Association between serum uric acid and deep venous thrombosis in European populations: A two-sample Mendelian randomization study.

BACKGROUND AND AIM: Previous experimental and observational studies showed that serum uric acid (SUA) was associated with deep venous thrombosis (DVT), but the causal relationship is unclear. This study aimed to explore the potential causal association between SUA and DVT. METHODS AND RESULTS: We designed a two-sample Mendelian randomization (MR) analysis by using summary-level data from large genome-wide association studies performed in European individuals. A total of 14 SUA-related single-nucleotide polymorphisms (SNPs) (P value < 5 × 10-8) were identified as instrumental variables. The inverse variance weighted method was used as the primary method to compute the odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for per standard deviation increase in SUA. MR Egger, weighted median, weighted mode, and simple mode were also applied to test the robustness of the results. We found no significant causal effects of serum uric acid on deep venous thrombosis (odds ratio [OR]: 1.000, 95 % confidence interval [CI]: 0.998-1.002, p = 0.78) by using inverse variance weighted. MR analyses based on other methods showed similar results. CONCLUSIONS: There was no potential causal associations between higher genetically predicted SUA levels and increased risk of deep venous thrombosis. Further, MR studies with more valid SNPs and more DVT cases are needed. Validation of the findings is also recommended.

Development and validation of a novel index for the differential diagnosis of corticotropin-dependent Cushing syndrome.

PURPOSE: To develop an index for the differential diagnosis of corticotropin-dependent Cushing syndrome (CS). METHODS: The development cohort included 112 consecutive patients with clinicopathologically confirmed corticotropin-dependent CS at the Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, from December 2004 to May 2020, and data of 126 patients from studies published from 2016 to August 2020, identified through search in PubMed, Embase and the Cochrane Library, was extracted for external validation. The index was calculated as the product of plasma adrenocorticotropic hormone (ACTH, pmol/L) and urinary free cortisol (UFC, nmol/24 h) divided by 10,000. The discriminative ability was tested using receiver operating characteristics (ROC) curve analysis. RESULTS: In development cohort, area under curve of ROC analysis of the ACTH-UFC index in identifying Cushing disease (CD) was 0.977. The diagnostic accuracy of ACTH-UFC index ≤ 11 was comparable to that of 48 h 8 mg/d high-dose dexamethasone test (HDDST) in identifying CD, with sensitivity, specificity, positive and negative likelihood ratios of 96.6%, 87.5%, 7.73, and 0.04, respectively. The sensitivity of ACTH-UFC index ≤ 11 in parallel combination with pituitary magnetic resonance imaging (MRI) was 100% for identifying CD. The performance of the ACTH-UFC index in parallel or serial combination with pituitary MRI was similar in the validation cohort. CONCLUSIONS: ACTH-UFC index provides a rapid, convenient and non-invasive adjunctive approach for the differential diagnosis of corticotropin-dependent CS, with no risk of aggravating metabolic disturbances. Investigations for ectopic causes of corticotropin-dependent CS should be performed with ACTH-UFC index > 11 and negative contrasted pituitary MRI.

Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in ß cells.

Insulin resistance in classic insulin-responsive tissues is a hallmark of type 2 diabetes (T2D). However, the pathologic significance of ß-cell insulin resistance and the underlying mechanisms contributing to defective insulin signaling in ß cells remain largely unknown. Emerging evidence indicates that proinsulin misfolding is not only the molecular basis of mutant INS-gene-induced diabetes of youth (MIDY) but also an important contributor in the development and progression of T2D. However, the molecular basis of ß-cell failure caused by misfolded proinsulin is still incompletely understood. Herein, using Akita mice expressing diabetes-causing mutant proinsulin, we found that misfolded proinsulin abnormally interacted with the precursor of insulin receptor (ProIR) in the endoplasmic reticulum (ER), impaired ProIR maturation to insulin receptor (IR), and decreased insulin signaling in ß cells. Importantly, using db/db insulin-resistant mice, we found that oversynthesis of proinsulin led to an increased proinsulin misfolding, which resulted in impairments of ProIR processing and insulin signaling in ß cells. These results reveal for the first time that misfolded proinsulin can interact with ProIR in the ER, impairing intracellular processing of ProIR and leading to defective insulin signaling that may contribute to ß-cell failure in both MIDY and T2D.-Liu, S., Li, X., Yang, J., Zhu, R., Fan, Z., Xu, X., Feng, W., Cui, J., Sun, J., Liu, M. Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in ß cells.

Positive charge in the n-region of the signal peptide contributes to efficient post-translational translocation of small secretory preproteins.

Increasing evidence indicates that many small secretory preproteins can undergo post-translational translocation across the membrane of the endoplasmic reticulum. Although the cellular machinery involved in post-translational translocation of small secretory preproteins has begun to be elucidated, the intrinsic signals contained within these small secretory preproteins that contribute to their efficient post-translational translocation remain unknown. Here, we analyzed the eukaryotic secretory proteome and discovered the small secretory preproteins tend to have a higher probability to harbor the positive charge in the n-region of the signal peptide (SP). Eliminating the positive charge of the n-region blocked post-translational translocation of newly synthesized preproteins and selectively impaired translocation efficiency of small secretory preproteins. The pathophysiological significance of the positive charge in the n-region of SP was underscored by recently identified preproinsulin SP mutations that impair translocation of preproinsulin and cause maturity onset diabetes of youth (MODY). Remarkably, we have found that slowing the polypeptide elongation rate of small secretory preproteins could alleviate the translocation defect caused by loss of the n-region positive charge of the signal peptide. Together, these data reveal not only a previously unrecognized role of the n-region's positive charge in ensuring efficient post-translational translocation of small secretory preproteins, but they also highlight the molecular contribution of defects in this process to the pathogenesis of genetic disorders such as MODY.

Endocrine Manifestations in POEMS Syndrome: a case report and literature review.

BACKGROUND: POEMS syndrome, a rare systemic disease, is characterized by 5 components: Peripheral neuropathy, Organomegaly, Endocrinopathy, M protein elevation, and Skin changes. It usually presents with multiplex endocrine manifestations and is easily misdiagnosed and incorrectly treated. CASE PRESENTATION: We report herein a case of POEMS syndrome that initially presented as hyperpigmentation and severe pitting edema of the lower extremities. Throughout the patient's multiple hospitalizations for more than one year, he was treated erroneously for Addison's disease and primary hypothyroidism due to the presence of limb numbness and weight loss. In addition, he was misdiagnosed with diabetic peripheral neuropathy due to a history of type 2 diabetes mellitus. CONCLUSION: Endocrinopathy is a critical feature of POEMS syndrome but its mechanisms are still poorly understood. The most common endocrine abnormality is hypogonadism, and the second is adrenal insufficiency, followed by hypothyroidism and subclinical hypothyroidism, then diabetes or glucose intolerance. In cases of the coexistence of endocrinopathy and unexplained peripheral neuropathy, especially in multisystem disorders, POEMS syndrome should be considered. Endocrine evaluation including thyrotropin, free thyroxine, fasting glucose, gonadal hormones, prolactin, cortisol, ACTH, and calcium should be assessed. The purpose of the current report was to provide increased awareness of POEMS syndrome.

Competitive Inhibition of the Endoplasmic Reticulum Signal Peptidase by Non-cleavable Mutant Preprotein Cargos.

Upon translocation across the endoplasmic reticulum (ER) membrane, secretory proteins are proteolytically processed to remove their signal peptide by signal peptidase (SPase). This process is critical for subsequent folding, intracellular trafficking, and maturation of secretory proteins. Prokaryotic SPase has been shown to be a promising antibiotic target. In contrast, to date, no eukaryotic SPase inhibitors have been reported. Here we report that introducing a proline immediately following the natural signal peptide cleavage site not only blocks preprotein cleavage but also, in trans, impairs the processing and maturation of co-expressed preproteins in the ER. Specifically, we find that a variant preproinsulin, pPI-F25P, is translocated across the ER membrane, where it binds to the catalytic SPase subunit SEC11A, inhibiting SPase activity in a dose-dependent manner. Similar findings were obtained with an analogous variant of preproparathyroid hormone, demonstrating that inhibition of the SPase does not depend strictly on the sequence or structure of the downstream mature protein. We further show that inhibiting SPase in the ER impairs intracellular processing of viral polypeptides and their subsequent maturation. These observations suggest that eukaryotic SPases (including the human ortholog) are, in principle, suitable therapeutic targets for antiviral drug design.

Chronic Fluoxetine Treatment Upregulates the Activity of the ERK1/2-NF-κB Signaling Pathway in the Hippocampus and Prefrontal Cortex of Rats Exposed to Forced-Swimming Stress.

OBJECTIVES: The aim of this study was to explore whether or not the antidepressant actions of fluoxetine (FLX) are correlated with extracellular signal-regulated kinase 1 and 2 (ERK1/2) and nuclear factor κ-light chain enhancer of activated B cells (NF-κB) in the hippocampus (HC) and prefrontal cortex (PFC) of rats. MATERIALS AND METHODS: A total of 108 male Sprague-Dawley rats were randomly divided into 6 groups of 18 rats each. Group 1 was the control group, while group 2 comprised the depressed model in which rats were subjected to 28 days of forced-swimming stress (FST); groups 3-6 were also subjected to 28 days of FST and treated with FLX once a day for 1 day (group 3; F1d), 1 week (group 4; F1w), 2 weeks (group 5; F2w), or 4 weeks (group 6; F4w). The control group was not subjected to FST or treated with FLX. Behavior tests that included the Morris water maze (MWM) and saccharin preference were performed, and ERK1/2 and NF-κB proteins were assayed using Western blot. RESULTS: The rats in the control group and in groups 5 and 6 (F2w and F4w, respectively) had a significantly shorter average escape latency, needed more attempts in order to successfully cross the platform, and had a greater saccharin preference than those in the depressed group (p < 0.05). In the depressed group, the phosphorylated ERK1/2 (p-ERK1/2) and phosphorylated NF-κB (p-NF-κB) expression in the HC and PFC were lower than in the control group (p < 0.05). Treatment with FLX reversed the changes in the expression of p-ERK1/2 and p-NF-κB in rats in the F2w and F4w groups. CONCLUSIONS: In this study, FLX treatment for 2 weeks or longer reversed the impaired spatial learning, memory, and anhedonia observed in the depressed model rats and upregulated the activities of the ERK1/2-NF-κB signaling pathway.

Fractional Excretion of Urate is Positively Associated with Type 2 Diabetes in HUA Patients: A Cross-Sectional Study.

Purpose: People with hyperuricemia (HUA) are often related to metabolic disorders such as diabetes, metabolic syndrome (MetS), and obesity. However, the correlation between excretion of uric acid and these diseases is unclear. Our study aimed to explore the relationship between uric acid excretion and type 2 diabetes (T2D). Methods: A total of 228 HUA patients from Tianjin Medical University General Hospital from 2022 to 2023 were included in this study. We collected demographic, biochemical, and anthropometric data on each subject. Urine uric acid excretion (UUAE) was calculated enzymatically from a single urine collection that lasted 24 hours. And fractional excretion of uric acid (FEUA) was calculated from serum uric acid and creatinine and uric acid and creatinine. Binary logistic regression modeling assessed the association between uric acid excretion and T2D. Results: Of the 228 subjects, 13.4% had T2D and 48.7% had obesity. The obesity group had a lower FEUA (p<0.05) and a higher UUAE compared to the control group (p<0.05). And FEUA had a stronger correlation with the risk of T2D (p<0.001). Also, there was a negative association between BMI and FEUA and a positive link between BMI and UUAE in the outpatients. Conclusion: Increased FEUA levels were significantly associated with T2D in HUA patients. Therefore, routine calculating of FEUA is essential for proper diagnosis and appropriate treatment T2D of in HUA patients.

A novel GATA3 frameshift mutation causes hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome.

Background: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome (Barakat syndrome) is a rare autosomal dominant disorder caused by mutations in the gene encoding GATA3 on chromosome 10p14. Method: Informed consent was obtained from a 38-year-old female patient. 5 mL of venous blood was collected and sent for whole-exome sequencing. GATA3 constructs of both wild-type and mutant were transfected into HEK-293 T cells. Three-dimensional modeling, luciferase-reporter gene test, western blotting and cellular immunofluorescence were used to evaluate the effect of the mutation. Results: A novel frameshift mutation c. 677dup(p.Pro227AlafsTer77), named P227Afs, was found in GATA3. Three-dimensional modeling revealed that the mutation caused the loss of the dual zinc finger structures 1 and 2 (ZNF1 and ZNF2) of the synthesized protein. Expression of wild-type GATA3 produced a six-fold increase in luciferase activity when compared with pcDNA3.1 vector only (P < 0.001), whereas the P227Afs mutant showed no increase. The mutation significantly reduced the transcriptional activity of GATA3. Immunofluorescence and western blotting analyses demonstrated that the mutation changed the nuclear location of GATA3 and caused difficulty in nuclearization. Conclusion: A novel heterozygous frameshift mutation in GATA3 was identified and showed to result in difficult nuclearization, and a dominant-negative effect on the wild-type.

Pancreatic ß cell TRAPδ deficiency reduces insulin production but improves insulin sensitivity.

The translocon-associated protein-δ (TRAPδ) plays a role in insulin biosynthesis within pancreatic ß cells. However, its pathophysiological significance in maintaining islet ß cell function and glucose homeostasis remains unclear. In this study, we generated a mouse model featuring pancreatic ß cell-specific deletion of TRAPδ (TRAPδ ßKO). Our findings revealed that TRAPδ ßKO resulted in decreased circulating insulin levels in mice fed either a normal chow diet or a high-fat diet. Multiple independent experiments established that, while TRAPδ deletion reduced insulin content in the islets, it had no discernible effect on insulin gene expression, the insulin/proinsulin ratio, or the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a pivotal role in the transcription of the insulin gene or proinsulin processing. However, untranslocated preproinsulin levels were significantly increased when islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency may hinder preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Remarkably, despite the moderate decrease in circulating insulin levels in TRAPδ ßKO mice, their glucose levels remained unaffected, indicating the presence of compensatory mechanisms that help maintain glucose homeostasis. Insulin tolerance tests further revealed improved insulin sensitivity, accompanied by upregulation of phosphorylated AKT in the peripheral tissues of TRAPδ ßKO mice. Collectively, these data highlight the important role of TRAPδ in insulin biosynthesis and ß cell function. The moderate reduction in circulating insulin appears to promote insulin sensitivity in insulin target tissues.

Association between hemoglobin glycation index and non-alcoholic fatty liver disease in the patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: The hemoglobin glycation index (HGI) represent the disparity between actual glycated hemoglobin measurements and predicted HbA1c. It serves as a proxy for the degree of non-enzymatic glycation of hemoglobin, which has been found to be positively correlated with diabetic comorbidities. In this study, we investigated the relationship between HGI and non-alcoholic fatty liver disease (NAFLD), along with other relevant biological markers in patients with diabetes. MATERIALS AND METHODS: This cross-sectional study consisted of 3,191 adults diagnosed with type 2 diabetes mellitus. We calculated the predicted glycated hemoglobin levels based on fasting blood glucose levels. Multivariate binary logistic regression analysis was conducted to examine the correlation between the HGI and NAFLD. Hepatic steatosis was diagnosed using ultrasonography. RESULTS: Among all participants, 1,784 (55.91%) were diagnosed with NAFLD. Participants with confirmed NAFLD showed elevated body mass index, diastolic blood pressure, liver enzyme, total cholesterol, triglyceride, low-density lipoprotein and uric acid levels compared with those without NAFLD. In the unadjusted model, participants in the last tertile of HGI were 1.40-fold more likely to develop NAFLD than those in the first tertile (95% confidence interval 1.18-1.66; P < 0.001). In the fully adjusted model, those in the last tertile of HGI had a 39% increased risk of liver steatosis compared with confidence interval in the first tertile of HGI (95% confidence interval 1.12-1.74; P < 0.001). CONCLUSIONS: A higher HGI suggests an elevated risk of developing NAFLD in patients with type 2 diabetes.

Acacetin attenuates the pancreatic and hepatorenal dysfunction in type 2 diabetic rats induced by high-fat diet combined with streptozotocin.

Acacetin is a natural flavonoid compound with multiple therapeutic potential in oxidative stress, inflammation, cancers, cardiovascular disease and infections. The present study aimed to detect the effect of acacetin on pancreatic and hepatorenal dysfunction in type 2 diabetic rats. The diabetic rats were induced by high-fat diet (HFD) followed by intraperitoneal injection of streptozotocin (STZ) at a dose of 45 mg/kg. Different doses of acacetin were orally administrated once a day for 8 weeks after the diabetic model was successfully established. The experimental results revealed that acacetin and acarbose displayed obvious attenuation in the levels of fasting blood glucose (FBG) and lipids compared to the untreated diabetic rats. In addition, the physiological function of liver and kidney was impaired in the persistent environment of hyperglycemia, while acacetin improved the damage of liver and kidney. Furthermore, hematoxylin-eosin (H&E) staining indicated that acacetin alleviated the pathological alterations of the pancreas, liver and kidney tissues. Besides, the increased levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8 and malondialdehyde (MDA) were recused by acacetin treatment, while the reduction of superoxide dismutase (SOD) levels were suppressed by acacetin treatment. In conclusion, the experimental results demonstrated that acacetin improved the lipids and glucose levels, and hepatorenal antioxidant capacity, as well as ameliorated hepatorenal dysfunction in type 2 diabetic rats, and the potential mechanism might be associated with its antioxidant and anti-inflammatory activities.

Association Between Different Metabolic Markers and Metabolic Syndrome in an Outpatient Hyperuricemia Population: A Cross-Sectional Study.

Background: Hyperuricemia (HUA) is often associated with metabolic syndrome (MetS). However, the role of different metabolic markers in the screening of MetS in out-patients with hyperuricemia is unclear. The study aims to investigate the relationship between different metabolic indexes and MetS. Methods: A total of 399 hyperuricemia patients from Tianjin Medical University General Hospital from 2022 to 2023 were included in this study. We collected demographic, anthropometric, and biochemical data on each subject. And calculate serum uric acid-to-creatinine ratio (SUA/Cr), serum uric acid to high-density lipoprotein cholesterol (UHR), triglyceride to high-density lipoprotein cholesterol (THR), and triglyceride and glucose (TyG) index. Binary logistic regression modeling was performed to explore the association between different metabolic markers and MetS. Results: Out of the 399 subjects, 28.3% had MetS. UHR, THR, and TyG index were significantly higher in the MetS group than those in the control group (p<0.05), which were associated with an increased risk of MetS. However, SUA/Cr was not associated with MetS (p>0.05). TyG index had a stronger relationship with the risk of MetS (OR 5.476, 95% CI 2.210-13.569, p<0.001). The cut-off with the biggest Youden index of the TyG index was 9.13 and the area under the curve (AUC) was 0.719. Conclusion: A high TyG index is associated with an increased risk of MetS in HUA patients. These findings might help screen MetS in individuals with HUA and could be more standardized management of patients with high uric acid in outpatient clinics.

The comparison of three different molecular imaging methods in localization and grading of insulinoma.

Aims: This cross-sectional study compared the value of molecular imaging (Exendin-4 positron emission tomography/computed tomography [PET/CT], 68Ga-DOTATATE PET/CT, 18F- fluorodeoxyglucose [FDG] PET/CT) in insulinoma localization by stratified tumor size and grading, and explored the correlation of the related the maximum standardized uptake value (SUVmax) with insulinoma grading, Ki-67, maximum tumor diameter, and glucose metabolism. Methods: In 28 insulinoma patients, the sensitivity of three types of PET/CT for localizing insulinoma was calculated according to tumor size and grade. We compared the SUVmax for different insulinoma grades and analyzed the correlation of SUVmax with Ki-67, maximum tumor diameter, and glucose metabolism indicators. Results: The study included 12 grade (G) 1 and 16 G2 cases, with maximum tumor diameters ranging from 9 to 40 mm. Without differentiation by size and grade, the sensitivity of Exendin-4 PET/CT to localize insulinoma was 100%, which significantly exceeded that of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT (75% and 57%, respectively). In tumors with a maximum diameter ≤ 20 mm and ≤ 15 mm, the sensitivity of Exendin-4 (both 100%) significantly exceeded that of 68Ga-DOTATATE PET/CT (74% and 64%, respectively) and 18F-FDG PET/CT (54% and 50%, respectively). In G1 tumors, the sensitivity of Exendin-4 PET/CT was significantly higher than that of 18F-FDG PET/CT, but not that of 68Ga-DOTATATE PET/CT, while in G2 tumors, the sensitivity of Exendin-4 PET/CT was significantly higher than that of both other types. However, all three PET/CT types missed a metastatic lymph node in one patient. The 18F-FDG PET/CT SUVmax was significantly lower than that of the other PET/CT types and that of 68Ga-DOTATATE PET/CT was significantly lower in G2 than in G1. 68Ga-DOTATATE PET/CT SUVmax correlated negatively with Ki-67. A receiver operating characteristic (ROC) curve suggested that 68Ga-DOTATATE PET/CT SUVmax > 19.9 could predict G1 tumors. Conclusion: Exendin-4 PET/CT was superior to 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT for insulinoma localization, particularly small and G2 tumors, but its diagnostic value in small metastatic lymph nodes requires further exploration. 68Ga-DOTATATE PET/CT SUVmax could be used as an adjunct to pathology, and a value > 19.9 could predict G1 tumors. No PET/CT SUVmax could predict tumor maximum diameter and glucose metabolism.

Vitamin D Status and All-Cause Mortality in Patients With Type 2 Diabetes in China.

Objective: To assess the association between vitamin D status and all-cause mortality among type 2 diabetes patients. Research Design and Methods: We prospectively followed 1,291 participants with type 2 diabetes aged 20-80 years during 2013-2018. Cox proportional hazard regression models were used to estimate the association between different vitamin D status and all-cause mortality risk among hospitalized patients with type 2 diabetes. Results: During a median follow-up of 4.15 years (5,365 person-years in total), 61 cases of death were identified. Multivariable-adjusted hazard ratios (HRs) for all-cause mortality across the quartiles of baseline circulating 25-hydroxy vitamin D (25-OH vitamin D) were 2.70 [95% confidence interval (CI) 1.12-6.54], 1.00, 1.39 (95% CI 0.53-3.65), 2.31 (95% CI 0.96-5.54), respectively. Multivariable-adjusted HRs for all-cause mortality by different groups of baseline 25-OH vitamin D concentrations (<25, 25-49, 50-100, and ≥100 nmol/L) were 1.31 (95% CI 0.58-2.96), 0.94 (95% CI 0.47-1.87), 1.00, and 3.58 (95% CI 1.43-8.98), respectively. Conclusions: Very low or high concentrations of vitamin D may be associated with a higher risk of all-cause mortality among patients with type 2 diabetes.

Low Serum Dehydroepiandrosterone Is Associated With Diabetic Kidney Disease in Men With Type 2 Diabetes Mellitus.

Background: The associations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with diabetic kidney disease (DKD) remained unclear. Thus, this cross-sectional study aimed to explore the associations of DHEA and DHEAS with the risk of DKD in patients with T2DM. Methods: The information of 1251 patients with T2DM were included in this study. Serum DHEA and DHEAS were quantified using liquid chromatography-tandem mass spectrometry assays. Multivariate logistic regression analyses were used to assess the associations of DHEA and DHEAS with DKD as well as high urine albumin to creatinine ratio (ACR). Results: In men with T2DM, the risk of DKD decreased with an increasing DHEA concentration after adjustment for traditional risk factors; the fully adjusted OR (95% CI) for tertile3 vs tertile1 was 0.37 (0.19-0.70; P = 0.010 for trend). Similarly, when taking high ACR as the outcome, low DHEA levels were still significantly associated with increased odds of high ACR (OR, 0.37; 95% CI, 0.19-0.72 for tertile3 vs tertile1; P = 0.012 for trend). The restricted cubic spline showed that the risk of DKD gradually decreased with the increment of serum DHEA levels (P-overall = 0.007; P-nonlinear = 0.161). DHEAS was not independently associated with the risk of DKD in men. In contrast, no significant relationships were found between DHEA and DHEAS and the risk of DKD in women (all P > 0.05). Conclusions: In men with T2DM, low serum DHEA levels were independently related to the risk of DKD after adjustment for traditional risk factors. Our finding highlights the potential role of DHEA in the development of DKD in men with T2DM.

Low Serum Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate Are Associated With Coronary Heart Disease in Men With Type 2 Diabetes Mellitus.

Aims: Sex hormones play an important role in the pathogenesis of cardiovascular disease (CVD). This cross-sectional study aimed to explore the associations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with coronary heart disease (CHD) and stroke in middle-aged and elderly patients with type 2 diabetes mellitus (T2DM). Materials and Methods: A total of 995 patients with T2DM were included in the study analysis. Serum levels of DHEA and DHEAS were quantified using liquid chromatography-tandem mass spectrometry. Binary logistic regression analyses were performed to assess the associations of DHEA and DHEAS with CHD and stroke. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal DHEA and DHEAS cutoff values for the detection of CHD in men with T2DM. Results: In men with T2DM, after adjustment for potential confounders in model 3, the risk of CHD decreased with an increasing serum DHEA level [odds ratio (OR) = 0.38, quartile 4 vs. quartile 1; 95% confidence interval (CI) = 0.16-0.90; p = 0.037 for trend). Consistently, when considered as a continuous variable, this association remained significant in the fully adjusted model (OR = 0.59, 95% CI = 0.40-0.87, p < 0.05). When taken as a continuous variable in model 3, serum DHEAS level was also inversely related to the risk of CHD among men (OR = 0.56, 95% CI = 0.38-0.82, p < 0.05). Similarly, this relationship remained statistically significant when DHEAS was categorized into quartiles (OR = 0.27, quartile 4 vs. quartile 1; 95% CI = 0.11-0.67; p = 0.018 for trend). ROC curve analyses revealed that the optimal cutoff values to detect CHD in men with T2DM were 6.43 nmol/L for DHEA and 3.54 µmol/L for DHEAS. In contrast, no significant associations were found between DHEA and DHEAS on the one hand and stroke on the other in men and women with T2DM (all p > 0.05). Conclusions: Serum DHEA and DHEAS were significantly and negatively associated with CHD in middle-aged and elderly men with T2DM. This study suggests potential roles of DHEA and DHEAS in CHD pathogenesis.

Serum Uric Acid Levels and Nonalcoholic Fatty Liver Disease: A 2-Sample Bidirectional Mendelian Randomization Study.

BACKGROUND: Observational studies have shown that nonalcoholic fatty liver disease (NAFLD) is highly correlated with serum uric acid (SUA). However, these studies have an inherent risk of bias due to reverse causality. Here, we perform a Mendelian randomization (MR) study to investigate causality between SUA and NAFLD. METHODS: We performed a 2-sample bidirectional MR analysis using summary-level data from genome-wide association studies of SUA (with up to 110 347 individuals) and NAFLD (1483 cases and 17781 controls) in European populations. First, 13 single nucleotide polymorphisms (SNPs) associated with SUA were selected as instruments to estimate the causal effect of elevated SUA levels on the risk of NAFLD using the inverse-variance weighted (IVW) method. Then we performed MR with 3 SNPs as genetic instruments for NAFLD. To test the reliability, further sensitivity analyses were also conducted. RESULTS: Our MR analyses demonstrated that NAFLD was associated with SUA levels (ß = 0.032, P = 0.003). Similar results were obtained using other MR methods and in sensitivity analyses. Genetic predisposition to elevated SUA levels was not associated with NAFLD (IVW MR, odds ratio = 1.02, 95% CI: 0.90-1.15, P = 0.775). Similar results were obtained using other 4 pleiotropy robust MR methods and in sensitivity analyses, excluding 9 SNPs associated with potential confounders. CONCLUSIONS: Our study supports the causal increased SUA levels by NAFLD, while our study does not confirm a causal association for SUA levels on risk of NAFLD. Further study is needed to interpret the potential mechanisms.

Low Serum Total Testosterone Is Associated with Non-Alcoholic Fatty Liver Disease in Men but Not in Women with Type 2 Diabetes Mellitus.

Materials and Methods: There were 1155 patients with T2DM included in the analysis. Serum levels of total testosterone and the precursors of androgens, including androstenedione, DHEA, and DHEAS, were quantified using liquid chromatography-tandem mass spectrometry assays. Results: The risk of NAFLD decreased as total testosterone concentration increased in men with T2DM. After adjusting for age, current smoking, current drinking, body mass index, duration of T2DM, diastolic blood pressure, total cholesterol, triglycerides, low-density lipoprotein/high-density lipoprotein cholesterol ratio, uric acid, C-reactive protein, and sex hormones in model 4, the adjusted odds ratio (OR) and 95% confidence interval (CI) of NAFLD for tertile3 vs tertile1 was 0.37 (0.17-0.77; P = 0.024 for trend). When taken as a continuous variable, this association was still robust in model 4 (OR, 0.58; 95% CI, 0.42-0.80; P < 0.05). No significant associations were found between increasing levels of the precursors of androgens and the odds of NAFLD in men with T2DM (all P > 0.05). Moreover, women showed no significant associations of total testosterone, androstenedione, DHEA, and DHEAS, with the odds of NAFLD (all P > 0.05). Conclusions: Serum total testosterone was independently associated with the risk of NAFLD among men with T2DM. This study highlights the potential role of testosterone as a risk factor for NAFLD in patients with T2DM.

Distribution of lean mass and mortality risk in patients with type 2 diabetes.

AIMS: The aim of the study is to evaluate the association of distribution of lean mass with the risk of all-cause mortality among patients with type 2 diabetes. METHODS: The present cohort study included 2 335 patients with type 2 diabetes. Lean mass was assessed by dual energy X-ray absorptiometry. Cox proportional hazards regressions were used to estimate the association of lean mass distribution on the risk of mortality. RESULTS: The average age of the patients was 58 years at baseline and 51.4% of patients were women. During a median follow-up of 4.31 years, 128 patients died. The multivariable-adjusted hazards ratios for all-cause mortality were 1.00, 1.63 (0.89-2.99), and 2.68(1.51-4.76) across the tertiles of android-to-gynoid lean mass ratio (P for trend < 0.001), respectively. The positive association of android-to-gynoid lean mass ratio with the risk of all-cause mortality was present among patients of different ages, body mass index ≥ 24 kg/m2, hemoglobin A1c ≥ 7.0%, nonsmokers, men, patients using insulin, and patients with diabetes durations of more than 10 years. CONCLUSIONS: Higher android-to-gynoid lean mass ratio, assessed by dual energy X-ray absorptiometry, was significantly associated with increased risk of all-cause mortality among patients with type 2 diabetes.