Body muscle-to-fat ratio gender-specific cut-off values for impaired insulin sensitivity in patients with treatment-naïve type 2 diabetes mellitus Abstract Purpose We previously reported that the body muscle-to-fat ratio (BMFR), measured using bioelectrical impedance, significantly correlated with whole-body insulin sensitivity. We examined BMFR gender-specific cut-off values for impaired insulin sensitivity in treatment-naïve type 2 diabetes mellitus (T2DM) patients. Methods Subjects included 101 untreated T2DM patients (male, 66; female, 35). We performed a hyperinsulinemic–euglycemic clamp examination to measure the steady-state glucose infusion rate (M value) as an indicator of whole-body insulin resistance. We defined the M value divided by the steady-state serum insulin value as the M/I value. We defined the existence of insulin resistance using an M/I ratio <9.0. The optimal cut-off value for BMFR was calculated by receiver operating characteristics (ROC) analysis. Results The cut-off value of the BMFR for insulin resistance was 2.75 (area under the curve [AUC] = 0.83, sensitivity 75%, and specificity 76%, P < 0.001) for males and 1.65 (AUC = 0.87, sensitivity 84%, and specificity 81%, P < 0.001) for females. Simple linear regression analysis showed that BMFR was significantly correlated with the M/I value in both genders (males, B = 0.77, P< 0.01; females, B = 0.83, P< 0.01). Conclusions BMFR cut-off values for impaired insulin sensitivity in treatment-naïve T2DM patients were 2.75 for males and 1.65 for females.

A nomogram for predicting the presence of germline mutations in pheochromocytomas and paragangliomas Abstract Purpose Up to 40% of patients with pheochromocytomas or paragangliomas (PPGLs) carry a germline mutation. This study aimed to build a nomogram using clinical information to predict the probability of germline mutation in PPGLs. Methods The data were collected from 563 patients who were diagnosed with PPGLs between 2002 and 2015. Clinical and pathologic features were assessed with a multivariable logistic regression analysis to predict the presence of germline mutations. A nomogram to predict the probability of germline mutation was constructed with R software. Discrimination and calibration were employed to evaluate the performance of the nomogram. Results By multivariate analysis, age at manifestation, bilateral, or multifocal tumors and family history were identified as independent predictors of the presence of any germline mutation. The nomogram was then developed using these three variables. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0. 841 (95% confidence interval [CI], 0.809–0.871). The calibration plot indicated that the nomogram-predicted probabilities compared very well with the actual probabilities (Hosmer–Lemeshow test: P = 0.888). Conclusion The nomogram is a valuable predictive tool for the presence of germline mutations in patients with PPGLs.

The prevalence of heterozygous CYP21A2 deficiency in patients with idiopathic acne, hirsutism, or both Abstract Purpose The purpose of this study is to assess the prevalence of heterozygous CYP21A2 mutation and analyze its correlation with clinical manifestation in patients with acne, hirsutism, or both. Methods Clinical evaluation, hormone testing, and genetic analysis of the CYP21A2 gene were performed in 60 female patients who visited department of endocrinology of Peking Union Medical College Hospital (PUMCH) for acne, hirsutism, or both from May to November of 2018. The average age of the patients was 26.72 ± 5.73 years. ACTH, Plasma cortisol, LH, FSH, PRL, estradiol, progesterone, testosterone, 17-hydroxyprogesterone (17-OHP), and dehydroepiandrosterone sulfate (DHEA-S) were measured in all participants. Polymerase chain reaction (PCR) combined with sequencing and multiplex ligation dependent probe amplification (MLPA) technique were used to detect the mutation of the CYP21A2 gene. The prevalence of CYP21A2 mutation was compared between the patients and 60 controls, as well as the data in different genetic variant database. Results A total of 8.3% (5/60) of individuals with acne, hirsutism, or both in this study were found to harbor heterozygotic CYP21A2 mutation, and the frequency was significantly higher than that in public databases. Identified mutations included V282L (n = 2), I173N (n = 1), E6 cluster [I237N, V238E, and M240K (n = 1)] and large deletion (n = 1). There was no significant difference in hormone levels between heterozygous carriers and subjects with normal CYP21A2 genes. Conclusions The prevalence of heterozygous CYP21A2 mutation detected in patients with acne, hirsutism, or both was significantly higher than in the general population. Whether the heterozygous mutation of CYP21A2 is the cause of clinical symptoms needs further assessment.

Postprandial leptin and adiponectin in response to sugar and fat in obese and normal weight individuals Abstract Purpose Adipokines produced by white adipose tissue are central in the development of lifestyle diseases. Individuals in industrialized countries spend a substantial part of life in the non-fasting, postprandial state, which is associated with increased oxidation and inflammation. The aim was to study postprandial adiponectin and leptin levels after an oral fat tolerance test (OFTT) and an oral glucose tolerance test (OGTT) in obese (OB) and healthy, normal weight individuals (NW). Methods Fifty adults with obesity (BMI ≥ 30) and 17 healthy, NW were included. Postprandial triglyceride (TG), adiponectin, and leptin levels were measured every second hour during an 8 h OFTT, and every half hour during a 2 h OGTT. Results Compared with the basal level, postprandial levels of adiponectin following OFTT showed a slight initial peak, followed by a significant decrease at 8 h, in the NW. In the OB these changes were abolished. Postprandial levels of leptin decreased significantly from basal levels in the OFTT, in the NW, whereas in the OB, leptin was unchanged except for a slight increase from 2 to 8 h. During the OGTT both adiponectin and leptin levels remained unchanged in the NW, but decreased significantly in the OB. In addition, the OB had delayed TG clearance at 6 h. Conclusions A fatty meal gives postprandial changes in the secretion of adiponectin and leptin in NW, but not in OB. Our observations indicate that a potential postprandial regulatory role of adiponectin and leptin is impaired in OB, and of importance in a more comprehensive understanding of the delayed postprandial TG clearance in obese individuals.

Clinicopathological correlations of mesenteric fibrosis and evaluation of a novel biomarker for fibrosis detection in small bowel neuroendocrine neoplasms Abstract Purpose Mesenteric fibrosis (MF) in small intestinal neuroendocrine neoplasms (SINENs) is often associated with significant morbidity and mortality. The detection of MF is usually based on radiological criteria, but no previous studies have attempted a prospective, multidimensional assessment of mesenteric desmoplasia to determine the accuracy of radiological measurements. There is also a lack of non-invasive biomarkers for the detection of image-negative MF. Methods A multidimensional assessment of MF incorporating radiological, surgical and histological parameters was performed in a prospective cohort of 34 patients with SINENs who underwent primary resection. Pre-operative blood samples were collected in 20 cases to evaluate a set of five profibrotic circulating transcripts—the “fibrosome”—that is included as an “omic” component of the NETest. Results There was a significant correlation between radiological and surgical assessments of MF (p < 0.05). However, there were several cases of image-negative MF. The NETest-fibrosome demonstrated an accuracy of 100% for the detection of microscopic MF. Conclusions The detection of MF by radiological criteria has limitations. The NETest-fibrosome is a promising biomarker for fibrosis detection and further validation of these results would be needed in larger, multicentre studies.

TLR4 knockout can improve dysfunction of β-cell by rebalancing proteomics disorders in pancreas of obese rats Abstract Purpose Studies showed that TLR4 knockout (TLR4KO) could mitigate obesity and insulin resistance induced by high-fat diet in rats. In this study, we further investigated the effects of TLR4KO on islet function and pancreatic proteomics in obese rats by high-fat diet. Methods PA-induced lipotoxicity β-cells, SD and TLR4KO rats were used in this study. iTRAQ was used to screen out meaningful differential proteins.The protein expression level was evaluated by Western blotting; the cell apoptosis was detected by TUNEL assay. Results TLR4KO could reduce inflammatory and regulate body composition in obese rats, and improve β-cells function. The quantitative analysis of protein revealed that TLR4KO rebalanced proteomics disorders in pancreas of obese rats. In addition, the pathways involved in differential proteins were mainly metabolic pathways, arachidonic acid metabolism, ECM–receptor interaction, pancreatic secretion, PI3K-Akt signaling pathway, and FoxO signaling pathway. Further analysis of protein–protein interaction (PPI) revealed that Stk39 and Ass1 interacting through Mapk14-Ywhae were node proteins and participated in inflammatory response, carboxylic acid metabolic process, and small molecule metabolic process. In vitro experiments we confirmed that silencing TLR4 can inhibit PA-induced β-cell apoptosis, insulin secretion disorders, and increase Ass1 expression. While, overexpression of Ass1 in β-cell inhibited PA or LPS-induced β-cell damage. Conclusions Our study confirmed that TLR4KO could improve dysfunction of β-cell, and the underlying mechanism might be involved in ebalancing proteomics disorders in pancreas, affecting the expression of Ass1.

Comprehensive relationships between gut microbiome and faecal metabolome in individuals with type 2 diabetes and its complications Abstract Purpose As the treatment regimens such as metformin could confound the correlation between type 2 diabetes (T2D) and gut microbiome, we should revisit the relationship between gut microbiota and T2D patients who are not currently treated with metformin. Methods The study recruited 65 T2D patients: 49 with and 16 without diabetic complications, and 35 healthy controls. We sequenced the 16S rRNA V3-V4 region of gut microbiota and detected metabolites based on liquid chromatography mass spectrometry (LC/MS) and gas chromatography mass spectrometry (GC/MS) in faecal samples. Results The composition of both the gut microbiota and faecal metabolites changed significantly with T2D patients. The abundance of Proteobacteria and the ratio of Firmicutes/Bacteroidetes were higher in T2D patients than healthy subjects, and the short chain fatty acids (SCFAs), bile acids and lipids of T2D patients were significantly disordered. Moreover, the abundances of certain SCFA-producing bacteria (Lachnospiraceae and Ruminococcaceae etc.) were significantly increased in T2D patients, while the faecal SCFAs concentrations were significantly decreased. It’s suggested that the role of SCFA-producing bacteria was not simply to produce SCFAs. Then we identified 44 microbial modules to explore the correlations between the gut microbiota and metabolic traits. Specially, most modules including certain SCFA-producing bacteria were comprehensively correlated to body mass index, the levels of blood glucose, blood pressure, blood cholesterol and faecal bile acids and lipids. Conclusions Our study identified the relationships between the gut microbiota and faecal metabolites, and provided a resource for future studies to understand host–gut microbiota interactions in T2D.

Enhancing the efficacy of 131 I therapy in non-toxic multinodular goitre with appropriate use of methimazole: an analysis of randomized controlled study Abstract Purpose It is possible to raise the rate of the uptake of 131I in the thyroid gland (RAIU) by increasing the endogenous TSH level through appropriate use of methimazole (MMI) prior to 131I therapy. The purpose of this paper is to assess the impact of pre treatment with MMI on the efficacy of 131I therapy in non-toxic multinodular goitre (NMG). Methods Thirty-one patients with NMG received 131I treatment in order to reduce the volume of the thyroid (TVR). Those in group 1 (n = 16) were administered 10 mg of methimazole for 6 weeks. Four days after its discontinuation, they received 131I. Patients in group 2 (n = 15) were given a placebo instead of MMI. The therapeutic activity of 131I was constant (800 MBq) and was repeated every 6 months. Treatment was discontinued when TVR reached <40 ml. Results In group 1, RAIU increased approximately twofold. Ten patients from group 2 and four patients from group 1 received further doses of 131I. The median of time until TVR decreased below 40 ml was 9 months [6–12 months] and 18 months [14–22 months] in group 2. At 2 years after the 131I therapy, the occurrence of hypothyroidism did not differ significantly (36% in group 1 and 33% in group2, p = 0.074). Conclusions Radioiodine treatment of NMG preceded with appropriate application of MMI is efficient thanks to increased RAIU, shorter period of treatment, and lower frequency of 131I administration, without an increase in the incidence of post-treatment hypothyroidism.

68 Ga-DOTATOC PET/CT in detecting neuroendocrine tumours responsible for initial or recurrent paraneoplastic Cushing’s syndrome Abstract Purpose Paraneoplastic Cushing’s syndrome (PCS) is frequently caused by neuroendocrine tumours (NETs). Approximately 20% of tumours are still occult years later. Gallium-68 somatostatin receptor-PET/CT is promising for the detection of the causal primary NET, but its role in case of recurrent PCS is rarely reported. We report our experience with DOTATOC PET/CT in localising the causal NET in cases of initial but also recurrent PCS, and its clinical impact. Methods A retrospective review of all DOTATOC PET/CTs performed in consecutive patients referred for PCS to our centre, between January 2011 and June 2017, was done. Nineteen patients underwent 26 PET/CTs, 13 for detection of a primary NET, seven for persistent or recurrent PCS after resection, and six for surveillance after resection of NETs previously detected on a DOTATOC PET/CT in our centre. Results Among the 13 PET/CTs performed to search for primary NET, five were positive: four carcinoid lung tumours were confirmed after resection and one lung focus was not confirmed since surgery would have carried a high risk. Clinical impact was 23% (3/13). Among the seven PET/CTs performed for persistent or recurrent PCS, six were true-positive, with confirmation of metastatic lymph nodes after resection. Clinical impact was 57% (4/7). All PET/CTs performed for surveillance were true-negative. Conclusions DOTATOC PET/CT seems to be a valuable tool for detection of the NET responsible for persistent or recurrent PCS after surgery. In this context, DOTATOC PET/CT was more effective than for the detection of the causal tumour in initial PCS.

Synchronous bilateral adrenalectomy in ACTH-dependent hypercortisolism: predictors, biomarkers and outcomes Abstract Introduction Hypercortisolism requires a prompt therapeutic management to reduce the risk of development of a potential fatal emergency. A synchronous bilateral adrenalectomy (SBA) is effective in recovering hypercortisolism. However, specific indications for an SBA are not available. We aimed to evaluate the outcome of patients who underwent an SBA and to identify biomarkers able to predict the requirements of an SBA. Patients and methods A mono-centric and longitudinal study was conducted on 19 consecutive patients who underwent SBA for ACTH-dependent hypercortisolism between December 2003 and December 2017. This study population was compared to two control groups composed of patients cured after the resection of the ACTH secreting pituitary adenoma (Group A: 44 patients) and of the ACTH-secreting neuroendocrine tumours (Group B: 8 patients). Results Short- or long-term SBA complications or the recurrence of hypercortisolism did not occur. A single patient experienced Nelson syndrome. Clinical features after SBA showed improvement in the glico-metabolic assessment, hypertension, bone metabolism and the occurrence of hypokalaemia and infections. The younger the age at the time of Cushing’s disease diagnosis, the longer the duration of active hypercortisolism, higher values of plasmatic ACTH and Cortisol (1 month after pituitary neurosurgery) and higher values of Ki67 in pituitary adenomas were detected in this study population as compared to Group A. Conclusions SBA is an effective and safe treatment for patients with unmanageable ACTH-dependent hypercortisolism. A multidisciplinary team in a referral centre with a high volume of patients is strongly recommended for the management of these patients and the identification of patients, for better surgical timing.