Identification of porcine fast/slow myogenic exosomes and their regulatory effects on lipid accumulation in intramuscular adipocytes.

BACKGROUND: Pork quality is affected by the type of muscle fibers, which is closely related to meat color, tenderness and juiciness. Exosomes are tiny vesicles with a diameter of approximately 30-150 nm that are secreted by cells and taken up by recipient cells to mediate communication. Exosome-mediated muscle-fat tissue crosstalk is a newly discovered mechanism that may have an important effect on intramuscular fat deposition and with that on meat quality. Various of adipose tissue-derived exosomes have been discovered and identified, but the identification and function of muscle exosomes, especially porcine fast/slow myotube exosomes, remain unclear. Here, we first isolated and identified exosomes secreted from porcine extensor digitorum longus (EDL) and soleus (SOL), which represent fast and slow muscle, respectively, and further explored their effects on lipid accumulation in longissimus dorsi adipocytes. RESULTS: Porcine SOL-derived exosomes (SOL-EXO) and EDL-derived exosomes (EDL-EXO) were first identified and their average particle sizes were approximately 84 nm with double-membrane disc- shapes as observed via transmission electron microscopy and scanning electron microscopy. Moreover, the intramuscular fat content of the SOL was greater than that of the EDL at 180 days of age, because SOL intramuscular adipocytes had a stronger lipid-accumulating capacity than those of the EDL. Raman spectral analysis revealed that SOL-EXO protein content was much greater than that of EDL-EXO. Proteomic sequencing identified 72 proteins that were significantly differentially expressed between SOL-EXO and EDL-EXO, 31 of which were downregulated and 41 of which were upregulated in SOL-EXO. CONCLUSIONS: Our findings suggest that muscle-fat tissue interactions occur partly via SOL-EXO promoting adipogenic activity of intramuscular adipocytes.

Nardosinone relieves metabolic-associated fatty liver disease and promotes energy metabolism through targeting CYP2D6.

BACKGROUND: Nardosinone, a major extract of Rhizoma nardostachyos, plays a vital role in sedation, neural stem cell proliferation, and protection of the heart muscle. However, the huge potential of nardosinone in regulating lipid metabolism and gut microbiota has not been reported, and its potential mechanism has not been studied. PURPOSE: To explore the regulation of nardosinone on liver lipid metabolism and gut microbiota. METHODS: In this study, the role of nardosinone in lipid metabolism was investigated in vitro and in vivo by adding it to mouse feed and HepG2 cell culture medium. And 16S rRNA gene sequencing was used to explore its regulatory effect on gut microbiota. RESULTS: Results showed that nardosinone could improve HFD-induced liver injury and abnormal lipid metabolism by promoting mitochondrial energy metabolism in hepatocytes, alleviating oxidative stress damage, and regulating the composition of the gut microbiota. Mechanistically, combined with network pharmacology and reverse docking analysis, it was predicted that CYP2D6 was the target of nardosinone, and the binding was verified by cellular thermal shift assay (CETSA). CONCLUSIONS: This study highlights a novel mechanism function of nardosinone in regulating lipid metabolism and gut microbiota. It also predicts and validates CYP2D6 as a previously unknown regulatory target, which provides new possibilities for the application of nardosinone and the treatment of metabolic-associated fatty liver disease.

Focused Exome Sequencing Gives a High Diagnostic Yield in the Indian Subcontinent.

The genetically isolated yet heterogeneous and highly consanguineous Indian population has shown a higher prevalence of rare genetic disorders. However, there is a significant socioeconomic burden for genetic testing to be accessible to the general population. In the current study, we analyzed next-generation sequencing data generated through focused exome sequencing from individuals with different phenotypic manifestations referred for genetic testing to achieve a molecular diagnosis. Pathogenic or likely pathogenic variants are reported in 280 of 833 cases with a diagnostic yield of 33.6%. Homozygous sequence and copy number variants were found as positive diagnostic findings in 131 cases (15.7%) because of the high consanguinity in the Indian population. No relevant findings related to reported phenotype were identified in 6.2% of the cases. Patients referred for testing due to metabolic disorder and neuromuscular disorder had higher diagnostic yields. Carrier testing of asymptomatic individuals with a family history of the disease, through focused exome sequencing, achieved positive diagnosis in 54 of 118 cases tested. Copy number variants were also found in trans with single-nucleotide variants and mitochondrial variants in a few of the cases. The diagnostic yield and the findings from this study signify that a focused exome test is a good lower-cost alternative for whole-exome and whole-genome sequencing and as a first-tier approach to genetic testing.

Evidence from 2100 index cases supports genome sequencing as a first-tier genetic test.

PURPOSE: Genome sequencing (GS) is one of the most comprehensive assays that interrogate single-nucleotide variants, copy number variants, mitochondrial variants, repeat expansions, and structural variants in a single assay. Despite the clear technical superiority, the full clinical utility of GS has yet to be determined. METHODS: We systematically evaluated 2100 clinical GS index cases performed in our laboratory to explore the diagnostic yield of GS as first-tier and as follow-up testing. RESULTS: The overall diagnostic yield was 28% (585/2100). The diagnostic yield for GS as the first-tier test was 26% (294/1146). Among cases with prior non-diagnostic genetic tests, GS provided a diagnosis for 27% (247/910) of cases, including 56 cases with prior exome sequencing (ES). Although re-analysis of previous ES might have resolved the diagnosis in 29 cases, diagnoses for 27 cases would have been missed because of the technical inferiority of ES. Moreover, GS further disclosed additional genetic etiology in 3 out of 44 cases with existing partial diagnosis. CONCLUSION: We present the largest-to-date GS data set of a clinically heterogeneous cohort from a single clinical laboratory. Our data demonstrate that GS should be considered as the first-tier genetic test that has the potential to shorten the diagnostic odyssey.

At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children.

Importance: Although the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored. Objective: To evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions. Design, Setting, and Participants: This case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022. Exposures: Genetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes. Main Outcomes and Measures: Molecular findings indicative of genetic disease risk. Results: Of 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P < .001). Conclusions and Relevance: In this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.

The role of Arabic gum on astringency by modulating the polyphenol fraction-protein reaction in model wine.

The potential contribution of Arabic gum to wine astringency was discussed in this study. Two universally used Arabic gum (concentration of 0.2-1.2 g/L) were investigated in model wine based on the polyphenol fractions (phenolic acids, monomeric/oligomeric, and polymeric procyanidin) and protein interaction system. Both physicochemical analyses and sensory evaluation revealed that the modulation of Arabic gum on astringency was affected by the structural properties and concentration of Arabic gum and polyphenolic fractions. Arabic gum at 0.2 g/L appeared as the optimal dose to reduce astringency compared to 0.6 and 1.2 g/L. It inhibited astringency induced by polymeric procyanidin more than that of oligomeric procyanidins and phenolic acids mainly by forming soluble ternary complexes with polyphenols and proteins, and preferentially binding proteins/polyphenols to decrease polyphenol-protein reactions. Arabic gum also inhibited the self-aggregation of polyphenols, exhibiting more binding sites when its higher molecular weight and more/longer branches, leading to competition with polyphenols for bind proteins.

Hesperidin methyl chalcone ameliorates lipid metabolic disorders by activating lipase activity and increasing energy metabolism.

Obesity has become an increasingly serious health issue with the continuous improvement in living standards. Its prevalence has become an economic burden on health care systems worldwide. Flavonoids have been shown to be beneficial in the prevention and treatment of obesity. Here, we evaluated the therapeutic potential of the flavonoid hesperidin methyl chalcone (HMC) on mice with high-fat diet (HFD)-induced hepatic steatosis in vivo and in vitro. Treatment with HMC reduced oleic and palmitic acid-induced increases in intracellular triglyceride accumulation in HepG2, AML12 and LMH cells. HMC also enhanced energy metabolism and lowered oxidative stress. We used Discovery studio to dock key proteins associated with lipid metabolism disorders to HMC, and found that HMC interacted with lipase. Furthermore, we demonstrated that HMC improved lipase activity and lipolysis. In addition, we found that HMC promoted glucose absorption, alleviated lipid metabolic disorders, improved HFD-induced liver injury, and regulated HFD-induced changes in energy metabolism. In conclusion, our study demonstrated that HMC ameliorated HFD-induced obesity and its complications by promoting lipase activity, and provides a novel approach for the prevention and treatment of obesity and related diseases.

The Roles of Natural Alkaloids and Polyphenols in Lipid Metabolism: Therapeutic Implications and Potential Targets in Metabolic Diseases.

The prevalence of obesity and its associated diseases has increased dramatically, and they are major threats to human health worldwide. A variety of approaches, such as physical training and drug therapy, can be used to reduce weight and reverse associated diseases; however, the efficacy and the prognosis are often unsatisfactory. It has been reported that natural food-based small molecules can prevent obesity and its associated diseases. Among them, alkaloids and polyphenols have been demonstrated to regulate lipid metabolism by enhancing energy metabolism, promoting lipid phagocytosis, inhibiting adipocyte proliferation and differentiation, and enhancing the intestinal microbial community to alleviate obesity. This review summarizes the regulatory mechanisms and metabolic pathways of these natural small molecules and reveals that the binding targets of most of these molecules are still undefined, which limits the study of their regulatory mechanisms and prevents their further application. In this review, we describe the use of Discovery Studio for the reverse docking of related small molecules and provide new insights for target protein prediction, scaffold hopping, and mechanistic studies in the future. These studies will provide a theoretical basis for the modernization of anti-obesity drugs and promote the discovery of novel drugs.

Investigating the effect of three phenolic fractions on the volatility of floral, fruity, and aged aromas by HS-SPME-GC-MS and NMR in model wine.

In this study, the volatility of three typical wine aromas in model wine was investigated by HS-SPME-GC-MS, NMR, and sensory evaluation as influenced by different concentrations and structural properties of phenolics. Results showed that three phenolic fractions (phenolic acids, monomeric/oligomeric and polymeric procyanidins) exhibited different matrix effects on floral, fruity, and aged aromas perception. Physico-chemical and sensory analyses together indicated that all fractions reduced the perceived intensity of fruity and aged aroma attributes, and displayed stronger retention effects on fruity aromas at higher mDP and concentrations. Monomeric/oligomeric and polymeric procyanidins promoted highly hydrophobic floral aromas release, whereas inhibiting the volatility of low hydrophobic fruity aromas. NMR confirmed that the reduction in the volatility of rose oxide, ethyl butanoate and whiskey lactone was attributed to interactions with epicatechin. This study aims to provide new thoughts and theoretical support for wine aroma regulation during winemaking by reconstructing the phenolic composition in wine.

Ruthenium 360 and mitoxantrone inhibit mitochondrial calcium uniporter channel to prevent liver steatosis induced by high-fat diet.

BACKGROUND AND PURPOSE: Non-alcoholic fatty liver disease (NAFLD) affects over 25% of the general population and lacks an effective treatment. Recent evidence implicates disrupted mitochondrial calcium homeostasis in the pathogenesis of hepatic steatosis. EXPERIMENTAL APPROACH: In this study, mitochondrial calcium uniporter (MCU) was inhibited through classical genetic approaches, viral vectors or small molecule inhibitors in vivo to study its role in hepatic steatosis induced by high-fat diet (HFD). In vitro, MCU was overexpressed or inhibited to change mitochondrial calcium homeostasis, endoplasmic reticulum-mitochondrial linker was adopted to increase mitochondria-associated membranes (MAMs) and MICU1-EF hand mutant was used to decrease the sensitivity of mitochondrial calcium uptake 1 (MICU1) to calcium and block MCU channel. KEY RESULTS: Here, we found that inhibition of liver MCU by AAV virus and classical genetic approaches can prevent HFD-induced liver steatosis. MCU regulates mitochondrial calcium homeostasis and affects lipid accumulation in liver cells. In addition, a HFD in mice enlarged the MAM. The high-calcium environment produced by MAM invalidated the function of MICU1 and led to persistent open of MCU channels. Therefore, it caused mitochondrial calcium overload and liver fat deposition. Inhibition of MAM and MCU alleviated HFD-induced hepatic steatosis. MCU inhibitors (Ru360 and mitoxantrone) can block MCU channels and reduce mitochondrial calcium levels. Intraperitoneal injection of MCU inhibitors (0.01-µM·kg-1 bodyweight) can alleviate HFD-induced hepatic steatosis. CONCLUSION AND IMPLICATIONS: These findings provide molecular insights into the way HFD disrupts mitochondrial calcium homeostasis and identify MCU as a promising drug target for the treatment of hepatic steatosis.

Translatomics Probes Into the Role of Lycopene on Improving Hepatic Steatosis Induced by High-Fat Diet.

Liver is an important organ for fat metabolism. Excessive intake of a high-fat/energy diet is a major cause of hepatic steatosis and its complications such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Supplementation with lycopene, a natural compound, is effective in lowering triglyceride levels in the liver, although the underlying mechanism at the translational level is unclear. In this study, mice were fed a high-fat diet (HFD) to induce hepatic steatosis and treated with or without lycopene. Translation omics and transcriptome sequencing were performed on the liver to explore the regulatory mechanism of lycopene in liver steatosis induced by HFD, and identify differentially expressed genes (DEGs). We identified 1,358 DEGs at the translational level. Through transcriptomics and translatomics joint analysis, we narrowed the range of functional genes to 112 DEGs and found that lycopene may affect lipid metabolism by regulating the expression of LPIN1 at the transcriptional and translational levels. This study provides a powerful tool for translatome and transcriptome integration and a new strategy for the screening of candidate genes.

Integrative ATAC-seq and RNA-seq Analysis of the Longissimus Muscle of Luchuan and Duroc Pigs.

Luchuan pig is a typical obese pig breed in China, and the diameter and area of its longissimus dorsi muscle fibers are significantly smaller than those of Duroc (lean) pig. Skeletal muscle fiber characteristics are related to meat quality of livestock. There is a significant correlation between the quality of different breeds of pork and the characteristics of muscle fiber, which is an important factor affecting the quality of pork. The diameter and area of muscle fibers are related to muscle growth and development. Therefore, we used the assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) analysis to investigate the potential mechanism underlying the difference in skeletal muscle growth and development between the two types of pigs. First, transposase-accessible chromatin was analyzed to map the landscape of open chromatin regions and transcription factor binding sites. We identified several transcription factors that potentially affected muscle growth and development, including TFAP4, MAX, NHLH1, FRX5, and TGIF1. We also found that transcription factors with basic helix-loop-helix structures had a preference for binding to genes involved in muscle development. Then, by integrating ATAC-seq and RNA-seq, we found that the Wnt signaling pathway, the mTOR signaling pathway, and other classical pathways regulate skeletal muscle development. In addition, some pathways that might regulate skeletal muscle growth, such as parathyroid hormone synthesis, secretion, and action, synthesis and degradation of ketone bodies, and the thyroid hormone signaling pathway, which were significantly enriched. After further study, we identified a number of candidate genes (ASNS, CARNS1, G0S2, PPP1R14C, and SH3BP5) that might be associated with muscle development. We also found that the differential regulation of chromatin openness at the level of some genes was contrary to the differential regulation at the level of transcription, suggesting that transcription factors and transcriptional repressors may be involved in the regulation of gene expression. Our study provided an in-depth understanding of the mechanism behind the differences in muscle fibers from two species of pig and provided an important foundation for further research on improving the quality of pork.

Integrated Transcriptomic and Translatomic Inquiry of the Role of Betaine on Lipid Metabolic Dysregulation Induced by a High-Fat Diet.

An excessive high-fat/energy diet is a major cause of obesity and linked complications, such as non-alcoholic fatty liver disease (NAFLD). Betaine has been shown to effectively improve hepatic lipid metabolism. However, the mechanistic basis for this improvement is largely unknown. Herein, integration of mRNA sequencing and ribosome footprints profiling (Ribo-seq) was used to investigate the means by which betaine alleviates liver lipid metabolic disorders induced by a high-fat diet. For the transcriptome, gene set enrichment analysis demonstrated betaine to reduce liver steatosis by up-regulation of fatty acid beta oxidation, lipid oxidation, and fatty acid catabolic processes. For the translatome, 574 differentially expressed genes were identified, 17 of which were associated with the NAFLD pathway. By combined analysis of transcriptome and translatome, we found that betaine had the greater effect on NAFLD at the translational level. Further, betaine decreased translational efficiency (TE) for IDI1, CYP51A1, TM7SF2, and APOA4, which are related to lipid biosynthesis. In summary, this study demonstrated betaine alleviating lipid metabolic dysfunction at the translational level. The transcriptome and translatome data integration approach used herein provides for a new understanding of the means by which to treat NAFLD.

A single NGS-based assay covering the entire genomic sequence of the DMD gene facilitates diagnostic and newborn screening confirmatory testing.

Molecular diagnosis for Duchenne and Becker muscular dystrophies (DMD/BMD) involves a two-tiered approach for detection of deletions/duplications using MLPA or array CGH, followed by sequencing of coding and flanking intronic regions to detect sequence variants, which is time-consuming and expensive. We have developed a comprehensive next-generation sequencing (NGS)-based single-step assay to sequence the entire 2.2 Mb of the DMD gene to detect all copy number and sequence variants in both index males and carrier females. Assay validation was 100% concordant with other methodologies. A total of 772 samples have been tested, of which 62% (N = 480) were index cases with a clinical suspicion of DMD. Carrier testing females account for 38% (N = 292). Molecular diagnosis was confirmed in 86% (N = 413) of the index cases. Intragenic deletions and duplications (single-exon or multi-exon) were detected in 60% (N = 247) and 14% (N = 58) of the index cases, respectively. Full-sequence analysis of the entire gene allows for detection of deep intronic pathogenic variants and accurate breakpoint detection of CNVs involving similar exons, which could have an impact on the outcome of clinical trials. This comprehensive assay is highly sensitive for diagnostic testing for DMD and is also suitable for confirmatory testing for newborn screening for DMD.

Low-Pass Genome Sequencing: Validation and Diagnostic Utility from 409 Clinical Cases of Low-Pass Genome Sequencing for the Detection of Copy Number Variants to Replace Constitutional Microarray.

DNA copy number variants (CNVs) account for approximately 300 Mb of sequence variation in the normal human genome. Significant numbers of pathogenic CNVs contribute toward human genetic disorders. Recent studies suggest a higher diagnostic and clinical significance of low-pass genome sequencing (LP-GS) compared with chromosomal microarrays (CMAs). The performance metrics of the 5X LP-GS was compared with CMA to validate a low-cost and high-throughput method. LP-GS test performed on 409 samples (including 78 validation and 331 clinical) was evaluated using American College of Medical Genetics and Genomics guidelines. The CNV accuracy, precision, specificity, and sensitivity were calculated to be 100% for all previously characterized CNVs by CMA. Samples (n = 6) run at both approximately 30X GS and approximately 5X GS (LP-GS) average depth detected a concordance of 89.43% to 91.8% and 77.42% to 89.86% for overall single-nucleotide variants and insertions/deletions, respectively. In the 331 clinical samples, 17.2% each were classified as pathogenic/likely pathogenic and uncertain clinical significance. In addition, several cases with pathogenic CNVs were detected that were missed by CMA. This study demonstrates that LP-GS (5X GS) was able to reliably detect absence of heterozygosity, microdeletion/microduplication syndromes, and intragenic CNVs with higher coverage and resolution over the genome. Because of lower cost, higher resolution, and greater sensitivity of this test, our study in combination with other reports could be used in an evidence-based review by professional societies to recommend replacing CMAs.

HbA1c Cutoff Point of 5.9% Better Identifies High Risk of Progression to Diabetes among Chinese Adults: Results from a Retrospective Cohort Study.

AIMS: This article performed a retrospective cohort study to estimate the annual incidence rates of diabetes and to assess the utility of HbA1c as a predictor for progression to diabetes in Chinese community adults aged 40 years or older. METHODS: In all, 2778 nondiabetic subjects (including 1901 women) underwent HbA1c testing and oral glucose tolerance test (OGTT) measurements at baseline and after 3 years. Diabetes and prediabetes were defined using the WHO criteria. The HbA1c cutoff points were evaluated to predict the future risks of diabetes. Relative risk (RR) was calculated using the chi-square test. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the predictive efficiency of fasting plasma glucose (FPG), 2 hr postprandial plasma glucose (2hPG), and HbA1c for progression to diabetes. A superior cutoff point was defined as the point on the ROC curve with a larger Youden index. RESULTS: Overall, 7.5% (210/2778) of the subjects progressed to diabetes, yielding an annual 2.5% diabetes incidence rate. Additionally, 4.5% (100/2227) of the subjects with normal glucose tolerance (NGT) and 19.6% (110/561) of the subjects with prediabetes progressed to diabetes, and the relative risk of progression to diabetes was 5.188 times higher in subjects with prediabetes than in subjects with NGT (p < 0.001). Compared to subjects with HbA1c values ≤ 5.6%, the RRs of progression to diabetes in subjects whose HbA1c ranged from 5.7 to 5.8%, 5.9 to 6.2%, 6.3 to 6.4%, and ≥6.5% were 1.165, 2.582, 5.732, and 16.619, respectively. However, the RRs for subjects with HbA1c ranging from 5.7 to 5.8% and those with HbA1c ≤ 5.6% did not differ significantly (p = 0.615). The AUCs for predicting diabetes after 3 years by FPG, 2hPG, and HbA1c were 0.752 (95% confidence interval 0.718-0.787), 0.710 (95% confidence interval 0.671-0.748), and 0.756 (95% confidence interval 0.720-0.793), respectively. The HbA1c cutoff point of 5.9% (sensitivity of 0.771 and specificity of 0.580) may better identify individuals at high risk of progression to diabetes than the 5.7% value (sensitivity of 0.862 and specificity of 0.371) due to the former's larger Youden index of 0.351, which exceeded the indices for FPG and 2hPG. CONCLUSIONS: The use of HbA1c values ≥ 5.9% may provide greater accuracy in evaluating the risk of progression to diabetes and identify individuals with prediabetes with greater reliability among Chinese adults.

Relationship of Hemoglobin A1c with ß Cell Function and Insulin Resistance in Newly Diagnosed and Drug Naive Type 2 Diabetes Patients.

OBJECTIVE: To investigate changes in the glycated hemoglobin A1c (A1c) level and those in ß cell function and insulin resistance in newly diagnosed and drug naive type 2 diabetes patients and to evaluate the relationship between them. DESIGN AND METHODS: A total of 818 newly diagnosed diabetic individuals who were ≥ 40 years of age were recruited. The subjects were grouped by A1c values (<6.5%, 6.5-7%, 7-8%, 8-9%, and ≥ 9%). The homeostasis model assessment (HOMA) was used to evaluate pancreatic ß cell function (HOMA-ß) and insulin resistance (HOMA-IR). ANOVA, t-tests, and binary logistic regression analysis were used for data analysis. RESULTS: Compared with subjects with A1c values <6.5%, individuals with an A1c of 6.5-7% exhibited an increased HOMA-ß index. However, the HOMA-ß index was significantly decreased at A1c values ≥ 7% and further decreased by 9.3% and by 23.7%, respectively, at A1c values of 7-8% and 8-9%. As A1c increased to ≥ 9%, a 62% reduction in ß cell function was observed, independently of age, gender, body mass index (BMI), blood pressure (BP), blood lipids, and hepatic enzyme levels. Meanwhile, insulin resistance was significantly increased with an increase in A1c values. CONCLUSIONS: Elevated A1c values (≥ 7%) were associated with substantial reductions in ß cell function.

Association of the Number of Years Since Menopause with Metabolic Syndrome and Insulin Resistance in Chinese Urban Women.

BACKGROUND: This study aimed to assess the prevalence of metabolic syndrome (MetS) and the association of years since menopause with MetS and Insulin Resistance (IR) in Chinese women. METHOD: A total of 4436 Chinese subjects aged 40-80 years participated in the study; 790 were premenopausal women, and 3646 were postmenopausal women. IR was arbitrarily defined as a homeostasis model assessment-IR index (HOMA-IR) value above the 75th percentile of normal glucose tolerance (NGT). MetS was defined according to the International Diabetes Federation consensus definition. To test whether there was an association between the number of years since menopause and MetS, multivariate logistic analysis was conducted. Premenopausal women were used as a comparison group in regression analyses. RESULTS: After adjustment for age, body mass index (BMI), and γ-glutamyltransferase (GGT), more years since menopause was highly associated with an increased risk of MetS (p for trend <0.05) ; the number of years since menopause was not correlated with fasting insulin and HOMA-IR. Postmenopausal women with 10 to 14 years since menopause had the highest risk (odds ratio [OR], 2.10; 95% confidence interval [CI], 1.52-2.89, p < .05) of MetS, high triglycerides (TG; OR, 1.80; 95% CI, 1.34-2.42, p < .05) and high glucose (OR, 1.52; 95% CI, 1.14-2.05, p < .05) and low high-density lipoprotein cholesterol (HDL-C; OR, 1.38; 95% CI, 1.18-2.32, p < .05). Postmenopausal women with more than 15 years since menopause had the highest risk of abdominal obesity (OR, 1.69; 95% CI, 1.05-2.71, p < .05). CONCLUSION: In China, more years since menopause was highly associated with an increased risk of MetS. Menopausal history may help identify women with increased risk of developing MetS.

Fasting blood glucose, but not 2-h postload blood glucose or HbA1c, is associated with mild decline in estimated glomerular filtration rate in healthy Chinese.

BACKGROUND: The association of blood glucose [including fasting blood glucose (FBG), 2-h postload blood glucose, and glycated hemoglobin (HbA1c)] with the risk of a mild decline in the estimated glomerular filtration rate (eGFR) in healthy subjects was unclear. The aim of the study was to investigate this association in middle-aged and elderly healthy Chinese. METHODS: The study included 1,112 healthy Chinese who were ≥40 years old, and all the subjects were divided into two groups based on FBG value of 5.6 mmol/L. A mildly reduced eGFR was defined as 60-90 mL/min/1.73 m2. Multiple linear or logistic regression analysis was used to estimate the association of blood glucose with eGFR and the risk of a mildly reduced eGFR, respectively. A generalized additive model was used to explore a possible nonlinear relationship between FBG and eGFR. RESULTS: FBG was significantly associated with decreased eGFR and increased risk of a mildly reduced eGFR independent of age, gender, body mass index, waist circumference, systolic blood pressure (BP), diastolic BP, triglyceride, high-density lipoprotein cholesterol, fasting insulin, smoking, and drinking. Additionally, FBG and eGFR showed a nonlinear association (P<0.001). Interestingly, the group with FBG≥5.6 mmol/L significantly increased the risk of a mildly reduced eGFR (OR 2.06, P=0.001) after multivariable adjustment. CONCLUSIONS: FBG is closely associated with decreased eGFR and increased risk of a mildly reduced eGFR. The ADA criteria using FBG=5.6 mmol/L instead of 6.1 mmol/L as cutoff point to define prediabetes are more suitable for the prevention of diabetes and related kidney disease.