Diagnostic accuracy of Afirma Gene Expression Classifier, Afirma Gene Sequencing Classifier, ThyroSeq v2 and ThyroSeq v3 for indeterminate (Bethesda III and IV) thyroid nodules: a meta-analysis.

OBJECTIVE: The management of thyroid nodules with indeterminate cytology (ITN) is still a challenge. To evaluate the performance of commercial molecular tests for ITN, we performed this comprehensive meta-analysis. METHODS: We performed an electronic search using PubMed/Medline, Embase and the Cochrane Library. Studies assessing the diagnostic accuracy of Afirma Gene Expression Classifier (GEC), Afirma Gene Sequencing Classifier (GSC), ThyroSeq v2 (TSv2) or ThyroSeq v3 (TSv3) in patients with ITN (only Bethesda category III or IV) were selected; Statistical analyses were performed by using Stata. RESULTS: 71 samples (GEC, n=38; GSC, n=16; TSv2, n=9; TSv3, n=8) in 53 studies, involving 6,490 fine needle aspirations (FNA) with ITN cytology with molecular diagnostics (GEC, GSC, TSv2 or TSv3) were included in the study. Meta-analysis showed the following pooled estimates: sensitivity 0.95 (95% CI, 0.94-0.97), specificity 0.35 (0.28-0.43), Positive Likelihood Ratio (LR+) 1.5 (1.3-1.6), and Negative Likelihood Ratio (LR-) 0.13 (0.09-0.19), with the best performance for TSv3 (area under the ROC curve 0.95 (0.93-0.96), followed by TSv2 (0.90 (0.87-0.92)), GSC (0.86 (0.82-0.88)) and GEC (0.82 (0.78-0.85)); with the best rule-out property for GSC (LR-, 0.07 (0.02-0.19)), followed by TSv3 (0.11 (0.05-0.24)) and GEC (0.16 (0.10-0.28); with the best rule-in for TSv2 (LR+, 2,9 (1.4-4.6)), followed by GSC (1.9 (1.6-2.4)). Meta-regression analysis revealed that study design, Bethesda category, and type of molecular test were independent factors. CONCLUSIONS: We showed that in patients with ITN, TSv3 has the best molecular diagnostic performance, followed by TSv2, GSC, and GEC. For rule-out malignancy, GSC, and for rule-in, TSV2 is superior to other tests.

Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled Trials.

CONTEXT: Few meta-analyses on incidence of endocrine immune-related adverse effects (eirAEs) have been published and many trials have been published since. OBJECTIVE: We performed a comprehensive meta-analysis with updated literature to assess risk and incidence of eirAEs of any grade and grade 3 to 5 by immune checkpoint inhibitor (ICI) monotherapy or combination therapy in solid tumors. METHODS: An electronic search using PubMed/Medline, Embase, and the Cochrane Library was performed. Randomized controlled studies (RCTs) assessing eirAEs under ICI monotherapy or ICI combination therapy were selected. Stata software (v17) was used for statistical analyses and risk of bias was evaluated using Review Manager version 5.3. RESULTS: A total of 69 RCTs with 80 independent reports, involving 42 886 patients, were included in the study. Meta-analysis revealed the following pooled estimates for risk ratio and incidence, respectively: for any grade hypothyroidism 7.81 (95% CI, 5.68-10.74, P < .0001) and 7.64% (95% CI, 6.23-9.17, P < .0001); significantly increased also for hyperthyroidism, hypophysitis/hypopituitarism, and adrenal insufficiency; and for insulin-dependent diabetes mellitus 1.52 (95% CI, 1.07-2.18, P = .02), and 0.087% (95% CI, 0.019-0.189, P = .0006), respectively. Meta-regression showed that combination of ICIs (nivolumab plus ipilimumab; durvalumab plus tremelimumab) is an independent risk factor for any grade hypophysitis/hypopituitarism, and that ICI agent is an independent factor of risk for adrenal insufficiency, but that cancer type is not an independent risk factor for eirAEs. CONCLUSION: We showed that risk, independent from cancer type, and incidence of eirAEs are substantially increased with ICI therapy. Combination of ICIs increases risk for eirAEs, especially for hypophysitis/hypopituitarism.

[Polycystic ovary syndrome as a gender-specific cardiometabolic risk factor]. / Das polyzystische Ovarsyndrom als genderspezifischer kardiometabolischer Risikofaktor.

With a prevalence of 15%, polycystic ovary syndrome (PCOS) is the most common endocrinopathy in fertile-aged women. Insulin resistance and obesity play a pivotal role in the pathophysiology of PCOS, modulate the severity of symptoms and are associated with an increased risk for cardiometabolic sequelae such as diabetes, non-alcoholic fatty liver disease and atherosclerotic cardiovascular disease. PCOS should be considered as a gender-specific cardiovascular risk factor. Therefore, if traits indicative for PCOS are present, affected women should undergo PCOS diagnostics as a first step, thereby making it possible to initiate cardiovascular primary prevention strategies in this population of young women at high cardiometabolic risk. In women with known PCOS, screening and treatment of cardiometabolic risk factors and/or diseases should be routinely integrated into the concept of PCOS care. The close link between insulin resistance/obesity and PCOS can be used to improve PCOS-specific symptoms and enhance cardiometabolic health.

Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals.

Context: The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. Objective: We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. Methods: Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes. Results: Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033). Conclusion: Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.

Continuous Glucose Monitoring of Steroid-Induced Hyperglycemia in Patients With Dermatologic Diseases.

BACKGROUND AND OBJECTIVES: Systemic administration of glucocorticoids is a mainstay therapy for various inflammatory diseases and may lead to hyperglycemia, which carries the risk of worsening preexisting diabetes and triggering steroid-induced diabetes. Therefore, we aimed to identify patients at risk and to quantify severity of steroid-induced hyperglycemia (SIH) by continuous glucose monitoring (CGM) in hospitalized patients needing systemic glucocorticoid treatment. PATIENTS AND METHODS: This prospective study included 51 steroid-naive, dermatological patients requiring systemic high-dose glucocorticoid treatment at the Department of Dermatology of the University Hospital Essen. After careful diabetes-specific assessment at admission, glucose monitoring was performed using a CGM system and glucose profile was analyzed in patients with and without SIH. RESULTS: SIH occurred in 47.1% of all treated patients, and a relevant part of patients with initial normoglycemia developed SIH (2/10 patients). Doubling of SIH incidence was observed with each severity grade of dysglycemia (4/10 in prediabetes; 9/10 in diabetes). Patients with SIH spend nearly 6 hours daily above targeted glucose range, and severe hyperglycemia was observed for 1.2 hours/day. CONCLUSIONS: Our study underlines the need for dedicated glucose monitoring in dermatologic patients on systemic glucocorticoid therapy by demonstrating its impact on glucose metabolism.

Implications of an HbA1c-based Diabetes Screening on Prevalence and Effect of Dysglycemia in Patients With COVID-19.

CONTEXT: In patients with severe acute respiratory syndrome coronavirus type 2 infection, diabetes is associated with poor COVID-19 prognosis. However, case detection strategy is divergent and reported prevalence varies from 5% to 35%. OBJECTIVE: We examined how far the choice of screening tools affects the detection rate of dysglycemia and in consequence the estimation of diagnosis-associated risk for moderate (mo) or severe (s) COVID-19. METHODS: Non-intensive care unit inpatients with COVID-19 were screened systematically at admission for diabetes (D) and prediabetes (PreD) by glycated hemoglobin A1c (HbA1c) (A), random blood glucose (B), and known history (C) from November 1, 2020 to March 8, 2021. Dysglycemia rate and effect on COVID-19 outcome were analyzed in 2 screening strategies (ABC vs BC). RESULTS: A total of 578 of 601 (96.2%) of admitted patients were screened and analyzed. In ABC, prevalence of D and PreD was 38.2% and 37.5%, respectively. D was significantly associated with an increased risk for more severe COVID-19 (adjusted odds ratio [aOR] [moCOVID-19]: 2.27, 95% CI, 1.16-4.46 and aOR [sCOVID-19]: 3.26, 95% CI, 1.56-6.38). Patients with PreD also presented more often with more severe COVID-19 than those with normoglycemia (aOR [moCOVID-19]: 1.76, 95% CI, 1.04-2.97 and aOR [sCOVID-19]: 2.41, 95% CI, 1.37-4.23). Screening with BC failed to identify only 96% of PreD (206/217) and 26.2% of D diagnosis (58/221) and missed associations of dysglycemia and COVID-19 severity. CONCLUSION: Pandemic conditions may hamper dysglycemia detection rate and in consequence the awareness of individual patient risk for COVID-19 severity. A systematic diabetes screening including HbA1c reduces underdiagnosis of previously unknown or new-onset dysglycemia, and enhances the quality of risk estimation and access of patients at risk to a diabetes-specific intervention.

High-Protein, Low-Glycaemic Meal Replacement Improves Physical Health-Related Quality of Life in High-Risk Persons for Metabolic Syndrome-A Subanalysis of the Randomised-Controlled ACOORH Trial.

While obesity impairs health-related quality of life (HRQOL), lifestyle interventions targeting weight reduction have been effective in improving HRQOL. Therefore, we hypothesised that a meal replacement-based lifestyle intervention, which has been shown to successfully reduce weight, would also improve HRQOL more effectively than a lifestyle intervention alone. In the international, multicenter, randomised-controlled ACOORH-trial (Almased-Concept-against- Overweight-and-Obesity-and-Related-Health-Risk), overweight or obese participants with elevated risk for metabolic syndrome (n = 463) were randomised into two groups. Both groups received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement for 6 months. HRQOL was estimated at baseline, after 3 and 12 months, using the SF-36 questionnaire, and all datasets providing HRQOL data (n = 263) were included in this predefined subanalysis. Stronger improvements in the physical component summary (PCS) were observed in the intervention compared to the control group, peaking after 3 months (estimated treatment difference 2.7 [1.2; 4.2]; p < 0.0001), but also in the long-term. Multiple regression analysis demonstrated that insulin levels and the achieved weight loss were associated with the mental component summary (MCS) after 12 months (p < 0.05). Thus, meal replacement-based lifestyle intervention is not only effective in weight reduction but, concomitantly, in enhancing HRQOL.

Early and Strong Leptin Reduction Is Predictive for Long-Term Weight Loss during High-Protein, Low-Glycaemic Meal Replacement-A Subanalysis of the Randomised-Controlled ACOORH Trial.

Lifestyle interventions including meal replacement are suitable for prevention and treatment of obesity and type-2-diabetes. Since leptin is involved in weight regulation, we hypothesised that a meal replacement-based lifestyle intervention would reduce leptin levels more effectively than lifestyle intervention alone. In the international, multicentre, randomised-controlled ACOORH-trial (Almased-Concept-against-Overweight-and-Obesity-and-Related- Health-Risk), overweight or obese participants with metabolic syndrome criteria (n = 463) were randomised into two groups and received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement. Data were collected at baseline, after 1, 3, 6, and 12 months. All datasets providing leptin data (n = 427) were included in this predefined subanalysis. Serum leptin levels significantly correlated with sex, body mass index, weight, and fat mass at baseline (p < 0.0001). Stronger leptin reduction has been observed in the intervention compared to the control group with the lowest levels after 1 month of intervention (estimated treatment difference −3.4 µg/L [1.4; 5.4] for females; −2.2 µg/L [1.2; 3.3] for males; p < 0.001 each) and was predictive for stronger reduction of body weight and fat mass (p < 0.001 each) over 12 months. Strongest weight loss was observed after 6 months (−5.9 ± 5.1 kg in females of the intervention group vs. −2.9 ± 4.9 kg in the control group (p < 0.0001); −6.8 ± 5.3 kg vs. −4.1 ± 4.4 kg (p = 0.003) in males) and in those participants with combined leptin and insulin decrease. A meal replacement-based lifestyle intervention effectively reduces leptin which is predictive for long-term weight loss.

Rapid amelioration of anorexia nervosa in a male adolescent during metreleptin treatment including recovery from hypogonadotropic hypogonadism.

With this case report we support our medical hypothesis that metreleptin treatment ameliorates starvation related emotional, cognitive and behavioral symptomatology of anorexia nervosa (AN) and show for the first time strong effects in a male patient with AN. A 15.9 year old adolescent with severe AN of eight-month duration was treated off-label with metreleptin. Hyperactivity was assessed with accelerometry. Visual analogue scales (VAS), validated self- and clinician rating scales and lab results tracked changes from baseline to end of the 24-day dosing period and a five-month follow-up. Substantial improvements of mood and eating disorder related cognitions and hyperactivity set in after two days of treatment. During dosing, sub-physiological testosterone and TT3 levels normalized; clinically libido reemerged. Weight did not increase substantially during the dosing period. During follow-up target weight was attained; mood did not deteriorate; hyperactivity ceased. The results substantiate the strong effects seen in female cases and underscore the need for a double-blind placebo-controlled trial to confirm the observed strong, multiple and rapid onset beneficial effects of metreleptin in AN.

Mental health burden of patients with diabetes before and after the initial outbreak of COVID-19: predictors of mental health impairment.

BACKGROUND: The COVID-19 pandemic is affecting people's mental health worldwide. Patients with diabetes are at risk for a severe course of illness when infected with SARS-CoV-2. The present study aims to retrospectively examine mental health changes in patients with diabetes in Germany before and after the initial COVID-19 outbreak, and to furthermore explore potential predictors of such changes. METHODS: Over the course of eight weeks from April to June 2020, 253 individuals diagnosed with diabetes participated in an online cross-sectional study. Participants completed an anonymous survey including demographics, depression (PHQ-2) and generalized anxiety symptoms (GAD-2), distress (DT), and health status (EQ-5D-3L). In addition, all instruments used were modified to retrospectively ask participants to recall their mental health and health status before the outbreak had started. Additionally examined factors were COVID-19-related fear, trust in governmental actions to face the pandemic, and the subjective level of information about COVID-19. RESULTS: This study shows a significant increase in prevalence of depression symptoms, generalized anxiety symptoms and distress, as well as significantly decreased health statuses in diabetes patients after the initial COVID-19 outbreak. Increased depression symptoms, generalized anxiety symptoms and distress were predicted by COVID-19-related fear, whereas trust in governmental actions to face COVID-19 predicted higher depression symptoms. CONCLUSIONS: The results indicate a negative impact of the initial COVID-19 outbreak on mental health and health status in patients with diabetes. In order to improve the efficacy of psychological support strategies for diabetes patients during the pandemic, possible predictors of mental health impairment such as the aforementioned should be examined more thoroughly and addressed more openly.

Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double-blind, phase 2 trial.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

High-Protein, Low-Glycaemic Meal Replacement Decreases Fasting Insulin and Inflammation Markers-A 12-Month Subanalysis of the ACOORH Trial.

Lifestyle interventions, including meal replacement, are effective in the prevention and treatment of type-2-diabetes and obesity. Since insulin is the key weight regulator, we hypothesised that the addition of meal replacement to a lifestyle intervention reduces insulin levels more effectively than lifestyle intervention alone. In the international multicentre randomised controlled ACOORH (Almased Concept against Overweight and Obesity and Related Health Risk) trial, overweight or obese persons who meet the criteria for metabolic syndrome (n = 463) were randomised into two groups. Both groups received nutritional advice focusing on carbohydrate restriction and the use of telemonitoring devices. The intervention group substituted all three main meals per day in week 1, two meals per day in weeks 2-4, and one meal per day in weeks 5-26 with a protein-rich, low-glycaemic meal replacement. Data were collected at baseline and after 1, 3, 6 and 12 months. All datasets providing insulin data (n = 446) were included in this predefined subanalysis. Significantly higher reductions in insulin (-3.3 ± 8.7 µU/mL vs. -1.6 ± 9.8 µU/mL), weight (-6.1 ± 5.2 kg vs. -3.2 ± 4.6 kg), and inflammation markers were observed in the intervention group. Insulin reduction correlated with weight reduction and the highest amount of weight loss (-7.6 ± 4.9 kg) was observed in those participants with an insulin decrease > 2 µU/mL. These results underline the potential for meal replacement-based lifestyle interventions in diabetes prevention, and measurement of insulin levels may serve as an indicator for adherence to carbohydrate restriction.

COVID-19-Related Fear, Risk Perception, and Safety Behavior in Individuals with Diabetes.

(1) The aim of the study is to assess the psychological burden of individuals with diabetes during the COVID-19 pandemic in comparison to matched controls. (2) Over the course of eight weeks, 9 April to 3 June 2020, 253 individuals with diabetes and 253 matched controls, using Propensity Score Matching (PSM), participated in this cross-sectional study. Participants completed an anonymous survey including demographics, depressive symptoms (PHQ-2), generalized anxiety (GAD-7), COVID-19-related fear, risk perception, and safety behavior. (3) While patients with diabetes expected their risk of infection similar to controls, they reported a higher probability of the occurrence of symptoms, severe course, and dying of COVID-19. Patients with diabetes showed no elevated generalized anxiety or depressive symptoms. However, they reported higher COVID-19-related fear and more adherent and dysfunctional safety behavior compared to controls. (4) From a public health view, it seems encouraging that despite the somatic risk condition, generalized anxiety and depression are not higher in patients with diabetes than in controls. Patients with diabetes report higher COVID-19-related fear, increased risk perception, and behavioral changes. This suggests that individuals with diabetes, as a significant risk group of severe COVID-19, show an adequate perception and functional reaction to the current pandemic.

Association between albuminuria and thyroid function in patients with chronic kidney disease.

PURPOSE: The relationship between proteinuria and thyroid function remains controversial in patients with chronic kidney disease (CKD). We prospectively investigated the association between kidney and thyroid function in thyroid antibody-negative patients through all CKD stages. METHODS: We enrolled 184 nondialysis patients (mean age: 63.1 ± 16.9 years) without previous thyroid disease or thyroid-specific antibodies. Kidney function was assessed by estimating the glomerular filtration rate (eGFR) classified according KDIGO (CKD G1-5). Kidney damage was assessed by albuminuria (albumin-to-creatinine ratio, ACR) and classified as mild, moderate, or severe (ACR1: <300, ACR2: 300-3000, and ACR3: 3000 mg/g). To evaluate thyroid function, TSH, T4, fT4, T3, fT3, reverse T3 (rT3), and thyroxine-binding globulin (TBG) were measured. RESULTS: rT3 concentrations correlated negatively with albuminuria (r = -0.286, p < 0.001) and were significantly lower in patients with severe albuminuria than in those with mild or moderate albuminuria (ACR3: 0.28 vs. ACR2: 0.32 vs. ACR1: 0.36 nmol/l, p < 0.001). The severity of albuminuria revealed no impact on TSH, fT4, T3, fT3, and TBG. EGFR correlated with increasing T4, fT4, T3, fT3, and TBG (T4: r = 0.289, p < 0.01; fT4: r = 0.196, p < 0.01; T3: r = 0.408, p < 0.01; fT3: r = 0.390, p < 0.01) but not with rT3. CONCLUSIONS: In thyroid antibody-negative patients presenting advanced CKD (stages 4 and 5), even severe kidney protein loss failed to influence thyroid hormone status. However, albuminuria severity correlated negatively with rT3, which was significantly lower in patients with albuminuria in the nephrotic range.

Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects.

To examine the hypothesis that normalization of low circulating leptin levels in patients with anorexia nervosa ameliorates hyperactivity, three seriously ill females with hyperactivity were treated off-label with metreleptin (recombinant human leptin) for up to 14 days. Drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased in two patients. Surprisingly, depression improved rapidly in all patients. No serious adverse events occurred. Due to obvious limitations of uncontrolled case series, placebo-controlled clinical trials are mandatory to confirm the observed rapid onset of beneficial effects. Our findings suggest an important role of hypoleptinemia in the mental and behavioral phenotype of anorexia nervosa.

Prediabetes Conversion to Normoglycemia Is Superior Adding a Low-Carbohydrate and Energy Deficit Formula Diet to Lifestyle Intervention-A 12-Month Subanalysis of the ACOORH Trial.

Lifestyle interventions have been shown to reverse hyperglycemia to normoglycemia. However, these effects are not long-lasting and are accompanied with high dropout rates. As formula diets have been shown to be simple in usage and effective in improving glycemic control, we hypothesised that adding a low-carbohydrate and energy deficit formula diet to a low-intensity lifestyle intervention is superior in reversing prediabetes compared with lifestyle intervention alone. In this predefined subanalysis of an international, multicenter randomised controlled trial (Almased Concept against Overweight and Obesity and Related Health Risk (ACOORH) study (ID DRKS00006811)), 141 persons with prediabetes were randomised (1:2) into either a control group with lifestyle intervention only (CON, n = 45) or a lifestyle intervention group accompanied with a formula diet (INT, n = 96). Both groups were equipped with telemonitoring devices. INT received a low-carbohydrate formula diet substituting three meals/day (~1200 kcal/day) within the first week, two meals/day during week 2-4, and one meal/day during week 5-26 (1300-1500 kcal/day). Follow-up was performed after 52 weeks and 105 participants (75%, INT: n = 74; CON: n = 31) finished the 26-week intervention phase. Follow-up data after 52 weeks were available from 93 participants (66%, INT: n = 65; CON: n = 28). Compared with CON, significantly more INT participants converted to normoglycemia after 52 weeks (50% vs. 31%; p < 0.05). The risk reduction led to a number-needed-to-treat of 5.3 for INT. Lifestyle intervention with a low-carbohydrate formula diet reduces prediabetes prevalence stronger than lifestyle intervention alone and is effective for type 2 diabetes prevention.

MicroRNA-183 and microRNA-96 are associated with autoimmune responses by regulating T cell activation.

MircoRNAs (miRs) are small molecules that regulate gene expression at the posttranscriptional level. They have been proposed to be involved in the regulation of several immune responses including autoimmunity. Here, we identified miR-183 and miR-96 to be highly expressed in CD4+ T cells from peripheral blood of Graves' orbitopathy (GO) patients as well as in human and murine T cells upon activation in vitro. By using Luciferase-based binding assays, we identified EGR-1 as target for miR-183 and miR-96. Overexpression of miR-183 and miR-96 in murine CD4+ T cells by retroviral gene transfer resulted in decreased EGR-1 and PTEN expression, elevated Akt phosphorylation and enhanced proliferation. In contrast, treatment of murine CD4+ T cells with specific antagomiRs increased EGR-1 and PTEN expression and interfered with the proliferative activity upon stimulation in vitro. Strikingly, adoptive transfer of miR-183 and miR-96 overexpressing antigen-specific T cells into INS-HA/Rag2KO mice accelerated the development of autoimmune diabetes, whereas transfer of antagomiR-treated cells delayed the disease onset. These results indicate that miR-183 and miR-96 have the ability to regulate the strength of T cell activation and thereby the development and severity of T cell-dependent autoimmune diseases.

Metabolic and androgen profile in underweight women with polycystic ovary syndrome.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a disorder associated with insulin resistance and obesity. Aim of our study is to clarify the prevalence of underweight in PCOS patients and whether metabolic and androgen profiles of PCOS differ depending on normal or low body weight. METHODS: Out of 1269 consecutive patients with PCOS recruited from the Department of Endocrinology and Metabolism at the University of Duisburg-Essen, 19 patients (1.5%) were underweight and were compared to 375 lean PCOS subjects (29.6%). Clinical and endocrine parameters were evaluated. Insulin resistance was assessed by 3-h oral glucose tolerance test (OGTT). RESULTS: Prevalence of type 2 diabetes and free androgen index did not differ between the two groups. Total cholesterol and low density lipoprotein levels were significantly lower in the group of underweight patients. While no significant difference was found for the Homeostasis model assessment (HOMA) index at fasting state, the HOMA-M120, calculated 2 h after glucose intake in OGTT, was significantly higher in underweight patients. Underweight patients also showed significantly higher postprandial insulin secretion after glucose intake in OGTT. Six underweight PCOS patients received metformin treatment for oligomenorrhea. An improvement of the menstrual cycle was observed in three cases, while two patients were lost to follow up and one discontinued therapy due to side effects. CONCLUSIONS: The prevalence of underweight in patients with PCOS is very low. Underweight in PCOS is associated with higher postprandial insulin levels. Several of our underweight patients were able to achieve regular menstrual cycle under metformin therapy.