, P < 0.001), and A1c (r = -0.294, P < 0.001). Age, sex, A1c, duration of DM1, GAD-ab, and systolic blood pressure were introduced as independent variables into a binary regression analysis. The stepwise model (R2: 0.106, P < 0.001) retained only age (β: -0.933, 95% CI: 0.933-0.976) as the significant predictor of the presence of CAN. Conclusion: GAD-ab unlikely have a role as a CAN marker in patients with DM1. Disclosure L. Nattero-chávez: None. E. Lecumberri: None. H. F. Escobar-morreale: Consultant; Self; InsudPharma. M. Luque-ramírez: None. J. Quiñones silva: None. L. Montanez: None. E. Fernández durán: None. B. Dorado avendaño: None. C. Sánchez rodríguez: None. M. Lorenzo: None. M. Fernández argüeso: None. N. Bengoa rojano: None. Funding Menarini International Foundation

Introduction: Increased prevalence of functional hyperandrogenism/polycystic ovary syndrome (PCOS) has been previously described in type 1 diabetes (T1DM) patients. However, the reported prevalence rates vary depending on different diagnostic criteria. Our study aim was to determine the prevalence of PCOS and hyperandrogenic traits in premeopausal women with T1DM. Methods: A cross-sectional study was conducted at a diabetes outpatient clinic in a tertiary Hospital from Madrid, Spain. We recruited consecutive premenopausal woman with T1DM, and menarche at least 2 years before the study. For this preliminary report, we included 40 patients. History data collection, physical exam, a complete hormonal analysis in follicular phase (including d4-androstenedione, DHEA-S, total testosterone, SHBG, 17-OH-progesterone, FSH, LH, prolactin, and TSH), and ovarian ultrasound were performed. Results: Mean age of patients was of 28 ± 8 yr; mean duration of T1DM was of 13 ± 8 yr-old. Twenty-seven patients were on multiple daily insulin therapy, while 13 of them were on continuous subcutaneous insulin infusion. Mean BMI was of 23.8 ± 3.7 Kg/m2. Mean daily insulin dose was 0.64 ± 0.2 U/kg and mean A1C was 7.5 ± 1.8%. PCOS was diagnosed in 7 patients resulting in a 18% (95% CI: 8; 32) prevalence of PCOS according to NIH-Rotterdam, and in 6 patients resulting in a 15% (95% CI: 7; 29) prevalence of PCOS according to AES-PCOS criteria. Three patients [7% (95% CI: 3; 20)] had isolated polycystic ovarian morphology (PCOM), and 7 patients [18% (95% CI: 8; 32)] presented with oligo-amenorrhea (ovulatory dysfunction-WHO class 2). Conclusion: Our preliminary data show a significant increase in prevalence of PCOS in premenopausal women with T1DM with respect to the general population. Disclosure A. Bayona: None. L. Nattero-chávez: None. E. Fernández durán: None. B. Dorado avendaño: None. H. F. Escobar-morreale: Consultant; Self; InsudPharma. M. Luque-ramírez: None.

The male predominance of cardiovascular disease is overridden by the presence of diabetes, as the sex-related burden of cardiovascular disease increases in postmenopausal women with diabetes (1). Sexual dimorphism in cardiovascular autonomic neuropathy (CAN) might contribute to these findings (1). We conducted a cross-sectional study hypothesizing that 1 ) the prevalence of CAN is different among women and men with type 1 diabetes, 2 ) such a difference is dependent on the pre- or postmenopausal status of women, and 3 ) sex steroids show opposite associations with CAN depending on sex. In this study, we recruited 279 consecutive patients with type 1 diabetes attending our clinic (ClinicalTrials.gov identifier NCT02910271) (2,3). Inclusion and exclusion criteria are detailed elsewhere (2,3). Assuming a global prevalence of CAN of ∼30% in our population of patients with type 1 diabetes (2) and setting α at 0.05 and β at 0.20 for a two-sided test, the inclusion of at least 160 men and 120 women was enough to identify a difference in prevalence among them above 15% (www.imim.cat/ofertadeserveis/software-public/granmo/). The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the local ethics committee of Hospital Universitario Ramon y Cajal (approval date 22 January 2016, protocol ID 464/15). Informed consent was obtained from all participants included in the study. Patients did not receive any economic compensation for their participation. For …

Context Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. Objectives (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. Design Randomized, parallel, open-label, clinical trial. Setting Academic hospital. Patients Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. Intervention After a 3-month run-in period of treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. Main outcome measures Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin Results From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: −1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels Conclusions Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.

Objective As copeptin is associated with lower-extremity amputation in patients with type 1 diabetes mellitus (T1DM), our study aimed to address the putative association between copeptin and asymptomatic peripheral artery disease (aPAD) in those patients. Design and methods This observational cross-sectional study included 112 patients with T1DM from a larger cohort (ClinicalTrials.gov: NCT02910271), selected (1:2) as per the presence of aPAD (n = 37) or not (n = 75). aPAD was evaluated by ankle–brachial index (ABI), toe–brachial index (TBI), and peripheral Doppler ultrasound. The two groups of patients were matched by age, gender distribution and duration of T1DM. Fasting serum copeptin was measured by high-sensitivity ELISA, and its relationships with clinical and biochemical variables as well as aPAD were evaluated too. Results The study population was aged 42 ± 8 years, duration of T1DM was 27 ± 7 years, and mean HbA1c was 7.7 ± 1.1%. No significant differences in copeptin concentrations were found between patients with or without aPAD (16.9 ± 10.8 vs 17.3 ± 14.7 pmol/L, respectively; P = 0.462). Considering all patients as a whole, copeptin correlated with systolic blood pressure (SBP; ρ = −0.209, P = 0.027), eGFR ρ = −0.271, P = 0.004), and serum sodium (ρ = −0.208, P = 0.027), but not with ABI (ρ = −0.068, P = 0.476). Stepwise multiple linear regression analysis (R2: 0.059; P = 0.035) retained SBP (β: −0.219, 95% CI: −1.391; −0.089) as the only significant predictor of copeptin concentration. Conclusion As serum copeptin does not appear to be associated with aPAD in patients with T1DM, further studies are now needed to elucidate whether it has any other potential role to play in the subclinical vascular disease of this patient population.

Aim: Describe the relationships between cardiovascular autonomic neuropathy (CAN) and glucose variability (GV) in patients with DM1 on continuous subcutaneous insulin infusion therapy (CSII). Methods Observational retrospective study (n=89). CAN was assessed by heart rate variability (HRV) in response to deep breathing, standing, Valsalva’s maneuver, and the amplitude of the low (LFa) and high (HFa) frequency of HRV. The standard deviation (SD), the coefficient of variation (CV) and time in range (TIR) were calculated from the capillary blood measurements downloaded of CSII (the mean of glucose capillary assessments was 5.8/day). Results The mean age was 38±13 and their average duration of DM1 was 22±10 years. The prevalence of CAN was 36% (95%CI: 27-46). The population characteristics according to the presence of CAN are summarized in Table 1. The age and the duration of diabetes correlated negatively with LFa (r= -0.496, P < 0.001) and HFa (r= -0.510, P < 0.001). Separate multivariate binary logistic models were constructed for clinical and GV parameters introducing CAN as dependent variable. Only the age (expB 1.1; CI 1.04-1.15. P < 0.001) was associated with CAN in the fully adjusted model. Conclusions Age and duration of diabetes, but not GV parameters, appear to be associated with CAN in our cohort of patients with DM1 on CSII. Disclosure L. Nattero-Chávez: None. J. Quiñones Silva: None. N. Bengoa: None. M. Fernández Argüeso: None. L. Montanez: None. E. Fernández Durán: None. B. Dorado: None. B. Arias Zamorano: None. E. Lecumberri: None. M. Luque Ramírez: None. Funding Menarini Group

Purpose Circulating micro-ribonucleic acids (miRNAs) are small noncoding RNA molecules that influence gene transcription. We conducted the present profiling study to characterize the expression of circulating miRNAs in lean and obese patients with polycystic ovary syndrome (PCOS), the most common endocrine and metabolic disorder in premenopausal women. Basic Procedures We selected 11 control women, 12 patients with PCOS and 12 men so that they were similar in terms of body mass index. Five control women, 6 men and 6 patients with PCOS had normal weight whereas 6 subjects per group were obese. We used miRCURY LNA™ Universal RT microRNA PCR for miRNA profiling. Main Findings The expression of 38 miRNAs and was different between subjects with PCOS and male and female controls. The differences in 15 miRNAs followed a pattern suggestive of androgenization characterized by expression levels that were similar in patients with PCOS and men but were different compared with those of control women. The expression of 13 miRNAs in women with PCOS was similar to that of control women and different compared with the expression observed in men, suggesting sexual dimorphism and, lastly, we observed 5 miRNAs that were expressed differently in women with PCOS compared with both men and control women, suggesting a specific abnormality in expression associated with the syndrome. Obesity interacted with the differences in several of these miRNAs, and the expression levels of many of them correlated with the hirsutism score, sex hormones and/or indexes of obesity, adiposity and metabolic dysfunction. Principal Conclusions The present results suggest that several serum miRNAs are influenced by PCOS, sex hormones and obesity. Our findings may guide the targeted search of miRNAs as clinically relevant markers for PCOS and its association with obesity and metabolic dysfunction in future studies.

Context Gut microbiota play a major role in health and disease by influencing physiology, metabolism, nutrition, and immune function. Objective To evaluate the composition of gut microbiota in women with polycystic ovary syndrome (PCOS), focusing on the influence of sex, sex hormones and obesity on the associations found. Design Cross-sectional study. Setting Academic hospital. Participants We recruited 15 women with PCOS, 16 nonhyperandrogenic control women, and 15 control men. Participants were classified as nonobese ( Interventions Standardization of diet for 3 consecutive days (at least 300 g of carbohydrates per day) followed by fecal sampling and a standard 75-g oral glucose tolerance test. Main Outcome Measures Analysis of bacterial abundance and composition of gut microbiota by massive sequencing of 16S ribosomal DNA amplicons in a MiSeq platform (Illumina). Results α Bacterial diversity was reduced in women compared with men, and β diversity was reduced particularly in obese patients with PCOS. Women with PCOS presented with specific abnormalities in gut microbiota consisting of an increased abundance of the Catenibacterium and Kandleria genera. When all participants as a whole were considered, indexes of bacterial diversity and the abundance of several bacterial genera correlated positively with serum androgen concentrations and negatively with estradiol levels. Conclusions The diversity and composition of the gut microbiota of young adults are influenced by the combined effects of sex, sex hormone concentrations, and obesity, presenting with specific abnormalities in women with PCOS.

Summary Background & aims Low-grade chronic inflammation is involved in the pathophysiology of obesity. However, little is known about the influence of sex and sex hormones on surrogate inflammatory markers and mediators, particularly after glucose ingestion. Design Observational study. Methods We measured the circulating concentrations of interleukin-6, interleukin-18, macrophage migration inhibitory factor, matrix metallopeptidase-9, monocyte chemotactic protein-1 and pentraxin-3, in the fasting state and during a 75 g oral glucose tolerance test, in 24 women and 25 men. Eleven men and 11 women were lean whereas 14 men and 13 women had weight excess. Results Anti-inflammatory cytokines (interleukin-6 and interleukin-18) were increased in the fasting state and/or decreased in some women during the oral glucose tolerance test, as opposed to inflammatory mediators such as macrophage migration inhibitory factor and matrix metallopeptidase-9 that increased during the oral glucose tolerance test especially in subjects with weight excess. Body mass index and waist circumference were the main determinants of these changes. Fasting pentraxin-3 levels were especially increased in lean women in parallel to a decrease in free testosterone levels, and decreased during the oral glucose tolerance test as opposed to the increase in insulin concentrations. Conclusions The circulating concentrations of markers of low-grade chronic inflammation in young healthy adults are not only influenced by obesity but also by abdominal adiposity, fasting and glucose ingestion and, in some cases, by sex and sex hormones. These influences should be considered when these markers are used as surrogate markers of the inflammatory milieu associated with obesity.

Postprandial dysmetabolism plays a major role in the pathogenesis of metabolic disorders such as obesity and the polycystic ovary syndrome (PCOS). The aim is to characterize the circulating lipoprotein particle profiles in response to oral glucose, lipid, and protein challenges.17 women with PCOS, 17 control women, and 19 healthy men selected to have similar age and body mass index are studied. Blood samples are collected following the ingestion of 300 kcal in the form of glucose, lipids, or proteins, and they are submitted to two-dimensional (2D) diffusion-orderedOral macronutrient challenges induce immediate class-specific postprandial changes in particle number and size of lipoproteins, with lipids inducing a more pro-atherogenic lipoprotein profile compared to glucose and proteins, particularly in obese subjects and women with PCOS.

Polycystic ovary syndrome (PCOS) is a mainly hyperandrogenic disorder and is possibly the most frequent endocrinopathy in premenopausal women. Androgen excess is the primary defect in PCOS, because ovarian theca cells secrete increased amounts of androgens even after several passes in primary culture. Excessive androgen amounts might favor the visceral deposition of body fat in affected women, resulting in insulin resistance, compensatory hyperinsulinism and further androgen excess. This vicious circle starts early during life in women with PCOS, even during fetal development, manifests clinically during puberty and does not end after menopause. All the steps in the vicious circle contribute to the association of PCOS with metabolic dysfunction and cardiovascular risk factors. Fortunately, most, if not all, of the therapeutic strategies currently in use for the management of PCOS, including lifestyle modification and diet, oral contraceptives, antiandrogens and insulin sensitizers, may ameliorate androgen excess and its long-term consequences.

Summary Background & aims Most evidence linking the polycystic ovary syndrome (PCOS) with chronic low-grade inflammation has been obtained in the fasting state. We have studied the postprandial inflammatory response to oral glucose, lipid and protein challenges and the possible influences of obesity, sex and PCOS on these responses. Methods On alternate days, we submitted 17 women with PCOS (9 non-obese, 8 obese), 17 control women (9 non-obese, 8 obese) and 19 control men (10 non-obese, 9 obese) to isocaloric (300 Kcal) oral macronutrient loads. We assayed serum for TNF-α, IL-6, IL-18, IL-10, pentraxin-3 and galectin-3 concentrations and leukocytes for expression of TNF, IL6, IL10 and their receptors TNFRSF1B, IL6R and IL10RA. Results Circulating IL-6 levels decreased after glucose and protein ingestion but slightly increased after oral lipid intake. Leukocyte IL6 expression did not change after the ingestion of any macronutrient yet IL6R expression increased during all macronutrient challenges, the largest increase being observed after glucose ingestion. Serum TNF-α similarly decreased during either macronutrient load, whereas TNF expression increased after macronutrient ingestion, the highest increase observed after oral glucose. TNFRSF1B expression also increased after glucose intake but not after lipid or protein ingestion. No global effect of obesity or group on postprandial circulating IL-6, TNF-α, or IL6, IL6R, TNF and TNFRSF1B expression was found. Circulating IL-18 concentrations decreased during all oral challenges, whereas in case of galectin-3 and pentraxin-3 only the protein load caused a reduction in its concentrations. Of the genes studied here, IL10 showed the largest increase in expression throughout all the postprandial curves, particularly after glucose. Obesity blunted the increase in IL10 expression. IL10RA expression decreased after glucose ingestion but remained unchanged during lipid and protein loads. Conclusions Glucose ingestion, as opposed to lipid and protein intake, results into the largest increase in leukocyte gene expression of inflammatory mediators. The expression of the anti-inflammatory cytokine IL10 was the largest observed here, suggesting a compensatory mechanisms against postprandial inflammation that may be blunted in obesity. However, these responses did not translate into the circulating concentrations of these inflammatory mediators during the immediate postprandial phase.

Context Cardiovascular autonomic neuropathy (CAN) appears to contribute to peripheral arterial stiffness (AS) in type 1 diabetes. Whether CAN in patients with AS is associated with concomitant asymptomatic peripheral arterial disease (aPAD) remains unclear. Objective To assess the risk of CAN in patients with type 1 diabetes and AS and its potential association with atherosclerosis. Design Cross-sectional study. Setting Type 1 diabetes clinic in an academic hospital. Patients Two hundred sixty-four patients with type 1 diabetes. Intervention AS was defined as an ankle-brachial index (ABI) >1.2, aPAD by the toe-brachial index and Doppler sonography, and CAN by blood pressure and heart rate responses to active standing and Ewing and Clarke tests. Main outcome measures Odds of having CAN among patients with AS. Odds for CAN were also calculated as a function of the presence of AS and concomitant aPAD. Results The study population's mean age was 35 ± 11 years, with a duration of disease of 19 ± 10 years and mean hemoglobin A1c of 7.5% ± 1.3%. Seventy-three patients (28%) had peripheral AS, of whom 28 showed aPAD. The prevalence of CAN among patients with AS was 48% but it was only 23% in subjects with normal ABI (OR: 3.1 [1.7; 5.4]). Concomitant aPAD increased the OR for CAN (OR: 4.5 [2.0; 10.1]). After adjustments for aPAD and relevant cardiovascular risk factors, AS remained associated with parasympathetic dysfunction. Conclusions In type 1 diabetes, both peripheral AS and atherosclerosis were associated with CAN. A simple method, such as the ABI, may identify a subset of patients with undiagnosed dysautonomia.

Background The risk of developing prediabetes and type 2 diabetes (dysglycemia) may be increased in women with PCOS. Whether an oral glucose tolerance test (OGTT) should be performed routinely in all PCOS women at presentation or should be recommended only to a selected subset of patients is still controversial. Basic Procedures At a tertiary care center, we conducted a retrospective, observational study including 400 women with PCOS submitted to an OGTT. Our primary objective was to assess the diagnostic agreement between two algorithms commonly used for the screening of dysglycemia in these women: i) relying only on fasting plasma glucose (FPG) or ii) considering both fasting and/or 120-min plasma glucose concentrations during an OGTT. We conducted the analysis considering all patients as a whole, and also after stratifying them by body weight, androgen concentrations and age. Main Findings The OGTT detected dysglycemia in 24.5% of patients, whereas only 14.3% women would have been diagnosed using FPG levels alone. The latter missed as many as 40% of women with dysglycemia in our series, including all cases of diabetes. Diagnostic agreement between both algorithms was only 0.55 (κ = 0.103; 95% CI: 0.05–0.16). Areas under the receiver operating characteristic curve for dysglycemia were 0.86 (95%CI: 0.81–0.91) for FPG and 0.91 (95%CI = 0.87–0.95) for 120-min plasma glucose during the OGTT. FPG was not accurate in predicting dysglycemia in women with PCOS regardless of the presence of insulin resistance, weight excess, hyperandrogenemia and age. Principal Conclusions Relying on FPG alone is not adequate for the screening of disorders of glucose tolerance in women with PCOS; such diagnosis should rely on the results of an OGTT regardless of age, weight and/or androgen concentrations.

Scope Postprandial dysmetabolism plays a major role in the pathogenesis of metabolic disorders such as obesity and the polycystic ovary syndrome (PCOS). The aim is to characterize the circulating lipoprotein particle profiles in response to oral glucose, lipid, and protein challenges. Methods and results 17 women with PCOS, 17 control women, and 19 healthy men selected to have similar age and body mass index are studied. Blood samples are collected following the ingestion of 300 kcal in the form of glucose, lipids, or proteins, and they are submitted to two-dimensional (2D) diffusion-ordered 1 H-NMR spectroscopy. Regardless of macronutrient administered, the number of very low-density (VLDL) particles increases whereas low density-lipoprotein (LDL) decreases. High density-lipoprotein (HDL) particles increase only after lipid ingestion. Obese subjects show an increase in the number of large VLDL particles and a decrease in large LDL particles, with a significant reduction in the average particle size of LDL. Patients with PCOS show a particularly unfavorably smaller LDL particle size response to oral lipid intake, regardless of obesity. Conclusions Oral macronutrient challenges induce immediate class-specific postprandial changes in particle number and size of lipoproteins, with lipids inducing a more pro-atherogenic lipoprotein profile compared to glucose and proteins, particularly in obese subjects and women with PCOS.

Aims Epidemiological data on subclinical atherosclerotic disease in type 1 diabetes mellitus (DM1) are scarce. We aimed to estimate the subclinical atherosclerosis profile of asymptomatic patients with DM1 and an abnormal ankle-brachial index (ABI). Material and methods In a cross-sectional design (ClinicalTrials.gov Identifier: NCT02910271), we estimated ABI in 289 consecutive asymptomatic patients with DM1. An abnormal ABI led to measurements of toe-brachial index (TBI) and peripheral doppler ultrasound (DUS) to diagnose peripheral artery disease (PAD) and/or atherosclerotic carotid plaques (ACP). Results A reduced (≤0.9) or increased (>1.2) ABI was detected in 17 (6%) and 75 (26%) patients, respectively. PAD was confirmed by TBI and DUS in 9 (53%) patients with a reduced ABI and 28 (37%) patients with an increased ABI, resulting in a 12.8% (9.4-17.2) prevalence of asymptomatic PAD. Fourteen patients with an abnormal ABI also exhibited ACP [4.8% (2.9-7.9)], with 64% of these patients showing bilateral disease. Artery stenosis was mild or moderate in 21% and 29% of patients, respectively. Thus, 46 [16% (12-21)] patients showed asymptomatic PAD, ACP, or both. According to our data, we would have to explore three asymptomatic patients with DM1 and normal pulses to unmask one case of PAD, and seven asymptomatic patients showing abnormal ABI values to detect one carotid disease. Conclusions Peripheral artery disease is often undiagnosed in asymptomatic patients with DM1. However, its presence may change medical management in a substantial percentage of cases, highlighting the potential benefit of a thorough vascular assessment on these patients.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since samedi 3 fevrier 2018

Objective We aimed to compare a combined oral contraceptive (COC) plus the antiandrogen spironolactone with the insulin sensitizer metformin in women with polycystic ovary syndrome (PCOS). Design We conducted a randomized, parallel, open-label, clinical trial comparing COC (30 μg of ethinylestradiol and 150 μg of desogestrel) plus spironolactone (100 mg/day) with metformin (850 mg b.i.d.) for one year in women with PCOS (EudraCT2008–004531–38). Methods The composite primary outcome included efficacy (amelioration of hirsutism, androgen excess and menstrual dysfunction) and cardiometabolic safety (changes in the frequencies of disorders of glucose tolerance, dyslipidemia and hypertension). A complete anthropometric, biochemical, hormonal and metabolic evaluation was conducted every three months and data were submitted to intention-to-treat analyses. Results Twenty-four patients were assigned to COC plus spironolactone and 22 patients to metformin. Compared with metformin, COC plus spironolactone caused larger decreases in hirsutism score (mean difference 4.6 points, 95% CI: 2.6–6.7), total testosterone (1.1 nmol/L, 0.4–1.7), free testosterone (25 pmol/L, 12–39), androstenedione (5.5 nmol/L, 1.8–9.2) and dehydroepiandrosterone sulfate (2.7 μmol/L, 1.4–4.0). Menstrual dysfunction was less frequent with COC plus spironolactone (OR: 0.06, 95% CI: 0.02–0.23). No differences were found in frequencies of abnormal glucose tolerance (OR: 1.7, 95% CI: 0.7–4.4), dyslipidemia (OR: 0.6, 95% CI: 0.2–1.8) or hypertension (OR: 0.3, 95% CI: 0.5–2.0). No major adverse events occurred and biochemical markers were similarly safe with both treatments. Conclusions COC plus spironolactone was more effective than metformin for symptoms of PCOS showing similar safety and overall neutral effects on cardiometabolic risk factors.

Whether or not blood pressure (BP) and heart function of women with polycystic ovary syndrome (PCOS) are altered remains unclear, albeit subtle abnormalities in the regulation of BP observed in these women might suggest a mild masculinization of their cardiovascular system. To study the influence of obesity and androgen excess on BP and echocardiographic profiles of women with the syndrome, we conducted a cross-sectional case–control study comparing office and ambulatory BP monitoring, as well as echocardiographic assessments, in 63 premenopausal women with the classic phenotype, 33 nonhyperandrogenic women with regular menses, and 25 young men. Forty-nine subjects were lean and 72 had weight excess (body mass index ≥25 kg/m 2 ). Participants had no previous history of hypertension and were nonsmokers. Men showed the highest BP readings, and the lowest readings were observed in control women, whereas women with PCOS had intermediate values. Undiagnosed hypertension was more common in subjects with weight excess irrespective of sex and hyperandrogenism. Women with PCOS and weight excess showed frequencies of previously undiagnosed hypertension that were similar to those of men with weight excess and higher than those observed in nonhyperandrogenic women. Lastly, male sex, weight excess and hypertension, the latter in men as well as in women with PCOS, increased left ventricular wall thickness. In summary, our results show that patients with classic PCOS and weight excess frequently have undiagnosed BP abnormalities, leading to target organ damage.

Sexual dimorphism suggests a role for androgens in body fat distribution. Women with polycystic ovary syndrome (PCOS), a mainly androgen excess disorder, often present with abdominal obesity and visceral adiposity.We hypothesized that women with PCOS have a masculinized body fat distribution favoring the deposition of fat in visceral and organ-specific adipose tissue depots.This was a case-control study.The study was conducted at an academic hospital.Women with PCOS (n = 55), women without androgen excess (n = 25), and men (n = 26) presenting with similar body mass index participated in the study.There were no interventions.Ultrasound measurements of adipose tissue depots including sc (minimum and maximum), preperitoneal, ip, mesenteric, epicardial, and perirenal fat thickness were obtained and total body fat mass was estimated using a body fat monitor.Men and patients with PCOS had increased amounts of total body fat compared with control women. Men had increased thickness of intraabdominal adipose tissue depots compared with the control women, with the women with PCOS showing intermediate values that were also higher than those of control women in the case of ip and mesenteric fat thickness and was close to reaching statistical significance in the case of epicardial fat thickness. Women with PCOS also showed increased minimum sc fat thickness compared with the control women. Obesity increased the thickness of all of the adipose tissue depots in the 3 groups of subjects.Women with PCOS have higher global adiposity and increased amounts of visceral adipose tissue compared with control women, especially in the ip and mesenteric depots.

BACKGROUND Testosterone (T) measurement in women is problematic leading to initiatives aiming to improve laboratory standardization of commercial assays. We assessed the impact on the clinical diagnosis of functional hyperandrogenic disorders of a total T immunoassay recently certified by the Centers for Diseases Control and Prevention (CDC). METHODS We conducted a cross-sectional study including 263 consecutive adult premenopausal women presenting with functional ovarian hyperandrogenism-including polycystic ovary syndrome (PCOS)-and 73 nonhyperandrogenic female volunteers who served to define reference ranges. Total T was measured by a local routine direct radioimmunoassay and by a CDC-certified immunochemiluminescence assay. The main outcome measures were total and calculated free T concentrations and percentage of patients with hyperandrogenaemia. RESULTS Both assays showed a poor concordance for total and calculated free T measurements. Hence, 147 (56%) and 109 (41%) of women had hyperandrogenaemia with the routine and CDC-certified assays, respectively [κ (95%CI): 0.538 (0.441-0.634)]. Free T levels calculated from total T using both assays showed similar correlations with metabolic variables. Women showing hyperandrogenaemia by both methods had the worst metabolic profiles, yet women presenting with hyperandrogenaemia only when using the CDC-certified assay did not show any significant difference compared to nonhyperandrogenic women in anthropometric or metabolic variables. Those women with hyperandrogenaemia only when using the routine assay were more obese and insulin resistant than normoandrogenaemic hirsute patients. CONCLUSIONS An isolated androgen measurement, even a very specific one, is unlikely to identify the hyperandrogenic milieu that characterizes patients with functional ovarian hyperandrogenism and PCOS.

ObjectiveWomen with polycystic ovary syndrome (PCOS) seeking health care in the United States may be more obese and hyperandrogenic than those present in the general population. We aimed to assess the impact of referral bias on European women with functional androgen excess disorders.DesignCross-sectional study.MethodsWe studied two groups of patients: i) 368 consecutive patients referred to our clinic for the study of functional hyperandrogenism (FH) (referral patients); ii) 57 consecutive premenopausal patients identified by screening during blood donation (unselected patients). We compared the anthropometric data from the groups of patients with those of two control populations: iii) a group of unselected premenopausal healthy female blood donors (unselected controls); and iv) data available from the local general premenopausal female population.ResultsReferral patients with FH were more hirsute, had a higher percentage of hyperandrogenemia, and fulfilled PCOS criteria more frequently than unselected patients. The prevalence of obesity in unselected controls was similar to that observed in the general population, whereas referral patients and unselected patients were more frequently obese. The prevalence of obesity was also higher among referral patients compared to unselected patients.ConclusionReferral bias influences the phenotype of patients with FH. Patients studied at the clinical setting may show more severe hyperandrogenic and obese phenotypes than patients from the general population, even though PCOS appears to be associated with weight excess also in the general European population. This fact should be considered when establishing reference values and control populations for clinical and research purposes.

cope : Oxidative stress and damage participate in the pathophysiology of obesity and its metabolic complications. We studied the influence of sex, obesity and ingestion of different macronutrients on fasting and postprandial thiobarbituric acid reactive substances (TBARS), which can be considered as an index of lipid peroxidation and oxidative damage. Methods and Results : We studied 19 men and 17 women, out of whom 9 men and 8 women had obesity. We collected blood samples in the fasting state and, on alternate days, following the ingestion of 300 kcal in the form of glucose, lipids or proteins. Fasting TBARS concentrations correlated with waist circumference and were increased in obese men compared with non-obese men. This increase was not, however, observed in women. TBARS concentrations showed a marked increase following the ingestion of glucose in parallel to the increase in plasma glucose when considering all subjects as a whole, but did not increase after the oral intake of lipids and proteins. Conclusion : Plasma TBARS concentrations are increased in the fasting state only in obese men in association with abdominal adiposity, and increases markedly after the ingestion of glucose, but not after oral intake of lipids and proteins, regardless of sex and obesity. This article is protected by copyright. All rights reserved

Risk stratification of patients with pulmonary embolism (PE) may identify patients at high risk of early death who may benefit from more intensive surveillance or aggressive therapy. Nontargeted proteomics may identify biomarkers useful for the risk stratification of patients with acute symptomatic pulmonary embolism (PE). We studied 6 patients presenting with low-risk PE and 6 patients presenting with intermediate (n = 3) or high-risk (n = 3) PE. Two-dimensional difference gel electrophoresis was used to compare their plasma protein abundances. Candidate protein markers were identified by matrix assisted laser desorption ionization time-of-flight mass spectrometry. A panel of four biomarkers (haptoglobin, hemopexin, α2-macroglobulin, and Ig α1-chain C region) showed differences in plasma abundance among patients with acute symptomatic PE of different severity. Haptoglobin and hemopexin were decreased, whereas α2-macroglobulin and Ig α1-chain C region were increased, in patients with high or intermediate-risk PE compared with low-risk PE patient. In a separate clinical population consisting of 104 adults with acute PE, serum haptoglobin concentrations had an 85% chance of correctly identifying patients with high-risk PE according to receiving operating characteristics curve analysis. Moreover, serum haptoglobin concentrations ≤1 g/l showed an 80% sensitivity and a 96% specificity for the diagnosis of high-risk PE. Nontargeted proteomics identified protein biomarkers for the severity of PE that are involved in iron metabolism pathways and acute-phase response. Among them, reduced serum haptoglobin concentrations show a high accuracy for the biochemical detection of high-risk PE.

MicroRNAs (miRNAs) are small, noncoding RNA sequences that negatively regulate gene expression at the post-transcriptional level. miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 have been associated with metabolic disorders such as obesity and diabetes, which are also associated with polycystic ovary syndrome (PCOS).We aimed to evaluate the effects of sex, sex hormones, and PCOS and their interactions with obesity on the expression in the circulation of these miRNAs.This was a case-control study.The setting was an academic hospital.We included 12 control women, 12 patients with PCOS, and 12 men selected as to have similar body mass index (BMI) and age. Six subjects per group had normal weight (BMI25 kg/m(2)), and six subjects per group were obese (BMI ≥ 30 kg/m(2)).Blood samples were collected early in the morning after a 12-hour fast.We measured whole blood expression of miRNA-21, miRNA-27b, miRNA-103, and miRNA-155.Obesity significantly reduced the expression of miRNA-21, miRNA-27b, and miRNA-103. However, there was a significant interaction between obesity and the group of subjects in the expression of miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 consisting of obesity reducing the expression of these miRNAs in control woman and men, but tending to increase their expression in women with PCOS. These differences paralleled those observed in serum T concentrations.The present results suggest that miRNAs that play an important role in metabolic and immune system processes are influenced by obesity and circulating androgen concentrations.

Objective To study the impact of adrenal hyperandrogenism (AH; defined as DHEAS concentration >95th percentile of a healthy female control population) on cardiometabolic risk factors associated with polycystic ovary syndrome (PCOS). Design Cross-sectional study. Setting Academic hospital. Patient(s) Two-hundred ninety-eight consecutive women with PCOS, of whom 120 were obese (body mass index [BMI] ≥30 kg/m 2 ) and 178 nonobese (BMI 2 ). Intervention(s) None. Main Outcome Measure(s) Comprehensive evaluation of cardiovascular risk factors, including 75-g oral glucose tolerance test, office blood pressure, lipid profile, and low-grade inflammatory markers. Result(s) Patients with AH (AH-PCOS) had higher insulin circulating levels and lower insulin sensitivity than their counterparts without AH (non-AH-PCOS). Obesity, but not AH, was the main contributor to the presence of glucose tolerance disorders. Both obesity and AH increased the prevalence of prehypertension and hypertension. AH diminished high-density lipoprotein (HDL) levels in nonobese PCOS women in parallel with a decrease in total cholesterol levels, leading to a total to HDL cholesterol ratio similar to that of nonobese non-AH-PCOS patients. Furthermore, AH blunted the deleterious effect of obesity on the total cholesterol/HDL ratio, with the ratio of obese AH-PCOS patients being similar to that of nonobese PCOS patients with or without AH. Conclusion(s) The presence of AH in women with PCOS is associated with reduced insulin sensitivity and increased blood pressure but may have beneficial impact on the lipid profile. Obesity is the main determinant of the clustering of cardiovascular risk factors in PCOS women.

Surrogate indexes of visceral adiposity, a major risk factor for metabolic and cardiovascular disorders, are routinely used in clinical practice because objective measurements of visceral adiposity are expensive, may involve exposure to radiation, and their availability is limited. We compared several surrogate indexes of visceral adiposity with ultrasound assessment of subcutaneous and visceral adipose tissue depots in 99 young Caucasian adults, including 20 women without androgen excess, 53 women with polycystic ovary syndrome, and 26 men. Obesity was present in 7, 21, and 7 subjects, respectively. We obtained body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), model of adipose distribution (MOAD), visceral adiposity index (VAI), and ultrasound measurements of subcutaneous and visceral adipose tissue depots and hepatic steatosis. WC and BMI showed the strongest correlations with ultrasound measurements of visceral adiposity. Only WHR correlated with sex hormones. Linear stepwise regression models including VAI were only slightly stronger than models including BMI or WC in explaining the variability in the insulin sensitivity index (yet BMI and WC had higher individual standardized coefficients of regression), and these models were superior to those including WHR and MOAD. WC showed 0.94 (95% confidence interval 0.88-0.99) and BMI showed 0.91 (0.85-0.98) probability of identifying the presence of hepatic steatosis according to receiver operating characteristic curve analysis. In conclusion, WC and BMI not only the simplest to obtain, but are also the most accurate surrogate markers of visceral adiposity in young adults, and are good indicators of insulin resistance and powerful predictors of the presence of hepatic steatosis.

Do the circulating levels of a panel of adipokines involved in glucose metabolism exhibit sexual dimorphism in the fasting state and after an oral glucose load?Our results indicate sexual dimorphism in the circulating concentrations of adipokines involved in intermediate metabolism in the fasting state and during an oral glucose load. This finding suggests an influence of sex steroids on adipose tissue function.Sexual dimorphism in adipose tissue distribution fully develops after puberty and modulates the risk for cardiometabolic disorders. However, the possibility that adipose tissue function exhibits sexual dimorphism as well as its distribution is unproved.Cross-sectional case-control study including 32 subjects.Sixteen subjects with weight excess (8 men and 8 women, including 4 overweight and 4 obese subjects in each group) and 16 normal weight healthy volunteers (8 men and 8 women) presenting with similar age were submitted to a 75-g oral glucose tolerance test (oGTT). We measured circulating concentrations of insulin, glucose, chemerin, lipocalin-2, omentin-1, leptin and adiponectin and calculated their areas under the oGTT curve (AUC).Leptin and adiponectin concentrations were higher throughout the oGTT in women compared with men. Lipocalin-2 concentrations decreased during the oGTT in the whole group of study subjects. However, these levels remained higher in men with weight excess compared with normal weight men, whereas in women with weight excess lipocalin-2 levels at the end of the oGTT were lower compared with normal weight women. Sex was among the main determinants of the AUC of omentin-1 and leptin in linear regression models, and lower estradiol and testosterone concentrations were related to higher AUC of chemerin and omentin-1, respectively. Subjects with weight excess had higher AUC of chemerin and leptin and lower AUC of omentin-1 and adiponectin levels, independently of sex.We included a relatively small sample size and, because this was a cross-sectional study, we cannot infer causality to the associations between the changes in circulating adipokine concentrations and the variables studied here.Sexual dimorphism in adipose tissue function should be considered when studying adiposity and obesity, and also when designing strategies for their diagnosis and management.