Management of dopamine agonist (DA) resistance in prolactinoma (PRLoma) remains challenging due to the lack of detecting approach and reliable imaging marker. In this cross-sectional study, PRLoma patients were recruited prospectively from a single-center outpatient clinic from May 2024 to September 2024. A noninvasive accelerated quantitative MR technique (GRAPPATINI, GeneRalized Autocalibrating Partially Parallel Acquisitions acceleraTed T2 mappINg) was applied to investigate the correlation between quantitative T2 values and DA resistance. The T2 values of tumors with multiple echo times (TEs) and signal intensity (SI) ratios were analyzed. A total of 30 participants were included, of which 20 were DA-sensitive and 10 were DA-resistant. The T2 values were significantly lower in DA-resistant PRLoma than those in DA-sensitive PRLoma (76.85 ​± ​29.84 ​ms vs 135.88 ​± ​69.86 ​ms, P ​= ​0.0048), whereas the T2 SI ratio revealed no significant difference. The area under the curve (AUC) of T2 values and T2 SI ratio for distinguishing DA sensitivity were 0.850 and 0.668, respectively. The ratio distributions at different TEs (TE10 ​ms, TE38 ​ms, TE42 ​ms, TE55 ​ms, and TE90 ​ms) were significantly different at TE38 ​ms (P ​= ​0.026) between two groups. The AUC of T2 values and TEs for DA sensitivity in PRLoma were 0.850 (T2map), 0.680 (TE10 ​ms), 0.730 (TE38 ​ms), 0.690 (TE42 ​ms), 0.520 (TE55 ​ms), and 0.670 (TE90 ​ms), respectively (P ​= ​0.0107). These findings highlight the translational potential of T2 values as a promising imaging biomarker for evaluating DA resistance in PRLoma.

ObjectiveTo investigate the relationship between circulating branched-chain amino acids (BCAAs) and the risk of major adverse cardiovascular events (MACE) in a national population-based cohort study.MethodsUK Biobank, a prospective study involving 22 recruitment centers across the United Kingdom. For this analysis, we included 266,840 participants from the UK Biobank who had available BCAA data and no history of MACE at baseline. Cox regression analysis was conducted to evaluate these associations, adjusting for potential confounders.ResultsDuring a 13.80 ± 0.83-year follow-up, 52,598 participants experienced MACE, with the incidence of MACE increasing progressively across quintiles of circulating BCAAs, isoleucine, leucine, and valine. Overall, the fifth quintile exhibited a 7-12% higher MACE risk compared to the second quintile. In males, BCAAs were not associated with MACE risk. However, increased risks were observed for isoleucine (8-12% in higher quintiles), leucine (9% in the first quintile and 6% in the fifth quintile), and valine (8% in the first quintile). In females, higher quintiles of BCAAs, isoleucine, leucine, and valine were associated with increased MACE risk, ranging from 9% to 12%. Among participants under 65y, higher quintiles of BCAAs, isoleucine, and leucine were associated with increased MACE risk, while valine showed no significant association. No association was found in participants aged 65 and older. These analyses were adjusted for multiple potential confounders.ConclusionGenerally, higher levels of BCAAs, isoleucine, leucine, and valine were associated with an increased risk of MACE, except in participants older than 65. Additionally, in males, the lowest quintiles of leucine and valine were also associated with an increased risk of MACE.

Background:Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, and its early identification is crucial for improving patient outcomes. Corneal confocal microscopy (CCM) can non-invasively detect changes in corneal nerve fibers (CNFs), making it a potential tool for the early diagnosis of DPN. However, the existing CNF analysis methods have certain limitations, highlighting the need to develop a reliable automated analysis tool. Methods:This study is based on data from two independent clinical centers. Various popular deep learning (DL) models have been trained and evaluated for their performance in CCM image segmentation using DL-based image segmentation techniques. Subsequently, an image processing algorithm was designed to automatically extract and quantify various morphological parameters of CNFs. To validate the effectiveness of this tool, it was compared with manually annotated datasets and ACCMetrics, and the consistency of the results was assessed using Bland--Altman analysis and intraclass correlation coefficient (ICC). Results:The U2Net model performed the best in the CCM image segmentation task, achieving a mean Intersection over Union (mIoU) of 0.8115. The automated analysis tool based on U2Net demonstrated a significantly higher consistency with the manually annotated results in the quantitative analysis of various CNF morphological parameters than the previously popular automated tool ACCMetrics. The area under the curve for classifying DPN using the CNF morphology parameters calculated by this tool reached 0.75. Conclusions:The DL-based automated tool developed in this study can effectively segment and quantify the CNF parameters in CCM images. This tool has the potential to be used for the early diagnosis of DPN, and further research will help validate its practical application value in clinical settings.

PURPOSE:Type 2 diabetes mellitus (T2DM) with distal symmetric polyneuropathy (DSPN) is a disease involving the nervous system caused by metabolic disorder, while the metabolic spectrum and key metabolites remain poorly defined. METHODS:Plasma samples of 30 healthy controls, 30 T2DM patients, and 60 DSPN patients were subjected to nontargeted metabolomics. Potential biomarkers of DSPN were screened based on univariate and multivariate statistical analyses, ROC curve analysis, and logistic regression. Finally, another 22 patients with T2DM who developed DSPN after follow-up were selected for validation of the new biomarker based on target metabolomics. RESULTS:Compared with the control group and the T2DM group, 6 metabolites showed differences in the DSPN group (P < 0.05; FDR < 0.1; VIP > 1) and a rising step trend was observed. Among them, phenylacetylglutamine (PAG) and sorbitol displayed an excellent discriminatory ability and associated with disease severity. The verification results demonstrated that when T2DM progressed to DSPN, the phenylacetylglutamine content increased significantly (P = 0.004). CONCLUSION:The discovered and verified endogenous metabolite PAG may be a novel potential biomarker of DSPN and involved in the disease pathogenesis.

Aims: Explore whether Glycogen synthesis kinase-3 beta (GSK3 beta) involved in the analgesic effect of liraglutide on diabetic neuropathic pain (DNP).Methods: DNP was induced by streptozocin (STZ) in WT and GSK3 beta(S9A) mice, which carried a constitutively active form of GSK3 beta. DNP mice were intracerebroventricularly injected with liraglutide 5 weeks after STZ in-jection. The behavior of neuropathic pain was evaluated 2 h after drugs administration. The microglial activation and the expression of NOD-like receptor protein 3 (NLRP3) in microglia in cortex were evaluated. The role of GSK3 beta in the inhibitory effect of liraglutide on the NLRP3 inflammasome was explored in BV2 microglia.Results: Intracerebroventricular administration of liraglutide significantly relieved neuropathic pain and inhibited the activation of cortical microglia in WT mice with DNP. But the effect of liraglutide disappeared in GSK3 beta(S9A) mice. In BV2 microglia, GSK3 beta inhibitor significantly suppressed NLRP3 inflammasome activation. And activating GSK3 beta through GSK3 beta(S9A) lentivirus significantly blocked the inhibitory effect of liraglutide on NLRP3 inflammasome in BV2 microglia. Intracerebroventricular administration of liraglutide significantly inhibited the expression of NLRP3 in cortex microglia of DNP group in WT mice but failed in GSK3 beta(S9A) mice. Conclusion: GSK3 beta involves in the analgesic effect of liraglutide on DNP through NLRP3 inflammasome in microglia.

Background:Confocal corneal microscopy is an excellent new noninvasive tool for assessing diabetic peripheral neuropathy. We aimed to investigate the clinical variables associated with corneal nerve parameters and establish reference values for clinical use in healthy Chinese adults.Methods:The study enlisted 257 healthy volunteers (137 females and 120 males) from two clinical academic centers in China. Two experts captured and selected images of the central corneal subbasal nerve plexus at each center using the same corneal confocal microscopy instrument according to a commonly adopted protocol. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fiber length (CNFL) were measured using fully automated software (ACCMetrics). The correlation between clinical indicators and confocal corneal microscopy measures was determined using partial correlation. Quantile regression was used to calculate reference values and estimate the effects of clinical factors on the normative values of confocal corneal microscopy measures.Results:Females had significantly higher CNFD, CNBD, and CNFL than males. There was no correlation between age, glycated hemoglobin (HbA1c), height, weight, body mass index (BMI), and any corneal nerve fiber parameter in both sexes. In either sex, age, weight, height, BMI, and HbA1c did not affect the 0.05th quantile values of any corneal nerve parameter.Conclusions:This study establishes sex-adjusted reference values for corneal confocal microscopy measures in Chinese adults and provides a reference for clinical practice and research with this technique.

Aims The relationship of albuminuria with hand grip strength in patients with type 2 diabetes was still uncertain. We carried out a cross-sectional study to examine the association between serum hand grip strength and albumin to creatinine ratio (ACR) among Chinese patients with Type 2 Diabetes in a community-based study. Methods A total of 427 Chinese type 2 diabetic patients were recruited from five clinical centers from March to May in 2019. Anthropometry indicators, hand grip strength, biochemical parameters and indices of glucose metabolism were measured. ACR was categorized as normo- (ACR<30 mg/g) and albuminuria (ACR≥30 mg/g). Both anthropometry and biochemical measurements were compared between these two groups categorized by ACR levels. Binary logistic regression analyses were carried out to evaluate the association of albuminuria and other clinical or biochemical variables. The correlation between hand grip strength and log(ACR) was examined by Pearson’s correlation analyses. P values<0.05 were considered statistically significant for all analyses. Results Age, HbA1c, FPG, TG, Scr and SBP were all higher in correlation with higher levels of ACR, while hand grip strength was the reverse. Binary logistic regression analyses showed that high hand grip strength was an independent protective factor of the presence of albuminuria. Conclusions High hand grip strength might have a protective role in the progression of type 2 diabetic nephropathy.

Background: Perioperative glycemic status after pancreatic surgery has never been described. However, it's essential for optimal perioperative glucose management and understanding the pathogenesis of new-onset diabetes mellitus (NODM) after pancreatectomy. Continuous glucose monitoring (CGM) system provides us a helpful tool for closely monitoring and studying perioperative glucose change. This study tried to describe and compare perioperative glucose level and glycemic variability between different types of pancreatic surgeries via CGM device. Methods: This study was designed as a prospective observational study. Eighteen patients were enrolled and were grouped by different types of surgery received: control group (CTRL), pancreaticoduodenectomy (PD), distal pancreatectomy (DP), and total pancreatectomy (TP). CGM devices were implanted and initiated right after the surgery. Mean glucose value (MGV), coefficient of variation (CV), mean of daily difference (MODD), continuous overall net glycemic action (CONGA), and time above range (TAR)/time below range (TBR) was compared between groups to assess glucose level and glycemic variability. Results: TP showed the highest MGV and CV among all groups (P<0.001), while CTRL showed the lowest (P<0.001). PD and DP had similar MGV and CV lower than TP but higher than CTRL (P<0.001). TP had the highest MODD and CONGA, CTRL had the lowest, but no significant differences were found between groups. TP had the highest TAR (24.29%) and the lowest TBR (1.28%), while the control group showed the opposite. The differences in TAR/TBR between groups were all significant (P<0.05). Conclusions: TP had the highest mean glucose level and the greatest glycemic variability. PD and DP had similar results: a higher mean glucose level than control but lower than TP. For glycemic variability, PD and DP seemed to have a near-normal result resembling the control group. CGM is useful for glucose monitoring in the perioperative management of pancreatic surgery.

Objective: To assess the current management of prolactinoma among endocrinologists in China. Methods: An online survey of a large sample of endocrinologists was conducted in China. The questionnaire included 21 questions related to controversial issues about the management of prolactinomas. Doctors in the endocrinology department of a university-affiliated hospital or a comprehensive secondary hospital in 12 cities from East, West, South, North and Middle China were surveyed. Results: A total of 290 valid questionnaires were collected, and the response rate was 40%. When hyperprolactinemia occurred, 97% of the respondents would test thyroid-stimulating hormone routinely. 22% of the respondents considered that prolactin levels <100 ng/mL exclude the presence of a prolactinoma. Only 9% of the respondents believed that prolactin >250 ng/mL could occur in all the following situations as macroprolactinoma, mircoprolactinoma, macroprolactinemia and drug-induced hyperprolactinemia. Surgery was not recommended by 272 (94%) endocrinologists as the first choice for treating microprolactinomas. 58% and 92% of endocrinologists would start drug treatment for microprolactinomas and macroprolactinomas at diagnosis. 70% and 40% chose to withdraw treatment after 2–3 years of prolactin normalization in microprolactinomas and macroprolactinomas. In case of pregnancy, 57% of the respondents considered bromocriptine as choice for women patients. Drug discontinuation after pregnancy was advocated in 63% and 27% for microprolactinoma and macroprolactinoma. Moreover, 44% of endocrinologists believed that breastfeeding was allowable in both micro- and macroprolactinoma. Conclusion: This is the first study to investigate the management of prolactinomas among endocrinologists in China. We found that the current clinical treatment was not uniform. Therefore, it is necessary to strengthen the training of endocrinologists to improve clinical diagnosis and treatment practices.

代谢综合征可能与慢性低度炎症反应有关,而肠道菌群失衡可能是引起全身慢性低度炎症反应的关键因素之一.大量研究显示,肠道微生态与代谢综合征的各组分均相关,而通过饮食、微生态调节剂(益生菌、益生元和合生元)、部分口服降血糖药和减重手术等可调整肠道微生态,从而改善代谢综合征各组分的控制情况.肠道微生态研究为代谢综合征管理提供了新的视野.

Glucagon-like peptide 1 (GLP-1) improves insulin resistance of adipose tissue in obese humans. However, the mechanism of this effect is unclear. Perturbation of endoplasmic reticulum (ER) homeostasis impairs insulin signaling. We hypothesized that GLP-1 could directly improve insulin signaling in ER-stressed adipocytes. Here, we examined the effects of GLP-1 on ER stress response in fat cells in an obese and insulin-resistant murine model. We found that GLP-1 analog liraglutide reduced ER stress related gene expression in visceral fat cells accompanied by improved systemic insulin tolerance. Consistently, GLP-1 decreased CHOP expression and increased insulin stimulated AKT phosphorylation (p-AKT) in thapsigargin, a ER stress inducer, treated white fat cells differentiated from visceral stromal vascular fraction. We further found blocking CHOP expression increased insulin stimulated p-AKT in ER-stressed fat cells. Of note, we found mTOR signaling pathway contributed to the expression of ATF4 and subsequently the CHOP expression in ER stress response, while GLP-1 inhibited mTOR activity as exemplified by elevated autophagosome formation and increased LC3II/LC3I ratio. These findings suggest that GLP-1 directly modulates the ER stress response partially via inhibiting mTOR signaling pathway, leading to increased insulin sensitivity in adipocytes.

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

BACKGROUND:Genome-wide association studies (GWAS) have reported that the polymorphism rs5219 of the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) is associated with type 2 diabetes mellitus (T2DM). Given that diabetic retinopathy (DR) is one of the most common microvascular complications of T2DM, GWAS have identified a number of potential susceptibility genes for DR. However, only a fraction of them have been replicated in different studies and show consistent genetic associations with the occurrence of DR. The aim of the present study was to investigate whether common variants of KCNJ11 confer DR in a cohort of the Chinese Han population.METHODS:A case-control study of 580 T2DM patients, including 105 T2DM with DR and 475 T2DM without DR was performed. A single nucleotide polymorphism (SNP) of KCNJ11 (rs5219) was genotyped, and its association with DR was explored using a dominant genetic model. Genotyping was performed by iPLEX technology. Univariate and multivariate logistic regression (MLR) analysis controlling for confounders was conducted to evaluate the association between rs5219 and DR.RESULTS:The A allele frequency of rs5219 was significantly higher in DR patients than that in the patients without DR (49.01% versus 38.68%, P <0.05). We found the minor A allele could increase the risk to develop DR (ORint = 1.58, 95% CI: 1.139 to 2.192 for allele and P = 0.006, ORint =1.607, 95% CI: 1.267 to 2.038 for genotype and P <0.001) in the Chinese Han population.CONCLUSIONS:Our findings provided evidence that KCNJ11 was associated with DR in Chinese Han patients with T2DM.

Previous studies on the apoptotic effect of aspirin mainly focus on colorectal cancer and breast carcinoma. Few studies have been designed to explore the effect of aspirin on hepatocellular carcinoma. In the present study, we observed that aspirin caused G0/G1 phase cell cycle arrest and reduced etoposide induced caspase-3 activation in hepatocellular carcinoma G2 (HepG2) cells. Further investigation demonstrated that aspirin notably enhanced the activity of Akt and ERK1/2. Blocking the activation of Akt by the PI3-K-selective inhibitor wortmannin abrogated the anti-apoptotic effect of aspirin while the MEK inhibitor U0126 did not. p21(cip), an important substrate of Akt, is involved in the regulation of cell cycle arrest and apoptosis. Our data showed that the protein expression and ser146 phosphorylation levels of p21(cip) were significantly increased after treatment with aspirin, whereas p53 or p27 showed no change. The increase of p21(cip) protein levels was also scavenged by wortmannin but not by U0126. Moreover, reduction of caspase-3 activity induced by aspirin was attenuated by silencing p21(cip) expression. These results indicated that the anti-apoptotic effect of aspirin was dependent on activation of Akt which inhibited cell apoptosis by up-regulating p21(cip) and blocking caspase-3 activation. These findings could have clinical relevance in anticancer therapy and aspirin co-treatment of human malignancies.