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Objective: There is no study on the relationship between triglyceride-glucose index (TyG index) and skeletal muscle mass in middle-aged and elderly C population. Therefore, the aim of the study is to investigate the relationship between the TyG index and weight-adjusted relative skeletal muscle index (RSMI) in middle-aged and elderly C population., Methods: We retrospectively studied 947 aged ⩾40 years subjects who got a routine medical examination in the Department of Geriatrics of R Hospital from May 2021 to March 2023. The RSMI was designed to evaluate skeletal muscle mass and calculated based on lean mass of the limbs(kg)/body weight(kg) × 100%. Skeletal muscle mass reduction was defined as a RSMI of 1-2 standard deviations (SD) below of healthy adults aged 30-49 years old. Considering the quartile groups of the TyG index, the subjects were assigned to 4 groups: Q1 (less than or equal to 8.171), Q2 (from 8.172 to 8.569), Q3 (from 8.570 to 8.992), and Q4 (greater than or equal to 8.993)., Results: With TyG index increased, RSMI levels significantly reduced( P < .001). Spearman's correlation analysis showed that the TyG index was negatively correlated with RSMI in males (r = -0.320) and females (r = -0.240). The TyG index was positively correlated with body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ( P < .05). Besides, binary logistic regression analysis showed that the risk of developing reduced skeletal muscle mass in the group Q4 was 2.131 (95%CI:1.118-4.064) in males; and was 2.472 (95%CI:1.581-3.867) in females compared to the Q1 group., Conclusion: TyG index was negatively correlated with relative skeletal muscle index, and a higher TyG index was associated with the development of reduced skeletal muscle mass independently of other influencing factors. Therefore, the TyG index promises to be a predictor of skeletal muscle mass loss., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

PD-1 monoclonal antibodies (mAb) have demonstrated remarkable efficacy in a variety of cancers, including Hepatocellular carcinoma (HCC). However, the patient response rates remain suboptimal, and a significant proportion of initial responders may develop resistance to this therapeutic approach. Akkermansia muciniphila (AKK), a microorganism implicated in multiple human diseases, has been reported to be more abundant in patients who exhibit favorable responses to PD-1mAb. However, the underlying mechanism has yet to be elucidated. In our study, we found that AKK could enhance the efficacy of PD-1mAb against HCC in a tumor-bearing mouse model. It promotes HCC tumor cells apoptosis and raise the CD8 + T proportion in the tumor microenvironment. Additionally, AKK downregulates PD-L1 expression in tumor cells. Furthermore, the analysis of metabonomics demonstrates that AKK induces alterations in the host's bile acid metabolism, leading to a significant increase in serum TUDCA levels. Considering the immunosuppresive roles of TUDCA in HCC development, it is plausible to speculate that AKK may reinforce the immunotherapy of PD-1mAb against HCC through its impact on bile acid metabolism., (© 2023 John Wiley & Sons, Ltd.)

Background: Skeletal muscle mass (SMM) plays an important part in diverse health and disease states. Bioelectrical impedance analysis (BIA) and computed tomography (CT) are available for its assessment. However, muscle mass assessed by BIA may be influenced by multiple factors. The erector spinae muscle area (ESA) on chest CT is recently presumed to be representative of SMM. This study aimed to derive BIA from the ESA and evaluate the magnitude of association (between ESA measured from chest CT) and BIA., Methods: Subjects hospitalized for health checkups between December 2020 and December 2021, having undergone both BIA (50 kHz, 0.8 mA) and chest CT, were included. ESA was quantified at the level of the 12th thoracic vertebra (T12-ESA) by a standardized semi-automated segmentation algorithm. Low SMM was defined using the Asian Working Group for Sarcopenia criteria. The association between T12-ESA and BIA was then evaluated. Stratified analyses by sex and BMI were also performed., Results: Among 606 included subjects (59.7 ± 16.6 years, 63.5% male), 110 (18.2%) had low SMM. BMI in low and normal SMM groups was 20.1 and 24.7 kg/m 2 , respectively. Current smoking, drinking, chronic obstructive pulmonary disease, and chronic renal dysfunction were more frequently seen in the low SMM group than in the normal SMM group. The final regression model included T12-ESA, weight, BMI, and age, and had an adjusted R 2 of 0.806 with BIA. In the validation group, the correlation between T12-ESA-derived BIA and BIA remained high (Pearson correlation = 0.899). Stratified analysis disclosed a stronger correlation between T12-ESA and BIA in male subjects than in female subjects (adjusted R 2 = 0.790 vs. adjusted R 2 = 0.711, p < 0.05), and a better correlation was observed in obese (BMI ≥ 30 kg/m 2 ) compared with underweight (BMI < 18.5 kg/m 2 ) subjects (adjusted R 2 = 0.852 vs. adjusted R 2 = 0.723, p < 0.05). Additional analysis revealed a significant correlation between T12-ESA and skeletal muscle cross-sectional area at the 3rd lumbar vertebra (L3-CSA) (adjusted R 2 = 0.935, p < 0.001)., Conclusions: CT-based assessment of ESA at the T12 level is feasible and correlated well with BIA, especially in male subjects and obese subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cao, Zuo, Han, Liu, Liu, Zhang, Weng, Jin, Chen and Hu.)

Studies have indicated that the skeletal muscle mass and strength was related to serum uric acid (UA), but there is a lack of research on the association of skeletal muscle fat content with UA. The purpose of this cross-sectional study is to investigate the correlation of skeletal muscle fat index (SMFI) and hyperuricemia (HUA) in Chinese adults. 500 subjects (306 men and 194 women) were included in the study. The participants were divided into four groups according to SMFI quartiles. Pearson's correlations between SMFI and metabolic variables were calculated. Logistic regression analysis was used to estimate the association between the quartiles of SMFI and risk of hyperuricemia. UA showed a positive association with SMFI after adjusted for BMI, age and gender. A significant association between the SMFI and risk of HUA was found, the OR for HUA was 2.79 (95% CI 1.18-6.59, p<0.05) in Q2, 2.41(95% CI 1.00-5.81, p<0.05) in Q3, and 2.63 (95% CI 1.03-6.72, p<0.05) in Q4, after adjusted for BMI. In conclusion, the SMFI was significantly associated with the level of serum UA, and the higher SMFI may indicate a higher risk of HUA, independent of BMI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer NW declared a shared parent affiliation with the authors to the handling editor at the time of review., (Copyright © 2022 Chen, Han, Liu, Cao, Liu, Zuo, Zhang, Lan, Jin, Weng and Hu.)

Introduction: Angiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors., Materials and Methods: 219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR. Angiogenesis inhibition in pituitary tumors was evaluated in vitro with the endothelial tube formation assay and in vivo in RbΔ19 mice., Results: 71 angiogenic genes, 40 of which are known to be involved in sprouting angiogenesis, were differentially expressed in pituitary tumors. Expression of endothelial markers CD31, CD34, and ENG was significantly higher in pituitary tumors, by 5.6, 22.3, and 8.2-fold, respectively, compared to in normal pituitary tissue. There was no significant difference in levels of the lymphatic endothelial marker LYVE1 in pituitary tumors compared with normal pituitary gland tissue. Pituitary tumors also expressed significantly higher levels of angiogenesis growth factors, including VEGFA (4.2-fold), VEGFB (2.2), VEGFC (19.3), PGF (13.4), ANGPT2 (9.2), PDGFA (2.7), PDGFB (10.5) and TGFB1 (3.8) compared to normal pituitary tissue. Expression of VEGFC and PGF was highly correlated with the expression of endothelial markers in tumor samples, including CD31, CD34, and ENG (endoglin, a co-receptor for TGFβ). Furthermore, VEGFR inhibitors inhibited angiogenesis induced by human pituitary tumors and prolonged survival of RbΔ19 mice., Conclusion: Human pituitary tumors are characterized by more active angiogenesis than normal pituitary gland tissue in a manner consistent with sprouting angiogenesis. Angiogenesis in pituitary tumors is regulated mainly by PGF and VEGFC, not VEGFA and VEGFB. Angiogenesis inhibitors, such as the VEGFR2 inhibitor cabozantinib, may merit further investigation as therapies for aggressive human pituitary tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Hu, Zhu, Nie, Zhao, Faje, Labelle, Swearingen, Lee, Hedley-Whyte, Zhang, Jones, Miller, Klibanski, Zhou and Soberman.)

Objective: Data are limited regarding how body composition is linked to insulin resistance in elderly patients with type 2 diabetes mellitus (T2DM). We examined the association between body composition and insulin resistance in elderly T2DM patients., Methods: The cross-sectional study included 488 Chinese elderly patients wth T2DM. Subjects were classified into four groups based on body composition: normal body composition (NBC), low muscle mass alone (LMM), high body fat alone (HBF), both low muscle mass and high body fat (LMMHBF)., Results: The percentage of subjects with LMMHBF was 14.5% (11.9% in men and 17.7% in women). Homeostasis model assessment of insulin resistance (HOMA2-IR) was higher in the LMMHBF group than in the HBF group (p = 0.045), and was also significantly higher in the LMMHBF or HBF group than in the NBC or LMM group. The HBF group showed the highest body mass index (BMI) of the four groups of different body compositions, and the LMMHBF group showed lower BMI than the HBF group; however, there was no significant difference in BMI or waist to hip ratio (WHR) between the LMMHBF group and the NBC group. The LMMHBF and HBF groups were significantly associated with increased risk of insulin resistance compared to the NBC group, with odds ratios (ORs) of 4.47 [95% confidence interval (CI) 2.06-9.68, p < 0.001] and 1.76 (95% CI 1.02-3.02, p = 0.041) respectively, even after the adjustment for covariates., Conclusion: In China, though elderly T2DM patients with the body composition of sarcopenic obesity (as defined by coexistence of low muscle mass and high body fat) seemed to have normal body size, they exhibited the most severe degree and the highest risk of insulin resistance., Competing Interests: The authors declare that they have no competing interests in this work., (© 2022 Han et al.)

Background: Numerous reports have highlighted that the tumor microenvironment (TME) is closely linked to survival outcome and therapeutic efficacy. However, a comprehensive investigation of the TME feature in breast cancer (BC) has not been performed. Methods: Here, we performed consensus clustering analysis based on TME cell expression profiles to construct TME pattern clusters and TME-related gene signature in BC. GSVA combined with CIBERSORT and ssGSEA algorithms were applied to evaluate the differences in biological pathway and immune cell infiltration level, respectively. The PCA method was employed to construct TME-score to quantify the TME-mediated pattern level in individual BC patients. Results: We determined two distinct TME gene clusters among 3,738 BC samples, which exhibited distinct survival outcome and enriched biological processes. The TME features demonstrated that these two clusters corresponded to the established immune profiles: hot and cold tumor phenotypes, respectively. Based on TME-related signature genes, we constructed the TME-score and stratified BC patients into low and high TME-score groups. Patients with high TME-score exhibited favorable outcome and increased infiltration of immune cells. Further investigation revealed that high TME-score was also related with high expression of immunosuppressive molecules, decreased tumor mutation burden (TMB), and high rate of mutation in significantly mutated genes (SMGs) (e.g., PIK3CA and CDH1). Conclusion: Assessing the TME-mediated pattern level of individual BC patients will assist us in better understanding the responses of BC patients to immunotherapies and directing more effective immunotherapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Hu and Liu.)

Purpose: Type 2 diabetes mellitus is characterized by insulin resistance and β-cell dysfunction. Elevated free fatty acids-induced lipotoxicity may play a vital role in the pathogenesis of β-cell insulin resistance. Exercise-stimulated myokine irisin has been reported to be closely related to T2DM. However, its function on β-cell insulin signaling and the underlying mechanisms are only partially elucidated as yet., Methods: High-fat diet-fed C57BL/6J mice and palmitic acid-treated MIN6 cell models were utilized as lipotoxic models. Factors associated with β-cell insulin signaling transduction and inflammatory responses were assessed in these models. Furthermore, the role of irisin in β-cells and the underlying mechanisms were also explored., Results: Irisin effectively decreased lipid levels in HFD mice, enhanced glucose-stimulated insulin secretion and nullified the expressions of inflammatory cytokines in vivo and in vitro experiments. Moreover, irisin improved PI3K/AKT insulin signaling pathway and inhibited TLR4/NF-κB inflammatory signaling pathway in both islets of HFD mice and PA-treated MIN6 cells. Mechanistic analysis indicated that FOXO1 might serve as a bridge between the two pathways., Conclusion: Irisin alleviates lipotoxicity-induced β-cell insulin resistance and inflammatory response through the activation of PI3K/AKT/FOXO1 signaling pathways and the inhibition of TLR4/NF-κB signaling pathways. Irisin might provide a novel therapeutic strategy for T2DM., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Numerous reports have highlighted that pyroptosis is closely linked to tumorigenesis and drug resistance of tumors. However, the potential role of pyroptosis in regulating immune cell infiltration in tumor microenvironment (TME) remains unclear., Methods: Here, we performed consensus clustering analysis based on the expression of 10 typical pyroptosis-related regulators (PRRs) to construct pyroptosis-mediated tumor pattern clusters and pyroptosis-related gene signature in breast cancer (BC). GSVA combined with ssGSEA methods were applied to evaluate the differences in biological pathway and immune cell infiltration level, respectively. The PCA method was employed to construct the pyro-score to quantify the pyroptosis pattern level of individual BC patient., Results: We determined three distinct pyro-clusters among 1852 BC samples, which exhibited different survival outcomes and enriched biological processes. The TME features demonstrated that these three clusters corresponded to three established immune profiles: immune-desert, immune-excluded and immune-inflamed phenotype, respectively. Based on pyroptosis-related signature genes, we constructed the pyro-score and stratified BC patients into high and low pyro-score group. Patients with high pyro-score exhibited favorable outcome and increased infiltration of immune cells. Further investigation revealed that high pyro-score was also related to high expression of immunosuppressive molecules, decreased tumor mutation burden (TMB) and high rate of mutation in significantly mutated genes (SMGs) (eg, PIK3CA and CDH1)., Conclusion: This research emphasizes the indispensable role of pyroptosis in TME complexity and diversity. Assessing the pyroptosis pattern level of individual BC patient will assist us in better understanding TME features and directing more effective immunotherapeutic approaches., Competing Interests: The authors declare that they have no competing interests., (© 2022 Xu et al.)

An intracranial aneurysm in a pituitary adenoma (PA) is not uncommon; however, preoperative angiography is not clinically used as a routine screening test for PA patients. Therefore an intracranial aneurysm is often missed while diagnosing PA patients. When an aneurysm is missed in patients with pituitary tumors, the supporting power by the tumor to the blood vessels or aneurysm will disappear when the tumor is removed and patients may suffer intraoperative or postoperative aneurysm rupture, which may lead to fatal, catastrophic hemorrhage. Herein, we report a case of a PA patient with the signal shadow of vessel flow void, observed vaguely in the right internal carotid artery cavernous segment on magnetic resonance imaging, and a small aneurysm was found via digital subtraction angiography. In order to ensure the safety of surgery, we first performed embolization of the aneurysm and then resected the tumor., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Gitelman syndrome (GS) is a tubulopathy characterized by hypokalemia, hypomagnesemia, hypocalciuria and metabolic alkalosis, which is caused by mutations in SLC12A3 gene., Objective: The objective of this study was to investigate the mutation of SLC12A3 gene in a pedigree with GS and analyzed the clinical manifestations., Methods: Next-generation sequencing and Sanger sequencing were performed to explore the mutations of SLC12A3 gene in a GS pedigree that included a 59-year-old male GS patient and a total of 11 family members within three generations., Results: A novel compound heterozygous mutation of SLC12A3 gene (c.1712T > C in exon14 and c.2986&#95;2987ins GCT in exon26) was identified by genetic testing in the proband. Moreover, we demonstrated that two brothers shared the same heterozygous mutation with the proband, but only one brother had the GS related symptoms. His nephew was the carrier of one mutation (c.1712T > C), and one of his brother, his sister and niece were carriers of the other (c.2986&#95;2987ins GCT)., Conclusions: This is the first study to report the novel pathogenic compound heterozygous mutation of SLC12A3 gene in GS. Our result further supports the lack of phenotype-genotype correlations in GS. Further functional studies are required to investigate pathophysiologic mechanisms of GS.

Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood., Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests., Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery., Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A 52-year-old male who had chronic hypertension for several years presented with abrupt epistaxis. The CT scan revealed a 40 mm × 40 mm mass in the nasal cavity intended to the maxillary sinus and the base of skull. Nasal endoscope biopsy and serum/urinary catecholamine detection conformed an ectopic noradrenaline-secreting pheochromocytoma. The present research was to discuss the clinical characteristics of the rare pheochromocytoma and the palliative interventional embolization for it.

Fatty acid-induced lipotoxicity plays an important role in the pathogenesis of diabetes mellitus. Our previous studies have documented that lipotoxicity contributes to the onset and development of diabetes via insulin resistance and/or compromised function of the pancreatic β-cells. However, the underlying molecular mechanisms associating lipotoxicity with insulin resistance remain to be fully elucidated. In this study, we explored the role of TRB3-COP1-SIRT1 in lipotoxicity leading to insulin resistance in hepatocytes. High fat diet (HFD)-fed mice and hepG2 cells stimulated with palmitate were utilized as models of lipid metabolism disorders. We analyzed the interactions of SIRT1 and COP1 with each other and with TRB3 using co-immunoprecipitation, western blotting. SIRT1 ubiquitination was also explored. Animal and cell experiments showed that lipotoxicity induced SIRT1 down-regulation at the protein level without altering the mRNA level, whereas, lipotoxicity led to up-regulation of TRB3 and COP1 at both the gene and protein levels. Mechanistic analysis indicated that COP1 functioned as an E3 Ub-ligase of SIRT1, responsible for its proteasomal degradation under lipotoxic conditions. TRB3 recruited COP1 to SIRT1 to promote its ubiquitination. Our data indicated for the first time that TRB3-COP1-SIRT1 pathway played an important role in lipotoxicity leading to insulin resistance in hepatocytes, and suggested that COP1 could be a potential therapeutic choice for the treatment of diabetes mellitus, with lipotoxicity being the important pathomechanism., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The study reported a case of an intrasellar arachnoid cyst with visual disturbances as the main symptom. Arachnoid cyst is a common intracranial benign space-occupying lesion, but rarely seen in intrasellar region with less than 100 cases reported available in English language literature. Therefore, it is still controversial about the diagnosis and treatment of such patients. This article reviewed previous literature and discussed the differential diagnosis and surgical strategies of intrasellar arachnoid cyst in combination with our own case.

Background: Infertility and dyslipidemia are frequently present in both women with polycystic ovary syndrome (PCOS) and subjects with thyroid dysfunction. Limited study regarding the association between thyroid stimulating hormone (TSH) level and phenotypes in euthyroid PCOS women. We aimed to determine whether the variation of TSH level associates with phenotypes in euthyroid PCOS patients. Methods: Cross-sectional study including 600 PCOS and 200 age, body mass index (BMI), and thyroid autoimmunity-matched Chinese women from Renji hospital, Shanghai Jiaotong university during January 2010 and August 2018. The anthropometric and serum biochemical parameters related to TSH, thyroid autoimmunity, lipid profiles, and sex steroids were detected. Results: The TSH level is higher in (2.29 ± 1.24 vs. 1.86 ± 0.90 mu/L, p < 0.001) in PCOS than controls. In euthyroid PCOS patients, TSH, TG, TC, LDL-c, and apoB level increased from non-hyperandrogenism (nonHA) to HA group (all p < 0.05). TSH level is positively associated with TG, apoB, free T, FAI, and negatively associated with apoA (all p < 0.05). The percentage of HA increased from TSH level (57.93% in TSH < = 2.5 group vs. 69.46% in TSH > 2.5 mU/L group, p = 0.006). HA phenotype is increased with TSH level independently of age, BMI, WC, LDL-C. Besides, in multivariate logistic regression analysis TSH and TG significantly associated with HA phenotype. Conclusions: Higher TSH level is associated with increased prevalence of HA phenotype independent of age, BMI and thyroid autoimmunity in euthyroid PCOS.

Long non-coding RNAs (lncRNAs) play vital roles in the pathobiology of glioblastoma multiforme (GBM). Though radiotherapy remains the most effective component of multiple therapies for patients with GBM, lncRNAs conferring GBM radioresistance are less unknown. Here, the present study identified that the antisense transcript of hypoxia-inducible factor-1α (AHIF) was upregulated in GBM cells after radiotherapy. The deregulation of AHIF affected GBM cell clonogenic formation, DNA repair and apoptosis. Notably, knockdown of AHIF inhibited tumorigenesis after radiotherapy in vivo. Further biochemical analysis identified that AHIF regulated proteins associated with apoptosis after radiotherapy. Thus, the present data illustrate that suppression of AHIF increases radiosensitivity in GBM cells, which may be a potential diagnostic and therapeutic target for GBM patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: The present study aimed to explore the mechanism of a potential beneficial effect of pre-existing diabetes in acute hyperglycemia during critical illness., Methods: Pathophysiological changes including blood glucose variability, changes of inflammatory and oxidative stress responses after lipopolysaccharide (LPS)-induced acute infection were compared between type 2 diabetic rat model (GK rats) and normal controls (Wistar rats)., Results: After LPS injection, Wistar rats showed serious infective symptoms while GK rats did not. Blood glucose (BG) levels were significantly elevated in both GK and Wistar rats; however, compared to Wistar rats, GK rats had lower BG variability, smaller increases in the serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels, a larger increase in the serum IL-10 level, and a smaller decrease in the IκB-α protein level of lung tissue. Serum malondialdehyde (MDA) levels increased and serum total antioxidant capacity (T-AOC) levels decreased for both GK and Wistar rats., Conclusions: We found diabetes was associated with adaptive changes at the cellular level that might actually be protective in acute hyperglycemia-mediated damage during sepsis. Chronic exposure to hyperglycemia potentially reduced the acute deleterious effects of acute hyperglycemia on septic mortality by decreasing BG variability, blunting the pro-inflammatory response and elevating the anti-inflammatory response., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Fatty acid-induced lipotoxicity and macrophage migration inhibitory factor (MIF) affect pancreatic β-cell function, and may promote the development of diabetes mellitus. However, the association of lipotoxicity with MIF and the effect of Fenofibrate on β-cell function remain unknown., Methods: LPL+/- mice and MIN6 cells stimulated with palmitic acid (PA) were utilized as models of lipid metabolism disorders. Factors associated with insulin secretion and apoptosis were assessed in the presence or absence of Fenofibrate. The possible mechanisms of lipotoxicity-induced β-cell dysfunction were also explored., Results: Fenofibrate effectively improved lipid accumulation in pancreatic β-cells, increased glucose-stimulated insulin secretion and β-cell mass, and significantly downregulated pro-apoptotic molecules, at the gene and protein levels, both in vivo and in vitro. Additionally, elevated MIF levels in serum from LPL+/- mice and PA-treated MIN6 cells were starkly decreased after Fenofibrate administration. Mechanistic analysis indicated that NF-κB signaling was remarkably triggered, which could further activate MIF transcription. Furthermore, Fenofibrate exerted beneficial effects on fatty acid-induced β-cell dysfunction likely by inhibiting the NF-κB/MIF dependent inflammatory response., Conclusions: Fenofibrate ameliorates lipotoxicity-induced β-cell dysfunction and apoptosis by inhibiting the NF-κB/MIF inflammatory pathway. These findings provide novel insights into the treatment of lipotoxicity-induced metabolic disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: To investigate the associations of dyslipidemia with insulin resistance and β cell function in individuals with normal glucose tolerance (NGT) and different categories of impaired glucose regulation (IGR)., Methods: 544 subjects (365 with dyslipidemia and/or IGR and 179 with normal lipid and glucose tolerance) were enrolled in the study. All subjects underwent oral glucose tolerance test (OGTT). HOMA-IR was used to evaluate insulin sensitivity. Disposition index (DI) was used to evaluate β cell function. Multiple linear regression analysis was performed to assess correlations among lipid profiles, insulin resistance and β cell function., Results: Among subjects with NGT, those with dyslipidemia had higher level of HOMA-IR but lower level of DI. While among subjects with different categories of IGR, those with dyslipidemia and CGI had significantly decreased DI. No obvious differences of insulin resistance or β cell function were found in IFG or IGT subjects with or without dyslipidemia. TG and HDL-C were correlated with HOMA-IR (β = 0.79, p <0.001; β = -0.38, p = 0.027, respectively, compared with subjects in the low level groups). Moreover, TG and TC were negatively correlated with DI (β = -2.17, p = 0.013; β = -2.01, p = 0.034 respectively, compared with subjects in the low level groups) after adjusting for confounding parameters., Conclusions: Dyslipidemia induces insulin resistance and impaired β cell response to insulin resistance in individuals with NGT. Furthermore, dyslipidemia diminishes β cell function in subjects with CGI. TG and HDL-C were correlated with insulin resistance, and TG, TC were negatively correlated with β cell response to insulin resistance in non-diabetic individuals.

Background: Apolipoprotein B/apolipoprotein A-I (ApoB/ApoA-I) ratio is a useful predictor of cardiovascular risk. However, the association between the ApoB/ApoA-I ratio and the risk of type 2 diabetes mellitus (T2DM) is still obscure., Aims: To investigate the associations between the ApoB/ApoA-I ratio and the risk of T2DM and pre-diabetes in a Chinese population, and to assess the role of gender in these associations., Methods: A stratified random sampling design was used in this cross-sectional study which included 264 men and 465 women with normal glucose tolerance (NGT), pre-diabetes or T2DM. Serum ApoB, ApoA-I and other lipid and glycaemic traits were measured. Pearson's partial correlation and multivariable logistic analysis were used to evaluate the associations between ApoB/ApoA-I ratio and the risk of T2DM and pre-diabetes., Results: The ApoB/ApoA-I ratios were significantly increased across the spectrum of NGT, pre-diabetes and T2DM. Women showed higher levels of ApoB/ApoA-I ratio and ApoB than men in the pre-diabetic and T2DM groups, but not in the NGT group. The ApoB/ApoA-I ratio was closely related with triglyceride, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and other glycaemic traits. Moreover, in women, the risk of diabetes and pre-diabetes in the top and middle tertiles of the ApoB/ApoA-I ratio were 3.65-fold (95% CI 1.69 to 6.10) and 2.19-fold (95% CI 1.38 to 2.84) higher than in the bottom tertile, respectively, after adjusting for potential confounding factors. However, the associations disappeared in men after adjusting for other factors., Conclusions: The ApoB/ApoA-I ratio showed positive associations with the risk of diabetes and pre-diabetes in Chinese women., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Body mass index (BMI), waist circumference (WC), visceral adiposity index (VAI), triglyceride glucose index (TyG), TyG-BMI, and TyG-WC have been reported as markers of insulin resistance or type 2 diabetes mellitus (T2DM). However, little is known about the associations between the aforementioned markers and the risk of prediabetes and diabetes in first-degree relatives (FDRs) of T2DM patients., Methods: 1544 FDRs of T2DM patients (635 men and 909 women) were enrolled in the initial cross-sectional study and all of them finished corresponding examinations. Logistic regression analysis and receiver operating characteristic (ROC) curve were used to compare and identify the associations of the six parameters (BMI, WC, VAI, TyG, TyG-BMI and TyG-WC) with the prevalence of prediabetes and diabetes. Subsequently, 452 of them were followed-up for an average of 5 years. Cox proportional hazard regression model was applied to confirm the predictive value of the optimal marker., Results: Among the indices, TyG-WC was more strongly associated with the prevalence of prediabetes and diabetes. Compared with participants in the lowest quartile of TyG-WC, the adjusted odds ratio and 95 % CIs for prediabetes and diabetes was 11.19 (7.62-16.42) for those in the top quartile of TyG-WC. Moreover, the largest AUC was also observed in TyG-WC (0.765, 95 % CIs 0.741-0.789, P < 0.001). The robust predictive value of TyG-WC was further confirmed in the follow-up study (HR: 7.13, 95 % CIs 3.41-14.90, P < 0.001)., Conclusions: TyG-WC is a novel and clinically effective marker for early identifying the risks of prediabetes and diabetes in FDRs of T2DM patients.

Objectives: To explore the association between the triglyceride to HDL-C ratio (TG/HDL-C) and insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus., Methods: Patients with newly diagnosed type 2 diabetes mellitus (272 men and 288 women) were enrolled and divided into three groups according to TG/HDL-C tertiles. Insulin resistance was defined by homeostatic model assessment of insulin resistance (HOMA-IR). Demographic information and clinical characteristics were obtained. Spearman's correlation was used to estimate the association between TG/HDL-C and other variables. Multiple logistic regression analyses were adopted to obtain probabilities of insulin resistance. A receiver operating characteristic analysis was conducted to evaluate the ability of TG/HDL-C to discriminate insulin resistance., Results: TG/HDL-C was associated with insulin resistance in Chinese patients with newly diagnosed T2DM (Spearman's correlation coefficient = 0.21, P < 0.01). Patients in the higher tertiles of TG/HDL-C had significantly higher HOMA-IR values than patients in the lower tertiles [T1: 2.68(1.74-3.70); T2: 2.96(2.29-4.56); T3: 3.09(2.30-4.99)]. Multiple logistic regression analysis showed that TG/HDL-C was significantly associated with HOMA-IR, and patients in the higher TG/HDL-C tertile had a higher OR than those in the lower TG/HDL-C tertile, after adjusting for multiple covariates including indices for central obesity [T1: 1; T2: 4.02(1.86-8.71); T3: 4.30(1.99-9.29)]. Following stratification of waist circumference into quartiles, the effect of TG/HDL-C on insulin resistance remained significant irrespective of waist circumference., Conclusions: TG/HDL-C was associated with insulin resistance independent of waist circumference. Whether it could be a surrogate marker for insulin resistance in Chinese patients with newly diagnosed type 2 diabetes mellitus still needs to be confirmed by more researches.

Objective: Lipid metabolism disturbance can result in insulin resistance and glucose intolerance; however, the features of glucose metabolism are still elusive in different dyslipidemia. Our study intended to explore the characteristics and molecular mechanisms of glucose metabolism abnormal in hypercholesterolemia and hypertriglyceridemia models., Methods: Two mouse models were used in this study, one was lipoprotein lipase gene-deleted (LPL(+/-)) mice, and the other was high fat dietary (HFD) mice. Levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterin (HDL-c) and low-density lipoprotein-cholesterin (LDL-c) in serum were measured by full-automatic biochemical analyzer. Intraperitoneal glucose tolerance test (IPGTT) was performed to evaluate insulin sensitivity and β-cell function. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) levels in serum were measured by colorimetric determination. mRNA expression of superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase 1 (Gpx1), nuclear factor erythroid 2-related factor 2 (Nrf2a) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) in liver, skeletal muscle, visceral fat and subcutaneous fat were measured by Real-Time PCR., Results: Compared with HFD mice, the levels of serum TG were significantly higher in LPL(+/-) mice, whereas the levels of TC, HDL-c, LDL-c were significantly lower. The plasma glucose levels were increased at each time point of intra-peritoneal glucose tolerance test (IPGTT) in both groups. Furthermore, the level of serum fasting insulin and homeostasis model assessment index-insulin resistance (HOMA-IR) increased with a decreased ISI in both groups. In addition, the plasma MDA of HFD group was higher than that of lipoprotein lipase-deficiency (LPL(+/-)) group, while the activity of T-SOD in HFD group was lower than that in LPL(+/-) group. Real-Time PCR revealed that the expressions of SOD1, CAT and Gpx1 in liver and subcutaneous fat were lower in HFD group than those in LPL(+/-) group, but higher in skeletal muscle and visceral fat., Conclusions: There are different in glucose metabolism between high TG mice and high TC mice. Impaired insulin sensitivity is more serious in HFD mice than that in LPL(+/-) mice. Oxidative stress could contribute to insulin resistance in hyperlipidemia mice.

Background: To explore clinical characteristics and beta cell function in Chinese patients with newly diagnosed drug naive type 2 diabetes mellitus (T2DM) with different levels of serum triglyceride (TG)., Methods: Patients with newly diagnosed T2DM (n = 624) were enrolled and divided into different groups according to levels of serum TG. All patients underwent oral glucose tolerance tests and insulin releasing tests. Demographic data, lipid profiles, glucose levels, and insulin profiles were compared between different groups. Basic insulin secretion function index (homeostasis model assessment for beta cell function index, HOMA-β), modified beta cell function index (MBCI), glucose disposition indices (DI), and early insulin secretion function index (insulinogenic index, IGI) were used to evaluate the beta cell function., Results: Patients of newly diagnosed T2DM with hypertriglyceridemia were younger, fatter and had worse lipid profiles, glucose profiles, and high insulin levels than those with normal TG. There is no difference in early phase insulin secretion among groups of newly diagnosed T2DM patients with different TG levels. The basal beta cell function (HOMA-β and MBCI) initially increased along rising TG levels and then decreased as the TG levels rose further. The insulin sensitivity was relatively high in patients with a low level of TG and low with a high level of TG., Conclusions: Hypertriglyceridemia influences clinical characteristics and β cell function of Chinese patients with newly diagnosed T2DM. A better management of dyslipidemia may, to some extent, reduce the effect of lipotoxicity, thereby improving glucose homeostasis in patients with newly diagnosed T2DM.

Objective: To evaluate the effects and safety of 300-600 mg α-lipoic acid (ALA) given i.v. for diabetic peripheral neuropathy (DPN)., Methods: We searched the databases of Medline, Embase, and Cochrane central register of Controlled Trials and Chinese biological medicine for clinical trials of ALA in the treatment of DPN. Data were extracted to examine methodological quality and describe characteristics of studies. The primary outcomes were efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, and peroneal SNCV. Secondary outcomes were adverse events., Results: Fifteen randomized controlled trials met the inclusion criteria. The treatment group involved the administration of ALA 300-600 mg i.v. per day. And the control group used the same interventions except for ALA. Compared with the control group, nerve conduction velocities increased significantly in the treatment group. The weighted mean differences in nerve conduction velocities were 4.63 (95% confidence interval 3.58-5.67) for median MNCV, 3.17 (1.75-4.59) for median SNCV, 4.25 (2.78-5.72) for peroneal MNCV, and 3.65 (1.50-5.80) for peroneal SNCV in favor of the treatment group. The odds ratio in terms of efficacy was 4.03 (2.73-5.94) for ALA. Furthermore, no serious adverse events were observed during the treatment period., Conclusions: The results of this meta-analysis provide evidence that treatment with ALA (300-600 mg/day i.v. for 2-4 weeks) is safe and that the treatment can significantly improve both nerve conduction velocity and positive neuropathic symptoms. However, the evidence may not be strong because most of the studies included in this meta-analysis have poor methodological quality.

The aim of this study is to assess the validity of combined use of fasting plasma glucose (FPG) and glycated hemoglobin A1c (HbA1c) as screening tests for diabetes and impaired glucose tolerance (IGT) in high-risk subjects. A total of 2,298 subjects were included. All subjects underwent a 75-g oral glucose tolerance test (OGTT) and HbA1c measurement. Receiver operating characteristic curve (ROC curve) analysis was used to examine the sensitivity and specificity of FPG and HbA1c for detecting diabetes and IGT, which was defined according to the 1999 World Health Organization (WHO) criteria. (1) Based on the ROC curve, the optimal cut point of FPG related to diabetes diagnosed by OGTT was 6.1 mmol/l that was associated with a sensitivity and specificity of 81.5 and 81.0%, respectively; The optimal cut point of HbA1c related to diabetes diagnosed by OGTT was 6.1%, which was associated with a sensitivity and specificity of 81.0 and 81.0%, respectively; The screening model using FPG > or = 6.1 mmol/l or HbA1c > or = 6.1% had sensitivity of 96.5% for detecting undiagnosed diabetes; the screening model using FPG > or = 6.1 mmol/l and HbA1c > or = 6.1% had specificity of 96.3% for detecting undiagnosed diabetes. (2) Based on the ROC curve, the optimal cut point of FPG related to IGT diagnosed by OGTT was 5.6 mmol/l that was associated with a sensitivity and specificity of 64.1 and 65.4%, respectively; The optimal cut point of HbA1c related to IGT diagnosed by OGTT was 5.6%, which was associated with a sensitivity and specificity of 66.2 and 51.0%, respectively; The screening model using FPG > or = 5.6 mmol/l or HbA1c > or = 5.6% had sensitivity of 87.9% for detecting undiagnosed IGT; The screening model using FPG > or = 5.6 mmol/l and HbA1c > or = 5.6% had specificity of 82.4% for detecting undiagnosed IGT. Compared with FPG or HbA1c alone, the simultaneous measurement of FPG and HbA1c (FPG and/or HbA1C) might be a more sensitive and specific screening tool for identifying high-risk individuals with diabetes and IGT at an early stage.

Aims: Isolated hyperglycemia is associated with atherosclerosis in individuals with type 2 diabetes, but the relationship between postchallenge glucose excursion and atherosclerosis is less clear. This study examines the relationships between postchallenge glucose spikes (PGS), carotid intima-media thickness (IMT), and traditional risk factors for atherosclerosis in individuals with type 2 diabetes., Methods: A total of 474 individuals with type 2 diabetes who were within the highest or lowest IMT distribution quartile were included. The Student's t-test, one-way analysis of variance (ANOVA), single variate and multivariate analyses were implemented to study the data. An additional healthy control group (n=896) was selected during routine health examination. They were Han nationality and unrelated to the diabetic patients., Results: (1) Compared with subjects of healthy control group, the subjects with type 2 diabetes had significantly higher levels of body mass index (BMI), waist-to-hip ratio (WHR), systolic blood pressure, triglyceride, total cholesterol, low density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), 120 min postchallenge glucose (PG120), hemoglobin A1c (HbA1c) and IMT (P < or = 0.01) and relatively lower levels of high density lipoprotein cholesterol (HDL-C) (P < or = 0.05). (2) According to the IMT which was measured by B-mode ultrasonography, the patients of type 2 diabetes could be divided into two subgroups: one was the subgroup of IMT > or = P(75) and another was the subgroup of IMT < or = P(25). Compared with subjects of IMT > or = P(25) subgroup, subjects being in the IMT > or = P(75) subgroup exhibited significantly increased age, WHR, diabetes duration, systolic blood pressure, total cholesterol, triglyceride, LDL-C, and significantly decreased HDL-C levels. And among all the plasma glucose variables, except for FPG and PG30, all the other variables (include PG60, PG120, PG180, PGS, HbA1C, under area curve of glucose) showed a significant increase in the IMT>/=P(75) subgroup. (3) A multivariate logistic regression analysis was performed to establish which were independently related with carotid IMT, and the results showed the PGS was identified as the strongest determinant of IMT from all the atherosclerosis risk factors. (4) PGS is significantly correlated to a variety of atherosclerosis risk factors., Conclusions: This study identified several important associations between PGS and known risk factors for atherosclerosis and suggested that PGS is independently related to carotid IMT. Wide postchallenge glucose excursions may contribute to the development of atherosclerosis in individuals with type 2 diabetes, independent of other risk factors., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Hyperglycaemia in diabetes mellitus (DM) alters gene expression regulation in various organs and contributes to long term vascular and renal complications. We aimed to generate novel renal genome-wide gene transcription data in rat models of diabetes in order to test the responsiveness to hyperglycaemia and renal structural changes of positional candidate genes at selected diabetic nephropathy (DN) susceptibility loci., Methods: Both Affymetrix and Illumina technologies were used to identify significant quantitative changes in the abundance of over 15,000 transcripts in kidney of models of spontaneous (genetically determined) mild hyperglycaemia and insulin resistance (Goto-Kakizaki-GK) and experimentally induced severe hyperglycaemia (Wistar-Kyoto-WKY rats injected with streptozotocin [STZ])., Results: Different patterns of transcription regulation in the two rat models of diabetes likely underlie the roles of genetic variants and hyperglycaemia severity. The impact of prolonged hyperglycaemia on gene expression changes was more profound in STZ-WKY rats than in GK rats and involved largely different sets of genes. These included genes already tested in genetic studies of DN and a large number of protein coding sequences of unknown function which can be considered as functional and, when they map to DN loci, positional candidates for DN. Further expression analysis of rat orthologs of human DN positional candidate genes provided functional annotations of known and novel genes that are responsive to hyperglycaemia and may contribute to renal functional and/or structural alterations., Conclusion: Combining transcriptomics in animal models and comparative genomics provides important information to improve functional annotations of disease susceptibility loci in humans and experimental support for testing candidate genes in human genetics.

Increased plasma triglyceride and free fatty acid levels are frequently associated with type 2 diabetes mellitus (T2DM). To test the hypothesis that LPL gene mutations contribute to the hypertriglyceridemia observed in members of T2DM pedigrees, we screened the LPL gene in 53 hypertriglyceridemic members of 26 families. Four known and three novel mutations were identified. All three novel mutations, Lys312insC, Thr361insA, and double mutation Lys312insC + Asn291Ser, are clinically associated with hypertriglyceridemia. In vitro mutagenesis and expression studies confirm that these variants are associated with a significant reduction in LPL activity. The modeled structures displaying the Lys312insC and Thr361insA mutations showed loss of the activity-related C-terminal domain in the LPL protein. Another novel double mutation, Lys312insC + Asn291Ser, resulted in the loss of the catalytic ability of LPL attributable to the complete loss of the C-terminal domain and alteration in the heparin association site. Thus, these novel mutations of the LPL gene contribute to the hypertriglyceridemia observed in members of type 2 diabetic pedigrees.

This systematic review attempted to summarize the associations between the Asn291Ser variant in the lipoprotein lipase (LPL) gene and dyslipidemia, the risk of type 2 diabetes mellitus (T2DM), and coronary heart disease (CHD). In addition, the relationships between the Asn291Ser variant and other metabolic diseases such as obesity and high blood pressure were also investigated in this systematic review. We systematically reviewed the literature by means of a meta-analysis. Twenty-one articles, including 19,246 white subjects, were selected for this meta-analysis. The summary standardized mean difference (SMD) of plasma triglyceride (TG) for carriers compared with noncarriers of the Asn291Ser variant was 3.23 (P < 0.00001). The summary SMD of plasma HDL-cholsterol (HDL-C) for carriers compared with noncarriers of the Asn291Ser variant was -3.42 (P < 0.0001). The summary SMD of the association of the Asn291Ser variant with plasma TG increased with increasing age and weight gain. Significant interactions between the LPL Asn291Ser variant and fasting glucose, T2DM, and CHD were seen (P = 0.02, 0.04, and 0.01, respectively). No significant interactions were seen between the LPL Asn291Ser variant and body mass index, waist-hip ratio, and blood pressure (P > 0.05). This meta-analysis indicates that the Asn291Ser variant in the LPL gene is a risk factor for dyslipidemia, characterized by hypertriglyceridemia and low HDL-C levels. And the Asn291Ser variant in the LPL gene predisposes to more severe dyslipidemia with increasing age and weight gain. Also, this meta-analysis shows that the LPL Asn291Ser variant is associated with CHD and T2DM.

Serum paraoxonase (PON) is a high-density lipoprotein-bound enzyme that can prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides and thus exert an anti-atherogenic effect. Recent studies have suggested that glutamine(Q isoform)/arginine(R isoform) polymorphism at position 192 of PON(1) gene is associated with macrovascular disease of type 2 diabetes mellitus (T2DM). We re-investigated this relationship using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. The genotype and allele frequency of PON(1) 192 Q/R polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism in 152 type 2 diabetic patients and 128 healthy subjects from a population of Chinese Han nationality in ChengDu area. The carotid IMT was measured by B-mode ultrasonography in type 2 diabetic patients. No differences were found in PON(1) gene Q/R polymorphism in the type 2 diabetic patients when compared with the control group. The mean carotid IMT in type 2 diabetic subjects with the QQ, QR and RR genotype was 0.65+/-0.27, 0.83+/-0.27 and 1.05+/-0.32 mm, respectively. One-way ANOVA showed that IMT was significantly greater in the RR subgroup than in both QR and QQ subgroups (P<0.01). Multivariate logistic regression analysis showed R allele to be the main determinant of IMT variability (OR 4.0 95% CI 2.10-7.40 P=0.005). Our data support the view that 192 R allele of PON(1) gene is a risk factor for macrovascular disease of T2DM in Chinese.