4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes.

BACKGROUND: Pancreatic beta cell dysfunction and activated macrophage infiltration are early features in type 1 diabetes pathogenesis. A tricarboxylic acid cycle metabolite that can strongly activate NF-E2-related factor 2 (Nrf2) in macrophages, itaconate is important in a series of inflammatory-associated diseases via anti-inflammatory and antioxidant properties. However, its role in type 1 diabetes is unclear. We used 4-octyl itaconate (OI), the cell-permeable itaconate derivate, to explore its preventative and therapeutic effects in mouse models of type 1 diabetes and the potential mechanism of macrophage phenotype reprogramming. METHODS: The mouse models of streptozotocin (STZ)-induced type 1 diabetes and spontaneous autoimmune diabetes were used to evaluate the preventative and therapeutic effects of OI, which were performed by measuring blood glucose, insulin level, pro- and anti-inflammatory cytokine secretion, histopathology examination, flow cytometry, and islet proteomics. The protective effect and mechanism of OI were examined via peritoneal macrophages isolated from STZ-induced diabetic mice and co-cultured MIN6 cells with OI-pre-treated inflammatory macrophages in vitro. Moreover, the inflammatory status of peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients was evaluated after OI treatment. RESULTS: OI ameliorated glycemic deterioration, increased systemic insulin level, and improved glucose metabolism in STZ-induced diabetic mice and non-obese diabetic (NOD) mice. OI intervention significantly restored the islet insulitis and beta cell function. OI did not alter the macrophage count but significantly downregulated the proportion of M1 macrophages. Additionally, OI significantly inhibited MAPK activation in macrophages to attenuate the macrophage inflammatory response, eventually improving beta cell dysfunction in vitro. Furthermore, we detected higher IL-1ß production upon lipopolysaccharide stimulation in the PBMCs from type 1 diabetes patients, which was attenuated by OI treatment. CONCLUSIONS: These results provided the first evidence to date that OI can prevent the progression of glycemic deterioration, excessive inflammation, and beta cell dysfunction predominantly mediated by restricting macrophage M1 polarization in mouse models of type 1 diabetes.

Age moderates the relationships between obesity, glucose variability, and intensive care unit mortality: a retrospective cohort study.

BACKGROUND: Although the associations between obesity, glucose variability (GV), and Intensive Care Unit (ICU) mortality have been studied extensively, whether age moderates these associations is not well understood. MATERIALS AND METHODS: The medical records of 1062 patients, who were admitted into ICU at Sir Run Run Shaw Hospital (Zhejiang, China), were studied. Logistic regression was used to test the associations between obesity, GV, and ICU mortality. Furthermore, the moderation effect of age was tested. RESULTS: After controlling for covariates, the underweight group had the highest odds of death (OR 2.38, 95% CI 1.43-3.95, p < 0.001) in comparison with the control group (overweight). However, normal weight (OR 1.29, 95% CI 0.88-1.89, p = 0.185) and obese (OR 1.08, 95% CI 0.61-1.90, p = 0.790) groups had similar odds of death, compared to the overweight group. Age significantly moderated the association between obesity and mortality, where being overweight was more advantageous than being normal weight in older adults (B = 0.03, SE = 0.01, OR 1.03, 95% CI 1.001-1.06, p = 0.045). Meanwhile, higher GV predicted greater mortality in adjusted models (OR 1.23, 95% CI 1.06-1.42, p = 0.005). We also found an interaction between age and GV (B = - 0.01, SE = 0.01, OR 0.99, 95% CI 0.98-0.999, p = 0.025), which suggested that the association between GV and mortality becomes weaker with increasing age. CONCLUSIONS: With increasing age, the association between BMI and mortality becomes stronger and the association between glucose variability and mortality becomes weaker. Future studies should investigate the underlying mechanisms of such phenomenon and the causal relationship between obesity, GV, and ICU mortality.

C-reactive protein and thyroid-stimulating hormone levels as risk factors for hypothyroidism in patients with subacute thyroiditis.

OBJECTIVE: This study was designed to explore the relationships between the clinical characteristics and outcomes of patients with subacute thyroiditis (SAT). DESIGN: This is a single-center retrospective study. PATIENTS: Eighty-nine patients with SAT who were hospitalized in the Sir Run Run Shaw Hospital in Zhejiang, China, from October 2014 to September 2020 were included. METHODS: The Mann-Whitney U-test, chi-square test, and Cox regression analysis were conducted to identify the relationships between clinical characteristics and outcomes. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff levels of C-reactive protein (CRP) and thyroid-stimulating hormone (TSH). RESULTS: The hypothyroidism and recurrence rates were 15.7 and 16.9%, respectively. CRP (≥72.0 mg/L), TSH (<0.02 mIU/L), and free triiodothyronine (fT3) (≥4.10 pg/mL) were associated with hypothyroidism. The cutoff level was 97.80 mg/L for CRP (area under the curve (AUC), 0.717, P = 0.014; sensitivity, 57.1%; specificity, 84.0%) and 0.10 mIU/L for TSH (AUC, 0.752, P = 0.004; sensitivity, 100%; specificity, 46.0%) by ROC curve analysis for hypothyroidism. The factors under study were not associated with recurrence. CONCLUSION: CRP and TSH were risk factors for hypothyroidism in SAT. Thyroid functions should be monitored closely for the early detection of hypothyroidism, especially in patients with CRP levels of more than 97.80 mg/L and TSH levels of less than 0.10 mIU/L.

Age moderates the associations between TRAbs, free T3 and outcomes of Graves' disease patients with radioactive iodine treatment.

OBJECTIVE: This study aimed to explore whether age moderates the associations between TSH receptor antibodies (TRAbs) with thyroid hormones and remission in patients with Graves' disease (GD) who undergo radioactive iodine (RAI) treatment. DESIGN: A single-centre retrospective study. PATIENTS: A total of 435 eligible consecutive patients diagnosed with GD and treated with RAI therapy were included. METHODS: TRAbs and thyroid hormones prior to RAI were recorded. Pearson's correlation, t tests and analysis of covariance were conducted to identify the associations between TRAbs, thyroid hormones and remission. Moderation analyses were conducted to test age as a moderator. RESULTS: Overall, 75.4% of the patients achieved remission with a single dose of iodine-131. TRAb levels before RAI were positively correlated with the circulating thyroid hormones (ps < 0.001). Age moderated the association between TRAbs and free T3 (FT3) (P = .01), but did not moderate the association between TRAbs and free T4 (FT4) (P = .07). TRAb levels before RAI only significantly predicted remission status in young patients (P = .03), but not in middle-aged (P = .36) or older patients (P = .74), after adjusting for covariates. When age was included as a continuous variable, moderation analyses revealed that the association between TRAbs and remission status was stronger in younger patients (P = .03). CONCLUSIONS: The majority of Graves' disease patients experienced a long-term remission following a single dose of iodine-131. Associations between TRAbs, FT3 and remission are moderated by age. TRAb level prior to RAI is a significant remission in younger patients, but not in middle-aged or older patients.