Daily Endocrinology Research Analysis

AIMS/HYPOTHESIS: In type 2 diabetes mellitus, beta cell failure is associated with pancreatic beta cell dedifferentiation and trans-differentiation into other types of islet cells. However, the mechanisms underlying this process remain unclear. Recently, meteorin-like (METRNL) protein, a newly discovered secretory protein, has demonstrated beneficial effects in obesity and insulin resistance. However, its role in islet cell function, particularly in differentiated beta cells, remains to be elucidated. This study aims to investigate the effects of Metrnl gene deletion in beta cells on islet function and determine whether METRNL-mediated maintenance of islet cell identity is necessary for beta cell compensation in diabetes. METHODS: Mice with a specific deletion of Metrnl in beta cells were studied under both normal (chow diet) and metabolic stress (high-fat diet [HFD]) conditions. The investigation focused on their glucose tolerance, insulin secretion, islet gene expression and glucose-stimulated insulin secretion (GSIS). Additionally, cell developmental trajectory and cell-cell interaction analyses of the isolated islets were conducted using single-cell RNA-seq. Furthermore, the impact of METRNL replenishment on the regulation of beta cells in response to HFD feeding or in db/db mice was also examined. RESULTS: METRNL was predominantly expressed in islet beta cells. However, its expression was reduced in the islets of db/db or HFD/streptozocin-induced mice, which positively correlated with insulin expression in these diabetic mice. Furthermore, the deletion of Metrnl in beta cells disrupted insulin secretion in mice fed with HFD, resulting in worsened diabetes and glucose intolerance. Pancreatic islets isolated from METRNL-deficient mice also exhibited reduced insulin secretion in GSIS assays in vitro. Additionally, single-cell RNA-seq analysis of isolated islets demonstrated that METRNL deficiency in beta cells was associated with a potential evolutionary differentiation relationship, indicating a trajectory toward alpha cells. This beta-to-alpha cell trans-differentiation was further evidenced by the upregulation of alpha cell genes (e.g. Gcg, Arx and Irx2) and downregulation of beta cell identity genes (e.g. Ins1, Ins2, Pdx1, and Mafa). Furthermore, METRNL deficiency was found to promote beta-to-alpha cell trans-differentiation during metabolic stress by impairing beta cell capacity, partially due to increased c-Jun levels. On the other hand, as a crucial executor of Kruppel-like transcription factor 6 (KLF6), METRNL may play an important role in maintaining beta cell integrity and function under metabolic stress. Moreover, recombinant METRNL administration significantly improved glucose uptake, lessened the severity of insulin resistance and increased plasma insulin levels in both HFD-fed and db/db mice. CONCLUSIONS/INTERPRETATION: METRNL helps to maintain beta cell integrity, preventing beta-to-alpha cell trans-differentiation, and is necessary for beta cell compensation under metabolic stress, thereby inhibiting the progression of diabetes. DATA AVAILABILITY: scRNA-seq data are accessible via the NCBI Sequence Read Archive ( http://www.ncbi.nlm.nih.gov/bioproject/ ) under accession no. PRJNA1224190. Original western blotting analysis is publicly available in the figshare repository, as part of this record: https://doi.org/10.6084/m9.figshare.28379006 .

AIMS: Severe liver disease (SLD) in nonalcoholic fatty liver disease (NAFLD) is often diagnosed late due to the long asymptomatic period of progressive fibrosis. We aimed to identify metabolomic profiles associated with SLD and develop a predictive model to improve risk stratification. MATERIALS AND METHODS: We enrolled 59 579 UK Biobank participants with a positive fatty liver index (≥60) and plasma metabolomic profiles, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma and/or liver transplantation. Cox regression models were applied to evaluate the associations between individual metabolites and SLD risk. Using an interpretable machine-learning framework, a metabolomics-integrated nomogram prediction model was developed and compared with conventional scoring systems. RESULTS: After Bonferroni correction, 110 of 249 metabolites were significantly associated with the risk of incident SLD in the Cox regression model. Among them, 11 metabolites were ultimately prioritised as predictors to construct the metabolomic score based on the optimal machine learning algorithm. The nomogram integrating metabolomic score, gamma glutamyltransferase, platelet count, waist/hip ratio, diabetes and sex showed better predictive capacity of 10-year SLD risk (area under the receiver operating characteristic 0.841 [95% CI: 0.800-0.881]) than the fibrosis-4 index (0.712, 0.662-0.763), NAFLD fibrosis score (0.659, 0.609-0.709) and aspartate aminotransferase-to-platelet ratio index (0.705, 0.652-0.759) in the validation cohort. Categorisation of participants according to selected cutoffs revealed a distinct cumulative risk of SLD, with a hazard ratio of 25.71 (95% CI: 17.10-38.66) for the high-risk group compared with the low-risk group. CONCLUSIONS: Integrating plasma metabolomics with routine indicators enhanced the predictive capacity for severe liver outcomes of NAFLD, which shows the potential benefits in disease risk stratification and precise interventions.

OBJECTIVE: Arginine vasopressin (AVP), synthesized in the hypothalamus and stored in the posterior pituitary, regulates osmotic balance and stress responses. During stress, AVP enhances corticotropin-releasing hormone-stimulated adrenocorticotropic hormone (ACTH) secretion, with cortisol and AVP providing negative feedback regulation. Disruption in AVP production might impair this feedback, leading to sustained cortisol elevations. The current analysis aims to investigate the effect of hypertonic saline (osmotic stress) and arginine infusion (non-osmotic stress) on the hypothalamic-pituitary-adrenal (HPA) axis response between patients with AVP-Deficiency and primary polydipsia (PP). DESIGN: Secondary sub-analysis of a prospective diagnostic study conducted at seven tertiary centers that utilized hypertonic saline and arginine infusion for diagnostic evaluation of patients with hypotonic polyuria-polydipsia syndrome. METHODS: ACTH and cortisol levels were measured at baseline and the expected peak for both stimulation tests and groups. A pooled linear mixed-effects model (without stimulation type as a variable) was used to compare hormone responses between groups, followed by stimulation test-specific linear regression models to assess differences between both tests. RESULTS: Twenty patients with AVP-Deficiency and 10 patients with PP were included. In the pooled analysis, patients with AVP-Deficiency showed a significantly greater increase in plasma ACTH [7.0 ng/L (95% CI, 0.8-13.3), P = .04] and plasma cortisol [106 nmol/L (95% CI, 24-188), P = .02] compared to patients with PP. Upon hypertonic saline, the changes in plasma ACTH [0.3 ng/L (95% CI, -10.0 to 11.0)] and plasma cortisol [78 nmol/L (95% CI, -32 to 188)] were similar. However, upon arginine infusion, plasma ACTH [9.2 ng/L (95% CI, 1.8-17)] and plasma cortisol [141 nmol/L (95% CI, 40-242)] increases were significantly greater in patients with AVP-Deficiency. CONCLUSION: An altered ACTH and cortisol response pattern to stress in patients with AVP-Deficiency was observed, indicating impaired regulation of the HPA axis. This alteration was primarily driven by differences observed for non-osmotic stress.