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A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease (NAFLD), coupled with hepatitis and insulin resistance. Yet the details of the underlying mechanisms are not fully understood. Here, we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD. Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation (FAO), and induced insulin resistance. Conversely, hepatic Zbtb18 overexpression alleviated hepato-steatosis, insulin resistance, and hyperglycemia in mice fed on a high-fat diet (HFD) or in diabetic mice. Notably, in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor (FXR) mediated FAO and Clathrin Heavy Chain (CLTC) protein hinders NLRP3 inflammasome activity. This key mechanism by which hepatocyte's Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR's deletion and forced expression in mice and cultured mouse primary hepatocytes (MPHs). Moreover, CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages. Altogether, Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression, which inhibits NLRP3 inflammasome's activity alleviating inflammatory stress and insulin resistance, representing an attractive remedy for hepatic steatosis and fibrosis., (© 2024. The Author(s).)

Context: Type B insulin resistance syndrome (TBIRS) is a rare condition, for which effective treatment remains challenging., Objective: This work aimed to summarize the clinical characteristics of TBIRS and explore effective therapeutic strategies., Methods: The clinical manifestations, biochemical indices, and treatment of 8 patients (3 men and 5 women) with TBIRS from Peking Union Medical College Hospital were retrospectively analyzed and their clinical outcomes were evaluated., Results: The average age of the patients was 49.5 ± 16.5 years, and the duration of the disease ranged from 2 months to 1 year. Seven patients with hyperglycemia had normal/lower triglycerides (TGs) and lower insulin-like growth factor 1 (IGF-1) levels. One patient complained of intractable hypoglycemia. Five patients had accompanied systemic lupus erythematosus, 2 had mixed connective tissue disease, and 1 had undifferentiated connective tissue disease. Five patients had acanthosis nigricans and 3 women of child-bearing age had hyperandrogenism. All 8 patients were treated with glucocorticoids combined with immunosuppressants, among whom, 5 received high-dose glucocorticoid pulse therapy followed by conventional-dose glucocorticoid therapy, all of whom achieved partial remission within 2 to 4 weeks. Among the 3 patients receiving conventional glucocorticoid therapy, 2 achieved partial remission within 2 to 4 weeks. Six patients were tracked for 10 weeks to 4 years; 4 and 2 achieved complete and partial remission, respectively., Conclusion: Decreased serum complement 3 and IGF-1 levels and normal/decreased TG levels act as striking biochemical features of TBIRS. High-dose glucocorticoid pulse therapy followed by conventional-dose long-term therapy combined with immunosuppressants achieves good clinical efficacy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Body mass index (BMI) is a common indicator in clinical practice, but it is not sufficient to predict insulin resistance (IR). Other anthropometric methods supplement BMI in the assessment of body composition, which can be predicted more accurately. This cross-sectional study aimed to evaluate the association between mid-upper arm circumference (MUAC), triceps skinfold (TSF) thickness, mid-arm muscle circumference (MAMC) and IR in Chinese adults., Methods: This cross-sectional study analyzed data from the 2009 China Health and Nutrition Survey database. The study population was divided into four groups according to the MUAC quartiles, and the homeostasis mode assessment was used to evaluate the degree of IR. Logistic regression analysis was performed to calculate odds ratios (ORs) with 95% confidence intervals (CIs), with adjustments for multiple covariates. Subgroup analyses stratified by age, sex, BMI, waist circumference (WC), smoking status, and alcohol consumption were performed., Results: In total, 8,070 participants were included in the analysis. As MUAC increased, BMI, TSF thickness, MAMC, and the proportion of IR tended to increase. However, we found that there was a significant negative association between MUAC and MAMC and IR in the logistic regression analysis, independent of BMI and WC, the ORs for the highest quartiles compared with the lowest quartiles were 0.662 (95%CI: 0.540-0.811) and 0.723 (95%CI: 0.609-0.860), respectively. There was no significant association was observed between the TSF thickness and IR (OR=1.035 [95%CI: 0.870-1.231]). The inverse associations were more pronounced among participants with lower BMI and WC. No significant age-specific differences were observed (P-heterogeneity > 0.05)., Conclusions: After adjusting for BMI and WC, MUAC was negatively associated with IR in Chinese adults, and the association between MUAC and IR was derived from arm muscle instead of subcutaneous fat. MUAC could be an additional predictor of IR besides BMI and WC in clinical practice., 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 Wang, He, Yang, Li, Xu, Li, Ping, Zhang and Li.)

Insulin signaling is essential for glucose metabolism, and insulin decreases insulin receptor (InsR) levels in a dose-dependent and time-dependent manner. However, the regulatory mechanisms of InsR reduction upon insulin stimulation remain poorly understood. Here, we show that Eph receptor B4 (EphB4), a tyrosine kinase receptor that modulates cell adhesion and migration, can bind directly to InsR, and this interaction is markedly enhanced by insulin. Due to the adaptor protein 2 (Ap2) complex binding motif in EphB4, the interaction of EphB4 and InsR facilitates clathrin-mediated InsR endocytosis and degradation in lysosomes. Hepatic overexpression of EphB4 decreases InsR and increases hepatic and systemic insulin resistance in chow-fed mice, whereas genetic or pharmacological inhibition of EphB4 improve insulin resistance and glucose intolerance in obese mice. These observations elucidate a role for EphB4 in insulin signaling, suggesting that EphB4 might represent a therapeutic target for the treatment of insulin resistance and type 2 diabetes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The interplays of cellular aging and oxidative stress (OS) markers form a complex network, which has been reported to be interrelated with numerous age-related and metabolic diseases, including metabolic syndrome (MS). However, given the multifactorial mechanisms of MS, several important confounders such as dietary factors and the reciprocal effect among these markers have not been considered and adjusted in previous investigations regarding the associations of cellular aging and OS markers with MS and its related metabolic abnormalities. To explicate this, we conducted a cross-sectional study among 533 Chinese adults. All the participants underwent a 75 g oral glucose tolerance test. Dietary data were collected via a 24-hour dietary recall and subsequently analyzed by a registered dietitian using nutrition calculation software. Clinical diagnosis of MS was made according to the revised National Cholesterol Education Program Adult Treatment Panel III criteria (2004) with waist circumference cutoff modified for an Asian population. The leukocyte telomere length, mitochondrial DNA copy number, 8-hydroxy-2-deoxyguanosine, superoxide dismutase (SOD) activity, and glutathione reductase were examined. SOD activity was significantly decreased in MS subjects (62.06 ± 16.89 U/mL vs. 56.25 ± 22.61 U/mL, P = 0.001) and exhibited a descending trend across sequential increase of MS component number ( P  for trend = 0.031). SOD activity is modestly correlated with glucose indicators and insulin sensitivity and β -cell function indices and was independently and negatively correlated with the level of triglyceride. An independent association between SOD activity and MS was observed after adjusting for metabolic indicators, dietary factors, cellular aging, and OS markers, as well as insulin sensitivity and β -cell function indices. However, the statistical significance of the association between SOD activity and MS was attenuated after adjusting for the Matsuda insulin sensitivity index (ISIM) and insulin secretion-sensitivity index-2 (ISSI-2), suggesting a possible mediating effect. Therefore, we conducted a mediation model analysis, which showed that decreased ISIM and ISSI-2 partially and synergistically mediated the contribution of decreased SOD activity to MS. In conclusion, decreased SOD activity is an independent predictor for increased risk of MS, and insulin resistance and β -cell dysfunction partially mediate the relationship between decreased SOD activity and MS., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Yiwen Liu et al.)

Background: Previous studies on the effects of lipotoxicity and oxidative stress on islet beta cell function mainly focused on patients with diabetes, whereas studies on normal glucose tolerance (NGT) are few. The aim of this study was to explore the relationships among triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), oxidative stress indicators, insulin resistance, and beta cell function in populations with different glucose and lipid metabolism states., Methods: A total of 517 individuals were recruited from a rural community in Beijing, China. Glucose metabolism status was defined according to the results of a 75-g oral glucose tolerance test (OGTT). Dyslipidemia was defined as abnormal TG, HDL-c, or LDL-c levels. The population was divided into four groups: individuals with normal glucose and lipid levels (group A, n = 62); those with dyslipidemia alone (group B, n = 82); those with dysglycemia alone (group C, n = 121); and those with dysglycemia and dyslipidemia (group D, n = 247). Oxidative stress indicators, including superoxide dismutase (SOD), glutathione reductase (GR) and 8-hydroxydeoxyguanosine (8-OHdG), were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) and glucose disposition index (DI 30 , DI 120 ) were calculated to assess insulin resistance and islet beta cell function, respectively. Stratified multiple linear regression analysis was used to explore relationships between TG, HDL-c, LDL-c, oxidative stress indicators, and insulin resistance (natural log transformation of HOMA-IR, LnHOMA-IR) and beta cell function (natural log transformation of DI 30 , Ln DI 30 )., Results: Compared with the control group, populations with dyslipidemia and/or dysglycemia showed significantly increased insulin resistance. Dyslipidemia aggravated insulin resistance and beta cell dysfunction in individuals with dysglycemia. Stratified regression analysis showed that TG positively correlated with LnHOMA-IR in individuals with normal glucose levels (beta = 0.321, 0.327, P = 0.011, 0.003 in groups A and B, respectively) and negatively correlated with LnDI 30 in participants with dyslipidemia (beta = - 0.225, - 0.122, P = 0.035, 0.048 in groups B and D, respectively). Reduced serum SOD levels in individuals with dysglycemia plus dyslipidemia were observed, and a negative association between TG and SOD levels was found (r = - 0.461, P < 0.001)., Conclusion: TG correlated with both insulin resistance and beta cell function in individuals with dyslipidemia alone. SOD negatively correlated with TG, indicating a close relationship between oxidative stress and glucose-lipid metabolism. Due to the adverse effect of hypertriglyceridemia on insulin sensitivity and islet beta cell function, more attention should be paid to the detection and management of hypertriglyceridemia.

Objective To identify the relationship between physical activity,insulin resistance and cardiovascular risk in individuals with different glucose tolerance status and to provide evidence for exercise intervention in people with different glucose tolerance status. Methods A total of 691 patients with different glucose metabolism status were recruited as subjects of the research. Spearman correlation analysis was used to study the relationship between exercise frequency and insulin resistance, insulin sensitivity, neck circumference (NC) and neck circumference height ratio (NHtR) in the subjects with different glucose metabolism status, the relationship between NC and insulin resistance and insulin sensitivity in different glucose metabolism groups. Results 171(62.9%) Subjects with diabetes were intervened by exercised every day. Spearman correlation analysis showed the correlation between exercise frequency and tri-glyceride triglyceride-glucose index (TyG index) (r=-0.120, P＜0.05) and NC (r=-0.168, P＜0.05) were negatively correlated. In subjects with diabetes, NC was positively correlated with triglycerides(TG) (r=-0.100, P＜0.05), homeostasis model assessment of insulin resistance(HOMA-R) (r=-0.163, P＜0.05), total cholesterol/high-density lipoprotein(TC/HDL-C)(r=-0.214, P＜0.05) and TyG index (r=-0.156, P＜0.05). Conclusions Increased frequency of exercise is associated with reduced NC, improved insulin resistance, and cardiovascular risk factors in subjects of our team with newly diagnosed diabetes. Exercise has no significant effect on insulin resistance of subjects with normal glucose tolerance and pre-diabetes.

Purpose: High dietary magnesium intake may reduce insulin resistance (IR) and metabolic syndrome (MetS). The aim of the cross-sectional analysis was to evaluate the association between dietary magnesium intake, IR, and MetS using data from China Health and Nutrition Survey. Methods: Dietary magnesium intake was defined as daily dietary magnesium intake divided by body weight. Logistic regression analysis was used to calculate the odds ratio (OR) for IR and the prevalence of MetS across the quartile categories of dietary magnesium intake. In addition, we used the macro PROCESS to perform the mediation analyses. Results: A total of 8120 participants were included in the final analysis. We found a significant negative association between dietary magnesium intake and IR, the multivariable-adjusted OR for HOMA-IR comparing the highest to the lowest quartile of dietary magnesium intake was 0.435 (95% confidence intervals [CI] 0.376 to 0.502). The prevalence of the MetS was 38.6%, 28.9%, 22.5%, and 16.5% for increasing quartiles of dietary magnesium intake (p < 0.001). The mediation model analysis displayed that insulin resistance mediated the effect of dietary magnesium on MetS. The direct effect and indirect effect of dietary magnesium on MetS were found significant, and the calculated percentage of mediation by insulin resistance was 19.6%. Conclusion: Our study demonstrated a significant and independent negative relationship among weight-adjusted dietary magnesium intake, HOMA-IR, and MetS in a large Chinese population. IR partly mediated the relationship between dietary magnesium intake and MetS. [ABSTRACT FROM AUTHOR]

Background: Abnormal hepatic gluconeogenesis is related to hyperglycemia in mammals with insulin resistance. Despite the strong evidences linking Krüppel-like factor 11 (KLF11) gene mutations to development of Type 2 diabetes, the precise physiological functions of KLF11 in vivo remain largely unknown. Results: In current investigation, we showed that KLF11 is involved in modulating hepatic glucose metabolism in mice. Overexpression of KLF11 in primary mouse hepatocytes could inhibit the expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase (cytosolic isoform, PEPCK-C) and peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), subsequently decreasing the cellular glucose output. Diabetic mice with overexpression of KLF11 gene in livers significantly ameliorated hyperglycemia and glucose intolerance; in contrast, the knockdown of KLF11 expression in db/m and C57BL/6J mice livers impaired glucose tolerance. Conclusions: Our data strongly indicated the involvement of KLF11 in hepatic glucose homeostasis via modulating the expression of PEPCK-C. [ABSTRACT FROM AUTHOR]

Background: The shape of the glucose response curve during an oral glucose tolerance test (OGTT) can predict β-cell function and insulin resistance. However, there have been few studies conducted on Chinese people. Thus, we aimed to verify the usefulness of the glucose response curve in a large Chinese population. Methods: A total of 9059 OGTT (3-h tests) were categorized into either a monophasic or a multiphasic group based on the shape of the glucose response. Homeostasis model assessments of fasting insulin resistance, the Matsuda Index, the insulinogenic index, and the disposition index were assessed by plasma glucose and serum insulin concentration obtained at fasting or during an OGTT. Results: The shape of the OGTT glucose response curve was monophasic in 87.3% and multiphasic in 12.7% of participants. Individuals in the multiphasic group were younger compared to those in the monophasic group (38.6 ± 13.6 vs. 35.4 ± 13.5, P < 0.001). Individuals in the monophasic group had significantly higher fasting plasma glucose (FPG 5.6 ± 13.5 vs. 5.2 ± 0.6, P < 0.001), fasting insulin (FINS 14.8 ± 8.7 vs. 13.5 ± 7.9, P < 0.01), and homeostasis model assessment of insulin resistance (HOMA-IR 3.8 ± 2.6 vs. 3.1 ± 2.0, P < 0.001) and impaired β-cell function (disposition index 12.7 ± 14.1 vs. 16.6 ± 17.8, P < 0.001) compared to those in the multiphasic group. Conclusion: The monophasic OGTT glucose response curve could reflect impaired β-cell function in a large Chinese population. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder strongly associated with hepatic glucose intolerance and insulin resistance. The trefoil peptides are a family of small regulatory proteins and Tff3 is widely expressed in multiple tissues including liver. But the roles of Tff3 in regulation of glucose metabolism and insulin sensitivity in liver remain unclear. Here we show that the hepatic Tff3 expression levels were decreased in ob/ob and high-fat diet-induced obese mice. Overexpression of Tff3 in primary mouse hepatocytes inhibited the expression of gluconeogenic genes, including G6pc, PEPCK and PGC-1α, subsequently decreasing cellular glucose output. GTT and ITT experiments revealed that adenovirus-mediated overexpression of Tff3 in diabetic or obese mice improved glucose tolerance and insulin sensitivity. Collectively, our results indicated that Tff3 peptides are involved in glucose homeostasis and insulin sensitivity, providing a promising peptide on new therapies against the metabolic disorders associated with T2DM. [ABSTRACT FROM AUTHOR]

Abstract RING finger 186 (RNF186) is involved in the process of endoplasmic reticulum (ER)-stress-mediated apoptosis and inflammation of different cell types, such as HeLa cells and colon epithelial cells. However, the physiological and functional roles of RNF186 in peripheral tissues remain largely unknown. In the current study, we investigate the physiological function of RNF186 in the regulation of ER stress with respect to its biological roles in regulating insulin sensitivity in mouse primary hepatocytes. RNF186 expression is induced in the livers of diabetic, obese and diet-induced obese (DIO) mice. Mouse primary hepatocytes were isolated and treated with Ad-RNF186 or Ad-GFP. The results suggest that overexpression of RNF186 increases the protein levels of the ER stress sensors inositol requiring kinase 1 (IRE1) and C/EBP homologous protein (CHOP) protein, as well as the phosphorylation level of eukaryotic initiation factor 2α (eIF2α), in mouse primary hepatocytes. This effect impedes the action of insulin through c-Jun N-terminal kinase (JNK)-mediated phosphorylation of insulin receptor substrate 1 (IRS1). Furthermore, overexpression of RNF186 also significantly increases the levels of proinflammatory cytokines, including TNFα, IL-6 and MCP1. In addition, tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, alleviates the expression of ER stress markers induced by RNF186 overexpression. Taken together, the results of the present study show that overexpression of RNF186 induces ER stress and impairs insulin signalling in mouse primary hepatocytes, suggesting that RNF186 merits further investigation as a potential therapeutic target for treatment of insulin-resistance-associated metabolic diseases. [ABSTRACT FROM AUTHOR]