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Background: Insulin resistance (IR) and adipose tissue amplify the metabolic and reproductive outcomes in women with polycystic ovary syndrome (PCOS). It has been widely discussed that body composition influences metabolic health. Still, limited studies were focused on the role of the fat-free mass index (FFMI) in assessing IR in PCOS women., Aims: We aimed to explore the associations between FFMI/fat mass index (FMI) and IR in women with PCOS and assess the role of FFMI in predicting IR in women with PCOS., Methods: In the current cross-sectional study, women with PCOS aged between 18 and 40 years were enrolled from October 2018 to July 2022. Baseline demographic information was obtained using standardized self-administered questionnaires. Anthropometric, biochemical, and hormonal information was measured and recorded by investigators. Pearson's correlation and multivariable logistical regression were used to analyze the associations of FFMI/FMI and IR. In addition, receiver operating characteristic (ROC) curves were implied to measure the predictive role of FFMI/FMI for IR in women with PCOS., Results: A total of 371 women with PCOS, reproductive age (27.58 ± 4.89) were enrolled. PCOS women with IR have higher levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), homeostatic model assessment of insulin resistance (HOMA-IR), FMI, and FFMI than that without IR. FMI (r = 0.492, p < 0.001) and FFMI (r = 0.527, p < 0.001) were positively associated with IR. After adjusting for potential confounders, FMI and FFMI were significantly associated with IR in PCOS women, and the OR was 1.385 (95%CI: 1.212-1.583) and 2.306 (95%CI: 1.675-3.174), respectively. Additionally, the FFMI (0.847, 95%CI: 0.784-0.888) has a larger area of ROC (AUC) than the FMI (0.836, 95%CI: 0.799-0.896), while there is no difference in predicting IR (95%CI: -0.18-0.41, p = 0.456)., Conclusion: These results indicated that FFMI and FMI could significantly increase the risk of IR, both of which could be feasible predictors of IR in PCOS women., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Skeletal muscle is crucial for preserving glucose homeostasis. Insulin resistance and abnormalities in glucose metabolism result from a range of pathogenic factors attacking skeletal muscle in obese individuals. To relieve insulin resistance and restore glucose homeostasis, blocking the cell signaling pathways induced by those pathogenic factors seems an attractive strategy. It has been discovered that insulin sensitivity in obese people is inversely linked with the activity of NF-κB inducing kinase (NIK) in skeletal muscle. In order to evaluate NIK's pathological consequences, mechanism of action, and therapeutic values, an obese mouse model reproduced by feeding a high-fat diet was treated with a NIK inhibitor, B022. C2C12 myoblasts overexpressing NIK were utilized to assess insulin signaling and glucose uptake. B022 thus prevented high-fat diet-induced NIK activation and insulin desensitization in skeletal muscle. The insulin signaling in C2C12 myoblasts was compromised by the upregulation of NIK brought on by oxidative stress, lipid deposition, inflammation, or adenoviral vector. This inhibition of insulin action is mostly due to an inhibitory serine phosphorylation of IRS1 caused by ERK, JNK, and PKC that were activated by NIK. In summary, NIK integrates signals from several pathogenic factors to impair insulin signaling by igniting a number of IRS1-inhibiting kinases, and it also has significant therapeutic potential for treating insulin resistance., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Berberine (BBR), a natural isoquinoline alkaloid exhibiting insulin sensitizing activity, has been applicated in the treatment of diabetes. However, until now, the exact target of BBR has not been well investigated. Here, primary hepatocytes pre-treated with TNF-α were used to evaluate the role of BBR on hepatic insulin sensitivity. Western blot and immunoprecipitation were used to investigate the effect of BBR on the crosstalk between TNF-α pathway and insulin signaling pathway. Molecular docking was used to verify the interactions between BBR and its potential targets. BBR inhibits the MEKK1 and MEK1/2, and thus suppresses the activation of their downstream ERK1/2. It attenuates the ERK1/2-induced serine phosphorylation of IRS-1 and thus enhances IRS-1 tyrosine phosphorylation and Akt activation. By molecular docking, BBR is proved to efficiently bind MEK1/2. MEKK1 is also considered as BBR target for its similarity in primary structure with MEK1/2. In conclusion, BBR ameliorates TNF-α-induced hepatic insulin resistance by targeting MEKK1 and MEK1/2., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The first-degree relatives of patients with diabetes (FDRs) share a common genetic background with patients with diabetes. Insulin resistance is recognized as a common contributor to diabetes and nonalcoholic fatty liver disease (NAFLD). The present study aimed to investigate the association between a first-degree family history of diabetes (FHD) and NAFLD and the influence of glucose metabolic status., Methods: The present work analyzed a part of the baseline data of the REACTION study conducted in a community population. A total of 11,162 participants with an average age of 55.57 ± 9.66 years were enrolled, including 9870 non-FDRs and 1292 FDRs. First-degree FHD was defined as at least one patient with diabetes among parents, siblings or children. The fatty liver index (FLI) was calculated to identify NAFLD., Results: The proportions of subjects without NAFLD, with intermediate FLI, and with NAFLD differed significantly between non-FDRs and FDRs (P < 0.001). FLI was one of the metabolic factors independently associated with first-degree FHD (P = 0.006). Multivariate variance analysis revealed positive associations of first-degree FHD and glucose metabolic status (both P < 0.001) with FLI, which were independent of each other (P for interaction = 0.182). Multiple stepwise linear regression analysis identified that first-degree FHD was independently and positively associated with FLI in men, premenopausal women, and postmenopausal women (all P < 0.05)., Conclusion: A first-degree FHD was an independent risk factor for NAFLD. Regardless of the status of glucose metabolism, FDRs were more susceptible to NAFLD., (Copyright © 2021. Published by Elsevier Inc.)

Pyroptosis plays a critical role in the development of obesity-associated inflammation and insulin resistantance (IR). Ginsenoside Rb2 (Rb2), the main component of ginsenosides has drawn appreciable interest in the context of glucose metabolism. In the present study, we investigated Rb2-mediated protection against obesity-induced IR and the related mechanisms. Rb2 could significantly reduce high-fat diet (HFD)-induced body weight changes, fat accumulation and IR. In addition, Rb2 treatment inhibited pyroptosis-related genes and proteins, such as caspase-1, ASC, NLRP3, IL-1β and GSDMD in HFD-fed mice. The above results were recapitulated in 3T3-L1 adipocytes and demonstrated that Rb2 improved TNF-α induced IR and pyroptosis in 3T3-L1 adipocytes. Furthermore, Rb2 reduced the phosphorylation levels of p65 and IκBα both in vitro and in vivo. The present study showed that Rb2, which could serve as a promising agent for the treatment of IR and obesity, ameliorated IR by inhibiting pyroptosis in adipocytes in vivo and in vitro through the NF-κB pathway.