Thyroid function spectrum in Cushing's syndrome.

PURPOSE: Thyroid disorders have been reported in hypercortisolism patients. Endogenous Cushing's syndrome (CS) potentially complicates its metabolic sequelae. We investigated thyroid function in CS patients to determine this relationship. METHODS: In this cross-sectional study, we screened CS patients from 2016 to 2019 at our hospital. Patient demographic, medical history, and laboratory data were collected. Additionally, we performed a meta-analysis to demonstrate the prevalence of thyroid dysfunction in patients with CS. RESULTS: Among 129 CS patients, 48.6% had triiodothyronine (TT3), 27.9% had thyroxine (TT4), 24.6% had free T3 (FT3), 27.7% had free T4 (FT4), and 6.2% had thyroid-stimulating hormone (TSH) levels below the reference values. Those with clinical CS showed more pronounced thyroid suppression than did those with subclinical CS. Cortisol levels were markedly greater in patients with pituitary hypothyroidism (P < 0.001). Serum cortisol levels throughout the day and post low-dose dexamethasone-suppression test (LDDST) results correlated with thyroid hormone levels, particularly in ACTH-independent CS. Correlations varied by thyroid status; FT3 and TSH were linked to cortisol in euthyroid individuals but not in those with low T3 or central hypothyroidism. TSH levels notably halved from the lowest to highest cortisol tertile post-LDDST. Finally, meta-analysis showed 22.7% (95% CI 12.6%-32.9%) central hypothyroidism in 528 CS patients of nine studies. CONCLUSION: Thyroid hormone levels are significantly correlated with cortisol levels and are impaired in patients with CS. However, the physiological adaptation and pathological conditions need further study.

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurs in polyglandular endocrinopathies.

BACKGROUND: With the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events. METHODS: A retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month. RESULTS: 28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18-39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up. CONCLUSIONS: IAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic ß-cells.

Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in ß-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic ß-cells. ß-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic ß-cells.

Mass spectrometry-based cortisol profiling during adrenal venous sampling reveals misdiagnosis for subtyping primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is a common form of secondary hypertension. Adrenal venous sampling (AVS) is the gold standard for subtyping PA. This study aimed to determine whether there is a difference between immunoassays and liquid chromatography-mass spectrometry (LC-MS/MS) methods for measuring cortisol levels that affect the judgement of AVS. DESIGN: This was a retrospective study. PATIENTS: Included 72 patients who were diagnosed with PA and had undergone AVS. MEASUREMENTS: Patients were grouped according to whether they received adrenocorticotropic hormone (ACTH) stimulation during AVS, and the cortisol results were measured using immunoassay and LC-MS/MS. RESULTS: There were 48 patients in the without ACTH stimulation group and 24 in the post-ACTH stimulation group during AVS (bilateral adrenal vein cannulation success rate, 56.25% vs. 83.33%). ACTH stimulation was beneficial for increasing the success rate of AVS (p < .001). Immunoassays were linearly correlated with LC-MS/MS when cortisol concentrations were <1750 nmol/L (r = .959, p < .001). When cortisol concentrations were >17,500 nmol/L, no correlation was found between the two methods (p = .093). The two methods were consistent for the detection of cortisol for evaluating the success of cannulation for AVS. Five percent of patients showed discordant lateralization of aldosterone production according to the cortisol LC-MS/MS and immunoassay results in the without ACTH group, and 15% showed discordant lateralization in the post-ACTH group. CONCLUSIONS: The immunoassay method can be used to determine whether cannulation is successful. The final decision for lateralization may be more appropriate based on LC-MS/MS results.

Diagnosis and genetic analysis of a case with Bardet-Biedl syndrome caused by compound heterozygous mutations in the BBS12 gene.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy, which is caused by mutations mainly in genes encoding BBSome complex and IFT complex. Here, we reported a 21-year-old female with BBS characterized by three primary features including obesity, retinitis pigmentosa sine pigmento and bilateral renal cysts. She also had some secondary features such as diabetes mellitus, nonalcoholic fatty liver disease, subclinical hypothyroidism and mild conductive hearing damage. Whole exome sequencing revealed two compound heterozygous mutations in exon 2 of the BBS12 gene (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) in this patient. Sanger sequencing showed that her father and mother carried c.188delC (p.T63fs) and c.1993_1995del (p.665_665del) variants, respectively, while her parents were free of BBS-related symptoms. In conclusion, this case reported two novel mutations (c.188delC, p.T63fs and c.1993_1995del, p.665_665del) of the BBS12 gene in a girl presented with BBS, which provides novel genetic resources for studies of the disease. Meanwhile, the BBS case shows the entire development progress from her birth to adulthood, which helps facilitate clinicians' understanding of BBS.

Thyroid function and non-alcoholic fatty liver disease in hyperthyroidism patients.

BACKGROUND: Although thyroid function has been demonstrated to be associated with non-alcoholic fatty liver disease (NAFLD) in different population, the prevalence and features of NAFLD in hyperthyroidism have not been reported. The present study aims to investigate the prevalence of NAFLD and association of thyroid function and NAFLD in hyperthyroidism patients. METHODS: This cross-sectional study was performed in Zhongshan Hospital, Fudan University, China. A total 117 patients with hyperthyroidism were consecutively recruited from 2014 to 2015. Thyroid function and other clinical features were measured, liver fat content was measured by color Doppler ultrasonically, NAFLD was defined in patients with liver fat content more than 9.15%. Statistical analyses were performed with SPSS software package version 13.0. RESULTS: The prevalence of NAFLD was 11.97% in hyperthyroidism. Patient with NAFLD had lower free triiodothyronine (FT3) and free thyroxine (FT4) levels than patients without NAFLD (P < 0.05). After adjusting for age, gender, metabolic parameters and inflammation factors, higher FT3 were associated with lower liver fat content (ß = - 0.072, P = 0.009) and decreased odds ratio of NAFLD (OR = 0.267, 95%CI 0.087-0.817, P = 0.021). CONCLUSIONS: FT3 level was negatively associated with the liver fat content in this population. These results may provide new evidence in the role of thyroid hormone on the regulation of liver fat content and NAFLD.

Activation of hypothalamic RIP-Cre neurons promotes beiging of WAT via sympathetic nervous system.

Activation of brown adipose tissue (BAT) and beige fat by cold increases energy expenditure. Although their activation is known to be differentially regulated in part by hypothalamus, the underlying neural pathways and populations remain poorly characterized. Here, we show that activation of rat-insulin-promoter-Cre (RIP-Cre) neurons in ventromedial hypothalamus (VMH) preferentially promotes recruitment of beige fat via a selective control of sympathetic nervous system (SNS) outflow to subcutaneous white adipose tissue (sWAT), but has no effect on BAT Genetic ablation of APPL2 in RIP-Cre neurons diminishes beiging in sWAT without affecting BAT, leading to cold intolerance and obesity in mice. Such defects are reversed by activation of RIP-Cre neurons, inactivation of VMH AMPK, or treatment with a ß3-adrenergic receptor agonist. Hypothalamic APPL2 enhances neuronal activation in VMH RIP-Cre neurons and raphe pallidus, thereby eliciting SNS outflow to sWAT and subsequent beiging. These data suggest that beige fat can be selectively activated by VMH RIP-Cre neurons, in which the APPL2-AMPK signaling axis is crucial for this defending mechanism to cold and obesity.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based assay to profile 20 plasma steroids in endocrine disorders.

Background: Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based assays are employed in more and more clinical laboratories to quantify steroids. The steroid quantification by LC-MS/MS shows great value in screening or diagnosing endocrine disorders; however, the number of functional steroids included in the LC-MS/MS methods is still limited. Methods: Here, we describe the performance and validation of a 20-steroid plasma panel by LC-MS/MS. The panel included progestogens (including mineralocorticoids and glucocorticoids), androgens and estrogens biosynthesized in steroid metabolic pathways. The LC-MS/MS method was validated according to guidance documents, and subsequently employed to profile steroid changes in endocrine disorders. Results: Using LC-MS/MS, 20 steroids were separated and quantified in 8 min. Coefficients of variation (CVs) of the 20 analytes at the lower limit of quantification (LLoQ) were all less than 15% (ranging from 1.84% to 14.96%). The linearity of the assay was demonstrated by all the R2 values greater than 0.995. Individual plasma steroids changed significantly in patients with subclinical Cushing's syndrome (SCS) and polycystic ovary syndrome (PCOS) - 17-hydroxypregnenolone (17-OH-PR), testosterone (T) and dihydrotestosterone (DHT) were significantly decreased in SCS patients, while in PCOS patients, pregnenolone, corticosterone (CORT), androstenedione (A4) and T were significantly increased and DHT was decreased. Conclusions: The LC-MS/MS method we developed for the quantification of 20 plasma steroids is clinical practicable. The steroid profiling data using this assay indicate its screening value for endocrine disorders. To further explore the value of the assay, more investigations are however needed.

TRAF6-mediated ubiquitination of APPL1 enhances hepatic actions of insulin by promoting the membrane translocation of Akt.

Insulin inhibits hepatic glucose production through activation of the protein kinase Akt, and any defect in this pathway causes fasting hyperglycaemia in Type 2 diabetes. APPL1 [adaptor protein, phosphotyrosine interaction, PH (pleckstrin homology) domain and leucine zipper containing 1] sensitizes hepatic insulin action on suppression of gluconeogenesis by binding to Akt. However, the mechanisms underlying the insulin-sensitizing actions of APPL1 remain elusive. In the present study we show that insulin induces Lys63-linked ubiquitination of APPL1 in primary hepatocytes and in the livers of C57 mice. Lys160 located within the BAR (Bin/amphiphysin/Rvs) domain of APPL1 is the major site for its ubiquitination. Replacement of Lys160 with arginine abolishes insulin-dependent ubiquitination and membrane localization of APPL1, and also diminishes membrane recruitment and activation of Akt, thereby abrogating the effects of APPL1 on alleviation of hepatic insulin resistance and glucose intolerance in obese mice. Further analysis identified TRAF6 (tumour-necrosis-factor-receptor-associated factor 6) as an E3 ubiquitin ligase for APPL1 ubiquitination. Suppression of TRAF6 expression attenuates insulin-mediated ubiquitination and membrane targeting of APPL1, leading to an impairment of insulin-stimulated Akt activation and inhibition of gluconeogenesis in hepatocytes. Thus TRAF6-mediated ubiquitination of APPL1 is a vital step for the hepatic actions of insulin through modulation of membrane trafficking and activity of Akt.

Diagnostic value of the fractional excretion of urine potassium for primary aldosteronism.

Background: Primary aldosteronism (PA) is a common form of secondary hypertension, which usually manifests low blood potassium levels. The fractional excretion of urine potassium (FEK) has been proposed as a useful tool to measure urinary potassium excretion. However, the role of the FEK in PA remains unclear. In the current study, we assessed the diagnostic value of FEK in PA. Methods: A total of 155 hypertension patients were included in this cross-sectional study, of which 62 were confirmed by a positive screening test for PA. We collected the serum, 24-hr urine samples, and spot urine samples to evaluate the diagnostic value of the spot and 24-hr FEK in the diagnosis of PA and renal potassium loss compared to other indices. The sensitivity and specificity of the related diagnostic indexes were analyzed using receiver operating characteristic (ROC) curves, and the optimal cut-point value of the diagnostic index was determined according to the Youden index (YI) (sensitivity + specificity - 1). Correlation analysis was performed between the spot FEK and 24-hr FEK using Pearson's correlation coefficient. Results: The spot FEK (7.3 vs. 5.9) and 24-hr FEK (9.3 vs. 8.0) levels were statistical differences between the PA and essential hypertension groups. PA patients had a significant tendency to lose potassium through the kidneys. We found that FEK from spot urine distinguished renal potassium loss with a sensitivity of 86.7% and a specificity of 87.1% at a cut-off of 9.8%. The sensitivity and specificity of the spot FEK in screening PA were 51.6% and 76.3%, respectively. Conclusions: FEK is significantly related to renal potassium loss. Spot FEK and 24-hr FEK performed a certain diagnostic value for PA, which may be potential indicators for the differential diagnosis of PA.

Ferroptosis related genes participate in the pathogenesis of spinal cord injury via HIF-1 signaling pathway.

BACKGROUND: Spinal cord injury (SCI) is a crushing disease without a effective and specific therapeutic strategy. Therefore, it is crucial to uncover underlying mechanism in order to identify potential treatments for SCI. Current studies show ferroptosis might pay important role in SCI. METHODS: In this study, we aimed to identify the key ferroptosis-related genes providing therapeutic targets for SCI. GSE45006, GSE19890 and GSE156999 from Gene Expression Omnibus (GEO) database were analyzed. RESULTS: A total of 61 ferroptosis-related DEGs were identified, followed by bioinformatics enrichment analyses and PPI network construction. Ten key ferroptosis-related genes were identified by Cytoscape (Cytohubba), most of which were enriched in the HIF-1 signaling pathway. Then we constructed a clip SCI rat model and qPCR was performed to assess the expressions of five genes enriched in HIF-1 signaling pathway (Stat3, Tlr4, Hmox1, Hif1a and Cybb). Finally, a ceRNA network, Stat3, Tlr4, Hmox1/miR127, miR383, miR485/rno-Mut_0003, rno-Pwwp2a_0002 was constructed and expression of mentioned molecules were validated by chip data. CONCLUSIONS: Five hub genes from HIF-1 signaling pathway were identified and might play a central role in SCI, which indicated that ferroptosis was correlated with HIF-1 signaling pathway. These results can provide a new insight into molecular mechanisms and identify potential therapeutic targets for SCI.

Risk factors for at-risk foot and peripheral artery disease among the population with diabetes: A multicommunity-based cross-sectional study.

AIMS: This study aimed to investigate the prevalence, characteristics, and influence factors of the at-risk foot with diabetes mellitus (DM). METHODS: This study included 3030 DM patients from the at-risk foot screening program of Shanghai in China between March 21 and April 30 in 2021. Data were collected from the questionnaire survey, physical examination, and fasting blood sample. RESULTS: The prevalence of at-risk foot was 27.8% among DM patients. After adjusted, the risk of higher at-risk grade increased with age and urinary albumin creatinine ratio (OR = 1.04, 95%CI = 1.02-1.06; OR = 1.001, 95%CI = 1.000-1.002, respectively), whereas decreased with estimated glomerular filtration rate (eGFR) (OR = 0.991, 95%CI = 0.984-0.998). The incidence of peripheral artery disease (PAD) was 11.1% in all people with DM, and age, pulse rate, and low-density lipoprotein were independent risk factors for PAD. In contrast, high-density lipoprotein, eGFR, and lymphocyte-to-monocyte ratio were independent protective factors for PAD. Glycated hemoglobin HbA1c was not an independent risk factor for increased risk grade or more severe PAD. CONCLUSIONS: The at-risk foot accounted for a high percentage among DM patients. Advanced age and renal dysfunction are independent risk factors for the at-risk foot. Glycemic control does not reduce the risk grade of at-risk foot and the incidence of PAD.

Impact of Daily Step Count on Diabetes Management and Complications Among Elderly Individuals - Jiangsu Province, China, 2020-2022.

What is already known about this topic?: Current literature underscores the significance of appropriate physical activity in managing diabetes, primarily utilizing self-reported data. Yet, the impact of objectively measured physical activity in older diabetic populations remains unclear. What is added by this report?: Our research on elderly diabetic patients indicated a correlation between an increased number of daily steps and improved metabolic profiles, as well as a decrease in the incidence of cardiovascular complications. What are the implications for public health practice?: Elevated daily step counts may confer significant benefits to elderly individuals with diabetes. The use of devices to monitor these steps could serve as a potent cardiovascular marker, and hold great potential as a screening or intervention tool in community-oriented settings.

Clinical expert consensus on the assessment and protection of pancreatic islet ß-cell function in type 2 diabetes mellitus.

Islet ß-cell dysfunction is a basic pathophysiological characteristic of type 2 diabetes mellitus (T2DM). Appropriate assessment of islet ß-cell function is beneficial to better management of T2DM. Protecting islet ß-cell function is vital to delay the progress of type 2 diabetes mellitus. Therefore, the Pancreatic Islet ß-cell Expert Panel of the Chinese Diabetes Society and Endocrinology Society of Jiangsu Medical Association organized experts to draft the "Clinical expert consensus on the assessment and protection of pancreatic islet ß-cell function in type 2 diabetes mellitus." This consensus suggests that ß-cell function can be clinically assessed using blood glucose-based methods or methods that combine blood glucose and endogenous insulin or C-peptide levels. Some measures, including weight loss and early and sustained euglycemia control, could effectively protect islet ß-cell function, and some newly developed drugs, such as Sodium-glucose cotransporter-2 inhibitor and Glucagon-like peptide-1 receptor agonists, could improve islet ß-cell function, independent of glycemic control.

Traditional Chinese medicine formula Qing Huo Yi Hao as superoxide anion scavenger in high glucose-treated endothelial cells.

AIM: To investigate the effects of a traditional Chinese medicine formula Qing Huo Yi Hao (QHYH) and its components on hydroxyl radical (HO(•)) production in vitro and the activity of QHYH against free radicals in cultured endothelial cells induced by high glucose. METHODS: Hydroxyl radicals (HO(•)) were generated through Fenton reactions in vitro, and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was used as a spin trap to form DMPO/HO(•) adducts detected using electron paramagnetic resonance (EPR). Immortalized mouse cerebral microvascular endothelial (bEnd.3) cells were treated with high glucose (35 mmol/L). The free radical scavenging ability of QHYH in the cells was evaluated using EPR. Superoxide dismutase (SOD) was used to identify the free radicals scavenged by QHYH in the cells. RESULTS: QHYH and its 8 components concentration-dependently reduced DMPO/HO(•) signaling. The DMPO/HO(•) adduct scavenging ability of QHYH was 82.2%, which was higher than each individual component. The free radical scavenging ability of 1% QHYH in high glucose-treated bEnd.3 cells was approximately 70%. In these cells, the free radicals were also specifically reduced by SOD (400 U/mL), implying that the free radicals were primarily superoxide anions. CONCLUSION: The results demonstrate that the QHYH formula is potent antioxidant acting as scavenge of superoxide anions in high glucose-treated endothelial cells.

[Correlation of serum uric acid and islet beta cell functions in female type 2 diabetics].

OBJECTIVE: To examine the correlation of serum uric acid and islet beta cell functions in female type 2 diabetics. METHODS: A total of 533 female type 2 diabetics were recruited. And their clinicobiochemical parameters were measured. The levels of acute insulin response (AIR) and acute C-peptide response (ACPR) were measured by a stimulation of arginine. Among them, 262 patients received the examinations of OGTT (oral glucose tolerance test), area under the curve of insulin (AUC-insulin) and C peptide (AUC-C peptide). Serum uric acid > 360 µmol/L was defined as hyperuricemia. RESULTS: The serum uric acid levels of the hyperuricemia and control groups were (430 ± 8) and (248 ± 3) µmol/L respectively. The AIR, ACPR, AUC-insulin and AUC-C peptide levels were significantly higher in the hyperuricemia group than those in the control group (P < 0.01). There was a significant positive correlation between serum uric acid and AIR, ACPR, AUC-insulin and AUC-C peptide (r = 0.194, P < 0.01; r = 0.146, P < 0.01; r = 0.307, P < 0.01 and r = 0.420, P < 0.01). The serum levels of uric acid were significantly different between tertile groups of AIR (260 ± 7), (264 ± 8), (302 ± 7) µmol/L, ACPR ((263 ± 8), (271 ± 7), (296 ± 7) µmol/L), AUC-insulin ((241 ± 10), (279 ± 10), (301 ± 8) µmol/L) and AUC-C peptide ((229 ± 8), (265 ± 9), (326 ± 10) µmol/L, P < 0.01). Multivariate linear regression demonstrated that the serum level of uric acid were associated with AIR (ß = 0.002, 95%CI 0.0010 - 0.0030, P < 0.01), ACPR (ß = 0.001, 95%CI 0.0002 - 0.0020, P = 0.02), AUC-insulin (ß = 0.002, 95%CI 0.0004 - 0.0030, P < 0.01) and AUC-C peptide (ß = 0.003, 95%CI 0.0020 - 0.0030, P < 0.01) after an adjustment of related risk factors. CONCLUSION: The serum level of uric acid is significantly correlated with AIR, ACPR, AUC-insulin and AUC-C peptide in female type 2 diabetics. And it may be an independent risk factor of predicting islet beta cell functions in female type 2 diabetics.

Interaction of Hypertension and Insulin Resistance Exacerbates the Occurrence of Diabetes Mellitus in Healthy Individuals.

Objective: Hypertension and type 2 diabetes are common complications. Patients with hypertension often show insulin resistance. The purpose of this study was to investigate the correlations between different blood pressure levels and different degrees of insulin resistance, as well as their interactions, with newly diagnosed diabetes mellitus. Methods: We conducted a retrospective study on 1251 adult medical examiners who were examined in the Physical Examination Center of Zhongshan Hospital, Fudan University (Shanghai, China) during 2015. All human subjects had no history of diabetes. General clinical data, including blood pressure, fasting glucose and 2-h post-load glucose levels, and lipid profiles, were collected. HOMA-IR was separately calculated. Statistical analyses were carried out by using SPSS software (version 13.0). Results: In 1251 physical examination subjects, a total of 166 cases of newly diagnosed diabetes were detected, with a total detection rate of 13.3%. The rates of newly diagnosed diabetes in the normal blood pressure group, high-normal blood pressure group, and hypertension group were 4.9%, 10.6%, and 19.0%, respectively. Compared with the normal blood pressure group, the proportion of newly diagnosed diabetes in the hypertension group was significantly increased [OR: 2.956, 95% CI 1.736-5.032, P < 0.001]. According to the stratification of HOMA-IR level, with the first quartile group (HOMA-IR<1.21) as a reference, the risk of newly diagnosed diabetes in the fourth quartile group (HOMA-IR ≥2.68) was significantly increased. After adjusting for gender and age, for every unit increase in HOMA-IR, the risk of developing newly diagnosed diabetes increased 9.67 times [OR: 9.670, 95% CI 5.086-18.384, P < 0.001]. When hypertension was combined with insulin resistance (HOMA-IR ≥2.68), the risk of newly diagnosed diabetes was 38.32 times compared with the control group [OR: 38.315, 95% CI 9.227-159.108, P < 0.001]. Conclusions: Elevated blood pressure levels and insulin resistance levels were associated with the risk of newly diagnosed diabetes. Hypertension was an independent risk factor for newly diagnosed diabetes, and the combination of hypertension with insulin resistance further increased the risk of newly diagnosed diabetes.

Genetic Characteristics of Incidental Pheochromocytoma and Paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are being increasingly discovered by imaging performed for unrelated conditions. The genetic landscape of incidental PPGLs remains to be elucidated. OBJECTIVE: We aimed to describe the genetic characteristics of PPGLs discovered incidentally in a large PPGL cohort. METHODS: This retrospective cross-sectional study included 697 patients with pathology confirmed PPGLs, including 283 incidentalomas and 414 nonincidentalomas, at 2 tertiary care centers in China in 2009-2019. Tumor DNA samples were sequenced by next-generation sequencing. Identified genetic mutations were confirmed by Sanger sequencing and tested in 277 available matched blood DNA samples. RESULTS: There was a lower proportion of patients with mutations identified (53% vs 63.3%; P = 0.0067) in incidental than nonincidental PPGLs. In incidental PPGLs, HRAS (11.7%), FGFR1 (11%), and RET (9.2%) were the top 3 mutated genes, whereas HRAS (17.9%), VHL (9.2%), and NF-1 (8.7%) exhibited the highest rate of mutations in nonincidental PPGLs. In incidental pheochromocytomas, the most frequently mutated genes were RET (10.9%), HRAS (10.4%), and VHL (8.6%), while in incidental paragangliomas, FGFR1 (32.8%), HRAS (16.4%), and EPAS1 (9.8%) topped the list. The frequency of NF-1 mutations was significantly lower in incidental than nonincidental pheochromocytomas (4.1% vs 11%; P = 0.0042), while FGFR1 mutations were far more common in incidental than nonincidental paragangliomas (32.8% vs 15.3%; P = 0.0076). CONCLUSION: More than half of patients with incidental PPGLs had mutations in common susceptibility genes. The search for susceptibility genes should take both the mode of discovery (incidental vs nonincidental) and tumor location (pheochromocytoma vs paraganglioma) into consideration.

Multiplexed nanomaterial-assisted laser desorption/ionization for pan-cancer diagnosis and classification.

As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. By multiplexing mass spectrometry fingerprints from two independent nanostructured matrixes through machine learning for highly sensitive detection and high throughput analysis, we report a laser desorption/ionization (LDI) mass spectrometry-based liquid biopsy for pan-cancer screening and classification. The Multiplexed Nanomaterial-Assisted LDI for Cancer Identification (MNALCI) is applied in 1,183 individuals that include 233 healthy controls and 950 patients with liver, lung, pancreatic, colorectal, gastric, thyroid cancers from two independent cohorts. MNALCI demonstrates 93% sensitivity at 91% specificity for distinguishing cancers from healthy controls in the internal validation cohort, and 84% sensitivity at 84% specificity in the external validation cohort, with up to eight metabolite biomarkers identified. In addition, across those six different cancers, the overall accuracy for identifying the tumor tissue of origin is 92% in the internal validation cohort and 85% in the external validation cohort. The excellent accuracy and minimum sample consumption make the high throughput assay a promising solution for non-invasive cancer diagnosis.

Associations of common polymorphisms in GCKR with type 2 diabetes and related traits in a Han Chinese population: a case-control study.

BACKGROUND: Several studies have shown that variants in the glucokinase regulatory protein gene (GCKR) were associated with type 2 diabetes and dyslipidemia. The purpose of this study was to examine whether tag single nucleotide polymorphisms (SNPs) in the GCKR region were associated with type 2 diabetes and related traits in a Han Chinese population and to identify the potential mechanisms underlying these associations. METHODS: We investigated the association of polymorphisms in the GCKR gene with type 2 diabetes by employing a case-control study design (1118 cases and 1161 controls). Four tag SNPs (rs8179206, rs2293572, rs3817588 and rs780094) with pairwise r2>0.8 and minor allele frequency>0.05 across the GCKR gene and its flanking regions were studied and haplotypes were constructed. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using a MassARRAY platform. RESULTS: The G alleles of GCKR rs3817588 and rs780094 were associated with an increased risk of type 2 diabetes after adjustment for year of birth, sex and BMI (OR=1.24, 95% CI 1.08-1.43, p=0.002 and OR=1.22, 95% CI 1.07-1.38, p=0.002, respectively). In the non-diabetic controls, the GG carriers of rs3817588 and rs780094 were nominally associated with a lower plasma triglyceride level compared to the AA carriers after adjustment for year of birth, sex and BMI (p for trend=0.00004 and 0.03, respectively). Furthermore, the association of rs3817588 with plasma triglyceride level was still significant after correcting for multiple testing. CONCLUSIONS: The rs3817588 A/G polymorphism of the GCKR gene was associated with type 2 diabetes and plasma triglyceride level in the Han Chinese population.