Ectopic adrenocortical adenoma characterized by hypogonadism: a case report and review of the literature.

BACKGROUND: Currently, there is a scarcity of cases and diagnostic data regarding ectopic adrenocortical adenomas, particularly in relation to their impact on gonadal function and localization diagnostic techniques. We report a typical case of ectopic adrenocortical adenomas and the data of treatment follow-up, and review the literature of 31 available cases of ectopic adrenocortical adenomas. CASE PRESENTATION: A 27-year-old Chinese female patient was admitted to our hospital for hypertension, hyperglycaemia and primary amenorrhea. The patient was functionally diagnosed with ACTH-independent CS and hypogonadotropic hypogonadism. Radiological evaluations, including Computed Tomography (CT) and functional imaging, identified a mass at the left renal hilum. Histological assessments post-surgical excision confirmed the mass to be an ectopic adrenocortical adenoma. A subsequent 3-month follow-up showed no signs of disease recurrence, a swift recovery of the cortisol axis was observed, with a partial recuperation of the gonadal axis. REVIEW: Our literature review shows that the most common ectopic areas of cortisol adenomas are renal hilum and hepatic region. The most positive biomarker is Melan A, and only a few cases have been diagnosed with functional localization. CONCLUSION: Ectopic adrenocortical adenomas may be asymptomatic in the early stage and can impact gonadal function. Physicians who treat hypogonadism must be aware of the need to test cortisol levels and perform functional localization in patients with lumps present.

Development and validation of machine learning-augmented algorithm for insulin sensitivity assessment in the community and primary care settings: a population-based study in China.

Objective: Insulin plays a central role in the regulation of energy and glucose homeostasis, and insulin resistance (IR) is widely considered as the "common soil" of a cluster of cardiometabolic disorders. Assessment of insulin sensitivity is very important in preventing and treating IR-related disease. This study aims to develop and validate machine learning (ML)-augmented algorithms for insulin sensitivity assessment in the community and primary care settings. Methods: We analyzed the data of 9358 participants over 40 years old who participated in the population-based cohort of the Hubei center of the REACTION study (Risk Evaluation of Cancers in Chinese Diabetic Individuals). Three non-ensemble algorithms and four ensemble algorithms were used to develop the models with 70 non-laboratory variables for the community and 87 (70 non-laboratory and 17 laboratory) variables for the primary care settings to screen the classifier of the state-of-the-art. The models with the best performance were further streamlined using top-ranked 5, 8, 10, 13, 15, and 20 features. Performances of these ML models were evaluated using the area under the receiver operating characteristic curve (AUROC), the area under the precision-recall curve (AUPR), and the Brier score. The Shapley additive explanation (SHAP) analysis was employed to evaluate the importance of features and interpret the models. Results: The LightGBM models developed for the community (AUROC 0.794, AUPR 0.575, Brier score 0.145) and primary care settings (AUROC 0.867, AUPR 0.705, Brier score 0.119) achieved higher performance than the models constructed by the other six algorithms. The streamlined LightGBM models for the community (AUROC 0.791, AUPR 0.563, Brier score 0.146) and primary care settings (AUROC 0.863, AUPR 0.692, Brier score 0.124) using the 20 top-ranked variables also showed excellent performance. SHAP analysis indicated that the top-ranked features included fasting plasma glucose (FPG), waist circumference (WC), body mass index (BMI), triglycerides (TG), gender, waist-to-height ratio (WHtR), the number of daughters born, resting pulse rate (RPR), etc. Conclusion: The ML models using the LightGBM algorithm are efficient to predict insulin sensitivity in the community and primary care settings accurately and might potentially become an efficient and practical tool for insulin sensitivity assessment in these settings.

Comparative Efficacy of Novel Antidiabetic Drugs on Albuminuria Outcomes in Type 2 Diabetes: A Systematic Review.

INTRODUCTION: Albuminuria, or elevated urinary albumin-to-creatine ratio (UACR), is a biomarker for chronic kidney disease that is routinely monitored in patients with type 2 diabetes (T2D). Head-to-head comparisons of novel antidiabetic drugs on albuminuria outcomes remain limited. This systematic review qualitatively compared the efficacy of novel antidiabetic drugs on improving albuminuria outcomes in patients with T2D. METHODS: We searched the MEDLINE database until December 2022 for Phase 3 or 4 randomized, placebo-controlled trials that evaluated the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on changes in UACR and albuminuria categories in patients with T2D. RESULTS: Among 211 records identified, 27 were included, which reported on 16 trials. SGLT2 inhibitors and GLP-1 RAs decreased UACR by 19-22% and 17-33%, respectively, versus placebo (P < 0.05 for all studies) over median follow-up of ≥ 2 years; DPP-4 inhibitors showed varying effects on UACR. Compared with placebo, SGLT2 inhibitors decreased the risk for albuminuria onset by 16-20% and for albuminuria progression by 27-48% (P < 0.05 for all studies) and promoted albuminuria regression (P < 0.05 for all studies) over median follow-up of ≥ 2 years. Evidence on changes in albuminuria categories with GLP-1 RA or DPP-4 inhibitor treatment were limited with varying outcome definitions across studies and potential drug-specific effects within each class. The effect of novel antidiabetic drugs on UACR or albuminuria outcomes at ≤ 1 year remains poorly studied. CONCLUSION: Among the novel antidiabetic drugs, SGLT2 inhibitors consistently improved UACR and albuminuria outcomes in patients with T2D, with continuous treatment showing long-term benefit.

Suppression of the hypothalamic-pituitary-thyroid axis is associated with the severity of prognosis in hospitalized patients with COVID-19.

BACKGROUND: The outbreak of severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide. SARS-CoV-2 has been found to cause multiple organ damage; however, little attention has been paid to the damage to the endocrine system caused by this virus, and the subsequent impact on prognosis. This may be the first research on the hypothalamic-pituitary-thyroid (HPT) axis and prognosis in coronavirus disease 2019 (COVID-19). METHODS: In this retrospective observational study, 235 patients were admitted to the hospital with laboratory-confirmed SARS-CoV-2 infection from 22 January to 17 March 2020. Clinical characteristics, laboratory findings, and treatments were obtained from electronic medical records with standard data collection forms and compared among patients with different thyroid function status. RESULTS: Among 235 patients, 17 (7.23%) had subclinical hypothyroidism, 11 (4.68%) severe non-thyroidal illness syndrome (NTIS), and 23 (9.79%) mild to moderate NTIS. Composite endpoint events of each group, including mortality, admission to the ICU, and using IMV were observed. Compared with normal thyroid function, the hazard ratios (HRs) of composite endpoint events for mild to moderate NTIS, severe NTIS, subclinical hypothyroidism were 27.3 (95% confidence interval [CI] 7.07-105.7), 23.1 (95% CI 5.75-92.8), and 4.04 (95% CI 0.69-23.8) respectively. The multivariate-adjusted HRs for acute cardiac injury among patients with NTF, subclinical hypothyroidism, severe NTIS, and mild to moderate NTIS were 1.00, 1.68 (95% CI 0.56-5.05), 4.68 (95% CI 1.76-12.4), and 2.63 (95% CI 1.09-6.36) respectively. CONCLUSIONS: Our study shows that the suppression of the HPT axis could be a common complication in COVID-19 patients and an indicator of the severity of prognosis. Among the three different types of thyroid dysfunction with COVID-19, mild to moderate NTIS and severe NTIS have a higher risk of severe outcomes compared with subclinical hypothyroidism.

Prognostic Value of Leucocyte to High-Density Lipoprotein-Cholesterol Ratios in COVID-19 Patients and the Diabetes Subgroup.

Background: Blood parameters, such as neutrophil-to-lymphocyte ratio, have been identified as reliable inflammatory markers with diagnostic and predictive value for the coronavirus disease 2019 (COVID-19). However, novel hematological parameters derived from high-density lipoprotein-cholesterol (HDL-C) have rarely been studied as indicators for the risk of poor outcomes in patients with severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection. Here, we aimed to assess the prognostic value of these novel biomarkers in COVID-19 patients and the diabetes subgroup. Methods: We conducted a multicenter retrospective cohort study involving all hospitalized patients with COVID-19 from January to March 2020 in five hospitals in Wuhan, China. Demographics, clinical and laboratory findings, and outcomes were recorded. Neutrophil to HDL-C ratio (NHR), monocyte to HDL-C ratio (MHR), lymphocyte to HDL-C ratio (LHR), and platelet to HDL-C ratio (PHR) were investigated and compared in both the overall population and the subgroup with diabetes. The associations between blood parameters at admission with primary composite end-point events (including mechanical ventilation, admission to the intensive care unit, or death) were analyzed using Cox proportional hazards regression models. Receiver operating characteristic curves were used to compare the utility of different blood parameters. Results: Of 440 patients with COVID-19, 67 (15.2%) were critically ill. On admission, HDL-C concentration was decreased while NHR was high in patients with critical compared with non-critical COVID-19, and were independently associated with poor outcome as continuous variables in the overall population (HR: 0.213, 95% CI 0.090-0.507; HR: 1.066, 95% CI 1.030-1.103, respectively) after adjusting for confounding factors. Additionally, when HDL-C and NHR were examined as categorical variables, the HRs and 95% CIs for tertile 3 vs. tertile 1 were 0.280 (0.128-0.612) and 4.458 (1.817-10.938), respectively. Similar results were observed in the diabetes subgroup. ROC curves showed that the NHR had good performance in predicting worse outcomes. The cutoff point of the NHR was 5.50. However, the data in our present study could not confirm the possible predictive effect of LHR, MHR, and PHR on COVID-19 severity. Conclusion: Lower HDL-C concentrations and higher NHR at admission were observed in patients with critical COVID-19 than in those with noncritical COVID-19, and were significantly associated with a poor prognosis in COVID-19 patients as well as in the diabetes subgroup.

Short-Term Changes in Metabolically Healthy Overweight/Obesity Status Impact the Susceptibility to Type 2 Diabetes in Chinese Adults.

PURPOSE: Changes in transition from metabolically healthy overweight/obesity (MHO) to metabolically unhealthy overweight/obesity (MUO) are associated with the risk for cardiometabolic complications. This study aims to investigate the effects of short-term dynamic changes in body mass index (BMI) and metabolic status on the risk of type 2 diabetes (T2D) and to identify biological predictors for the MHO-to-MUO transition. PATIENTS AND METHODS: A total of 4604 subjects from the REACTION study were included for a 3-year follow-up. Subjects were categorized based on their BMI and metabolic syndrome status. Overweight/obesity was defined as BMI ≥ 24 kg/m2. Metabolically healthy was defined as having two or fewer of the metabolic syndrome components proposed by the Chinese Diabetes Society. Thus, subjects were divided into four groups: metabolically healthy normal weight (MHNW), MHO, metabolically unhealthy normal weight (MUNW), and MUO. RESULTS: Compared with MHNW, MHO was not predisposed to an increased risk for T2D (OR 1.08, 95% CI 0.64-1.83, P = 0.762). However, a 3-year transition probability of 20.6% was identified for subjects who shifted from MHO to MUO; this conversion increased the risk of T2D by 3-fold (OR 3.04, 95% CI 1.21-7.68, P = 0.018). The fatty liver index independently predicted the MHO-to-MUO transition with an OR 3.14 (95% CI 1.56-7.46, P = 0.002) when comparing the fourth quartile to the first quartile. CONCLUSION: This study reveals that metabolic changes affect the short-term susceptibility to T2D in the overweight/obese Chinese population, and the fatty liver index is an efficient clinical parameter for identifying those with a metabolic deterioration risk.

Vascular endothelial growth factor B promotes transendothelial fatty acid transport into skeletal muscle via histone modifications during catch-up growth.

Caloric restriction (CR) followed by refeeding, a phenomenon known as catch-up growth (CUG), results in excessive lipid deposition and insulin resistance in skeletal muscle, but the underlying mechanisms remain elusive. Recent reports have suggested that vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation by regulating endothelial fatty acid transport. Here, we found continuous activation of VEGF-B signaling and increased lipid uptake in skeletal muscle from CR to refeeding, as well as increased lipid deposition and impaired insulin sensitivity after refeeding in the skeletal muscle of CUG rodents. Inhibiting VEGF-B signaling reduced fatty acid uptake in and transport across endothelial cells. Knockdown of Vegfb in the tibialis anterior (TA) muscle of CUG mice significantly attenuated muscle lipid accumulation and ameliorated muscle insulin sensitivity by decreasing lipid uptake. Furthermore, we showed that aberrant histone methylation (H3K9me1) and acetylation (H3K14ac and H3K18ac) at the Vegfb promoter might be the main cause of persistent VEGF-B upregulation in skeletal muscle during CUG. Modifying these aberrant loci using their related enzymes [PHD finger protein 2 (PHF2) or E1A binding protein p300 (p300)] could regulate VEGF-B expression in vitro. Collectively, our findings indicate that VEGF-B can promote transendothelial lipid transport and lead to lipid overaccumulation and insulin resistance in skeletal muscle during CUG, which might be mediated by histone methylation and acetylation.

Impaired Fasting Glucose and Diabetes Are Related to Higher Risks of Complications and Mortality Among Patients With Coronavirus Disease 2019.

Background: Diabetes correlates with poor prognosis in patients with COVID-19, but very few studies have evaluated whether impaired fasting glucose (IFG) is also a risk factor for the poor outcomes of patients with COVID-19. Here we aimed to examine the associations between IFG and diabetes at admission with risks of complications and mortality among patients with COVID-19. Methods: In this multicenter retrospective cohort study, we enrolled 312 hospitalized patients with COVID-19 from 5 hospitals in Wuhan from Jan 1 to Mar 17, 2020. Clinical information, laboratory findings, complications, treatment regimens, and mortality status were collected. The associations between hyperglycemia and diabetes status at admission with primary composite end-point events (including mechanical ventilation, admission to intensive care unit, or death) were analyzed by Cox proportional hazards regression models. Results: The median age of the patients was 57 years (interquartile range 38-66), and 172 (55%) were women. At the time of hospital admission, 84 (27%) had diabetes (and 36 were new-diagnosed), 62 (20%) had IFG, and 166 (53%) had normal fasting glucose (NFG) levels. Compared to patients with NFG, patients with IFG and diabetes developed more primary composite end-point events (9 [5%], 11 [18%], 26 [31%]), including receiving mechanical ventilation (5 [3%], 6 [10%], 21 [25%]), and death (4 [2%], 9 [15%], 20 [24%]). Multivariable Cox regression analyses showed diabetes was associated increased risks of primary composite end-point events (hazard ratio 3.53; 95% confidence interval 1.48-8.40) and mortality (6.25; 1.91-20.45), and IFG was associated with an increased risk of mortality (4.11; 1.15-14.74), after adjusting for age, sex, hospitals and comorbidities. Conclusion: IFG and diabetes at admission were associated with higher risks of adverse outcomes among patients with COVID-19.

Newly diagnosed diabetes is associated with a higher risk of mortality than known diabetes in hospitalized patients with COVID-19.

AIM: To evaluate the association between different degrees of hyperglycaemia and the risk of all-cause mortality among hospitalized patients with COVID-19. MATERIALS AND METHODS: In a retrospective study conducted from 22 January to 17 March 2020, 453 patients were admitted to Union Hospital in Wuhan, China, with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection. Patients were classified into four categories: normal glucose, hyperglycaemia (fasting glucose 5.6-6.9 mmol/L and/or HbA1c 5.7%-6.4%), newly diagnosed diabetes (fasting glucose ≥7 mmol/L and/or HbA1c ≥6.5%) and known diabetes. The major outcomes included in-hospital mortality, intensive care unit (ICU) admission and invasive mechanical ventilation (IMV). RESULTS: Patients with newly diagnosed diabetes constituted the highest percentage to be admitted to the ICU (11.7%) and require IMV (11.7%), followed by patients with known diabetes (4.1%; 9.2%) and patients with hyperglycaemia (6.2%; 4.7%), compared with patients with normal glucose (1.5%; 2.3%), respectively. The multivariable-adjusted hazard ratios of mortality among COVID-19 patients with normal glucose, hyperglycaemia, newly diagnosed diabetes and known diabetes were 1.00, 3.29 (95% confidence interval [CI] 0.65-16.6), 9.42 (95% CI 2.18-40.7) and 4.63 (95% CI 1.02-21.0), respectively. CONCLUSION: We showed that COVID-19 patients with newly diagnosed diabetes had the highest risk of all-cause mortality compared with COVID-19 patients with known diabetes, hyperglycaemia and normal glucose. Patients with COVID-19 need to be kept under surveillance for blood glucose screening.

High fat-induced inflammation in vascular endothelium can be improved by Abelmoschus esculentus and metformin via increasing the expressions of miR-146a and miR-155.

BACKGROUND: Obesity is associated with chronic inflammation, which contributes to cardiovascular diseases. MicroRNAs (miRNAs) are reported to be involved in vascular inflammation and atherosclerosis. Abelmoschus esculentus (AE) and metformin have been suggested to improve inflammation in vascular system. The aim of this study is to evaluate whether miRNAs are involved in high fat induced endothelial inflammation, and whether AE and metformin improve endothelial inflammation by regulating miRNAs. METHODS: We established high fat treated rats and human aortic endothelial cells (HAECs). AE and metformin were added to explore their effects on endothelial inflammation induced by high fat and the possible mechanism. RESULTS: The vascular inflammatory genes were increased in rats treated with high fat diet. The decreased miR-146a and miR-155 were involved in endothelial inflammation induced by high fat through targeting IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6) and nuclear factor-κB p65 (NF-κB p65), respectively. While AE and metformin could ameliorate the endothelial inflammation by increasing miR-146a and miR-155. CONCLUSIONS: These results indicate that miR-146a and miR-155 play roles in the high fat induced endothelial inflammation, which could be potential therapeutic targets. AE and metformin can attenuate endothelial inflammation through regulating miR-146a and miR-155.

Evaluation of Serum microRNAs in Patients with Diabetic Kidney Disease: A Nested Case-Controlled Study and Bioinformatics Analysis.

BACKGROUND Diabetic kidney disease (DKD) can result in end-stage kidney disease and renal failure. This study aimed to examine the expression of serum microRNAs (miRNAs), miR-20a, miR-99b, miR-122-5p, and miR-486-5p, and to use bioinformatics data to investigate the pathways involved in DKD. MATERIAL AND METHODS Serum miRNAs were obtained from 25 healthy volunteers, 50 patients with non-complicated type 2 diabetes mellitus (T2DM), and 42 patients with T2DM and DKD. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of serum miRNAs. Specificity and sensitivity of the association between serum miRNAs in DKD were evaluated by analysis of the receiver operating characteristic (ROC) area under the curve (AUC). Serum miRNAs and clinical parameters of the patients were compared. Bioinformatics data analysis accessed the miRNA targets involved in the pathways related to the pathogenesis of DKD. RESULTS Serum levels of miR-99b and miR-122 significantly increased, and mir-20a and miR-486 decreased in the DKD group compared with healthy controls. Serum levels of miR-20a, miR-99b, miR-486-5p, and miR-122-5p were significantly correlated with albuminuria, estimated glomerular filtration rate (eGFR), blood glucose and lipid profiles. ROC curve analysis showed that diagnostic accuracy of serum levels of miR-99b for DKD was superior to miR-486-5p, miR-122-5p, and miR-20a, resulting in AUCs of 0.895, 0.853, 0.80, and 0.697, respectively. These four miRNAs regulate several genes affecting oxidative stress, inflammation, and apoptosis. CONCLUSIONS Serum miR-99b, miR-486-5p, miR-122-5p, and miR-20a were differentially expressed in patients with T2DM and DKD and should be evaluated further as potential biomarkers for DKD.

NADPH oxidase 4 and endothelial nitric oxide synthase contribute to endothelial dysfunction mediated by histone methylations in metabolic memory.

"Metabolic memory" is identified as a phenomenon that transient hyperglycemia can be remembered by vasculature for quite a long term even after reestablishment of normoglycemia. NADPH oxidases (Noxs) and endothelial nitric oxide synthase (eNOS) are important enzymatic sources of reactive oxygen species (ROS) in diabetic vasculature. The aim of this study is to explore the roles of epigenetics and ROS derived from Noxs and eNOS in the metabolic memory. In this study, we demonstrated that vascular ROS was continuously activated in endothelium induced by transient high glucose, as well as sustained vascular endothelial dysfunction. The Nox4 and uncoupled eNOS are the major sources of ROS, while inhibition of Nox4 and eNOS significantly attenuated oxidative stress and almost recovered the endothelial function in metabolic memory. Furthermore, the aberrant histone methylation (H3K4me1, H3K9me2, and H3K9me3) at promoters of Nox4 and eNOS are the main causes for the persistent up-regulation of these two genes. Modifying the histone methylation could reduce the expression levels of Nox4 and eNOS, thus obviously attenuating endothelial dysfunction. These results indicate that histone methylation of Nox4 and eNOS play a key role in metabolic memory and may be the potential intervention targets for metabolic memory.

The MicroRNAs in the Pathogenesis of Metabolic Memory.

"Metabolic memory" is identified as a phenomenon that previous exposure to hyperglycemia results in the long-lasting deleterious effects on cardiovascular events. More and more researches show that epigenetics plays an important role in the pathogenesis of metabolic memory. It remains unclear whether microRNA (miRNA) dysfunctions participate in the event. In this study, the miRNA arrays on human aortic endothelial cells were adopted to seek the miRNAs that may be involved in the metabolic memory and were verified in vivo and in vitro. Sixteen miRNAs were found differentially expressed. Among these miRNAs, the expressions of miR-125b, miR-146a-5p, and miR-29a-3p were associated with persistent impaired endothelial function and altered proinflammatory gene expressions, including nuclear factor-κB (NF-κB) subunit p65. Direct inhibition of miR-125b expression or increased miR-146a-5p expression blunted NF-κB signals and improved the endothelial function. Luciferase reporter assays confirmed the biochemical relationship for miR-125b targeting on TNF-α-induced protein 3 and miR-146a-5p targeting on TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 during the activation of NF-κB pathway. Thus, our findings demonstrate that glucose induced changes in miR-125b and miR-146a-5p are related to the long-lasting activation of NF-κB pathway and contribute to follow-up metabolic memory.