Characteristics of changes in plasma proteome profiling after sleeve gastrectomy.

Bariatric surgery (BS), recognized as the most effective intervention for morbid obesity and associated metabolic comorbidities, encompasses both weight loss-dependent and weight loss-independent mechanisms to exert its metabolic benefits. In this study, we employed plasma proteomics technology, a recently developed mass spectrometric approach, to quantitatively assess 632 circulating proteins in a longitudinal cohort of 9 individuals who underwent sleeve gastrectomy (SG). Through time series clustering and Gene Ontology (GO) enrichment analysis, we observed that complement activation, proteolysis, and negative regulation of triglyceride catabolic process were the primary biological processes enriched in down-regulated proteins. Conversely, up-regulated differentially expressed proteins (DEPs) were significantly associated with negative regulation of peptidase activity, fibrinolysis, keratinocyte migration, and acute-phase response. Notably, we identified seven proteins (ApoD, BCHE, CNDP1, AFM, ITIH3, SERPINF1, FCN3) that demonstrated significant alterations at 1-, 3-, and 6-month intervals post SG, compared to baseline. These proteins play essential roles in metabolism, immune and inflammatory responses, as well as oxidative stress. Consequently, they hold promising potential as therapeutic targets for combating obesity and its associated comorbidities.

DNA methylation age acceleration contributes to the development and prediction of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is prevalent in the aging society. Despite body weight reduction, the prevalence of NAFLD has been increasing with aging for unknown reasons. Here, we investigate the association of DNA methylation age acceleration, a hallmark of aging, with risk of NAFLD. Genome-wide DNA methylation profiles were measured in 95 participants who developed type 2 diabetes during 4-year follow-up, and 356 randomly sampled participants from Shanghai Changfeng Study. DNA methylation age was calculated using the Horvath's method, and liver fat content (LFC) was measured using a quantitative ultrasound method. Subjects with highest tertile of DNA methylation age acceleration (≥ 9.5 years) had significantly higher LFC (7.2% vs 3.1%, P = 0.008) but lower body fat percentage (29.7% vs 33.0%, P = 0.032) than those with lowest tertile of DNA methylation age acceleration (< 4.0 years). After adjustment for age, sex, alcohol drinking, cigarette smoking, BMI, waist circumference, and different type blood cell counts, the risk of NAFLD was still significantly increased in the highest tertile group (OR, 4.55; 95% CI, 1.06-19.61). Even in subjects with similar LFC at baseline, DNA methylation age acceleration was associated with higher increase in LFC (4.0 ± 10.7% vs 0.9 ± 9.5%, P = 0.004) after a median of 4-year follow-up. Further analysis found that 6 CpGs of Horvath age predictors were associated with longitudinal changes in LFC after multivariate adjustment and located on genes that might lead to fat redistribution from peripheral adipose to liver. Combination of the key CpG methylation related to liver fat content with conventional risk factors improves the performance for NAFLD prediction.

Quantitative Diagnosis of Nonalcoholic Fatty Liver Disease with Ultrasound Attenuation Imaging in a Biopsy-Proven Cohort.

RATIONALE AND OBJECTIVES: To evaluate the performance of attenuation imaging (ATI) based on ultrasound for detection of hepatic steatosis in patients with nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This prospective study was approved by our institutional review board (B2021-092R). Written informed consent was obtained from all patients. This study included 60 patients who had clinical suspicion of NAFLD and were referred for liver biopsy after ATI and controlled attenuation parameter (CAP) examinations between September 2020 and December 2021. The histologic hepatic steatosis was graded. The area under curve (AUC) analysis was performed. RESULTS: The success rate of the ATI examination was 100%. The intraobserver reproducibility of ATI was 0.981. The AUCs of ATI for detecting ≥S1, ≥S2, and S3 were 0.968 (cut-off value of 0.671 dB/cm/MHz), 0.911 (cut-off value of 0.726 dB/cm/MHz), and 0.766 (cut-off value of 0.757 dB/cm/MHz), respectively. The AUCs of CAP for detecting ≥S1, ≥S2, and S3 were 0.916 (cut-off value of 258.5 dB/m), 0.872 (cut-off value of 300.0 dB/m), and 0.807 (cut-off value of 315.0 dB/m), respectively. The diagnostic values showed no significant difference between ATI and CAP in detecting ≥S1, ≥S2, and S3 (P = .281, P = .254, and P = .330, respectively). The ATI had significant correlations with high-density lipoprotein cholesterol (P < .001), and with triglycerides (P = .015). CONCLUSION: ATI showed good feasibility and diagnostic performance in the detection of varying degrees of hepatic steatosis in NAFLD patients.

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

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

A novel model for detecting advanced fibrosis in patients with nonalcoholic fatty liver disease.

AIMS: The study aimed to develop a novel noninvasive model to detect advanced fibrosis based on routinely available clinical and laboratory tests. MATERIALS AND METHODS: A total of 309 patients who underwent liver biopsy were randomly divided into the estimation group (n = 201) and validation group (n = 108). The model was developed using multiple regression analysis in the estimation group and further verified in the validation group. Diagnostic accuracy was evaluated using the receiver operating characteristic (ROC) curve. RESULTS: The model was named NAFLD Fibrosis Index (NFI): -10.844 + 0.046 × age - 0.01 × platelet count + 0.19 × 2h postprandial plasma glucose (PG) + 0.294 × conjugated bilirubin - 0.015 × ALT + 0.039 × AST + 0.109 × total iron binding capacity -0.033 × parathyroid hormone (PTH). The area under the ROC curve (AUC) of NFI was 0.86 (95% CI: 0.79-0.93, p < 0.001) in the estimation group and 0.80 (95% CI: 0.69-0.91, p < 0.001) in the validation group, higher than NFS, FIB4, APRI, and BARD, and similar to FibroScan (NFI AUC = 0.77, 95% CI: 0.66-0.89, p = 0.001 vs. FibroScan AUC = 0.76, 95% CI: 0.62-0.90, p = 0.002). By applying the low cut-off value (-2.756), advanced fibrosis could be excluded among 49.3% and 48% of patients in the estimation group (sensitivity: 93.1%, NPV: 97.9%, specificity: 55.2%, and PPV: 26.0%) and validation group (sensitivity: 81.3%, NPV: 94.2%, specificity: 53.3%, and PPV: 23.2%), respectively, allowing them to avoid liver biopsy. CONCLUSIONS: The study has established a novel model for advanced fibrosis, the diagnostic accuracy of which is superior to the current clinical scoring systems and is similar to FibroScan.

Postprandial glucose is correlated with an increasing risk of liver fibrosis in Chinese patients with nonalcoholic fatty liver disease.

AIM: Type 2 diabetes (T2DM) is closely related to nonalcoholic fatty liver disease (NAFLD) and is an important risk factor for the progression of liver fibrosis, but the role of 2-h postprandial blood glucose (PPG) as a biomarker in this process remains unclear. This study was designed to investigate the relationship between PPG and liver fibrosis in Chinese NAFLD populations with or without T2DM. METHODS: This study included three independent NAFLD populations: 1) 618 inpatients with T2DM or pre-diabetes, 2) 255 patients with T2DM or pre-diabetes who underwent liver biopsy, and 3) a prospective community-based cohort without diabetes who completed a median of 4.22 years follow-up. The degree of liver fibrosis was assessed by liver fibrosis stage in subjects with a liver biopsy, and by NAFLD fibrosis score (NFS) in subjects without liver biopsy. RESULTS: In the first population, PPG {OR 0.02, [95% CI (0.01-0.03)], P< 0.001} was positively correlated with NFS. In the second population, an increasing PPG was associated with increase in the proportion of advanced liver fibrosis (P = 0.012). Multivariate line regression revealed that PPG {OR 0.03 [95% CI (0.00-0.06)], P = 0.049}was positively associated with liver fibrosis stages. In the third population, PPG {OR 0.103, [95% CI (0.011-0.194) P = 0.028} at baseline was positively associated with NFS at follow-up. Furthermore, changes in PPG were significantly associated with NFS change after follow-up. We did not find a similar association between fasting glucose or HbA1c and liver fibrosis. CONCLUSIONS: PPG was independently associated with the severity of liver fibrosis in the Chinese NAFLD population.

Myeloid Piezo1 Deletion Protects Renal Fibrosis by Restraining Macrophage Infiltration and Activation.

BACKGROUND: Macrophages play important roles in renal fibrosis, partially by sensing mechanical forces, including shear stress and increased stiffness. The mechanically activated cationic channel Piezo1 drives vascular formation and blood pressure regulation to inflammatory responses, or cancer, but its role in macrophages in fibrotic kidney is elusive. Here, we hypothesized that Piezo1 in macrophages may have functions in renal fibrosis. METHODS: We established a genetically engineered mouse model with Piezo1 specific knockout in myeloid cells and challenged with unilateral ureteric obstruction operation and folic acid treatment to induce the renal fibrosis, aiming to investigate the function of the mechanical-sensitive protein Piezo1 in macrophages in renal fibrosis and its underlying mechanisms. RESULTS: Myeloid Piezo1 was indispensable for renal fibrosis generation. Piezo1 gene deletion in the myeloid lineage was protective in mice with renal fibrosis. Further analyses revealed that macrophage accumulation in the injured kidney depended on the Piezo1-regulated C-C motif chemokine ligand 2, C-C motif chemokine receptor 2 pathway, and Notch signaling cascade. Moreover, Piezo1 deletion restrained macrophage inflammation and consequently suppressed kidney fibrosis and epithelial-mesenchymal transition. In vitro assays showed that Piezo1 deficiency blocked lipopolysaccharide and Piezo1 activation-induced inflammatory responses in bone marrow-derived macrophages. Mechanistically, Piezo1 regulated inflammation through the Ca2+-dependent intracellular cysteine protease, as the pharmacological inhibition of calpain blocked the proinflammatory role of Piezo1. CONCLUSIONS: This study characterized the important function of Piezo1 in renal fibrosis. Targeting the Piezo1 channels by genetic or pharmacological manipulations may be a promising strategy for the treatment of renal fibrosis.

Acute Effects of Sleeve Gastrectomy on Glucose Variability, Glucose Metabolism, and Ghrelin Response.

PURPOSE: This study aims to examine the changes of glucose metabolism, glucose variability (GV), and ghrelin secretion within 1 week following SG in Chinese patients with obesity. MATERIALS AND METHODS: Forty-nine patients with obesity (15 with type 2 diabetes) were enrolled to undergo SG. Within 1 week before and after surgery, liquid meal tests were performed in all subjects, and continuous glucose monitoring (CGM) was performed in diabetic patients. Blood samples were collected at 0, 15, 30, 45, 60, 120, and 180 min for glucose, C-peptide, insulin, and ghrelin analysis in liquid meal test. Mean amplitude of glucose excursions (MAGE), standard deviations (SD), and percent time-in-range (%TIR) determined by CGM were analyzed. RESULTS: Both in diabetic and non-diabetic groups, significant decrease was observed in glucose, insulin, C-peptide, and ghrelin. Homeostasis model assessment-insulin resistance and liver fat content was decreased. In diabetic group, MAGE and SD were decreased significantly, and the percent time-in-range was higher. The decrease in blood glucose was positively correlated with the decrease in ghrelin concentration in non-diabetic group. CONCLUSION: Within 1 week after SG, both glucose metabolism and glucose variability were improved significantly. Suppression of ghrelin secretion postoperatively might be a driver of this early improved glycemia homeostasis.

Performance of liver stiffness measurements obtained with FibroScan is affected by glucose metabolism in patients with nonalcoholic fatty liver disease.

BACKGROUND: The performance of liver stiffness measurements (LSMs) obtained using FibroScan can be affected by several factors, and cut-off values are different for fibrosis caused by various aetiologies. The study aims to evaluate the diagnostic accuracy of LSM in nonalcoholic fatty liver disease (NAFLD) patients with abnormal glucose metabolism and investigate whether the LSM value would be affected by metabolic indicators. METHODS: The study involved 91 NAFLD patients with abnormal glucose metabolism who underwent liver biopsy. The diagnostic accuracy of LSM value was evaluated by the receiver operator characteristic (ROC) curves, with the biopsy results taken as the gold standard. Multivariate linear regression and subgroup analysis were performed to determine the correlated indicators. RESULTS: The areas under the ROC curves (AUROCs) of LSM values for detecting fibrosis stage ≥1, 2, 3 and 4 were 0.793 (95% confidence interval [CI]: 0.695-0.871), 0.764 (95% CI: 0.663-0.846), 0.837 (95% CI: 0.744-0.906) and 0.902 (95% CI: 0.822-0.955), with cut-off values of 6.3, 7.6, 8.3 and 13.8 kPa, respectively. Multivariate linear regression demonstrated that haemoglobin A1c (HbA1c, ß = 0.205, P = 0.026) and alanine aminotransferase (ALT, ß = 0.192, P = 0.047) were independently associated with the LSM value after adjustment for fibrosis stage, ballooning and inflammation grade from liver biopsy. Subgroup analysis demonstrated that LSM values were slightly higher in patients with HbA1c ≥7% than in those with HbA1c < 7% and in patients with body mass index (BMI) ≥30 kg/m2 than in those with BMI < 30 kg/m2. CONCLUSIONS: FibroScan was valuable for the evaluation of liver fibrosis in NAFLD patients with abnormal glucose metabolism. FibroScan is recommended to evaluate severe fibrosis, especially to exclude advanced fibrosis. Glucose metabolism state may affect LSM values.

Diagnosis of Fibrosis Using Blood Markers and Logistic Regression in Southeast Asian Patients With Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of fibrosis. Liver biopsy remains the gold standard for the confirmation of fibrosis in NAFLD patients. Effective and non-invasive diagnosis of advanced fibrosis is essential to disease surveillance and treatment decisions. Herein we used routine medical test markers and logistic regression to differentiate early and advanced fibrosis in NAFLD patients from China, Malaysia, and India (n 1 = 540, n 2 = 147, and n 3 = 97) who were confirmed by liver biopsy. Nine parameters, including age, body mass index, fasting blood glucose, presence of diabetes or impaired fasting glycemia, alanine aminotransferase, γ-glutamyl transferase, triglyceride, and aspartate transaminase/platelet count ratio, were selected by stepwise logistic regression, receiver operating characteristic curve (ROC), and hypothesis testing and were used for model construction. The area under the ROC curve (auROC) of the model was 0.82 for differentiating early and advanced fibrosis (sensitivity = 0.69, when specificity = 0.80) in the discovery set. Its diagnostic ability remained good in the two independent validation sets (auROC = 0.89 and 0.71) and was consistently superior to existing panels such as the FIB-4 and NAFLD fibrosis score. A web-based tool, LiveFbr, was developed for fast access to our model. The new model may serve as an attractive tool for fibrosis classification in NAFLD patients.

Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism.

BACKGROUND: Pioglitazone is a promising therapeutic method for nonalcoholic fatty liver disease (NAFLD) patients with or without type 2 diabetes. However, there is remarkable variability in treatment response. We analyzed our previous randomized controlled trial to examine the effects of gender and other factors on the efficacy of pioglitazone in treating Chinese nonalcoholic fatty liver disease (NAFLD) patients with abnormal glucose metabolism. METHODS: This is a post hoc analysis of a previous randomized, parallel controlled, open-label clinical trial (RCT) with an original purpose of evaluating the efficacy of berberine and pioglitazone on NAFLD. The total population (n = 185) was randomly divided into three groups: lifestyle intervention (LSI), LSI + pioglitazone (PGZ) 15 mg qd, and LSI + berberine (BBR) 0.5 g tid, respectively, for 16 weeks. The study used proton magnetic resonance spectroscopy (1H-MRS) to assess liver fat content. RESULTS: As compared with LSI, PGZ + LSI treatment further decreased liver fat content in women (- 15.24% ± 14.54% vs. - 8.76% ± 13.49%, p = 0.025), but less decreased liver fat content in men (- 9.95% ± 15.18% vs. - 12.64% ± 17.78%, p = 0.046). There was a significant interaction between gender and efficacy of pioglitazone before and after adjustment for age, smoking, drinking, baseline BMI, BMI change, treatment adherence, baseline liver fat content, and glucose metabolism. CONCLUSION: The study recommends pioglitazone plus lifestyle intervention for Chinese NAFLD female patients with abnormal glucose metabolism. TRIAL REGISTRATION: Role of Pioglitazone and Berberine in Treatment of Non-Alcoholic Fatty Liver Disease, NCT00633282 . Registered on 3 March 2008, https://register.clinicaltrials.gov .

Osteocalcin and Non-Alcoholic Fatty Liver Disease: Lessons From Two Population-Based Cohorts and Animal Models.

Osteocalcin regulates energy metabolism in an active undercarboxylated/uncarboxylated form. However, its role on the development of non-alcoholic fatty liver disease (NAFLD) is still controversial. In the current study, we investigated the causal relationship of circulating osteocalcin with NAFLD in two human cohorts and studied the effect of uncarboxylated osteocalcin on liver lipid metabolism through animal models. We analyzed the correlations of serum total/uncarboxylated osteocalcin with liver steatosis/fibrosis in a liver biopsy cohort of 196 participants, and the causal relationship between serum osteocalcin and the incidence/remission of NAFLD in a prospective community cohort of 2055 subjects from Shanghai Changfeng Study. Serum total osteocalcin was positively correlated with uncarboxylated osteocalcin (r = 0.528, p < .001). Total and uncarboxylated osteocalcin quartiles were inversely associated with liver steatosis, inflammation, ballooning, and fibrosis grades in both male and female participants (all p for trend <.05). After adjustment for confounding glucose, lipid, and bone metabolism parameters, the male and female participants with lowest quartile of osteocalcin still had more severe liver steatosis, with multivariate-adjusted odds ratios (ORs) of 7.25 (1.07-49.30) and 4.44 (1.01-19.41), respectively. In the prospective community cohort, after a median of 4.2-year follow-up, the female but not male participants with lowest quartile of osteocalcin at baseline had higher risk to develop NAFLD (hazard ratio [HR] = 1.90; 95% confidence interval [CI] 1.14-3.16) and lower chance to achieve NAFLD remission (HR = 0.56; 95% CI 0.31-1.00). In wild-type mice fed a Western diet, osteocalcin treatment alleviated hepatic steatosis and reduced hepatic SREBP-1 and its downstream proteins expression. In mice treated with osteocalcin for a short term, hepatic SREBP-1 expression was decreased without changes of glucose level or insulin sensitivity. When SREBP-1c was stably expressed in a human SREBP-1c transgenic rat model, the reduction of lipogenesis induced by osteocalcin treatment was abolished. In conclusion, circulating osteocalcin was inversely associated with NAFLD. Osteocalcin reduces liver lipogenesis via decreasing SREBP-1c expression. © 2020 American Society for Bone and Mineral Research (ASBMR).

Sarcopenia, sarcopenic overweight/obesity and risk of cardiovascular disease and cardiac arrhythmia: A cross-sectional study.

BACKGROUND: Sarcopenia is an age-dependent skeletal muscle disorder that is common in patients with heart failure. The current study aimed to investigate the associations of sarcopenia with carotid atherosclerosis, cardiovascular disease and cardiac arrhythmia in a middle-aged and elderly population without clinical heart failure. METHODS: A total of 2432 participants (992 men and 1440 women) from Shanghai Changfeng Study were included for analysis. The degree of sarcopenia was measured using height-adjusted appendicular skeletal muscle mass (ASM/height2). Carotid plaques were detected by carotid artery ultrasonography, and myocardial ischemia, infarction and cardiac arrhythmia were diagnosed based on electrocardiogram, past history and clinical manifestations. RESULTS: Sarcopenia was associated with higher prevalence of carotid atherosclerosis (26.4% vs 20.4%, P = 0.027), myocardial infarction (4.0% vs 1.1%, P = 0.001), and premature ventricular contraction (4.0% vs 2.0%, P = 0.034) in the participants with normal body weight, and higher prevalence of carotid atherosclerosis (45.0% vs 31.2%, P = 0.016), myocardial infarction (10.0% vs 4.3%, P = 0.020) and atrial fibrillation (7.5% vs 1.3%, P < 0.001) in those with overweight/obese status. After adjustment for age, gender, cigarette smoking, alcohol drinking, menopausal status in women and other metabolic and inflammatory confounding factors, sarcopenia was independently associated with the risk of myocardial infarction in the whole population, and the risk of atrial fibrillation in the overweight/obese participants (all P < 0.05). Compared with nonsarcopenic lean participants, the risk of myocardial infarction was gradually increased in sarcopenic lean (OR 3.08 [1.28-7.45], P = 0.012) and sarcopenic overweight/obese participants (OR 4.07 [1.31-12.62], P = 0.015). For the atrial fibrillation, the participants with either sarcopenia or overweight/obesity alone showed no higher risk. However, concomitant sarcopenia and overweight/obesity was associated with approximately 5-fold risk of atrial fibrillation (OR 5.68 [1.34-24.12], P = 0.019) after multiple adjustment. CONCLUSION: Sarcopenia is associated with myocardial infarction and atrial fibrillation in middle-aged and elderly adults without clinical heart failure.

Effect of Electro-acupuncture on Expression of IRS-1/PI3K/GLUT4 Pathway in Ovarian Granulosa Cells of Infertile Patients with Polycystic Ovary Syndrome-Insulin Resistance of Phlegm-Dampness Syndrome.

OBJECTIVE: To evaluate the effect of electro-acupuncture (EA) in infertile patients with phlegm-dampness polycystic ovary syndrome-insulin resistance (PCOS-IR). METHODS: Seventy-six PCOS-IR patients who underwnet in vitro fertilization and embryo transfer (IVF-ET) were equally assigned to two groups according to a random digital table: the EA group and the control group, with 38 cases in each group. Before undergoing IVF, the two groups were treated with EA or pseudo-acupuncture, respectively, for 3 menstrual cycles. The intervention was 25 min twice a week until the day of oocyte collection. The selected acupoints were Zhongwan (RN 12), Tianshu (ST 25), Daheng (SP 15), Daimai (GB 26), Qihai (CV 6), Guanyuan (CV 4), and bilateral points including Xuehai (SP 10), Fenglong (ST 40), Zusanli (ST 36), and Yinlingquan (SP 9). Evaluation of phlegm-dampness syndrome score and IR score were carried out before and after treatment. Additionally, the number of oocytes retrieved, transplantable embryo rate, high-quality embryo rate, clinical pregnancy rate and live birth rate were compared between the two groups. Real-time polymerase chain reaction analysis was used to monitor the mRNA expression of the insulin receptor substrate (IRS-1), phosphatidylinositiol 3-kinase (PI3K) and glucose transport factor 4 (GLUT4) in ovarian granulosa cells. RESULTS: EA treatment reduced the phlegm-dampness syndrome score as well as the IR scores compared with the control group (P<0.05). No significant differences in the number of oocytes retrieved and clinical pregnancy rate between the two groups (P>0.05). Moreover, the transplantable embryo rate [49.0% (284/580) vs. 41.9% (273/652)], high-quality embryo rate [36.6% (104/284) vs. 27.8% (76/273)], and live birth rate [50% (19/38) vs. 26.3% (10/38)] in the EA group were significantly higher than in the control group (P<0.05). Gene expression analyses revealed significantly elevated IRS-1, PI3K and GLUT4 mRNA in ovarian granulosa cells of the EA group compared with the control group (P<0.05). CONCLUSIONS: EA may ameliorate the effects of phlegm-dampness syndrome and ovarian IR in PCOS-IR patients. Mechanistically, this effect might be through an upregulation of the IRS-1/PI3K/GLUT4 signaling pathway, which may result in improved oocyte quality and embryonic development potential. (Registration No. ChiCTR1800015453).

DS21, a new noninvasive technology, is effective and safe for screening for prediabetes and diabetes in Chinese population.

BACKGROUND: Screening for prediabetes and asymptomatic diabetes is important for preventing development to an irreversible stage. The current diagnosis of prediabetes and diabetes is based on blood glucose or HbA1c (an invasive method). The aim of this study was to assess the efficacy and safety of DS21, a new noninvasive technology, for noninvasive screening for prediabetes and diabetes. METHODS: A total of 939 subjects were divided into a normal control group (NC, n = 308), impaired glucose regulation group (IGR, n = 312), and diabetes (DM) group (n = 319). All subjects underwent the DS21 test, and mean hands-feet, hand, and feet conductance values were analyzed. The diagnostic accuracy of the conductance value was analyzed by receiver-operating characteristic (ROC) curve. RESULTS: The conductance values for hands-feet, hands, and feet in the DM and IGR groups were significantly lower than those in the NC group (all P < 0.01). The area under the ROC curve  (AUCROC) for distinguishing NC/IGR was highest when using hands-feet conductance values (0.766 [95% confidence interval, CI 0.730, 0.803]). However, the AUCROCs of distinguishing NC/abnormal glucose metabolism (AGM, including IGR+DM), non-diabetes (NDM)/DM, and IGR/DM were highest when using conductance values for hands at 0.782 [95% CI 0.752, 0.812], 0.688 [95% CI 0.653, 0.723] and 0.573 [95% CI 0.528, 0.617], respectively (all P < 0.01). Hand conductance of values 75.0 (sensitivity 0.769, specificity 0.660), 77.1 (sensitivity 0.718, specificity 0.695), 68.4 (sensitivity 0.726, specificity 0.555), and 58.1 (sensitivity 0.384, specificity 0.744) were recommended as the screening thresholds for NC/AGM, NC/IGR, NDM/DM, and IGR/DM, respectively. A hand conductance value 66.0 was also recommended to distinguish NC/AGM due to its high sensitivity and high PPV. No adverse events occurred in the test. CONCLUSIONS: DS21 is fast, noninvasive, low cost, reliable and safe, which makes it a feasible device for screening for prediabetes and diabetes, especially in a large population.

Association between non-alcoholic fatty liver disease-associated hepatic fibrosis and bone mineral density in postmenopausal women with type 2 diabetes or impaired glucose regulation.

INTRODUCTION: To evaluate the association of non-alcoholic fatty liver disease (NAFLD)-associated hepatic fibrosis with bone mineral density (BMD) in postmenopausal women with type 2 diabetes mellitus (T2DM) or impaired glucose regulation (IGR). RESEARCH DESIGN AND METHODS: Two cohorts including 46 subjects with biopsy-proven NAFLD and 445 subjects with proton magnetic resonance spectrum-proven NAFLD were enrolled in this study. All subjects were postmenopausal women with T2DM or IGR. BMD at the lumbar spine L1-L4 and hip was measured using dual-energy X-ray absorptiometry. NAFLD fibrosis stage and NAFLD fibrosis score were used to evaluate the severity of liver fibrosis. RESULTS: In subjects with liver biopsy-proven NAFLD, BMD (T-score, Z-score and BMD value) in the advanced fibrosis group were significantly lower than that in the non-advanced fibrosis group (p<0.05). Fibrosis stage was negatively associated with T-score, Z-score and BMD value after adjusting for age, body mass index (BMI) and fasting plasma glucose (FPG). Additionally, fibrosis stage was independently associated with T-score, Z-score and BMD value after adjusting for age, BMI and FPG. These results were validated in a large cohort of 445 subjects. Additionally, bone metabolism-associated factors, including calcium and phosphate, were associated with liver fibrosis, indicating that bone metabolism may play a critical role in the association between liver fibrosis and BMD. Mechanically, parathyroid hormone and biomarkers of bone formation (osteocalcin and procollagen type 1 N-terminal propeptide) and bone resorption (procollagen type I carboxy terminal peptide ß special sequence) were increased in subjects with advanced liver fibrosis than in subjects without advanced liver fibrosis, indicating that liver fibrosis decreased BMD probably via increasing bone turnover. CONCLUSIONS: NAFLD-associated hepatic fibrosis was negatively associated with decreased BMD in postmenopausal women with T2DM or IGR. Liver fibrosis decreased BMD probably via increasing bone turnover. Severe liver fibrosis may represent high risk for osteoporosis in postmenopausal women with T2DM or IGR.

Fasting Serum Fructose Levels Are Associated With Risk of Incident Type 2 Diabetes in Middle-Aged and Older Chinese Population.

OBJECTIVE: We investigated the relationship between fasting serum fructose levels and the risk of incident type 2 diabetes in a prospective Chinese cohort. RESEARCH DESIGN AND METHODS: Among 949 community-based participants aged ≥40 years without diabetes at baseline, fasting serum fructose levels were measured using liquid chromatography-tandem mass spectrometry. The participants were followed up for the occurrence of diabetes. Cox regression models were performed to analyze the effect of fasting serum fructose levels on risk of incident diabetes. RESULTS: During a median of 3.5 years' follow-up, 179 of 949 (18.9%) participants developed type 2 diabetes. Elevated fasting serum fructose levels were associated with an increased risk of incident diabetes in a dose-response manner. After adjustment for age, sex, BMI, lipid profiles, blood pressure, liver function, smoking and drinking status, baseline glucose level, and sugar-sweetened beverage consumption, a 1-SD increased fasting fructose level was associated with a 35% (95% CI 1.08-1.67) increased risk of developing diabetes. After further adjustment for serum uric acid and estimated glomerular filtration rate, the association was partially attenuated (hazard ratio 1.33 [95% CI 1.07-1.65]). The association was similar by age, prediabetes status, BMI, and family history of diabetes but attenuated in women (P for heterogeneity = 0.037). CONCLUSIONS: Elevated fasting serum fructose levels were independently associated with increased risk of incident type 2 diabetes in a middle-aged and older Chinese population. Our data suggest that higher fasting serum fructose levels might serve as a biomarker and/or a contributor to incident diabetes.

Regional difference in the susceptibility of non-alcoholic fatty liver disease in China.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a global health problem with high geographic heterogeneity. We aimed to investigate regional-specific concomitant rate of NAFLD and quantitative relationship between liver fat content (LFC) and glucose metabolism parameters in representative clinical populations from six provinces/municipalities of China. RESEARCH DESIGN AND METHODS: A total of 2420 eligible Han Chinese were enrolled consecutively from 10 clinics of obesity, diabetes and metabolic diseases located at six provinces/municipalities of China, and divided into North (Tianjin, Shandong and Heilongjiang) and South (Shanghai, Jiangsu and Henan) groups according to their geographical latitude and proximity of NAFLD concomitant rate. LFC was assessed by a quantitative ultrasound method. Multivariate regression models and analysis of covariance were used to assess the regional difference in the risk of NAFLD. RESULTS: The concomitant rate of NAFLD was 23.3%, 44.0% and 55.3% in individuals with normal glucose tolerance (NGT), pre-diabetes and diabetes, respectively. A higher concomitant rate of NAFLD was found in the participants from the North comparing with the South group, regardless of glucose metabolism status (34.7% vs 16.2% in NGT, 61.5% vs 34.7% in pre-diabetes and 67.1% vs 48.1% in diabetes). This regional difference remained significant after adjustment for age, gender, alcohol drinking, cigarette smoking, confounding metabolic parameters and liver enzymes. For any given blood glucose, participants from the North had higher LFC than those from the South group. CONCLUSIONS: Half of Han Chinese with pre-diabetes/type 2 diabetes had NAFLD, and the individuals from the North cities were more susceptible to NAFLD.

Thrombospondin 1 improves hepatic steatosis in diet-induced insulin-resistant mice and is associated with hepatic fat content in humans.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with altered production of secreted proteins. Increased understanding of secreted proteins could lead to improved prediction and treatment of NAFLD. Here, we aimed to discover novel secreted proteins in humans that are associated with hepatic fat content using unbiased proteomic profiling strategy, and how the identified Thbs1 modulates lipid metabolism and hepatic steatosis. METHOD: NAFLD patients were enrolled and treated with lifestyle intervention. Patients who underwent liver biopsy were enrolled for analyzing the correlation between circulating Thbs1 and liver steatosis. Mice were fed on high-fat, high-sucrose diet and treated with recombinant Thbs1. Primary hepatocytes isolated from CD36 knockout (CD36-/-) mice and their wild-type littermates (controls) were treated with glucose plus insulin for 24 h together with or without recombinant Thbs1. FINDING: Serum Thbs1 levels are increased in participants with NAFLD and positively associated with liver steatosis grades. Improvement of liver steatosis after lifestyle intervention was accompanied with significant reduction of serum Thbs1 levels. Pharmacological administration of recombinant human Thbs1 attenuates hepatic steatosis in diet-induced obese mice. Treatment with Thbs1 protein or stably overexpression of Thbs1 causes a significant reduction of lipid accumulation in primary hepatocytes or HepG2 cells exposed to high glucose plus insulin, suggesting that Thbs1 regulates lipid metabolism in a hepatocyte-autonomous manner. Mechanistically, Thbs1 inhibits cleavage and processing of SREBP-1, leading to a reduction of target lipogenic gene expression and hepatic steatosis. Inhibitory effects of Thbs1 on lipogenesis and triglyceride accumulation are abrogated in CD36 deficient primary hepatocytes exposed to high glucose plus insulin. Interestingly, beneficial effects of Thbs1 on lipid accumulation are observed in primary hepatocytes treated with a Thbs1 nonapeptide mimetic ABT-526. INTERPRETATION: Thbs1 is a biomarker for NAFLD in humans, and pharmacological and genetic approaches for the modulation of Thbs1 activity may have the therapeutic potential for treating hepatic steatosis. FUND: A full list of funding bodies that contributed to this study can be found in the Funding Sources section.

IMPACT OF TYPE 2 DIABETES ON NONALCOHOLIC STEATOHEPATITIS AND ADVANCED FIBROSIS IN PATIENTS WITH NONALCOHOLIC FATTY LIVER DISEASE.

Objective: Type 2 diabetes mellitus (T2DM) is a risk factor for nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the effect of T2DM on nonalcoholic steatohepatitis (NASH) and advanced fibrosis. Methods: A total of 221 NAFLD patients who had undergone a liver biopsy were included in this study. Subjects were divided into a non-T2DM group and a T2DM group based on glycemic control. NASH was diagnosed by the joint presence of steatosis, ballooning, and lobular inflammation. The steatosis, activity, and fibrosis (SAF) score and NAFLD activity score (NAS) were used to evaluate the severity of NAFLD. The severity of liver fibrosis was evaluated based on the fibrosis stage. Results: The total percentages of NASH and advanced fibrosis in this study were 95.0% and 50.2%, respectively. The percentages of NASH and advanced fibrosis in NAFLD patients with T2DM were 96.1% and 56.5%, respectively, which were higher than those in the non-T2DM group. SAF score (especially activity and fibrosis stage) and NAS (especially ballooning) were higher in NAFLD patients with T2DM than in NAFLD patients without T2DM. Glycemic control and insulin resistance were positively associated with SAF, NAS, and fibrosis stage. Additionally, T2DM elevated the risk of a high NAS and advanced fibrosis. Conclusion: T2DM increases the risk of serious NASH and advanced fibrosis in patients with NAFLD. Liver biopsy can be performed in NAFLD patients with T2DM to confirm the stage of NAFLD. Screening of NASH and advanced fibrosis in NAFLD patients with T2DM is needed. Abbreviations: ALT = alanine aminotransferase; APO = apolipoprotein; AST = aspartate aminotransferase; BMI = body mass index; CI = confidence interval; FPG = fasting plasma glucose; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HDL-c = high-density-lipoprotein cholesterol; 1H-MRS = proton magnetic resonance spectroscopy; HOMA-IR = homeostasis model assessment of insulin resistance; 2hPG = postprandial plasma glucose at 2 hours; LDL-c = low-density-lipoprotein cholesterol; LFC = liver fat content; NAFLD = nonalcoholic fatty liver disease; NAS = NAFLD activity score; NASH = nonalcoholic steatohepatitis; OGTT = oral glucose tolerance test; OR = odds ratio; T2DM = type 2 diabetes mellitus; TC = total cholesterol; TG = triglyceride; SAF = steatosis, activity, and fibrosis; US-FLI = ultrasonographic fatty liver indicator.