Endocrine Connections最新文献

Introduction: Most phaeochromocytomas produce insulin, and some produce glucagon-like peptide 1 receptor (GLP-1R). In pancreatic β-cells, stimulation of GLP-1R causes insulin release. A few phaeochromocytoma patients experience hypoglycaemic attacks. Therefore, we studied the distribution of GLP-1R-containing and insulin-containing phaeochromocytoma cells and their relation.

Methods: In 20 phaeochromocytomas, we performed sequential double staining with anti-insulin and anti-GLP-1R antibodies and, in selected cases, staining with anti-insulin alone. We quantified tumour cells with positive staining and compared their distribution to that of randomly distributed cells using simulations. We obtained GLP-1R transcript data from 182 such tumours from The Cancer Genome Atlas (TCGA) Research Network.

Results: GLP-1R-containing cells were found in six of the 20 tumours, and insulin-containing cells were found in fifteen. Moreover, in the TCGA cohort, almost half of the tumours produce GLP-1R transcripts, and patients with the highest number of transcripts show longer disease-free survival. In the tumours, we found that cells expressing insulin were present in the cytoplasm and GLP-1R in the membrane, with a frequency of 2.59 and 1.34%, respectively. These cells showed clustering, and one tumour showed a large clonal expansion. Interestingly, we found deposits of insulin, which we suggest naming insulin bodies in two tumours. Very few cells contained both proteins.

Conclusion: Most phaeochromocytomas contain tumour cells producing insulin. About half produce GLP-1R. The producing cells show clustering, and clonal expansion occurs. Insulin release might cause hypoglycaemia. Increased GLP-1R levels might induce less aggressive tumours.

Objective: Strain imaging serves as a sensitive marker for detecting early subclinical myocardial systolic dysfunction. The purpose of this study was to evaluate the diagnostic and prognostic value of myocardial work indices in assessing subclinical myocardial systolic dysfunction in active acromegaly patients.

Methods: 27 active acromegaly patients and 27 healthy controls matched for age, sex, height, weight, body mass index and body surface area were included in the study. Active acromegaly was diagnosed based on elevated serum insulin-like growth factor 1 (IGF-1) (>1× upper limit of normal) or insufficient GH suppression (nadir ≥0.4 ng/mL) during an OGTT. All participants underwent two-dimensional speckle-tracking echocardiography (2D-STE) for the assessment of cardiac function. STE extracted the corresponding strain parameters (such as global longitudinal strain (GLS), global circumferential strain and global radial strain) and work parameters (such as global work index, global constructive work, global wasted work (GWW) and global work efficiency (GWE)) by analyzing the motion (strain)-velocity (strain rate) of two or more local myocardial segments, combined with the left ventricular non-invasive pressure estimation technique. At the same time, correlation analysis was used to explore the factors affecting GWW and GWE in the acromegaly group.

Results: In comparison with the control group, conventional echocardiography revealed that acromegaly patients did not exhibit a significant difference in left ventricular ejection fraction (60.3 ± 3.7 vs 59.1 ± 4.8, P = 0.312), a commonly used index to evaluate ventricular systolic function, STE showed that there was no significant difference in GLS (-18.3 ± 2.4 vs -17.4 ± 2.9, P = 0.514) between the control group and the acromegaly group. However, significant differences can be found in GWW (44.8 ± 31.1 vs 80.6 ± 75.6, P = 0.027) and GWE (97.0 ± 1.8 vs 95.0 ± 3.8, P = 0.020), and a significant correlation was observed between myocardial work parameters and 1.5 × ULN IGF-1.

Conclusion: GWW and GWE are sensitive markers for identifying subclinical myocardial systolic dysfunction, suggesting their potential as early markers for detecting subclinical myocardial systolic dysfunction in active acromegaly patients.

Objective: Cystic fibrosis (CF) is a congenital condition caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF-related diabetes (CFRD) is a common comorbidity among people with CF (pwCF) and is associated with increased morbidity. Previous in vitro studies have suggested that CFTR dysfunction is involved in the pathogenesis of CFRD. This prospective study aimed to evaluate the role of CFTR in glucose homeostasis by comparing glucose, insulin, C-peptide, glucagon and GLP-1 responses during an oral glucose tolerance test (OGTT) in pwCF and healthy controls and in pwCF before and after initiating elexacaftor-tezacaftor-ivacaftor (ETI) therapy.

Methods: Twenty-four pwCF were enrolled, of which 18 underwent OGTT both before and after ETI initiation. Ten healthy controls were included for comparison. Plasma samples were collected at standard OGTT time points, including an additional 15 min sample. Hormonal and glucose responses during OGTT were compared across groups and in pwCF before and after starting ETI.

Results: Compared with healthy controls, pwCF exhibited impaired glucose regulation, delayed insulin secretion, decreased insulin sensitivity index and reduced disposition index, indicating beta-cell dysfunction. In addition, p-glucagon levels were elevated in pwCF. Following ETI therapy, pwCF showed improved glucose control, increased first-phase insulin secretion and normalized glucagon secretion.

Conclusions: These findings support a role for CFTR in islet hormone regulation, implicating direct effects on beta-cell function and a potential role in suppressing glucagon secretion.

Background: Metformin, the first-line treatment for type 2 diabetes, often induces gastrointestinal side effects, affecting treatment adherence. Recent research suggests that the gut microbiome mediates both the efficacy and tolerability of metformin. This study evaluates the effect of a polyherbal formulation, used as an add-on to metformin, on the gut microbiota in patients with type 2 diabetes and metformin intolerance.

Methods: We report preliminary findings from the first 7-day intervention phase of an ongoing randomized, placebo-controlled, crossover trial (NCT06846138) in 27 adults with type 2 diabetes. Participants received either polyherbal formulations or a placebo alongside metformin for 7 days. Stool samples were collected pre- and post-intervention for shotgun metagenomic sequencing. Microbial diversity, composition, and pathway functions were analyzed using Kraken2, Bracken, and HUMAnN3. Continuous glucose monitoring was used to assess glycemic metrics.

Results: No significant alpha-diversity changes were observed; however, beta-diversity differed significantly between arms (PERMANOVA R 2 = 0.04, P = 0.04). In the polyherbal formulation group, 17 species changed post-treatment (FDR < 0.25), with significant increases in six Bifidobacterium spp. (e.g., B. adolescentis, B. ruminantium). In contrast, the placebo group showed no major microbial shifts. Polyherbal formulation also altered ten microbial pathways (FDR < 0.25). Continuous glucose monitoring revealed no short-term changes in glycemic levels.

Conclusion: Short-term polyherbal formulation co-administration significantly modulates gut microbiota, promoting beneficial taxa, such as Bifidobacterium in metformin-treated type 2 diabetes patients. This supports the potential role of the polyherbal formulation in microbiome-targeted strategies to improve metformin tolerability and effectiveness.

Background: Graves' orbitopathy (GO) profoundly affects patients' quality of life, even in its mild form, yet the underlying factors contributing to this impairment remain underexplored. Recent evidence suggests the potential immune tolerance-inducing effect of immunoglobulin G4 (IgG4) in the pathogenesis of GO. However, its specific impact on quality of life and its significance in mild GO have not been well characterized.

Methods: This prospective multicenter study included patients with mild GO who were in euthyroidism. Quality of life was assessed using the validated GO-quality of life questionnaire (GO-QoL). Serum IgG4 levels and IgG4/IgG ratios were measured and analyzed in relation to GO-QoL scores and other clinical and biochemical parameters.

Results: Patients with mild GO exhibited significantly impaired quality of life, with the greatest impact seen in the appearance subscale. Notably, serum IgG4 levels were positively correlated with visual functioning scores in the GO-QoL (ρ = 0.248, P = 0.0466). Higher serum IgG4 levels were also associated with less limitation in driving and a longer duration of GO. Moreover, serum IgG4 levels and IgG4/IgG ratios showed significant positive correlations with male sex and clinical activity score.

Conclusions: This study highlights the significant impairment in the quality of life experienced by patients with mild GO and identifies serum IgG4 as a promising indicator for evaluating disease chronicity and quality of life, which may help guide different treatment strategies. Further prospective and basic studies are required to explore the role of IgG4 in the pathogenesis of GO.

Background: This study aimed to investigate the association between cerebrovascular disease (CBVD) and adverse in-hospital outcomes in patients with diabetic ketoacidosis (DKA).

Methods: We conducted a retrospective analysis using the National Inpatient Sample data from 2016 to 2022, identifying 445,863 hospitalizations among adults with diabetes and CBVD. Within this cohort, 4,363 patients had DKA and 1,648 had hyperosmolar hyperglycemic state (HHS). Multivariable logistic regression was employed to control for demographic, socioeconomic, admission, comorbidity, and hospital factors.

Results: Our findings revealed that among hospitalized adults with type 2 diabetes (T2DM) and CBVD, patients experiencing DKA had a significantly higher rate of in-hospital mortality compared to those with non-DKA/HHS cases. The likelihood of severe complications was notably increased in DKA patients. Furthermore, DKA hospitalizations were associated with an extended length of stay and an increased financial burden. When compared to HHS patients, those with DKA exhibited a greater risk of mortality, higher rate of complications, and higher resource utilization. In addition, within the cohort of patients with a primary diagnosis of T2DM DKA, those with CBVD had higher resource utilization and an increased incidence of complications.

Conclusions: Patients with DKA and CBVD experienced significantly poorer clinical outcomes and increased healthcare resource utilization compared to those with non-DKA/HHS and HHS. These findings highlight the adverse impact of CBVD on in-hospital outcomes for DKA patients, emphasizing the need for targeted prevention and timely multidisciplinary management strategies for this vulnerable population.

Objective: This study aimed to identify risk factors for osteoporosis (OP) in patients with primary aldosteronism (PA) and to develop a predictive nomogram for estimating OP risk in this population.

Methods: We retrospectively enrolled PA patients diagnosed at our hospital between January 2020 and December 2024. The dataset was randomly divided into training (n = 185) and validation (n = 79) sets in a 7:3 ratio. Least absolute shrinkage and selection operator (LASSO) regression combined with multivariate logistic regression was used to identify predictive factors for OP and construct the nomogram. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). Additional performance assessments included the Hosmer-Lemeshow test, calibration curves, and decision curve analysis (DCA).

Results: The study included 264 PA patients (mean age 61.2 ± 10.0 years; 110 men, 154 women), with an OP prevalence of 11.4%. LASSO regression identified seven independent predictors: age, sex, body mass index, diabetes history, fasting insulin, plasma aldosterone concentration, and serum creatinine. The nomogram demonstrated strong predictive performance, with AUC values of 0.931 (95% CI: 0.879-0.982) in the training set and 0.842 (95% CI: 0.749-0.935) in the validation set. Calibration curves and DCA confirmed the model's clinical utility.

Conclusion: The developed nomogram effectively predicts OP risk in PA patients, offering valuable clinical utility for early identification of high-risk individuals.

Background: Alcohol consumption was shown to increase endogenous fibroblast growth factor 21 (FGF21), but knowledge about the effect of alcohol cessation on FGF21 is limited. The effects of cigarette smoking and cessation on FGF21 levels are unknown. The objective of this study was to investigate moderate alcohol and cigarette consumption and their cessation on FGF21 levels.

Methods: This is a secondary analysis of two prospective intervention studies. Study 1: ten healthy men undergoing a beer or water intervention with blood sampling over 720 min. Differences in FGF21 levels between alcohol and water intake were assessed using a mixed-effect model. Study 2: 144 alcohol-drinking men or women undergoing a 12-week intervention of glucagon-like peptide 1 (GLP-1) receptor agonist dulaglutide vs placebo on smoking and alcohol cessation. Differences in FGF21 levels after 12 weeks of treatment with GLP-1 in persistent drinkers/smokers compared to those who had stopped drinking/smoking, were assessed using mixed-effect models.

Results: Study 1: FGF21 levels at 240 min following beer intake were higher compared to water intake (1.386.0 pg/mL (95% CI: 934.55; 1,837.44), P < 0.001). Study 2: participants who stopped drinking alcohol had lower FGF21 levels compared to persistent drinkers (-228.65 pg/mL (95% CI: -440.4; -14.6), P = 0.03). Smoking cessation had no effect on FGF21 levels (P = 0.13).

Conclusion: Our findings demonstrate a dynamic response in FGF21 levels, with acute moderate alcohol consumption inducing elevated FGF21 levels, and cessation of drinking lowering FGF21 levels, indicative of potential liver recovery. No effect of cigarette smoking cessation on plasma FGF21 levels was observed.

Insulin resistance (IR) is a pathogenic mechanism for type 2 diabetes mellitus (T2DM), and receptor-interacting serine-threonine kinase 2 (RIPK2) participates in mediating IR. To investigate the specific role of RIPK2 in IR, this study utilized bovine serum albumin-conjugated palmitic acid (0.5 mmol/L) to create an IR model in rat L6 myotubes, followed by transfection with/without short hairpin RNA against RIPK2 (shRIPK2)/RIPK2 overexpression plasmid, and X-linked inhibitor of apoptosis (XIAP) overexpression plasmids. The expressions of RIPK2 and XIAP were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Oxidative stress markers superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) were quantified. Western blot was performed to detect the levels of phosphorylation of extracellular signal-regulated kinases 1/2 (p-ERK1/2)/ERK1/2, p-p38/p38, and p-serine/threonine kinase (p-AKT)/AKT, as well as the influence of XIAP on RIPK2 ubiquitination. Glucose absorption was quantified using fluorescent probes (2-NBDG). In the IR model, RIPK2 expression was significantly increased, whereas XIAP expression was reduced. RIPK2 overexpression diminished SOD levels, CAT levels, and GPx levels and elevated MDA levels, accompanied by increased p-ERK1/2/ERK1/2 and p-p38/p38 ratios. Overexpression of RIPK2 lowered glucose absorption and the p-AKT/AKT ratio. RIPK2 was ubiquitinated by XIAP in the IR model. RIPK2 overexpression offset the impact of XIAP overexpression on SOD levels, CAT levels, GPx levels, and MDA levels, p-ERK1/2/ERK1/2 ratios, and p-p38/p38 ratios. XIAP overexpression enhanced glucose absorption and the p-AKT/AKT ratio. Our results demonstrate that XIAP deficiency reduces RIPK2 ubiquitination, thereby mediating IR in T2DM.

Abstract: Childhood-onset growth-hormone deficiency (GHD) requires growth-hormone therapy (GHT) to optimize final height. GHT may also have benefits after final height is achieved, notably on bone. The objective of this retrospective single-center observational cohort study of patients who had persistent GHD after achieving their final height was to assess bone parameters at the transition to adult care and then more than 6 months later (6.08 (3.33-10.25) years). Bone mineral density (BMD) and Z-score at the lumbar spine and hip were determined. Of 162 patients transitioned to adult care in 1994-2021, 105 received GHT for longer than 6 months (GHT group) and 57 received either no GHT or GHT for less than 6 months (no-GHT group); however, BMD and Z-score data from both evaluations were available for only a minority of patients. Lumbar-spine BMD was significantly higher at the second evaluation in the GHT group than in the no-GHT group (P = 0.034). The lumbar-spine Z-scores at the first and second evaluations were -1.61 and -1.32 in the no-GHT group vs -1.09 and -0.61 in the GHT group (P = 0.047 for the difference in median change over time between groups). Changes in BMD at the lumbar spine and in BMD and Z-score at the femoral neck were not significantly different between the two groups. These results suggest beneficial effects of continued GHT in patients with persistent GHD after final height attainment, adding evidence to continue GH therapy during and after the transition period.

Plain language summary: Children with insufficient growth-hormone levels are given growth-hormone injections to allow them to gain height. Once the final height is achieved, the treatment is often stopped. However, further treatment during the transition to adulthood may have benefits, notably on bone.