Cardiac involvement in acromegaly is traditionally attributed to GH/IGF-1 excess, yet the subclinical impact of disease activity and metabolic comorbidities remains inadequately quantified. This study aims to characterize subclinical myocardial dysfunction in acromegaly using speckle-tracking echocardiography (STE) and explore its associations with disease activity, metabolic parameters, and treatment status. In this cross-sectional study, 74 patients with acromegaly (39 females) underwent detailed clinical, biochemical, and STE evaluation. STE-derived parameters of myocardial strain and work were analyzed including global longitudinal strain (GLS), left ventricular systolic dyssynchrony (LVSD), and global wasted work (GWW), and global work efficiency (GWE). Stratification by sex, treatment (naïve/active/remission), and metabolic profile was performed. Multivariable linear regressions identified predictors of cardiac structure/function. Male patients exhibited higher IGF-1 level, BMI, and more pronounced cardiac alterations than females (all p < 0.05). IGF-1 z-score was strongly correlated with cardiac structural indices (IVS thickness, r = 0.564; LVPW thickness, r = 0.431) and dysfunction (LVSD, r = 0.359; GWE, r = − 0.361; all p < 0.01). These associations were significantly potentiated in high-BMI and high-triglyceride-glucose (TyG) index subgroups. Patients achieving biochemical remission showed superior cardiac structure and function compared to untreated/active groups (p < 0.05). Multivariable linear regressions analysis identified IGF-1 z-score as an independent predictor of both LVPW thickness (β = 0.210, p = 0.045) and LVSD index (β = 2.249, p = 0.048), with BMI and male sex as additional predictors of LVPW thickening. Subclinical cardiac dysfunction in acromegaly is driven by IGF-1, exacerbated by metabolic factors, and improved with remission. STE supports early risk stratification and integrated management.

Pituitary surgical intervention remains the preferred treatment for Cushing’s disease (CD) while postoperative venous thromboembolism (VTE) is a significant risk. Whether to prescribe pharmacological thromboprophylaxis presents a clinical dilemma, balancing the benefit of reducing VTE risk with the potential for increasing hemorrhagic events in these patients. Currently, strong evidence and established protocols for routine pharmacological thromboprophylaxis in this population are lacking. Therefore, a randomized, controlled trial is warranted to determine the efficacy and safety of combined pharmacological and mechanical thromboprophylaxis in reducing postoperative VTE risk in patients with CD. This investigator-initiated, multi-center, prospective, randomized, open-label trial with blinded outcome assessment aims to evaluate the efficacy and safety of combined pharmacological and mechanical thromboprophylaxis compared to mechanical thromboprophylaxis alone in postoperative patients with CD. A total of 206 patients diagnosed with CD who will be undergoing transsphenoidal surgery will be randomized in a 1:1 ratio to receive either combined pharmacological and mechanical thromboprophylaxis (intervention) or mechanical thromboprophylaxis only (control). The primary outcome is the risk of VTE within 12 weeks following surgery. This trial represents a significant milestone in evaluating the efficacy of combined pharmacological and mechanical prophylaxis in reducing VTE events in postoperative CD patients. ClinicalTrials.gov Identifier: NCT04486859, first registered on 22 July 2020.

The carnivorous fish, largemouth bass (Micropterus salmoides), has difficulty metabolizing dietary carbohydrates, frequently resulting in issues with energy metabolism and fatty liver disease. Nevertheless, the molecular mechanisms involved are still not fully understood. The results of high-carbohydrate (HC) diets and high-glucose (HG) treatments in largemouth bass hepatocytes showed that high-glucose causes liver damage and glycolipid accumulation. High-glucose promoted the lipogenesis process by activating AMPK/ACC/SREBP-1 pathway and reduced bile acid synthesis by downregulating cholesterol 7-hydroxylase (cyp7a1) and sterol 12-hydroxylase (cyp8b1). Concurrently, HG treatments also caused mitochondrial fission and damage by increasing the expression of dynamin-related protein 1 (Drp1), leading to impaired mitochondria accumulation and mitochondria-dependent apoptosis via the p38 MAPK/Bcl-2/Casp3 pathway. Additionally, HG treatments decreased Sirt1 expression and relocated it from the nucleus to the cytoplasm, where it interacts with autophagosomes and lysosomes, inhibiting Pink1/Parkin-mediated mitophagy. This also led to the cytoplasmic translocation of Pink1 and its co-localization with Sirt1, indicating that Sirt1 regulates high glucose-induced metabolic stress by inhibiting the Pink1/Parkin mitophagy pathway. In summary, HG treatment induces mitochondrial damage and glycolipid accumulation in largemouth bass through mechanisms involving AMPK/SREBP1/ACC1-mediated lipogenesis, bile acid metabolism, Sirt-mediated mitophagy, and p38 MAPK/Bcl-2/Casp3-activated apoptosis.

To compare the detection ability of 68Ga-labelled DOTA-l-Nal3-octreotide ([68Ga]Ga-DOTA-NOC) and 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]DOPA) in patients with phaeochromocytomas and paragangliomas (PPGLs) of different origins and gene mutations, such as germline succinate dehydrogenase complex genes (SDHx). Eighty-five patients with histopathologically confirmed PPGLs who underwent both [68Ga]Ga-DOTA-NOC and [18F]DOPA PET/CT from March 2017 to June 2023 were enrolled in this retrospective study. For comparative analyses, PPGLs were classified as phaeochromocytoma (PCC), sympathetic paraganglioma (sPGL), and head/neck paraganglioma (HNPGL). Detection rates were analyzed on per-patient and per-lesion bases and compared using the Chi-square/Fischer’s exact test. Among 85 patients with PPGLs (48 males; 43 years ± 17 [SD]), the patient-based detection rates of [68Ga]Ga-DOTA-NOC and [18F]DOPA PET/CT were 87.1

Objective To evaluate whether the intense simplified strategy, which comprises short term intensive insulin therapy (SIIT) followed by subsequent oral antihyperglycaemic regimens, could improve long term glycaemic outcomes in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. Design Multicentre, open label, randomised trial. Setting 15 hospitals in China between December 2017 and December 2020. Participants 412 patients with newly diagnosed type 2 diabetes and significant hyperglycaemia (HbA(1c) >= 8.5%). Interventions All randomised participants initially received SIIT for 2-3 weeks, followed by linagliptin 5 mg/day, metformin 1000 mg/day, combination linagliptin plus metformin, or lifestyle modification alone (control) for 48 weeks. Main outcome measures The primary outcome was the percentage of participants achieving HbA(1c) <7.0% at week 48 after SIIT. Secondary outcomes included glycaemic control, beta cell function, and variations in insulin sensitivity. Results 412 participants were randomised. At baseline, the mean age was 46.8 (standard deviation 11.2) years, mean body mass index was 25.8 (2.9), and mean HbA(1c) was 11.0% (1.9%). At week 48, 80% (78/97), 72% (63/88), and 73% (69/95) of patients in the linagliptin plus metformin, linagliptin, and metformin groups, respectively, achieved HbA(1c) <7.0%, compared with 60% (56/93) in the control group (P=0.02 overall; P=0.003 for linagliptin plus metformin versus control; P=0.12 for linagliptin versus control; P=0.09 for metformin versus control). Additionally, 70% (68/97), 68% (60/88), and 68% (65/95) of patients in the linagliptin plus metformin, linagliptin, and metformin group, respectively, achieved HbA(1c) <6.5% compared with 48% (45/93) in the control group (P=0.005 overall; P=0.005 for linagliptin plus metformin versus control; P=0.01 for linagliptin versus control; P=0.008 for metformin versus control; all were significant after adjustment for multiple comparisons). Thus, compared with the control group, participants in the linagliptin plus metformin group were more likely to achieve HbA(1c) <7.0% at week 48 (odds ratio 2.78, 95% confidence interval 1.37 to 5.65; P=0.005). Moreover, the linagliptin plus metformin group showed the most significant improvement in fasting plasma glucose and beta cell function indices. All treatments were well tolerated. Conclusions The intense simplified strategy using subsequent oral therapies post-SIIT, especially the linagliptin plus metformin combination, sustainably improved glycaemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. This approach offers a promising direction for decision making in the clinical management of type 2 diabetes mellitus. Trial registration ClinicalTrials.gov NCT03194945

Background: Short-term intensive insulin therapy (SIIT) had immediate and significant effect on early type 2 diabetes mellitus (T2DM) control, but the benefit diminished over time. This study aimed to evaluate whether sequential oral antihyperglycemic regimens- comparing combination therapy or mono-therapy to lifestyle- following SIIT could further improve long-term outcomes.Methods: In this 48-week, multi-centre, open-label, randomised trial across 15 Chinese centres, newly diagnosed T2DM patients (HbA1c≥8·5%) initially underwent SIIT for 2 weeks. Post-SIIT, participants were randomised to receive either linagliptin combined with metformin (LIN+MET), linagliptin (LIN), metformin (MET), or lifestyle modification alone for 48 weeks. The primary outcome was the percentage of participants achieving HbA1c<7·0% at week 48,with secondary outcomes including glycemic control, β-cell function, and insulin sensitivity variations.Findings: In total, 412 participants were randomised. At baseline, the mean age was 46·9±11·1 years, mean BMI was 25·8±2·9 kg/m2, and mean HbA1c was 11·1±1·9%. At week 48, 82·5%, 75·0%, and 75·8% of patients in the LIN+MET, LIN, and MET groups achieved HbA1c <7·0%, compared to 60·2% in the control group (P < 0·001, P = 0·040, and P=0·028, respectively). Additionally, 69·1%, 63·6%, and 67·4% of patients in the LIN+MET, LIN, and MET group achieved HbA1c<6·5%, respectively, compared with 43·0% in the control group (all P<0·001), The LIN+MET group showed the most significant improvement in fasting plasma glucose and Insulin Secretion-Sensitivity Index-2. All treatments were well tolerated.Interpretation: The Intensifying-Simplifying strategy using sequential oral therapies post-SIIT, especially the LIN+MET combination, significantly improves glycemic control, β-cell function, and insulin sensitivity in newly diagnosed T2DM patients with significant hyperglycemia. This approach offers a promising direction for decision-making in clinical management of T2DM.Trial Registration: This trial was registered at www.ClinicalTrials.gov (NCT03194945).Funding: The National Key R&D Program of China, Key-Area R&D Program of Guangdong, Guangzhou Science and Technology Programme, Natural Science Fund of Guangdong, and Boehringer-Ingelheim.Declaration of Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Ethical Approval: The trial was conducted under the principles of the Declaration of Helsinki and Good Clinical Practice guidelines of the International Conference for Harmonization, gaining approval from the research ethics board of Sun Yat-Sen University. All participants provided signed informed consent.

Two-dimensional speckle tracking echocardiography is a novel ultrasound technique, which can detect early subclinical myocardial dysfunction with high sensitivity. The purpose of this study was to explore the value of speckle tracking echocardiography in the evaluation of subclinical myocardial injury in patients with Cushing’s syndrome. 35 patients with Cushing’s syndrome and 29 healthy controls matched for age, sex, BMI, and systolic blood pressure were included in the study. All subjects were assessed using both conventional Doppler echocardiography and speckle tracking echocardiography. Among patients, they were further divided into inactive group (n = 7) and active group (n = 28) based on cortisol levels. Trend analysis was used among patients in different disease activity. Correlation analysis and linear regression analysis were used to explore influence factors related to subclinical myocardial dysfunction. Left ventricular ejection fraction value showed no statistical difference between patients Cushing’s syndrome and control group. However, GLS and LVSD, show significant differences in Cushing’s syndrome group. Also, among active Cushing’s syndrome group, inactive Cushing’s syndrome group and control group, GLS (−15.4 ± 3.0 vs −18.1 ± 3.1 vs-19.4 ± 2.4, P < 0001) and LVSD (48.9 ± 21.5 vs 43.5 ± 17.9 vs 28.5 ± 8.3, P < 0001) changed significantly with the disease activity status. In addition, GLS and LVSD were both linearly corrected with 24-hour urinary cortisol level. GLS and LVSD are sensitive parameters in detecting and monitoring subclinical myocardial systolic dysfunction in patients with Cushing’s syndrome. Myocardial injury is linearly correlated with cortisol level, which can be partially reversed after the biochemical control of cortisol.

Cushing's disease is associated with increased morbidity and mortality. Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provided rapid, sustained mean urinary free cortisol (mUFC) normalization in Cushing's disease patients in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734). Here, we evaluate the efficacy and safety of osilodrostat in Cushing's disease in patients of Asian origin compared with patients of non-Asian origin. Pooled data from LINC 3 and LINC 4 were analyzed. Outcomes were evaluated separately for Asian and non-Asian patients. For the analysis, 210 patients were included; 56 (27%) were of Asian origin. Median (minimum-maximum) osilodrostat dose was 3.8 (1-25) and 7.3 (1-47) mg/day in Asian and non-Asian patients, respectively. mUFC control was achieved at weeks 48 and 72 in 64.3% and 68.1% of Asian and 68.2% and 75.8% of non-Asian patients. Improvements in cardiovascular and metabolic-related parameters, physical manifestations of hypercortisolism, and quality of life were similar in both groups. Most common adverse events (AEs) were adrenal insufficiency (44.6%) in Asian and nausea (45.5%) in non-Asian patients. AEs related to hypocortisolism and pituitary tumor enlargement occurred in more Asian (58.9% and 21.4%) than non-Asian patients (40.3% and 9.1%). Of Asian and non-Asian patients, 23.2% and 13.6%, respectively, discontinued because of AEs. Asian patients with Cushing's disease generally required numerically lower osilodrostat doses than non-Asian patients to achieve beneficial effects. Hypocortisolism-related AEs were reported in more Asian than non-Asian patients. Together, these findings suggest that Asian patients are more sensitive to osilodrostat than non-Asian patients.

Abstract Background Extrachromosomal circular DNA (eccDNA) has emerged as a promising biomarker for disease diagnosis and prognosis prediction. However, its role in type 2 diabetes remains unexplored. Objective To investigate the characteristics and dynamics of circulating eccDNAs in newly diagnosed type 2 diabetes mellitus (T2DM) patients undergoing short‐term intensive insulin therapy (SIIT), a highly effective treatment for inducing long‐term glycemic remission. Methods We conducted Circle‐Seq analysis on plasma samples from 35 T2DM patients at three time points: pre‐SIIT, post‐SIIT, and 1‐year post‐SIIT. Our analysis encompassed the characterization of eccDNA features, including GC content, eccDNA length distribution, genomic distribution, and the genes in eccDNAs. Results Following SIIT, we observed an increase in plasma eccDNA load, suggesting metabolic alterations during therapy. Notably, a correlation was identified between eccDNA profiles and glycemia in T2DM, both quantitatively and genetically. Our analysis also revealed the frequent presence of metabolism‐related genes within T2DM plasma eccDNAs, some of which spanned gene exons and/or fractions. Conclusion This study represents the first report of cell‐free eccDNA in T2DM and underscores a compelling association between cell‐free eccDNA and profound glycemic changes. These findings highlight the potential of eccDNAs as crucial players in the context of T2DM and glycemic control.

Background Thyroid cancer (THCA) is the most common type of endocrine cancers, and the disease recurrences were usually associated with the risks of metastasis and fatality. Butyrophilin-like protein 9 (BTNL9) is a member of the immunoglobulin families. This study investigated the prognostic role of BTNL9 in THCA.Methods Gene enhancers of BTNL9 were identified by interrogating H3K27ac ChIP-seq and RNA-seq data of papillary thyroid cancer (PTC) and benign thyroid nodule (BTN) tissues. Meanwhile, BTNL9 expression level was verified by qRT-PCR in 30 pairs of primary THCA and adjacent normal tissues. Clinicopathological and RNA sequencing data were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to analyze the relations between BTNL9 expression and immune cell infiltration, chemokines/cytokines, immune checkpoint genes, clinical parameters and prognosis values. Besides, survival analysis combining BTNL9 expression and immune cell infiltration scores was conducted. Functional enrichment analysis was performed to investigate the potential biological mechanisms. Cox regression analyses were used to explore independent clinical indicators, and a nomogram model incorporating BTNL9 expression with clinical parameters was established.Results BTNL9 showed significantly stronger H3K27ac modifications in BTN than PTC tissues at the promoter region (chr5: 181,035,673-181,047,436) and gene body (chr5: 181,051,544-181,054,849). The expression levels of BTNL9 were significantly down-regulated in THCA samples compared to normal tissues, and were strongly associated with different tumor stages, immune cell infiltrations, chemokines/cytokines and immune checkpoint genes in THCA. Functional enrichment analyses indicated that BTNL9 was involved in immune-related and cancer-related pathways. The Kaplan-Meier analysis showed lower BTNL9 expression was associated with poorer progression-free interval (PFI). BTNL9 expression and pathologic stages were independent prognostic indicators of PFI in THCA.Conclusions The results implied an important role of BTNL9 in the tumor progression, with the possibility of serving as a novel prognostic biomarker and a potential therapeutic target for THCA.

Abstract Disclosure: P.J. Snyder: Consulting Fee; Self; Teva Pharmaceutical Industries Ltd. B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge). M. Fleseriu: Consulting Fee; Self; Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge), HRA Pharmaceuticals. Grant Recipient; Self; Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge). R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor Farmaceutici, S&R Farmaceutici, Organon Italia, Siunergos Pharma, Biohealth Italia. Research Investigator; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merck Serono, IBSA. E.J. Lee: None. R. Leelawattana: None. J.H. Kim: None. R. Walia: None. Y. Yu: None. Z. Liao: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. A. Shimatsu: Consulting Fee; Self; Recordati. Speaker; Self; Recordati. Introduction: Osilodrostat, a potent oral 11β-hydroxylase inhibitor, has demonstrated rapid and sustained normalization of cortisol in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734) in patients (pts) with Cushing’s disease (CD). Relative osilodrostat bioavailability is estimated to be 20% higher in pts of Asian origin than other ethnicities, and body weight is not a major determinant of this difference. This analysis of the LINC 3 and LINC 4 studies evaluated the efficacy and safety of osilodrostat in pts of Asian and non-Asian origin with CD. Methods: Data were pooled from the LINC 3 and LINC 4 Phase III studies. LINC 3 comprised a 48-week (W) core phase, including an 8W randomized withdrawal for eligible pts. LINC 4 included a 12W, double-blind, placebo-controlled period and 36W of open-label osilodrostat. Both studies had an optional extension. Efficacy and safety outcomes were evaluated separately in pts of Asian and non-Asian origin. Periods where pts received placebo were excluded. Results: In total, 56/210 (27%) pts were of Asian origin, enrolled in China (n=16), South Korea (n=14), Japan (n=9), Thailand (n=9), India (n=7) and USA (n=1). Most non-Asian pts were Caucasian (n=138/154, 90%). Median (min−max) osilodrostat dose was 3.8 (1−25) and 7.3 mg/day (1−47) in pts of Asian and non-Asian origin, respectively. mUFC control was achieved at W48 and W72 in 64.3% and 68.1% of Asian pts and in 68.2% and 75.8% of non-Asian pts, respectively. Improvements from baseline in most cardiovascular and metabolic-related parameters and in physical manifestations of hypercortisolism were similar across both groups during osilodrostat treatment. Osilodrostat was well tolerated; the most common investigator-reported adverse events (AEs) in Asian pts were adrenal insufficiency (44.6%), nausea (33.9%) and decreased appetite (26.8%), and in non-Asian pts, nausea (45.5%), fatigue (40.9%) and headache (39.0%). The most common serious AE in Asian and non-Asian pts was adrenal insufficiency (5.4% and 5.2%, respectively). Hypocortisolism-related AEs occurred in 58.9% of Asian pts and 40.3% of non-Asian pts, most commonly reported by the investigator as adrenal insufficiency (44.6% and 22.1%). AEs related to pituitary tumor enlargement occurred in 21.4% of Asian and 9.1% of non-Asian pts. AEs related to arrhythmogenic potential and QT prolongation were infrequent in all pts. Conclusions: Osilodrostat demonstrated similar beneficial effects in Asian and non-Asian pts in terms of mUFC control and improvements in cardiovascular and metabolic-related parameters and physical manifestations of hypercortisolism. The mean dose to achieve beneficial effects was lower in pts of Asian than non-Asian origin. Osilodrostat was generally well tolerated in Asian and non-Asian pts; AEs related to hypocortisolism and pituitary enlargement were reported more frequently in Asian than non-Asian pts. Presentation: Thursday, June 15, 2023

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

In recent years, cardiovascular disease has garnered increasing attention as the second leading cause of death in individuals with acromegaly, following malignancy. Identifying cardiac dysfunction early in acromegaly patients for timely intervention has become a focal point of clinical research. Speckle tracking echocardiography, a well-established ultrasound technique, surpasses conventional Doppler ultrasound in its sensitivity to assess both local and global cardiac mechanics. It can accurately detect subclinical and clinical myocardial dysfunction, including myocardial ischemia, ventricular hypertrophy, and valvular changes. Over the past five years, the use of speckle tracking echocardiography in acromegaly patients has emerged as a novel approach. Throughout the cardiac cycle, speckle tracking echocardiography offers a sensitive evaluation of the global and regional myocardial condition by quantifying the motion of myocardial fibres in distinct segments. It achieves this independently of variations in ultrasound angle and distance, effectively simulating the deformation of individual ventricles across different spatial planes. This approach provides a more accurate description of changes in cardiac strain parameters. Importantly, even in the subclinical stage when ejection fraction remains normal, the strain parameters assessed by speckle tracking echocardiography hold a good predictive value for the risk of cardiovascular death and hospitalization in acromegaly patients with concomitant cardiovascular disease. This information aids in determining the optimal timing for interventional therapy, offering important insights for cardiac risk stratification and prognosis. In the present study, we comprehensively reviewed the research progress of speckle tracking echocardiography in evaluating of cardiac dysfunction in acromegaly patients, to pave the way for early diagnosis of acromegaly cardiomyopathy.

Abstract Context Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. Objective We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11βhydroxylase inhibitor, compared with placebo in patients with Cushing disease. Methods LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks’ open-label osilodrostat). Results Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P < 0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC ≤ ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). Conclusion Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.

Background: Boucher–Neuhäuser syndrome (BNS, MIM 215470) is a rare autosomal recessive syndrome caused by mutations in the PNPLA6 gene. Few BNS cases have been reported for functional validation at the RNA level. Herein, we report on the family of a 17-year-old girl with clinical characteristics of BNS, genetic validation, and a systematic review of PNPLA6 variants related to BNS.Methods: Clinical data and blood samples were collected from the patient and their parents, and whole-exome sequencing was performed and confirmed by Sanger sequencing. RNA-sequencing (RNA-Seq) and quantitative RT-PCR (qRT-PCR) were performed, and the three-dimensional protein structures of the variants were predicted.Results: We report a 17-year-old female with progressive night blindness since the age of four, primary amenorrhea, and non-development of secondary sexual characteristics. Her impaired vision was diagnosed as retinal pigmentary degeneration of the retina. She had congenital hypogonadotropic hypogonadism (CHH) but no cerebellar ataxia at present. Two novel compound heterozygous variants (c.2241del/p.Met748TrpfsTer65 and c.2986A>G/p.Thr996Ala) of the PNPLA6 gene (NM_006702.4) were identified by whole-exome sequencing. The former variant was carried from her healthy father and has not been reported previously. The latter was inherited from her healthy mother and was noted in a report without functional studies. The RT-PCR results showed that the mRNA expression of PNPLA6 was lower in this patient and her father than in the control group. She was diagnosed with BNS. Both variants (c.2241del and c.2986A>G) were likely pathogenic according to the ACMG criteria. The novel variants in the PNPLA6 gene related to Boucher–Neuhäuser syndrome were summarized in this article.Conclusion: The possibility of Boucher–Neuhäuser syndrome should be considered when patients present with night blindness, impaired vision, and hypogonadotropic hypogonadism. Gene sequencing is currently the primary diagnostic method. Herein, novel compound heterozygous variants of PNPLA6 were identified in a BNS patient, and its function was verified at the RNA level. The PNPLA6 c.2241del variant is novel and potentially pathogenic, expanding the mutation spectrum in PNPLA6.

Diabetes mellitus was a chronic low‐grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short‐term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII).

Abstract Background Diabetes mellitus was a chronic low‐grade inflammatory disease and had increased circulating inflammatory cytokines and acute phase proteins. We aimed to identify the changes of inflammatory cytokines in newly diagnosed type 2 diabetic patients after short‐term intensive insulin therapy using continuous subcutaneous insulin infusion (CSII). Methods Thirty‐three newly diagnosed type 2 diabetic patients were enrolled between September 2020 to December 2020. Expression of 40 inflammatory cytokines of the patients were tested with RayBiotech antibody array before and after 1 week of intensive insulin therapy of CSII. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was carried out to explore the signaling pathway involved in the therapy. Results Five inflammatory cytokines were downregulated significantly after 1 week of CSII therapy. They were interleukin‐6 receptor (IL‐6R), regulated upon activation normal T‐cell expressed and secreted (RANTES), intercellular adhesion molecule‐1 (ICAM‐1), tissue inhibitor of metalloproteinase‐1 (TIMP‐1), and platelet‐derived growth factor type BB (PDGF‐BB) (p < 0.05 and foldchange <0.83). Among patients with baseline glycated hemoglobin (HbA1c) < 10%, three proinflammatory cytokines were decreased significantly after therapy: IL‐6R, RANTES, and ICAM‐1. As for the patients with baseline HbA1c ≥ 10%, eight inflammatory cytokines were inhibited significantly after the treatment, including ICAM‐1, IL‐6R, RANTES, TIMP‐1, TIMP‐2, macrophage inflammatory protein‐1 beta (MIP‐1β), PDGF‐BB, and tumor necrosis factor receptor type II (TNF RII). No matter which subgroup of baseline HbA1c level was considered, the decreased cytokines after CSII therapy were significantly involved in TNF signaling pathway. Nuclear factor‐kappa B (NF‐κB) signaling pathway was mainly enriched in patients with baseline HbA1c ≥ 10%. Conclusions A panel of 40 inflammatory cytokines, measured by protein microarray, were evaluated for 1 week of CSII treatment in newly diagnosed type 2 diabetic patients. After treatment, many proinflammatory cytokines decreased. In the higher baseline HbA1c subgroup, more proinflammatory cytokines improved. No matter which subgroup of HbA1c level was considered, IL‐6R, RANTES, and ICAM‐1, which were involved in TNF signaling pathway, decreased significantly after CSII therapy. This was the first report showing that the cytokines of IL‐6R, TIMP‐2, PDGF‐BB, and TNF RII decreased after the CSII therapy.

The distinction between congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) in patients with delayed puberty is difficult to distinguish, but important for timely treatment. The aim of this study is to perform a systematic review and meta-analysis to determine the diagnostic performance of serum inhibin B (INHB) levels for differentiating CHH and CDGP. PubMed, EMBASE, and Cochrane Library databases were systematically searched from the date of database inception to November 10, 2019 for studies examining the use of serum INHB to discriminate between CHH and CDGP. Pooled odds ratios (OR), sensitivity, specificity, and 95% confidence intervals (CI) were calculated. The Quality Assessment of Diagnostic Studies-2 (QUADAS-2) was used to assess the quality of the included studies. Sub-analyses were performed including that based on testicular volume (TV) and study design. Seven studies, comprising of 349 patients (96 CHH and 253 CDGP), were included in the meta-analysis. For differentiating between CHH and CDGP, INHB level exhibited good diagnostic accuracy with a pooled sensitivity of 92% (95% confidence interval [CI]: 0.86–0.96, I2 = 0.4%, p = 0.4343), specificity of 92% (95% CI: 0.88–0.94, I2 = 68.1%, p = 0.0009), and pooled area under the receiver operating characteristic curve (AUC) of 0.9619. The cut-off values of INHB for boys were 56, 66, 80, 96, 94.7, 111, and 113 pg/ml (assay method standardized to Gen II ELISA). Sub-analyses showed that testicular volume and study design could be a source of statistically significant heterogeneity in specificity. In boys with a testicular volume of ≤3 ml, INHB performed well with a sensitivity of 92%, specificity of 98%, and AUC of 0.9956. INHB exhibits excellent diagnostic efficiency in distinguishing CHH from CDGP, especially in boys with severe puberty deficiency (TV ≤ 3 ml).

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Background: Osteogenesis imperfecta (OI) is a rare hereditary connective tissue disease. It is mainly associated with pathogenic variants in COL1A1 or COL1A2. Patients with OI usually have repeated history of bone fractures. Besides, osteogenesis imperfecta is associated with some cardiovascular complications, such as aortic and mitral valve dysfunction, aneurysm and aortic dissection. But the relationship between these diseases has not been well studied. Case Presentation: A 55-year-old man was admitted to our hospital mainly due to “dizziness for 2 hours”. He had a 4-month history of hypertension and a history of smoking for more than 20 years. He had no history of drinking alcohol. He had hunchback and O-type legs. Besides, the patient and some of his relatives had a history of repeated brittle fractures,which was considered as “osteogenesis imperfecta”. The clinical manifestation of OI in this family varies to a certain extent, from simple tooth disintegration to severe fracture deformity. The most serious patient of his family was unable to walk. CT and MRI revealed multiple systemic arteriosclerosis, including vertebral artery, posterior inferior cerebellar artery, cervical artery, and bilateral cerebellar multiple lacunar cerebral infarction. The blood sample of the patient was tested by whole exome sequencing, and the saliva samples of the patient’s family members were tested by Sanger sequencing. A mutation c.3159 + 2T > A was detected in COL1A2 gene associated with OI, also found in the other affected family members, which had not been reported before. It was a segregating mutation in the family. The clinical severity of the family members was heterogeneous. Discussion: This case is worth learning from the following aspects: 1. A pathogenic heterozygous mutation, c.3159 + 2T > A was detected in COL1A2 gene in the patient with OI, which is not reported in previous cases of OI. 2. The clinical manifestation of OI in this family varies to a certain extent, from simple tooth disintegration to severe fracture deformity. The most serious patient of his family was unable to walk. It presented the clinical heterogeneity of OI. Further basic researh on the mutation site of related gene of OI are needed. 3. We found the possibility of developing cerebral atherosclerosis in patients with OI. Therefore, patients with OI should give up smooking, exercise properly and keep on a low fat diet. They should pay attention to control blood pressure and blood lipid so as to reduce the risk of atherosclerosis. Conclusion: A c.3159 + 2T>A mutation in COL1A2 gene detected by whole exome sequencing was the causing reason of OI, the discovery enriched the gene mutation spectrum of OI. We also found that OI may have relationship with premature atherosclerosis, and the abnormal bones of the cervical spine may lead to vertebrobasilar ischemia.