Destabilization of ß Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes.

SignificanceWith obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage-inducing transmembrane protein 2 (FIT2)-facilitated, pancreatic ß cell LD biogenesis, which in turn induces ß cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)-associated degradation. Loss of ß cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.

Multifunctional DNA-Based Hydrogel Promotes Diabetic Alveolar Bone Defect Reconstruction.

Diabetic alveolar bone defect (DABD) causes persistent bacterial infection, prolonged inflammation, and delayed bone healing, making it a considerable clinical challenge. In this study, by integrating silver nanoclusters (AgNCs) and M2 macrophage-derived extracellular vesicles (M2EVs), a multifunctional DNA-based hydrogel, called Agevgel, is developed with antibacterial, anti-inflammatory, immunomodulatory, and osteogenic properties to promote DABD rebuilding. AgNCs are tightly embedded into the DNA scaffolds and exhibit effective anti-bacterial activity, while immunomodulatory M2EVs are encapsulated within the shape-variable DNA scaffolds and exhibit potent anti-inflammatory and osteogenic properties. The results reveal that Agevgel effectively prolongs the local retention time and bioactivity of M2EVs in vivo. In particular, the sustained release of M2EVs can last for at least 7 days when applying Agevgel to DABD. Compared to free M2EVs or Aggel (AgNCs encapsulated within the DNA hydrogel) treatments, the Agevgel treatment accelerates the defect healing rate of alveolar bone and dramatically improves the trabecular architecture. Mechanistically, Agevgel plays a key role in regulating macrophage polarization and promoting the expression of proliferative and osteogenic factors. In summary, Agevgel provides a comprehensive treatment strategy for DABD with a great clinical translational value, highlighting the application of DNA hydrogels as an ideal bioscaffolds for periodontal diseases.

The effect of hyperlipidemia and body fat distribution on subclinical left ventricular function in obesity: a cardiovascular magnetic resonance study.

BACKGROUND: Obesity is often associated with multiple comorbidities. However, whether obese subjects with hyperlipidemia in the absence of other complications have worse cardiac indices than metabolically healthy obese subjects is unclear. Therefore, we aimed to determine the effect of hyperlipidemia on subclinical left ventricular (LV) function in obesity and to evaluate the association of cardiac parameters with body fat distribution. MATERIALS AND METHODS: Ninety-two adults were recruited and divided into 3 groups: obesity with hyperlipidemia (n = 24, 14 males), obesity without hyperlipidemia (n = 25, 13 males), and c ntrols (n = 43, 25 males). LV strain parameters (peak strain (PS), peak diastolic strain rate (PDSR), peak systolic strain rate) derived from cardiovascular magnetic resonance tissue tracking were measured and compared. Dual-energy X-ray absorptiometer was used to measure body fat distribution. Correlations of hyperlipidemia and body fat distribution with LV strain were assessed by multivariable linear regression. RESULTS: Obese individuals with preserved LV ejection fraction showed lower global LV longitudinal, circumferential, and radial PS and longitudinal and circumferential PDSR than controls (all P < 0.05). Among obese patients, those with hyperlipidemia had lower longitudinal PS and PDSR and circumferential PDSR than those without hyperlipidemia (- 12.8 ± 2.9% vs. - 14.2 ± 2.7%, 0.8 ± 0.1 s-1 vs. 0.9 ± 0.3 s-1, 1.2 ± 0.2 s-1 vs. 1.4 ± 0.2 s-1; all P < 0.05). Multivariable linear regression demonstrated that hyperlipidemia was independently associated with circumferential PDSR (ß = - 0.477, P < 0.05) in obesity after controlling for growth differences, other cardiovascular risk factors, and central fat distribution. In addition, android fat had an independently negative relationship with longitudinal and radial PS (ß = - 0.486 and ß = - 0.408, respectively; all P < 0.05); and visceral fat was negatively associated with longitudinal PDSR (ß = - 0.563, P < 0.05). Differently, gynoid fat was positively correlated with circumferential PS and PDSR and radial PDSR (ß = 0.490, ß = 0.481, and ß = 0.413, respectively; all P < 0.05). CONCLUSION: Hyperlipidemia is independently associated with subclinical LV diastolic dysfunction in obesity. Central fat distribution (android and visceral fat) has a negative association, while peripheral fat distribution (gynoid fat) has a positive association on subclinical LV function. These results suggest that appropriate management of hyperlipidemia may be beneficial for obese patients, and that the differentiation of fat distribution in different regions may facilitate the precise management of obese patients. Clinical trials registration Effect of lifestyle intervention on metabolism of obese patients based on smart phone software (ChiCTR1900026476).

Myocardial tissue remodeling in early adult obesity and its association with regional adipose tissue distribution and ectopic fat deposits: a prospective study.

OBJECTIVES: To evaluate the left ventricular (LV) myocardial tissue characteristics in early adult obesity and its association with regional adipose tissue and ectopic fat deposition. METHODS: Forty-nine obese adults (mean body mass index: 29.9 ± 2.0 kg/m2) and 44 healthy controls were prospectively studied. LV native and post-contrast T1 values, extracellular volume fraction (ECV), regional adipose tissue (epicardial, visceral, and subcutaneous adipose tissue (EAT, VAT, and SAT)), and ectopic fat deposition (hepatic and pancreatic proton density fat fractions (H-PDFF and P-PDFF)) based on magnetic resonance imaging were compared. The association was assessed by multivariable linear regression. RESULTS: The obese participants showed reduced global ECV compared to the healthy controls (p < 0.05), but there was no significant difference in global native or post-contrast T1 values between the two groups. Additionally, the obese individuals exhibited higher EAT, VAT, SAT, H-PDFF, and P-PDFF than the controls (p < 0.05). ECV was associated with insulin resistance, dyslipidemia, and systolic blood pressure (SBP) (p < 0.05). Multiple linear regression demonstrated that H-PDFF and SAT were independently associated with ECV in entire population (ß = - 0.123 and - 0.012; p < 0.05). CONCLUSIONS: Reduced myocardial ECV in patients with mild-to-moderate obesity and its relationship to SBP may indicate that cardiomyocyte hypertrophy, rather than extracellular matrix expansion, is primarily responsible for myocardial tissue remodeling in early adult obesity. Our findings further imply that H-PDFF and SAT are linked with LV myocardial tissue remodeling in this cohort beyond the growth difference and cardiovascular risk factors. CLINICAL TRIALS REGISTRATION: Effect of lifestyle intervention on metabolism of obese patients based on smart phone software (ChiCTR1900026476). CLINICAL RELEVANCE STATEMENT: Myocardial fibrosis in severe obesity predicts poor prognosis. We showed that cardiomyocyte hypertrophy, not myocardial fibrosis, is the main myocardial tissue characteristic of early obesity. This finding raises the possibility that medical interventions, like weight loss, may prevent cardiac fibrosis. KEY POINTS: • Myocardial tissue characteristics in early adult obesity are unclear. • Myocardial extracellular volume fraction (ECV) can be quantitatively evaluated using T1 mapping based on cardiac magnetic resonance imaging (MRI). • Cardiac MRI-derived ECV may noninvasively evaluate myocardial tissue remodeling in early adult obesity.

Association of abdominal adiposity, hepatic shear stiffness with subclinical left-ventricular remodeling evaluated by magnetic resonance in adults free of overt cardiovascular diseases: a prospective study.

BACKGROUND: Abdominal ectopic fat deposition and excess visceral fat depots in obesity may be related to cardiovascular disease (CVD) as both are involved in the metabolic syndrome (MetS). The awareness of the link between abdominal adiposity and subclinical cardiac remodeling would help improve treatment and outcome. Besides, liver fibrosis has also shown a potential relationship with cardiac dysfunction. Thus, we aimed to investigate the associations of magnetic resonance (MR)-based abdominal adiposity and hepatic shear stiffness with subclinical left ventricular (LV) remodeling while taking account of MetS-related confounders in adults free of overt CVD. METHODS: This was an exploratory, prospective study of 88 adults (46 subjects with obesity, 42 healthy controls) who underwent 3 T cardiac and body MR exams. Measures of abdominal MR included hepatic and pancreatic proton density fat fraction (H-PDFF and P-PDFF), hepatic shear stiffness by MR elastography, and subcutaneous and visceral adipose tissue (SAT and VAT). Cardiac measures included epicardial adipose tissue (EAT) and parameters of LV geometry and function. Associations were assessed using Pearson correlation and multivariable linear regression analyses, in which age, sex, and MetS-related confounders were adjusted for. RESULTS: The LV ejection fractions of all participants were within the normal range. Higher H-PDFF, P-PDFF, SAT and VAT were independently associated with lower LV global myocardial strain parameters (radial, circumferential and longitudinal peak strain [PS], longitudinal peak systolic strain rate and diastolic strain rate) (ß = - 0.001 to - 0.41, p < 0.05), and P-PDFF, SAT and VAT were independently and positively associated with LV end-diastolic volume and stroke volume (ß = 0.09 to 3.08, p ≤ 0.02) in the over-all cohort. In the obesity subgroup, higher P-PDFF and VAT were independently associated with lower circumferential and longitudinal PS, respectively (ß = - 0.29 to - 0.05, p ≤ 0.01). No independent correlation between hepatic shear stiffness and EAT or LV remodeling was found (all p ≥ 0.05). CONCLUSIONS: Ectopic fat depositions in the liver and pancreas, and excess abdominal adipose tissue pose a risk of subclinical LV remodeling beyond MetS-related CVD risk factors in adults without overt CVD. VAT may play a more considerable role as a risk factor for subclinical LV dysfunction than does SAT in individuals with obesity. The underlying mechanisms of these associations and their longitudinal clinical implications need further investigation.

The effects of first-line pharmacological treatments for reproductive outcomes in infertile women with PCOS: a systematic review and network meta-analysis.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common causes of infertility in reproductive-age women. However, the efficacy and optimal therapeutic strategy for reproductive outcomes are still under debate. We conducted a systematic review and network meta-analysis to compare the efficacy of different first-line pharmacological therapies in terms of reproductive outcomes for women with PCOS and infertility. METHODS: A systematic retrieval of databases was conducted, and randomized clinical trials (RCTs) of pharmacological interventions for infertile PCOS women were included. The primary outcomes were clinical pregnancy and live birth, and the secondary outcomes were miscarriage, ectopic pregnancy and multiple pregnancy. A network meta-analysis based on a Bayesian model was performed to compare the effects of the pharmacological strategies. RESULTS: A total of 27 RCTs with 12 interventions were included, and all therapies tended to increase clinical pregnancy, especially pioglitazone (PIO) (log OR 3.14, 95% CI 1.56 ~ 4.70, moderate confidence), clomiphene citrate (CC) + exenatide (EXE) (2.96, 1.07 ~ 4.82, moderate confidence) and CC + metformin (MET) + PIO (2.82, 0.99 ~ 4.60, moderate confidence). Moreover, CC + MET + PIO (2.8, -0.25 ~ 6.06, very low confidence) could increase live birth most when compared to placebo, even without a significant difference. For secondary outcomes, PIO showed a tendency to increase miscarriage (1.44, -1.69 ~ 5.28, very low confidence). MET (-11.25, -33.7 ~ 0.57, low confidence) and LZ + MET (-10.44, -59.56 ~ 42.11, very low confidence) were beneficial for decreasing ectopic pregnancy. MET (0.07, -4.26 ~ 4.34, low confidence) showed a neutral effect in multiple pregnancy. Subgroup analysis demonstrated no significant difference between these medications and placebo in obese participants. CONCLUSIONS: Most first-line pharmacological treatments were effective in improving clinical pregnancy. CC + MET + PIO should be recommended as the optimal therapeutic strategy to improve pregnancy outcomes. However, none of the above treatments had a beneficial effect on clinical pregnancy in obese PCOS. TRIAL REGISTRATION: CRD42020183541; 05 July 2020.

Pancreatic ß cell microRNA-26a alleviates type 2 diabetes by improving peripheral insulin sensitivity and preserving ß cell function.

Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic ß cell failure. ß cell factors are traditionally thought to control glucose homeostasis by modulating insulin levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of ß-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in ß cells not only modulates insulin secretion and ß cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in ß cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in ß cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and ß cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of ß cells and offer opportunities for the treatment of T2D.

Preclinical models for Type 1 Diabetes Mellitus - A practical approach for research.

Numerous preclinical models have been developed to advance biomedical research in type 1 diabetes mellitus (T1DM). They are essential for improving our knowledge of T1DM development and progression, allowing researchers to identify potential therapeutic targets and evaluate the effectiveness of new medications. A deeper comprehension of these models themselves is critical not only to determine the optimal strategies for their utilization but also to fully unlock their potential applications in both basic and translational research. Here, we will comprehensively summarize and discuss the applications, advantages, and limitations of the commonly used animal models for human T1DM and also overview the up-to-date human tissue bioengineering models for the investigation of T1DM. By combining these models with a better understanding of the pathophysiology of T1DM, we can enhance our insights into disease initiation and development, ultimately leading to improved therapeutic responses and outcomes.

The association of plasma NT-proBNP level and progression of diabetic kidney disease.

AIMS: Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD). The identification of risk factors involved in the progression of DKD to ESKD is expected to result in early detection and appropriate intervention and improve prognosis. This study aimed to explore whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with kidney outcomes in patients with type 2 diabetes mellitus (T2DM) and biopsy-proven DKD. METHODS: Patients with biopsy-proven DKD who were followed up at West China Hospital over 12 months were enrolled. The kidney outcome was defined as progression to ESKD. The cutoff value of plasma NT-proBNP concentration was calculated by using receiver operating characteristic (ROC) curve analysis. The influence of NT-proBNP levels on kidney outcome in patients with DKD was assessed using Cox regression analysis. RESULTS: A total of 30 (24.5%) patients reached ESKD during a median follow-up of 24.1 months. The baseline serum NT-proBNP level had a significant correlation with baseline proteinuria, kidney function, glomerular lesions, interstitial fibrosis tubular atrophy (IFTA), and arteriolar hyalinosis. Multivariate Cox regression analysis indicated that increased NT-proBNP level was significantly associated with a higher risk of progression to ESKD (HR 6.43; 95% CI (1.65-25.10, p = 0.007), and each 1 SD increase in LG (NT-proBNP) was also associated with a higher risk (HR 2.43; 95% CI 1.94-5.29, p = 0.047) of an adverse kidney outcome after adjusting for confounding factors. CONCLUSIONS: A higher level of plasma NT-proBNP predicts kidney prognosis in patients with biopsy-proven DKD. This warrants further investigation into the potential mechanisms.

Adiponectin gene therapy prevents islet loss after transplantation.

Significant pancreatic islet dysfunction and loss shortly after transplantation to the liver limit the widespread implementation of this procedure in the clinic. Nonimmune factors such as reactive oxygen species and inflammation have been considered as the primary driving force for graft failure. The adipokine adiponectin plays potent roles against inflammation and oxidative stress. Previous studies have demonstrated that systemic administration of adiponectin significantly prevented islet loss and enhanced islet function at post-transplantation period. In vitro studies indicate that adiponectin protects islets from hypoxia/reoxygenation injury, oxidative stress as well as TNF-α-induced injury. By applying adenovirus mediated transfection, we now engineered islet cells to express exogenous adiponectin gene prior to islet transplantation. Adenovirus-mediated adiponectin transfer to a syngeneic suboptimal islet graft transplanted under kidney capsule markedly prevented inflammation, preserved islet graft mass and improved islet transplant outcomes. These results suggest that adenovirus-mediated adiponectin gene therapy would be a beneficial clinical engineering approach for islet preservation in islet transplantation.

Molecular diagnosis of adult patients with clinically unexplained hypokalemia without hypertension demonstrated a diagnostic yield of 30.5.

Hypokalemia is a common disorder in clinical settings; however, nonmolecular diagnostic testing cannot explain some causes of hypokalemia. To determine the etiology of clinically unexplained hypokalemia without hypertension (CUHypoNH) and to obtain a diagnostic yield of monogenic hypokalemia without hypertension in adults (MHNHA), we enrolled 82 patients with CUHypoNH for whole-exome sequencing or targeted gene sequencing of genes associated with 4000 monogenic disorders. Through molecular diagnosis, 25 patients were diagnosed with monogenic hypokalemia, and a diagnostic yield of 30.5% was obtained. Among patients with MHNHA, 18 patients (18/82, 22.0% and 72% of MHNHA) with Gitelman syndrome accounted for the largest proportion. Among the 29 diagnostic variants found, eight mutations have not been reported previously; these include three point mutations, one frameshift mutation, and four exon deletions. Based on the clinical presentation of patients with CUHypoNH, the diagnostic yield of monogenic hypokalemia was the highest for chronic asymptomatic hypokalemia (8/11, 72.7%). Twenty-one patients had concomitant hypomagnesemia, when accompanied with hypocalciuria, the molecular diagnostic yield of Gitelman syndrome increased to 88.2%. Overall, this study on hospitalized adult patients explored the etiology of CUHypoNH using high-throughput sequencing. Molecular diagnosis of CUHypoNH is clinically significant in guiding precision treatment and improving disease prognosis.

Risk prediction models for incident type 2 diabetes in Chinese people with intermediate hyperglycemia: a systematic literature review and external validation study.

BACKGROUND: People with intermediate hyperglycemia (IH), including impaired fasting glucose and/or impaired glucose tolerance, are at higher risk of developing type 2 diabetes (T2D) than those with normoglycemia. We aimed to evaluate the performance of published T2D risk prediction models in Chinese people with IH to inform them about the choice of primary diabetes prevention measures. METHODS: A systematic literature search was conducted to identify Asian-derived T2D risk prediction models, which were eligible if they were built on a prospective cohort of Asian adults without diabetes at baseline and utilized routinely-available variables to predict future risk of T2D. These Asian-derived and five prespecified non-Asian derived T2D risk prediction models were divided into BASIC (clinical variables only) and EXTENDED (plus laboratory variables) versions, with validation performed on them in three prospective Chinese IH cohorts: ACE (n = 3241), Luzhou (n = 1333), and TCLSIH (n = 1702). Model performance was assessed in terms of discrimination (C-statistic) and calibration (Hosmer-Lemeshow test). RESULTS: Forty-four Asian and five non-Asian studies comprising 21 BASIC and 46 EXTENDED T2D risk prediction models for validation were identified. The majority were at high (n = 43, 87.8%) or unclear (n = 3, 6.1%) risk of bias, while only three studies (6.1%) were scored at low risk of bias. BASIC models showed poor-to-moderate discrimination with C-statistics 0.52-0.60, 0.50-0.59, and 0.50-0.64 in the ACE, Luzhou, and TCLSIH cohorts respectively. EXTENDED models showed poor-to-acceptable discrimination with C-statistics 0.54-0.73, 0.52-0.67, and 0.59-0.78 respectively. Fifteen BASIC and 40 EXTENDED models showed poor calibration (P < 0.05), overpredicting or underestimating the observed diabetes risk. Most recalibrated models showed improved calibration but modestly-to-severely overestimated diabetes risk in the three cohorts. The NAVIGATOR model showed the best discrimination in the three cohorts but had poor calibration (P < 0.05). CONCLUSIONS: In Chinese people with IH, previously published BASIC models to predict T2D did not exhibit good discrimination or calibration. Several EXTENDED models performed better, but a robust Chinese T2D risk prediction tool in people with IH remains a major unmet need.

Development and internal validation of machine learning algorithms for end-stage renal disease risk prediction model of people with type 2 diabetes mellitus and diabetic kidney disease.

AIMS: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) and is associated with increased morbidity and mortality in patients with diabetes. Identification of risk factors involved in the progression of DKD to ESRD is expected to result in early detection and appropriate intervention and improve prognosis. Therefore, this study aimed to establish a risk prediction model for ESRD resulting from DKD in patients with type 2 diabetes mellitus (T2DM). METHODS: Between January 2008 and July 2019, a total of 390 Chinese patients with T2DM and DKD confirmed by percutaneous renal biopsy were enrolled and followed up for at least 1 year. Four machine learning algorithms (gradient boosting machine, support vector machine, logistic regression, and random forest (RF)) were used to identify the critical clinical and pathological features and to build a risk prediction model for ESRD. RESULTS: There were 158 renal outcome events (ESRD) (40.51%) during the 3-year median follow up. The RF algorithm showed the best performance at predicting progression to ESRD, showing the highest AUC (0.90) and ACC (82.65%). The RF algorithm identified five major factors: Cystatin-C, serum albumin (sAlb), hemoglobin (Hb), 24-hour urine urinary total protein, and estimated glomerular filtration rate. A nomogram according to the aforementioned five predictive factors was constructed to predict the incidence of ESRD. CONCLUSION: Machine learning algorithms can efficiently predict the incident ESRD in DKD participants. Compared with the previous models, the importance of sAlb and Hb were highlighted in the current model.HighlightsWhat is already known? Identification of risk factors for the progression of DKD to ESRD is expected to improve the prognosis by early detection and appropriate intervention.What this study has found? Machine learning algorithms were used to construct a risk prediction model of ESRD in patients with T2DM and DKD. The major predictive factors were found to be CysC, sAlb, Hb, eGFR, and UTP.What are the implications of the study? In contrast with the treatment of participants with early-phase T2DM with or without mild kidney damage, major emphasis should be placed on indicators of kidney function, nutrition, anemia, and proteinuria for participants with T2DM and advanced DKD to delay ESRD, rather than age, sex, and control of hypertension and glycemia.

Addition of glomerular lesion severity improves the value of anemia status for the prediction of renal outcomes in Chinese patients with type 2 diabetes.

We aimed to determine the utility of biopsy data and anemia for the prediction of renal outcomes in Chinese patients with type 2 diabetes. In total, 441 Chinese patients with type 2 diabetes and biopsy-confirmed diabetic nephropathy (DN) were enrolled in a retrospective study. Their renal pathology was assessed using the Renal Pathology Society system. Cox proportional hazards models were used to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), and immunofluorescence staining was used to assess the expression of hypoxia-inducible factor (HIF)-α in patients' kidneys. We found that glomerular pathology classification was an independent pathological predictor of low hemoglobin concentration, according to linear and logistic regression analyses. Each 1 g/dL decrease in baseline hemoglobin concentration was associated with a 42% higher risk of an adverse renal outcome, after adjustment for clinical and pathologic covariates. In patients with severe glomerular lesions, the risk of progression to ESRD was significantly higher if mild or moderate/severe anemia was present, but in patients with mild glomerular lesions, the risk was only significantly higher in those with moderate or severe anemia than in the absence of anemia. Harrell's C Concordance was improved, but the Akaike information criterion was worsened by adding the glomerular pathology classification to the use of anemia status and clinical data. Immunofluorescence staining revealed that renal HIF-1α and HIF-2α expression was significantly higher in classes II-IV than class I. Thus, the addition of glomerular pathology classification increases the value of anemia status for the prediction of the progression to ESRD.

[Iodine Nutritional Status and Prevalence of Thyroid Disorders among Adults in Chengdu].

Objective: To investigate the prevalence of thyroid disorders, iodine nutritional status and relevant risk factors among adults in Chengdu city on the basis of two population-based surveys, one conducted between 2016 and 2017 and the other, between 2019 and 2020, and to provide references for making health-related administrative decisions. Methods: Two population-based sampling surveys were conducted. The first one was done between October 2016 and December 2017, using stratified cluster random sampling to select subjects from 2 urban and 2 rural communities in Chengdu. Then, between December 2019 and February 2020, sequential cluster sampling was used to select subjects from communities in the peripheral regions of Longquanyi District, Chengdu. Both surveys covered natural populations of people who were 18 or older and who met the inclusion criteria. In the first survey, questionnaires, physical examination, thyroid ultrasound, and examinations of serum thyroid biochemical markers and urine iodine were performed, while in the second survey, only questionnaire concerning thyroid disorders and physical examination were performed. Statistical analysis of the nutritional status of iodine, the prevalence of thyroid disorders, and potential risk factor was conducted. Results: A total of 1859 subjects were enrolled for the first survey and 16152 for the second. According to the results of the first survey, the median urine iodine concentration was 172.10 µg/L, and the group with adequate or more than adequate iodine accounted for more than 60% of the surveyed population. The prevalence of thyroid disorders was found to be 0.48% for overt hyperthyroidism, 0.43% for subclinical hyperthyroidism, 0.43% for Grave's disease, 1.34% for overt hypothyroidism, 16.62% for subclinical hypothyroidism, 16.73% for positive thyroid antibody, 12.96% for TPOAb positive, 10.06% for TGAb positive, 0.81% for goiter, 14.85% for single nodule, 14.42% for multi-nodules, and 29.26% for thyroid nodules. Excess iodine is a risk factor for subclinical hypothyroidism ( OR=1.50, 95% confidence interval [ CI]: 1.07-2.10, P<0.05), and iodine deficiency is a risk factor for multiple thyroid nodules ( OR=1.45, 95% CI: 1.02-2.05, P<0.05). The total prevalence of hyperthyroidism, hypothyroidism and Hashimoto's thyroiditis in the two surveys was 6.58% and 5.95%, respectively, showing no significant difference. The second survey lacked accurate data on thyroid nodules. Conclusion: The iodine nutritional status of adults in Chengdu in recent years was appropriate. The total prevalence of hyperthyroidism, hypothyroidism and Hashimoto's thyroiditis remained stable, while that of thyroid nodule increased in recent years. We should continue with the implementation of the universal salt iodization policy and reinforce efforts in monitoring. Furthermore, we should make an active effort to look into the etiology of thyroid nodules.

Hepatic stellate cells specific liposomes with the Toll-like receptor 4 shRNA attenuates liver fibrosis.

The hepatic stellate cells (HSCs) play a significant role in the onset of liver fibrosis, which can be treated by the inhibition and reversal of HSC activation. The RNA interference-mediated TLR4 gene silencing might be a potential therapeutic approach for liver fibrosis. The crucial challenge in this method is the absence of an efficient delivery system for the RNAi introduction in the target cells. HSCs have an enhanced capacity of vitamin A intake as they contain retinoic acid receptors (RARs). In the current study, we developed cationic liposomes modified with vitamin A to improve the specificity of delivery vehicles for HSCs. The outcome of this study revealed that the VitA-coupled cationic liposomes delivered the TLR4 shRNA to aHSCs more efficiently, as compared to the uncoupled cationic liposomes, both in the in vitro and in vivo conditions. Besides, as evident from the outcome of this study, the TLR4 gene silencing inhibited the HSCs activation and attenuated the liver fibrosis via the NF-κB transcriptional inactivation, pro-inflammatory cytokines secretion and reactive oxygen species (ROS) synthesis. Thus, the VitA-coupled liposomes encapsulated with the TLR4-shRNA might prove as an efficient therapeutic agent for liver fibrosis.

Identification of MDM2, YTHDF2 and DDX21 as potential biomarkers and targets for treatment of type 2 diabetes.

Type 2 diabetes (T2D) is a multifactorial and polygenetic disease, although its exact etiology remains poorly understood. The objective of this study was to identify key biomarkers and potential molecular mechanisms in the development of T2D. Human RNA-Seq datasets across different tissues (GSE18732, GSE41762, and GSE78721) were collected from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) between T2D and controls were identified using differential analysis. A total of 90 overlapping DEGs were identified, among which YTHDF2, DDX21, and MDM2 were considered as key genes due to their central positions in the PPI network and the same regulatory pattern in T2D. Logistic regression analysis showed that low expression of the key genes increased the risk of T2D. Enrichment analysis revealed that the key genes are involved in various important biological functions and signaling pathways including Notch, Fork head box O (FOXO), and phosphoinositide 3-kinase (PI3K)-Akt. RT-qPCR and Western blot analysis showed that all three key genes were down-regulated in pancreatic islets of both prediabetic and diabetic mouse models. Finally, the insulin-sensitizer, pioglitazone was used to treat db/db mice and immunofluorescence analysis showed that the expression of all three key genes was significantly down-regulated in db/db islets, an effect that was overcome by pioglitazone treatment. Together, these results suggest that the identified key genes could be involved in the development of T2D and serve as potential biomarkers and therapeutic targets for this disease.

A negative association between urinary iodine concentration and the prevalence of hyperuricemia and gout: a cross-sectional and population-based study in Mainland China.

BACKGROUND AND AIMS: Iodine is one of the most important trace elements in the human body. It is not only the main component of thyroid hormones but also has extrathyroid biological functions. To date, there have been no large-scale epidemiological studies on the relationship between hyperuricemia and iodine intake, although both are closely related to health. A population-based epidemiological survey in China offers such an opportunity. METHODS: This population-based cross-sectional study recruited 75,653 adults aged ≥ 18 years from 2015 to 2017 with a randomized, multistage, stratified sampling strategy. Serum uric acid levels and urinary iodine concentrations (UICs) were measured. RESULTS: Stratified by UIC, the prevalence of hyperuricemia was 17.8%, 18.8%, 16.0% and 13.7% in the UIC < 100, 100-199, 200-299, and ≥ 300 µg/L groups, respectively; the prevalence of gout was 4.0%, 3.4%, 2.4% and 1.7%, respectively. The prevalence of gout decreased significantly as the UIC increased. The prevalence of hyperuricemia and gout were markedly higher in postmenopausal females than in the premenopausal population (hyperuricemia: 15.9% vs. 8.3%, X2 = 520.072, p < 0.001; gout: 3.6% vs. 1.3%, X2 = 219.889, p < 0.001), and the prevalence decreased as the UIC increased. Subjects in the more than adequate and excessive iodine groups had lower likelihoods of having hyperuricemia [aOR = 0.81 (95% CI 0.77-0.85), aOR = 0.68 (95% CI 0.64-0.72)] and lower odds of having gout than subjects in the adequate iodine (AI) group [aOR = 0.77 (95% CI 0.68-0.86), aOR = 0.59 (95% CI 0.51-0.68)]. CONCLUSIONS: UIC was inversely associated with the occurrence of hyperuricemia and gout. More in-depth research and prospective studies are needed to explore the molecular mechanisms and confirm the observed association.

Unusual ectopic ACTH syndrome in a patient with orbital neuroendocrine tumor, resulted false-positive outcome of BIPSS:a case report.

BACKGROUND: Cushing's syndrome has been described as a complex endocrine disorder characterized with high cortisol concentration. Correct and early diagnosis of Cushing's syndrome is challenging. According to the latest guideline, bilateral inferior petrosal sinus sampling (BIPSS) is considered to be the gold standard for the differential diagnosis. However, in some unusual cases, this method may be false positive. Here, we presented a rare case of orbital neuroendocrine tumor secreting adrenocorticotrophic hormone with false positive inferior petrosal sinus sampling. CASE PRESENTATION: A 48-year-old woman was admitted to West China Hospital of Sichuan University, presenting with fatigue, whole body edema for 1 year, alopecia and skin pigmentation for 5 months. Hormonal profiles including plasma cortisol and adrenocorticotrophic hormone (ACTH) measurements and low-dose dexamethasone inhibition test suggested that the patient had Cushing's syndrome. However, during tumor location phase, the results of high-dose dexamethasone inhibition test (HDDST) contradicted desmopressin (DDAVP) stimulation test. Thus, BIPSS was employed, and its results indicated a pituitary origin. Interestingly, MRI of sellar region showed an innocent pituitary but caught a serendipitous lesion in the lateral rectus muscle of left eye, which was later proved to be an orbital neuroendocrine tumor secreting ACTH by pathological and immunohistochemical results. ACTH level of the patients was < 0.1 ng/L and cortisol level was 51.61 nmol/L 1 week after surgery. At 24 months follow-up, the patient appeared stable with no complaints nor any symptoms of Cushing's syndrome, including moon face, purple striate and central obesity. The patient's life quality also improved significantly. CONCLUSION: We reported a rare case of endogenous Cushing's syndrome due to ectopic ACTH secreting from an orbital neuroendocrine tumor. This unique case of orbital EAS suggests that orbital venous blood backflow, owning to abnormal anatomic structures, may possibly lead to false positive BIPSS results.

DIABETIC RETINOPATHY, CLASSIFIED USING THE LESION-AWARE DEEP LEARNING SYSTEM, PREDICTS DIABETIC END-STAGE RENAL DISEASE IN CHINESE PATIENTS.

Objective: To characterize the relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in Chinese patients and to determine whether the severity of DR predicts end-stage renal disease (ESRD). Methods: Bilateral fundic photographs of 91 Chinese type 2 diabetic patients with biopsy-confirmed DN, not in ESRD stage, were obtained at the time of renal biopsy in this longitudinal study. The baseline severity of DR was determined using the Lesion-aware Deep Learning System (RetinalNET) in an open framework for deep learning and was graded using the Early Treatment Diabetic Retinopathy Study severity scale. Cox proportional hazard models were used to estimate the hazard ratio (HR) for the effect of the severity of diabetic retinopathy on ESRD. Results: During a median follow-up of 15 months, 25 patients progressed to ESRD. The severity of retinopathy at the time of biopsy was a prognostic factor for progression to ESRD (HR 2.18, 95% confidence interval 1.05 to 4.53, P = .04). At baseline, more severe retinopathy was associated with poor renal function, and more severe glomerular lesions. However, 30% of patients with mild retinopathy and severe glomerular lesions had higher low-density lipo-protein-cholesterol and more severe proteinuria than those with mild glomerular lesions. Additionally, 3% of patients with severe retinopathy and mild glomerular changes were more likely to have had diabetes a long time than those with severe glomerular lesions. Conclusion: Although the severity of DR predicted diabetic ESRD in patients with type 2 diabetes mellitus and DN, the severities of DR and DN were not always consistent, especially in patients with mild retinopathy or microalbuminuria. Abbreviations: CI = confidence interval; DM = diabetic mellitus; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = hemoglobin A1c; HR = hazard ratio; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; VEGF = vascular endothelial growth factor.