Evolving liver disease insights from NAFLD to MASLD.

The recent renaming of 'non-alcoholic fatty liver disease' (NAFLD) to 'metabolic dysfunction-associated steatotic liver disease' (MASLD) emphasizes metabolic dysfunction in steatotic liver disease and advocates for tailored, comprehensive treatment strategies, driving forward the development of personalized care and innovative therapeutic approaches.

High lymphocyte signature genes expression in parathyroid endocrine cells and its downregulation linked to tumorigenesis.

BACKGROUND: To date, because of the difficulty in obtaining normal parathyroid gland samples in human or in animal models, our understanding of this last-discovered organ remains limited. METHODS: In the present study, we performed a single-cell transcriptome analysis of six normal parathyroid and eight parathyroid adenoma samples using 10 × Genomics platform. FINDINGS: We have provided a detailed expression atlas of parathyroid endocrine cells. Interestingly, we found an exceptional high expression levels of CD4 and CD226 in parathyroid endocrine cells, which were even higher than those in lymphocytes. This unusual expression of lymphocyte markers in parathyroid endocrine cells was associated with the depletion of CD4 T cells in normal parathyroid glands. Moreover, CD4 and CD226 expression in endocrine cells was significantly decreased in parathyroid adenomas, which was associated with a significant increase in Treg counts. Finally, along the developmental trajectory, we discovered the loss of POMC, ART5, and CES1 expression as the earliest signature of parathyroid hyperplasia. INTERPRETATION: We propose that the loss of CD4 and CD226 expression in parathyroid endocrine cells, coupled with an elevated number of Treg cells, could be linked to the pathogenesis of parathyroid adenoma. Our data also offer valuable information for understanding the noncanonical function of CD4 molecule. FUNDING: This work was supported by the National Key R&D Program of China (2022YFA0806100), National Natural Science Foundation of China (82130025, 82270922, 31970636, 32211530422), Shandong Provincial Natural Science Foundation of China (ZR2020ZD14), Innovation Team of Jinan (2021GXRC048) and the Outstanding University Driven by Talents Program and Academic Promotion Program of Shandong First Medical University (2019LJ007).

Ultrasonic backscattering model for Rayleigh waves in polycrystals with Born and independent scattering approximations.

This paper presents theoretical and numerical models for the backscattering of 2D Rayleigh waves in single-phase, untextured polycrystalline materials with statistically equiaxed grains. The theoretical model, based on our prior inclusion-induced Rayleigh wave scattering model and the independent scattering approximation, considers single scattering of Rayleigh-to-Rayleigh (R-R) waves. The numerical finite element model is established to accurately simulate the scattering problem and evaluate the theoretical model. Good quantitative agreement is observed between the theoretical model and the finite element results, especially for weakly scattering materials. The agreement decreases with the increase of the anisotropy index, owing to the reduced applicability of the Born approximation. However, the agreement remains generally good when weak multiple scattering is involved. In addition, the R-R backscattering behaviour of 2D Rayleigh waves is similar to the longitudinal-to-longitudinal and transverse-to-transverse backscattering of bulk waves, with the former exhibiting stronger scattering. These findings establish a foundation for using Rayleigh waves in the quantitative characterisation of polycrystalline materials.

Combined association of abdominal obesity and depressive symptoms with risk of type 2 diabetes: A cohort study.

OBJECTIVE: To explore the combined effect of abdominal obesity and depressive symptoms on the risk to type 2 diabetes, while also assessing the potential influence of various glycemic states and gender on this combined relationship. METHODS: Data is acquired from the China Health and Retirement Longitudinal Study, and 5949 participants were included for analysis. Participants were divided into four groups: neither have abdominal obesity nor depressive symptoms (AO-/DS-), only have depressive symptoms (AO-/DS+), only have abdominal obesity (AO+/DS-), and have both abdominal obesity and depressive symptoms (AO+/DS+). Stratified analyses differentiating the glycemic statuses and sex of the participants were also carried out. RESULTS: After adjusting for the confounders, the AO-/DS+, AO+/DS- and AO+/DS+ phenotypes were all discovered to be risk factors for type 2 diabetes (OR = 1.38, 95%CI: 1.06-1.79; OR = 2.07, 95%CI: 1.63-2.63; OR = 2.38, 95%CI: 1.83-3.11, respectively) compared with the AO-/DS- phenotype in the overall population. In further stratified analyses, we arrived at the same conclusion for normoglycemic individuals, especially in females. For prediabetes and males, the AO+/DS- and AO+/DS+ phenotypes are risk factors for type 2 diabetes compared with the AO-/DS- phenotype, but not with AO-/DS+. CONCLUSION: Regardless of glycemic status and sex, the coexistence of abdominal obesity and depressive symptoms were associated with an increased risk of type 2 diabetes. Depressive symptoms were independent risk factors for type 2 diabetes only in normoglycemic individuals and females.

The short- and long-term readmission of four major categories of digestive system cancers: does obesity or metabolic disorder matter?

Purpose: Patients with digestive system cancers (DSCs) are at a high risk for hospitalizations; however, the risk factors for readmission remain unknown. Here, we established a retrospective cohort study to assess the association between metabolic obesity phenotypes and readmission risks of DSC. Experimental design: A total of 142,753 and 74,566 patients at index hospitalization were ultimately selected from the Nationwide Readmissions Database (NRD) 2018 to establish the 30-day and 180-day readmission cohorts, respectively. The study population was classified into four groups: metabolically healthy non-obese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO). Multivariate Cox regression analysis was used to estimate the effect of metabolic obesity phenotypes on DSC readmission. Results: The MUNO phenotype had 1.147-fold (95% CI: 1.066, 1.235; p < 0.001) increased 180-day readmission risks in patients with neoplasm of the upper digestive tract. The MUNO phenotype had 1.073-fold (95% CI: 1.027, 1.121; p = 0.002) increased 30-day readmission risks and 1.067-fold (95% CI: 1.021, 1.115; p = 0.004) increased 180-day readmission risks in patients with neoplasm of the lower digestive tract. The MUNO and MUO phenotypes were independent risk factors of readmission in patients with liver or pancreatic neoplasm. Metabolic obesity status was independently associated with a high risk of severe and unplanned hospitalization within 30 days or 180 days. Conclusion: Both obesity and metabolic abnormalities are associated with a high risk for the poor prognosis of DSC patients. The effect of metabolic categories on the short- or long-term readmission of liver or pancreas cancers may be stronger than that of obesity.

Association between the peripheral neutrophil-to-lymphocyte ratio and metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes frequently co-occur, imposing a tremendous medical burden. A convenient and effective MASLD indicator will be beneficial to the early diagnosis of disease. In the clinical laboratory, the neutrophil-to-lymphocyte ratio (NLR) is a readily accessible hematological marker. This study designed to determine the relation between the NLR and MASLD in type 2 diabetes patients. Methods: Data from 1,151 type 2 diabetes inpatients without infections, malignancy or hematological diseases who were recruited from 2016 through 2022 were analyzed in the retrospective study. The patients were stratified into NLR tertiles (total population: high NLR level > 2.18; middle NLR level: 1.58-2.18; low NLR level < 1.58), with additional subgroup stratification by sex (men: high NLR level > 2.21; middle NLR level: 1.60-2.21; and low NLR level < 1.60; women: high NLR level > 2.12; middle NLR level: 1.53-2.12; and low NLR level < 1.53). After adjusting for confounders (age, sex, weight, Glu, ALT and TG) associated with MASLD, the odds ratio (OR) and the corresponding 95% confidence interval (CI) of the NLR were obtained by using a binary logistic regression analysis to verify the correlation between the NLR and MASLD. Results: Compared to non-MASLD patients, MASLD patients had higher weight, blood glucose, insulin and C-peptide, worse liver function (higher ALT and GGT), lower HDL (all p < 0.05), and lower NLR (p < 0.001). The prevalence of MASLD was 43.75% (high NLR level), 55.21% (middle NLR level) and 52.22% (low NLR level) (p < 0.05). Compared to those of the high NLR level, the adjusted ORs and 95% CIs of the middle and low NLR levels were 1.624 (95% CI: 1.141-2.311) and 1.456 (95% CI: 1.025-2.068), for all subjects, while they were 1.640 (95% CI: 1.000-2.689) and 1.685 (95% CI: 1.026-2.766), for men. Conclusion: A low NLR is associated with a greater risk of MASLD.

Dominant-negative HNF1α mutant promotes liver steatosis and inflammation by regulating hepatic complement factor D.

Patients with HNF1A variants may develop liver steatosis, while the underlying mechanism is still unclear. Here, we established a mouse model carrying the dominant-negative HNF1α P291fsinsC mutation (hHNF1Amut/-) and found that the mutant mice developed liver steatosis spontaneously under the normal chow diet. Transcriptome analysis showed significant upregulation of Cfd and other genes related to innate immune response in the liver of hHNF1Amut/- mice. The changes in lipid metabolism and complement pathways were also confirmed by proteomics. We demonstrated that HNF1α inhibited CFD expression in hepatocytes, and the P291fsinsC mutant could reverse this inhibitory effect. Furthermore, the suppression of CFD with specific inhibitor or siRNAs reduced triglyceride levels in hepatocytes, suggesting that CFD regulated hepatocyte lipid deposition. Our results demonstrate that the HNF1α P291fsinsC mutant promotes hepatic steatosis and inflammation by upregulating CFD expression, and targeting CFD may delay the progression of nonalcoholic fatty liver disease.

The Transcription Factor ZmNAC89 Gene Is Involved in Salt Tolerance in Maize (Zea mays L.).

The NAC gene family has transcription factors specific to plants, which are involved in development and stress response and adaptation. In this study, ZmNAC89, an NAC gene in maize that plays a role in saline-alkaline tolerance, was isolated and characterized. ZmNAC89 was localized in the nucleus and had transcriptional activation activity during in vitro experiments. The expression of ZmNAC89 was strongly upregulated under saline-alkaline, drought and ABA treatments. Overexpression of the ZmNAC89 gene in transgenic Arabidopsis and maize enhanced salt tolerance at the seedling stage. Differentially expressed genes (DEGs) were then confirmed via RNA-sequencing analysis with the transgenic maize line. GO analyses showed that oxidation-reduction process-regulated genes were involved in ZmNAC89-mediated salt-alkaline stress. ZmNAC89 may regulate maize saline-alkali tolerance through the REDOX pathway and ABA signal transduction pathway. From 140 inbred maize lines, 20 haplotypes and 16 SNPs were found in the coding region of the ZmNAC89 gene, including the excellent haplotype HAP20. These results contribute to a better understanding of the response mechanism of maize to salt-alkali stress and marker-assisted selection during maize breeding.

Cyclophilin D as a potential therapeutic target of liver ischemia/reperfusion injury by mediating crosstalk between apoptosis and autophagy.

Background: Liver ischemia/reperfusion (I/R) injury is a complex and multifactorial pathophysiological process. It is well recognized that the membrane permeability transition pore (mPTP) opening of mitochondria plays a crucial role in cell death after I/R injury. Cyclophilin D (CypD) is a critical positive regulator of mPTP. However, the effect of CypD on the pathogenesis of liver I/R injury and whether CypD is a potential therapeutic target are still unclear. Methods: We constructed liver-specific CypD knockout and AAV8-peptidyl prolyl isomerase F (PPIF) overexpression mice. Then, a 70% liver I/R injury model was established in mice, with 90 min of ischemia and 6 h of reperfusion. The liver function was detected by the level of serum glutamic pyruvic transaminase (alanine transaminase) and glutamic oxaloacetic transaminase (aspartate aminotransferase), the liver damage score and degree of necrosis were measured by hematoxylin and eosin (H&E) staining of liver tissues. Reactive oxygen species (ROS) staining, apoptosis, and autophagy-related molecules were used to detect apoptosis and autophagy during liver I/R. Results: The liver-specific knockout of CypD alleviated necrosis and dysfunction in liver I/R injury, by reducing the excessive production of ROS, and inhibiting cell apoptosis and autophagy. On the contrary, overexpression of CypD exacerbated I/R-induced liver damage. Conclusion: We found that the downregulation of CypD expression alleviated liver I/R injury by reducing apoptosis and autophagy through caspase-3/Beclin1 crosstalk; in contrast, the upregulation of CypD expression aggravated liver I/R injury. Therefore, interfering with the expression of CypD seems to be a promising treatment for liver I/R injury.

Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice.

Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.

Obesity and risk of hearing loss in the middle-aged and elderly: a national cohort of Chinese adults.

BACKGROUND: The relationship between obesity and hearing loss among the middle-aged and older population remained unclear. Moreover, few studies have focused on the impact of gender on this association. METHODS: This cohort study extracted the data from the China Health and Retirement Longitudinal Study, a national survey of adults aged 45 years or over. Waist circumference was categorized into three groups: normal, pre-central obesity, and central obesity. We classified BMI into four categories: underweight, normal weight, overweight, and obese. The primary endpoint was the incidence of self-reported hearing loss. RESULTS: Of the 14,237 participants, 1972 incidents of hearing loss were identified during a median 6.9 years of follow-up. The cumulative incidence of hearing loss was 13.9% (95% CI 13.3% -14.4%). Our study showed that central obesity was significantly associated with hearing loss (HR 0.84, 95%CI 0.75-0.94), and this relationship was more prominent in males (HR 0.76, 95%CI 0.63-0.91). Among male participants, the underweight group was at the highest risk of hearing loss (HR 1.39, 95%CI 1.08-1.79). Compared with the normal weight group, the adjusted HR for hearing loss in the obese groups was 0.69 (95%CI 0.51-0.94) among men. Among female participants, only the overweight group had a lower risk of hearing loss than the normal weight group (HR 0.83, 95%CI 0.71-0.96). CONCLUSIONS: Being overweight and obese were significantly associated with a decreased risk of hearing loss, whereas being underweight was associated with an increased risk of hearing loss.

Lithium ameliorates Niemann-Pick C1 disease phenotypes by impeding STING/SREBP2 activation.

Niemann-Pick disease type C (NP-C) is a genetic lysosomal disorder associated with progressive neurodegenerative phenotypes. Its therapeutic options are very limited. Here, we show that lithium treatment improves ataxia and feeding phenotypes, attenuates cerebellar inflammation and degeneration, and extends survival in Npc1 mouse models. In addition, lithium suppresses STING activation, SREBP2 processing to its mature form and the expression of the target genes in the Npc1 mice and in Npc1-deficient fibroblasts. Lithium impedes STING/SREBP2 transport from the ER to the Golgi, a step required for STING activation and SREBP2 processing, probably by lowering cytosolic calcium concentrations. This effect of lithium on STING/SREBP2 transport provides a mechanistic explanation for lithium's effects on Npc1 mice. Thus, this study reveals a potential therapeutic option for NP-C patients as well as a strategy to reduce active STING/SREBP2 pathway.

CD16+ monocytes are involved in the hyper-inflammatory state of Prader-Willi Syndrome by single-cell transcriptomic analysis.

Background: Patients with Prader-Willi syndrome (PWS) have a reduced life expectancy due to inflammation-related disease including cardiovascular disease and diabetes. Abnormal activation of peripheral immune system is postulated as a contributor. However, detailed features of the peripheral immune cells in PWS have not been fully elucidated. Methods: Serum inflammatory cytokines were measured in healthy controls (n=13) and PWS patients (n=10) using a 65- multiplex cytokine assays. Changes of the peripheral immune cells in PWS was assessed by single-cell RNA sequencing (scRNA-seq) and high-dimensional mass cytometry (CyTOF) using peripheral blood mononuclear cells (PBMCs) from PWS patients (n=6) and healthy controls (n=12). Results: PWS patients exhibited hyper-inflammatory signatures in PBMCs and monocytes were the most pronounced. Most inflammatory serum cytokines were increased in PWS, including IL-1ß, IL-2R, IL-12p70, and TNF-α. The characteristics of monocytes evaluated by scRNA-seq and CyTOF showed that CD16+ monocytes were significantly increased in PWS patients. Functional pathway analysis revealed that CD16+ monocytes upregulated pathways in PWS were closely associated with TNF/IL-1ß- driven inflammation signaling. The CellChat analysis identified CD16+ monocytes transmitted chemokine and cytokine signaling to drive inflammatory process in other cell types. Finally, we explored the PWS deletion region 15q11-q13 might be responsible for elevated levels of inflammation in the peripheral immune system. Conclusion: The study highlights that CD16+ monocytes contributor to the hyper-inflammatory state of PWS which provides potential targets for immunotherapy in the future and expands our knowledge of peripheral immune cells in PWS at the single cell level for the first time.

Theoretical and numerical modeling of Rayleigh wave scattering by an elastic inclusion.

This work presents theoretical and numerical models for the backscattering of two-dimensional Rayleigh waves by an elastic inclusion, with the host material being isotropic and the inclusion having an arbitrary shape and crystallographic symmetry. The theoretical model is developed based on the reciprocity theorem using the far-field Green's function and the Born approximation, assuming a small acoustic impedance difference between the host and inclusion materials. The numerical finite element (FE) model is established to deliver a relatively accurate simulation of the scattering problem and to evaluate the approximations of the theoretical model. Quantitative agreement is observed between the theoretical model and the FE results for arbitrarily shaped surface/subsurface inclusions with isotropic/anisotropic properties. The agreement is excellent when the wavelength of the Rayleigh wave is larger than, or comparable to, the size of the inclusion, but it deteriorates as the wavelength gets smaller. Also, the agreement decreases with the anisotropy index for inclusions of anisotropic symmetry. The results lay the foundation for using Rayleigh waves for quantitative characterization of surface/subsurface inclusions, while also demonstrating its limitations.

The effects of obesity and metabolic abnormalities on severe COVID-19-related outcomes after vaccination: A population-based study.

Breakthrough SARS-CoV-2 infections of vaccinated individuals are being reported globally, resulting in an increased risk of hospitalization and death among such patients. Therefore, it is crucial to identify the modifiable risk factors that may affect the protective efficacy of vaccine use against the development of severe COVID-19 and thus to initiate early medical interventions. Here, in population-based studies using the UK Biobank database and the 2021 National Health Interview Survey (NHIS), we analyzed 20,362 participants aged 50 years or older and 2,588 aged 18 years or older from both databases who tested positive for SARS-COV-2, of whom 33.1% and 67.7% received one or more doses of vaccine, respectively. In the UK Biobank, participants are followed from the vaccination date until October 18, 2021. We found that obesity and metabolic abnormalities (namely, hyperglycemia, hyperlipidemia, and hypertension) were modifiable factors for severe COVID-19 in vaccinated patients (all p < 0.05). When metabolic abnormalities were present, regardless of obesity, the risk of severe COVID-19 was higher than that of metabolically normal individuals (all p < 0.05). Moreover, pharmacological interventions targeting such abnormalities (namely, antihypertensive [adjusted hazard ratio (aHR) 0.64, 95% CI 0.48-0.86; p = 0.003], glucose-lowering [aHR 0.55, 95% CI 0.36-0.83; p = 0.004], and lipid-lowering treatments [aHR 0.50, 95% CI 0.37-0.68; p < 0.001]) were significantly associated with a reduced risk for this outcome. These results show that more proactive health management of patients with obesity and metabolic abnormalities is critical to reduce the incidence of severe COVID-19 after vaccination.

The causal effect of bioavailable testosterone on primary biliary cholangitis in female patients: A Bidirectional Mendelian randomization analysis.

BACKGROUND: Primary biliary cholangitis (PBC) primarily affects female in their 4th to 6th decade of life at which stage female's sex hormones change dramatically. Sex hormones have a wide range of effects on the liver and immune system. However, it remains unclear whether sex hormonal changes mediate the onset of PBC. AIMS: This study investigated the causal effect between total testosterone (TT), bioavailable testosterone (BAT), sex hormone binding globulin (SHBG) in female and PBC using public GWAS summary data. METHODS: Data on TT, BAT, SHBG in female were obtained from a previous study based on the UK Biobank. PBC GWAS summary data was obtained from a genome-wide meta-analysis. We used several methods to make the conclusion robust. Various sensitivity analyses had been conducted to assess the consistency of our findings. RESULTS: Our Mendelian randomization analysis revealed that the genetically predicted BAT in female was positively associated with PBC and SHBG in female was negatively associated with PBC. The results obtained from different methods are similar, which proves the reliability of the results. CONCLUSIONS: Our study supported a causal relationship of BAT and SHBG in female on PBC. To confirm the association between testosterone and PBC, more research should be conducted.

Atypical pituitary hormone-target tissue axis.

A long-held belief is that pituitary hormones bind to their cognate receptors in classical target glands to actuate their manifold functions. However, a number of studies have shown that multiple types of pituitary hormone receptors are widely expressed in non-classical target organs. Each pituitary gland-derived hormone exhibits a wide range of nonconventional biological effects in these non-classical target organs. Herein, the extra biological functions of pituitary hormones, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, adrenocorticotrophic hormone, and prolactin when they act on non-classical organs were summarized, defined by the novel concept of an "atypical pituitary hormone-target tissue axis." This novel proposal explains the pathomechanisms of abnormal glucose and lipid metabolism, obesity, hypertension, fatty liver, and atherosclerosis while offering a more comprehensive and systematic insights into the coordinated regulation of environmental factors, genetic factors, and neuroendocrine hormones on human biological functions. The continued exploration of the physiology of the "atypical pituitary hormone-target tissue axis" could enable the identification of novel therapeutic targets for metabolic diseases.

Berberine chloride (dual topoisomerase I and II inhibitor) modulate mitochondrial uncoupling protein (UCP1) in molecular docking and dynamic with in-vitro cytotoxic and mitochondrial ATP production.

Obesity initiates numerous diseases like cardiovascular, metabolic, and type 2 diabetes, and obesity is a vital cause of death worldwide. Plants are necessary to the source of life. Several drug compounds isolated from plants are called phytochemicals which are safe, effective drug moieties to treat several diseases. Berberine chloride is a dual topoisomerase I and II inhibitor, that exhibited potent antitumor activities against several malignancies. However, the effect of Berberine on mitochondria remains unknown. The focus of this study was to determine the role of Berberine on mitochondrial uncoupling protein (UCP1), ATP production, and cytotoxic effect of HEK293T cell at a time and dose-dependent manner analysis by CCK8 assay. The upregulation of mitochondrial UCP1 gene expression reduces adipocyte content by initiating thermogenesis. In this study, berberine chloride significantly up-regulates UCP1 gene expression in brown adipocytes. AT 10 µM concentration of Berberine 48 h treatment demonstrated significant cell death. The decreased level of ATP production leads to mitochondrial uncoupling. Initiate thermogenesis reducing fat droplets in adipocytes. The first time, we used molecular docking and dynamic of Berberine with UCP1 gene in this study and revealed therapeutic potential of Berberine via modulation of mitochondrial UCP1 gene. Further investigation will reveal new insight into mechanisms to treat metabolic-related diseases.Communicated by Ramaswamy H. Sarma.

Predictive Efficiency of Prediabetes for Diabetes Among Chinese Middle-Aged and Older Populations: a 5-Year National Prospective Cohort Study.

BACKGROUND: Limited studies have explored the predictive efficiency of prediabetes based on two definitions for diabetes among Chinese middle-aged and older populations with prediabetes. OBJECTIVE: To evaluate the predictive efficiency of prediabetes based on two definitions for diabetes and the clinical and public health benefit in Chinese middle-aged and older populations. DESIGN: A 5-year cohort study from the China Health and Retirement Longitudinal Study. PARTICIPANTS: A total of 5208 participants who had blood sample data at baseline in 2011. MAIN MEASURES: The exposure was prediabetes based on American Diabetes Association (ADA) and World Health Organization (WHO) definition. The main outcome was incident diabetes. The ability of prediabetes for predicting diabetes was assessed by sensitivity, specificity, positive predictive value, and negative predictive value. Cox proportional hazards regression was used to explore the associations between prediabetes and the 5-year risk of diabetes and all-cause mortality. KEY RESULTS: Among those with prediabetes according to the ADA definition, only 426 (15.45%) with baseline prediabetes progressed to total diabetes, while according to the WHO definition, 208 (21.89%) progressed to total diabetes. In terms of the ability of predicting the incident total diabetes in 5 years, the ADA definition has a higher sensitivity than the WHO definition (70.76% versus 34.55%, P < 0.001), while the WHO definition has a higher specificity than the ADA definition (84.09% versus 49.35%, P < 0.001). Positive predictive values based on the two definitions were low (< 24%); negative predictive values were high (> 90%). CONCLUSIONS: Neither definition of prediabetes is robust for predicting diabetes development in Chineses middle-aged and older populations.