Sex differences and sex steroids influence on the presentation and severity of cardiovascular autonomic neuropathy of patients with type 1 diabetes.

BACKGROUND: Sex differences characterize cardiovascular outcomes in patients with type 1 diabetes. Cardioautonomic neuropathy is a common complication of type 1 diabetes that associates increased morbi-mortality. Data regarding the interplay between sex and cardiovascular autonomic neuropathy are scarce and controversial in these patients. We aimed to address sex-related differences in the prevalence of seemingly asymptomatic cardioautonomic neuropathy in type 1 diabetes, and their associations with sex steroids. METHODS: We conducted a cross-sectional study including 322 consecutively recruited patients with type 1 diabetes. Cardioautonomic neuropathy was diagnosed using Ewing's score and power spectral heart rate data. We assessed sex hormones by liquid chromatography/tandem mass spectrometry. RESULTS: When considering all subjects as a whole, asymptomatic cardioautonomic neuropathy prevalence was not significantly different between women and men. When age was taken into account, the prevalence of cardioautonomic neuropathy was similar among young men and those > 50 years. However, in women > 50 years, the prevalence of cardioautonomic neuropathy doubled that of young women [45.8% (32.6; 59.7) vs. 20.4% (13.7; 29.2), respectively]. The OR of having cardioautonomic neuropathy was 3.3 higher in women > 50 years than in their younger counterparts. Furthermore, women presented more severe cardioautonomic neuropathy than men. These differences were even more marked when women were classified according their menopausal status instead of age. Peri- and menopausal women had an OR 3.5 (1.7; 7.2) of having CAN compared with their reproductive-aged counterparts [CAN prevalence: 51% (37; 65) vs. 23% (16; 32), respectively]. A binary logistic regression model (R2: 0.161; P = 0.001) displayed age > 50 years as a significant determinant of cardioautonomic neuropathy only in women. Androgens were positively associated with heart rate variability in men, and negatively in women. Accordingly, cardioautonomic neuropathy was associated with increased testosterone/estradiol ratio in women but to decreased testosterone concentrations in men. CONCLUSIONS: Menopause in women with type 1 diabetes is accompanied by an increase in the prevalence of asymptomatic cardioautonomic neuropathy. This age-related excess risk of cardioautonomic neuropathy is not observed in men. Men and women with type 1 diabetes have opposite associations between circulating androgens and indexes of cardioautonomic function. Trial registration ClinicalTrials.gov Identifier: NCT04950634.

Glycoprotein A and B Height-to-Width Ratios as Obesity-Independent Novel Biomarkers of Low-Grade Chronic Inflammation in Women with Polycystic Ovary Syndrome (PCOS).

The polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women in reproductive age. Obesity and low-grade chronic inflammation are frequently associated with PCOS. Recently, proton nuclear magnetic resonance (1H-NMR)-derived glycoprotein profiles have emerged as potential biomarkers that reflect systemic inflammation in type 2 diabetes, obesity, and other pathological processes. The aim of this work is to study plasma glycoprotein profiles as metabolic/inflammatory biomarkers underlying PCOS and its association with inflammation and obesity. We used 1H-NMR spectroscopy to study five glycoprotein variables, namely GlycA, GlycB, and GlycF and the height-to-width (H/W) ratio of GlycA and GlycB, in 17 women with PCOS (9 non-obese and 8 obese), 17 control women (9 non-obese and 8 obese), and 19 healthy men (10 non-obese and 9 obese). H/W ratios of GlycA and GlycB, but not glycoprotein areas, were specifically associated with PCOS independently of obesity. When considered as a whole, obese subjects presented higher GlycA, GlycB, and GlycF areas and higher H/W GlycA and GlycB ratios than their non-obese counterparts. All glycoprotein variables were associated with hsCRP, IL-6, and TNF-α, showing different correlations among PCOS, women, and men. Our present exploratory results suggest that 1H-NMR-derived glycoprotein profiles might serve as novel diagnostic markers of low-grade chronic inflammation in women with PCOS.

The peripheral atherosclerotic profile in patients with type 1 diabetes warrants a thorough vascular assessment of asymptomatic patients.

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.

Certified testosterone immunoassays for hyperandrogenaemia.

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.

The striking similarities in the metabolic associations of female androgen excess and male androgen deficiency.

Androgen excess in women and androgen deficiency in men facilitate abdominal adiposity and related metabolic disorders. Moreover, obesity-associated gonadal dysfunction consists of hyperandrogenism in women but hypogonadism in men. We have reviewed the existing evidence on the interplay between sex steroids, adipose tissue and lean mass distribution, and developed a novel hypothesis to explain these apparent paradoxes. We hypothesize that the most beneficial adipose tissue distribution and function is that of normal women, who have low androgen and high estrogen concentrations. Any imbalance favoring an increase in androgen levels in women, and the very high androgen levels characteristic of healthy men, influence adipose tissue distribution and function. Sex steroids determine a favorable (female) or unfavorable (male) body fat distribution and function. However, sex hormones also provide defensive mechanisms against visceral fat accumulation: androgens increase lean and muscle mass in men, decreasing the amount of visceral fat relative to total body mass and its negative consequences, whereas estrogens determine the metabolically safer deposition of body fat into the subcutaneous gluteal-femoral depot in women. This delicate equilibrium may be altered by the presence of gonadal dysfunction, a sedentary life-style or the normal ageing process leading to sarcopenia, and by the development of obesity leading to abdominal adiposity and metabolic disorders in both sexes. In conclusion, sex hormones and gonadal dysfunction play important roles in the pathogenesis of diabesity and its metabolic associations.

Polycystic ovary syndrome as a paradigm for prehypertension, prediabetes, and preobesity.

The polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder affecting 5-10 % of premenopausal women. These patients gather multiple cardiovascular risk factors from early ages. Hence, PCOS is currently considered a paradigm of cardiometabolic disease. Research about its pathogenesis has grown over the last years, covering from the potential fetal developmental programming to the molecular basis of adipose tissue dysfunction, insulin resistance, inflammation, oxidative stress, sympathetic hyperactivity, and endothelial dysfunction. All these abnormalities put these patients at an increased risk of vascular events. Thus, practitioners attending these women must have a broad pathophysiological knowledge of PCOS. We here review recent scientific insights about its cardiometabolic phenotype focusing on the pathogenesis of obesity, type 2 diabetes mellitus, and hypertension. We emphasize that a diagnosis of PCOS, especially if accompanied by excess weight, must be followed by a complete and periodical cardiometabolic evaluation and by the aggressive management of the abnormalities identified, with the aim of preventing future cardiovascular morbidity.

Familial ApoB-specific familial hypobetalipoproteinemia in a patient with non-classical congenital adrenal hyperplasia. / Hipobetalipoproteinemia familiar ApoB específica en una paciente con hiperplasia suprarrenal congénita no clásica.

Familial hypobetalipoproteinaemia is a disorder of lipid metabolism characterized by low levels of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B. ApoB-related familial hypolipoproteinemia is an autosomal condition with a codominance inheritance pattern. Non-classical congenital adrenal hyperplasia is an autosomal recessive disorder due to mutations in the CYP21A2, a gene encoding for the enzyme 21-hydroxylase, which results in an androgen excess production from adrenal source. We here present the case of a 25-year-old woman with NCAH showing decreased levels of total-cholesterol, low-density lipoprotein cholesterol and triglycerides. Her parent had digestive symptoms and severe hepatic steatosis with elevated liver enzymes, as well as decreased levels of total and low-density lipoprotein cholesterol. A genetic-molecular study of the proband identified a mutation in the APOB gene, which allowed a diagnosis of heterozygous ApoB-related hypolipoproteinaemia to be made.

Obesity and polycystic ovary syndrome influence on intestinal permeability at fasting, and modify the effect of diverse macronutrients on the gut barrier.

Women with the extremely prevalent polycystic ovary syndromegather multiple cardiovascular risk factors and chronic subclinical inflammation. Interactions between diet, adiposity, and gut microbiota modulate intestinal permeabilityand bacterial product translocation, and may contribute to the chronic inflammation process associated with the polycystic ovary syndrome. In the present study, we aimed to address the effects of obesity, functional hyperandrogenism, and diverse oral macronutrients on intestinal permeabilityby measuring circulating markers of gut barrier dysfunction and endotoxemia. Participants included 17 non-hyperandrogenic control women, 17 women with polycystic ovary syndrome, and 19 men that were submitted to glucose, lipid, and protein oral loads. Lipopolysaccharide-binding protein, plasma soluble CD14, succinate, zonulin family peptide, and glucagon-like peptide-2 were determined at fasting and after oral challenges. Macronutrient challenges induced diverse changes on circulating intestinal permeabilitybiomarkers in the acute postprancial period, with lipids and proteins showing the most unfavorable and favorable effects, respectively. Particularly, lipopolysaccharide-binding protein, zonulin family peptide, and glucagon-like peptide-2 responses were deregulated by the presence of obesity after glucose and lipid challenges. Obese subjects showed higher fasting intestinal permeabilitybiomarkers levels than non-obese individuals, except for plasma soluble CD14. The polycystic ovary syndromeexacerbated the effect of obesity further increasing fasting glucagon-like peptide-2, lipopolysaccharide-binding protein, and succinate concentrations. We observed specific interactions of the polycystic ovary syndromewith obesity in the postprandial response of succinate, zonulin family peptide, and glucagon-like peptide-2. In summary, obesity and polycystic ovary syndromemodify the effect of diverse macronutrients on the gut barrier, and alsoinfluence intestinal permeabilityat fasting,contributing to the morbidity of functional hyperandrogenism by inducing endotoxemia and subclinical chronic inflammation.

Investigating the Link between Intermediate Metabolism, Sexual Dimorphism, and Cardiac Autonomic Dysfunction in Patients with Type 1 Diabetes.

Sexual dimorphism influences cardiovascular outcomes in type 1 diabetes (T1D), with women facing a higher relative risk of macrovascular events compared to men, especially after menopause. This study hypothesizes that abnormalities in intermediate metabolism may be associated with cardiac autonomic neuropathy (CAN) in T1D. We aim to assess low molecular weight metabolites (LMWM) as markers of CAN in T1D, considering the effects of sexual dimorphism and age. In this cross-sectional study, we included 323 subjects with T1D (147 women and 176 men), with a mean age of 41 ± 13 years. A total of 44 women and 41 men were over 50 years old. CAN was assessed using Ewing's tests, and serum metabolites were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMR). Patients with CAN had lower levels of valine, isoleucine, and threonine, and higher levels of lactate, compared to those without CAN. These differences persisted after adjusting for BMI and estimated glucose disposal rate (eGDR). In a logistic regression model (R² = 0.178, p < 0.001), the main determinants of CAN included isoleucine [Exp(ß) = 0.972 (95% CI 0.952; 0.003)], age [Exp(ß) = 1.031 (95% CI 1.010; 1.053)], A1c [Exp(ß) = 1.361 (95% CI 1.058; 1.752)], and microangiopathy [Exp(ß) = 2.560 (95% CI 1.372; 4.778)]. Sex influenced LMWM profiles, with over half of the metabolites differing between men and women. However, no interactions were found between CAN and sex, or between sex, age, and CAN, on metabolomics profiles. Our findings suggest an association between CAN and LMWM levels in T1D. The sexual dimorphism observed in amino acid metabolites was unaffected by the presence of CAN.

Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge.

STUDY QUESTION: 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? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: Cross-sectional case-control study including 32 subjects. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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). MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: Sexual dimorphism in adipose tissue function should be considered when studying adiposity and obesity, and also when designing strategies for their diagnosis and management.

PCOS during the menopausal transition and after menopause: a systematic review and meta-analysis.

BACKGROUND: Current knowledge about the consequences of PCOS during the late reproductive years and after menopause is limited. OBJECTIVE AND RATIONALE: We performed a systematic review and meta-analysis of data on the pathophysiology, clinical manifestations, diagnosis, prognosis, and treatment of women ≥45 years of age-peri- or postmenopausal-with PCOS. SEARCH METHODS: Studies published up to 15 April 2023, identified by Entrez-PubMed, EMBASE, and Scopus online facilities, were considered. We included cross-sectional or prospective studies that reported data from peri- or postmenopausal patients with PCOS and control women with a mean age ≥45 years. Three independent researchers performed data extraction. Meta-analyses of quantitative data used random-effects models because of the heterogeneity derived from differences in study design and criteria used to define PCOS, among other confounding factors. Sensitivity analyses restricted the meta-analyses to population-based studies, to studies including only patients diagnosed using the most widely accepted definitions of PCOS, only menopausal women or only women not submitted to ovarian surgery, and studies in which patients and controls presented with similar indexes of weight excess. Quality of evidence was assessed using the GRADE system. OUTCOMES: The initial search identified 1400 articles, and another six were included from the reference lists of included articles; 476 duplicates were deleted. We excluded 868 articles for different reasons, leaving 37 valid studies for the qualitative synthesis, of which 28 studies-published in 41 articles-were considered for the quantitative synthesis and meta-analyses. Another nine studies were included only in the qualitative analyses. Compared with controls, peri- and postmenopausal patients with PCOS presented increased circulating total testosterone (standardized mean difference, SMD 0.78 (0.35, 1.22)), free androgen index (SMD 1.29 (0.89, 1.68)), and androstenedione (SMD 0.58 (0.23, 0.94)), whereas their sex hormone-binding globulin was reduced (SMD -0.60 (-0.76, -0.44)). Women with PCOS showed increased BMI (SMD 0.57 (0.32, 0.75)), waist circumference (SMD 0.64 (0.42, 0.86)), and waist-to-hip ratio (SMD 0.38 (0.14, 0.61)) together with increased homeostasis model assessment of insulin resistance (SMD 0.56 (0.27, 0.84)), fasting insulin (SMD 0.61 (0.38, 0.83)), fasting glucose (SMD 0.48 (0.29, 0.68)), and odds ratios (OR, 95% CI) for diabetes (OR 3.01 (1.91, 4.73)) compared to controls. Women with PCOS versus controls showed decreased HDL concentrations (SMD -0.32 (-0.46, -0.19)) and increased triglycerides (SMD 0.31 (0.16, 0.46)), even though total cholesterol and LDL concentrations, as well as the OR for dyslipidaemia, were similar to those of controls. The OR for having hypertension was increased in women with PCOS compared with controls (OR 1.79 (1.36, 2.36)). Albeit myocardial infarction (OR 2.51 (1.08, 5.81)) and stroke (OR 1.75 (1.03, 2.99)) were more prevalent in women with PCOS than controls, the ORs for cardiovascular disease as a whole, coronary artery disease as a whole, breast cancer and age at menopause, were similar in patients and controls. When restricting meta-analysis to studies in which women with PCOS and controls had a similar mean BMI, the only difference that retained statistical significance was a decrease in HDL-cholesterol concentration in the former and, in the two studies in which postmenopausal women with PCOS and controls had similar BMI, patients presented with increased serum androgen concentrations, suggesting that hyperandrogenism persists after menopause, regardless of obesity. WIDER IMPLICATIONS: Hyperandrogenism appeared to persist during the late-reproductive years and after menopause in women with PCOS. Most cardiometabolic comorbidities were driven by the frequent coexistence of weight excess and PCOS, highlighting the importance of targeting obesity in this population. However, the significant heterogeneity among included studies, and the overall low quality of the evidence gathered here, precludes reaching definite conclusions on the issue. Hence, guidelines derived from adequately powered prospective studies are definitely needed for appropriate management of these women.

Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism and masculinization of intermediate metabolism in women with polycystic ovary syndrome (PCOS).

BACKGROUND: The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the art proton nuclear magnetic resonance spectroscopy metabolomics profiling, that androgen excess in women induces also a certain masculinization of intermediate metabolism that is modulated by obesity. METHODS: Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected in order to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity defined by a body mass index ≥ 30 kg/m2. Subjects maintained the same diet unrestricted in carbohydrates for 3 days before sampling and maintained their lifestyle and exercise patterns prior and during the study. Plasma samples were submitted to proton nuclear magnetic resonance spectroscopy metabolomics profiling. RESULTS: Obesity associated a metabolomics profile mainly characterized by increased branched chain and aromatic aminoacids. Regardless of obesity, this unfavorable profile also characterized men as compared with control women, and was shared by women with PCOS. Notably, the negative impact of obesity on metabolomics profile was restricted to women, with obese men showing no further deterioration when compared with their non-obese counterparts. CONCLUSIONS: Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism, and masculinization of intermediate metabolism in women with PCOS, further suggesting a role for sex and sex hormones in the regulation of intermediate metabolism.

Serum metabolomics profiling by proton nuclear magnetic resonance spectrometry of the response to single oral macronutrient challenges in women with polycystic ovary syndrome (PCOS) compared with male and female controls.

BACKGROUND: The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the-art proton nuclear magnetic resonance spectrometry (1H-NMRS) metabolomics profiling, that androgen excess in women induces a certain masculinization of postprandial metabolism that is modulated by obesity. MATERIALS AND METHODS: Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity. Patients were submitted to isocaloric separate glucose, lipid and protein oral challenges in alternate days and fasting and postprandial serum samples were submitted to 1H-NMRS metabolomics profiling for quantification of 36 low-molecular-weight polar metabolites. RESULTS: The largest postprandial changes were observed after glucose and protein intake, with lipid ingestion inducing smaller differences. Changes after glucose intake consisted of a marked increase in carbohydrates and byproducts of glycolysis, and an overall decrease in byproducts of proteolysis, lipolysis and ketogenesis. After the protein load, most amino acids and derivatives increased markedly, in parallel to an increase in pyruvate and a decrease in 3-hydroxybutyric acid and glycerol. Obesity increased ß- and D-glucose and pyruvate levels, with this effect being observed mostly after glucose ingestion in women with PCOS. Regardless of the type of macronutrient, men presented increased lysine and decreased 3-hydroxybutyric acid. In addition, non-obese men showed increased postprandial ß-glucose and decreased pyroglutamic acid, compared with non-obese control women. We observed a common pattern of postprandial changes in branched-chain and aromatic amino acids, where men showed greater amino acids increases after protein intake than control women and patients with PCOS but only within the non-obese participants. Conversely, this increase was blunted in obese men but not in obese women, who even presented a larger increase in some amino acids compared with their non-obese counterparts. Interestingly, regardless of the type of macronutrient, only obese women with PCOS showed increased leucine, lysine, phenylalanine and tryptophan levels compared with non-obese patients. CONCLUSIONS: Serum 1H-NMRS metabolomics profiling indicated sexual dimorphism in the responses to oral macronutrient challenges, which were apparently driven by the central role of postprandial insulin effects with obesity, and to a lesser extent PCOS, exerting modifying roles derived from insulin resistance. Hence, obesity impaired metabolic flexibility in young adults, yet sex and sex hormones also influenced the regulation of postprandial metabolism.

The polycystic ovary syndrome (PCOS) is a common endocrine disorder in women. PCOS is associated with diabetes, obesity and cardiometabolic disease. Mild excess of androgens (male hormones) characterize PCOS, and facilitate that body fat accumulates in the visceral abdominal area. Visceral fat promotes insulin resistance increasing the risk for diabetes and cardiometabolic disease, and further androgen excess. We here explored intermediate metabolism after the separate administration of either carbohydrates, fats or proteins, in young adult women with or without PCOS and in men, using state-of-the-art proton nuclear magnetic resonance metabolomics profiling. Results suggest that postprandial metabolomics profiles reflect mostly insulin actions, with changes derived from insulin resistance being more important with obesity but also being influenced by male sex and PCOS in women.

"Arterial stiffness is not associated with changes in the circadian pattern of blood pressure in patients with type 1 diabetes mellitus and cardiovascular autonomic dysfunction".

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 (ß: ‒ 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.

Switching to an advanced hybrid closed-loop system in real-world practice improves hypoglycemia awareness and metabolic control in adults with type 1 diabetes, particularly in those with impaired perception of hypoglycemia symptoms.

AIMS: To evaluate the efficacy of an advance closed-loop (AHCL) system in restoring awareness of hypoglycemia in patients with type 1 diabetes (T1D). METHODS: We conducted a prospective study including 46 subjects with T1D flash glucose monitoring (FGM) or continuous glucose monitoring (CGM) switching to a Minimed 780G® system. Patients were classified in three groups according to the therapy used before switching to Minimed® 780G: multiple dose insulin (MDI) therapy + FGM (n = 6), continuous subcutaneous insulin infusion + FGM (n = 21), and sensor-augmented pump with predictive low-glucose suspend (n = 19). FGM/CGM data were analyzed at baseline, after 2 and 6 months on AHCL. Clarke's score of hypoglycemia awareness was compared at baseline and 6 months recordings. We also compared the efficacy of the AHCL system in improving A1c among patients with appropriate perception of symptoms of hypoglycemia compared to those presenting with impaired awareness of hypoglycemia (IAH). RESULTS: Participants had a mean age of 37 ± 15 and a diabetes duration of 20 ± 10 years. At baseline, 12 patients (27%) showed IAH as defined by a Clarke's score ≥ 3. Patients with IAH were older and had lower estimated glomerular filtration rate (eGFR) compared with those who did not have IAH; with no differences in baseline CGM metrics or A1c. An overall decrease in A1c was observed after 6 months on AHCL system (from 6.9 ± 0.5% to 6.7 ± 0.6%, P < 0.001), regardless of prior insulin therapy. The improvement in metabolic control was greater in patients with IAH, showing a reduction in A1c from 6.9 ± 0.5 to 6.4 ± 0.4% vs 6.9 ± 0.5 to 6.8 ± 0.6% (P = 0.003), showing a parallel increase in total daily boluses of insulin and automatic bolus correction administered by the AHCL system. In patients with IAH Clarke's score decreased from 3.6 ± 0.8 at baseline to 1.9 ± 1.6 after 6 months (P < 0.001). After 6 months on AHCL system, only 3 patients (7%) presented with a Clarke's score ≥ 3, resulting in an absolute risk reduction of 20% (95% confidence interval: 7-32) of having IAH. CONCLUSIONS: Switching from any type of insulin administration to AHCL system improves restoration of hypoglycemia awareness and metabolic control in patients with T1D, particularly in adults with impaired perception of hypoglycemia symptoms. TRIAL REGISTRATION: ClinicalTrial.gov ID NCT04900636.

Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: plasma metabolomic approach using GC-MS.

BACKGROUND: Abdominal adiposity and obesity influence the association of polycystic ovary syndrome (PCOS) with insulin resistance and diabetes. We aimed to characterize the intermediate metabolism phenotypes associated with PCOS and obesity. METHODS: We applied a nontargeted GC-MS metabolomic approach to plasma samples from 36 patients with PCOS and 39 control women without androgen excess, matched for age, body mass index, and frequency of obesity. RESULTS: Patients with PCOS were hyperinsulinemic and insulin resistant compared with the controls. The increase in plasma long-chain fatty acids, such as linoleic and oleic acid, and glycerol in the obese patients with PCOS suggests increased lipolysis, possibly secondary to impaired insulin action at adipose tissue. Conversely, nonobese patients with PCOS showed a metabolic profile consisting of suppression of lipolysis and increased glucose utilization (increased lactic acid concentrations) in peripheral tissues, and PCOS patients as a whole showed decreased 2-ketoisocaproic and alanine concentrations, suggesting utilization of branched-chain amino acids for protein synthesis and not for gluconeogenesis. These metabolic processes required effective insulin signaling; therefore, insulin resistance was not universal in all tissues of these women, and different mechanisms possibly contributed to their hyperinsulinemia. PCOS was also associated with decreased α-tocopherol and cholesterol concentrations irrespective of obesity. CONCLUSIONS: Substantial metabolic heterogeneity, strongly influenced by obesity, underlies PCOS. The possibility that hyperinsulinemia may occur in the absence of universal insulin resistance in nonobese women with PCOS should be considered when designing diagnostic and therapeutic strategies for the management of this prevalent disorder.

High serum copeptin may be a marker of an increased carotid intima-media thickness in asymptomatic patients with type 1 diabetes.

We aimed to study the association of copeptin with carotid intima-media thickness in 60 patients with type 1 diabetes (T1DM-patients). Our results suggest that copeptin might improve the stratification of cardiovascular risk in T1DM-patients. Further research is needed to determine the value in identifying carotid disease of this biochemical marker.

Point-of-care sural nerve conduction could predict the presence of cardiovascular autonomic neuropathy in type 1 diabetes mellitus.

AIMS: Assessment for cardiovascular autonomic neuropathy (CAN) in patients with type 1 diabetes mellitus remains time-consuming in the clinical setting. We aimed to examine the diagnostic performance of a portable point-of-care diagnostic tool (POCD) for assessing sural nerve conduction during the screening of CAN. METHODS: Nerve amplitude (AMPPOCD ) and conduction velocity (CVPOCD ) were measured in a cross-sectional study including 198 asymptomatic patients with type 1 diabetes. CAN was diagnosed by the Ewing score and power spectral heart rate [low-frequency (LF) and high-frequency (HF) activity]. Diagnostic accuracy was determined by ROC curves. RESULTS: CVPOCD and AMPPOCD showed positive correlations with LF and HF, and a negative correlation with age. Overall, AMPPOCD had an 81.7% accuracy in identifying CAN [AUC = 0.817 (95% CI 0.692-0.942)] with an AMPPOCD ≤6 µV showing 90% sensitivity and 73% specificity. In a stepwise binary logistic regression analysis, the model (R2 : 0.297; P < 0.001) retained the duration of type 1 diabetes [ß: 1.131 (95% CI: 1.051-1.216); P = 0.001) and A1c [ß: 2.131 (95% CI: 1.060-4.283); P = 0.034) as significant predictors of CAN. The combination of AMPPOCD ≤6 µV + a type 1 diabetes duration of ≥8 years maximized the sensitivity, showing a diagnostic performance of 87% [AUC = 0.867 (95% CI 0.769-0.965)] with 90%, 76%, and 99%, sensitivity, specificity, and NPV, respectively. Adding A1c ≥ 7% to this model maintained accuracy [AUC = 0.867 (95% CI: 0.788-0.963) and NPV (99%), while increasing specificity to 84%. CONCLUSIONS: The combination of AMPPOCD with A1c and the duration of type 1 diabetes mellitus showed a good performance for the detection of asymptomatic CAN, making POCD an easy and rapid test for its routine screening in the clinical setting.

Prevalence of PCOS and related hyperandrogenic traits in premenopausal women with type 1 diabetes: a systematic review and meta-analysis.

BACKGROUND: An increased prevalence of functional hyperandrogenism-including polycystic ovary syndrome (PCOS)-has been described in women with type 1 diabetes (T1D). However, heterogeneity between studies is frequent, and prevalence rates vary according to different criteria used for the diagnosis of PCOS and the population studied. OBJECTIVE AND RATIONALE: We aimed to perform a systematic review and meta-analysis of the prevalence of PCOS and related hyperandrogenic traits in premenopausal women with T1D. This way, we intend to increase the precision of the estimates of prevalence of PCOS and related traits in women with T1D, and to explore sources of heterogeneity while providing prevalence estimates for clinically relevant subgroups such as the different phenotypes. SEARCH METHODS: We conducted a systematic review of the literature using Medline-OVID and Embase databases (Open Science Framework registry for systematic review protocols, https://osf.io/6cv9p/). Studies published up to 29 March 2021 were considered. We selected cross-sectional or prospective studies that reported, in patients with T1D, prevalence data on PCOS according to current definitions and different phenotypes, and/or prevalence rates of other related traits (hirsutism, hyperandrogenaemia, oligo-amenorrhoea and/or polycystic ovarian morphology: PCOM). Exclusion criteria for the review were studies addressing types of diabetes other than T1D; and studies using diagnostic definitions of PCOS different than those mentioned above. Two independent researchers performed data extraction. To assess the risk of bias, we used a tool developed specifically to appraise population-based prevalence studies. OUTCOMES: We selected 19 studies (1042 women) reporting the prevalence of PCOS and/or other hyperandrogenic traits. Regarding bias, 12 studies were considered of low-risk, and the remaining seven studies were considered intermediate risk. The pooled prevalence of PCOS when considering all possible phenotypes (ESHRE- American Society for Reproductive Medicine criteria) in T1D was 26% (95% CI: 19-34%; 13 studies, 684 women). Pooled prevalence of classic PCOS (US National Institutes of Health criteria) was 16% (95% CI: 10-22%; 9 studies, 614 women). Pooled prevalence of hyperandrogenic PCOS (Androgen Excess and PCOS Society criteria) was 26% (95% CI: 16-41%; 5 studies, 329 women). Hirsutism (24%), hyperandrogenaemia (29%), oligomenorrhoea (24%) and PCOM (34%) were also prevalent. Heterogeneity was high in almost all these meta-analyses. WIDER IMPLICATIONS: This systematic review and meta-analysis showed that PCOS and related hyperandrogenic traits are present in approximately one in every four women with T1D. Larger studies are needed to confirm this association, to address the effect of different variables on the occurrence of PCOS.