Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system. METHODS: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB-/- mice were generated, and relevant in vivo experiments were performed. RESULTS: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage. CONCLUSION: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.

A Nomogram for Predicting the Risk of CKD Based on Cardiometabolic Risk Factors.

Background: In China, the spectrum of causes for CKD has been changing in recent years, and the proportion of CKD caused by cardiometabolic diseases, such as diabetes and hypertension continues to increase. Thus, predicting CKD based on cardiometabolic risk factors can to a large extent help identify those at increased risk and facilitate the prevention of CKD. In this study, we aimed to develop a nomogram for predicting CKD risk based on cardiometabolic risk factors. Methods: We developed a nomogram for predicting CKD risk by using a subcohort population of the 4C study, which was located in central China. The prediction model was designed by using a logistic regression model, and a backwards procedure based on the Akaike information criterion was applied for variable selection. The performance of the model was evaluated by the concordance index (C-index), and Hosmer‒Lemeshow goodness-of-fit test. The bootstrapping method was applied for internal validation. Results: During the 3-years follow-up, 167 cases of CKD developed. By using univariate and multivariate logistic regression models, the following factors were identified as predictors in the nomogram: age, sex, HbA1c, baseline eGFR, low HDL-C levels, high TC levels and SBP. The bootstrap-corrected C-index for the model was 0.84, which indicated good discrimination ability. The Hosmer‒Lemeshow goodness-of-fit tests yielded chi-square of 13.61 (P=0.192), and the calibration curves demonstrated good consistency between the predicted and observed probabilities, which indicated satisfactory calibration ability. Conclusion: We developed a convenient and practicable nomogram for the 3­year risk of incident CKD among a population in central China, which may help to identify high-risk individuals for CKD and contribute to the prevention of CKD.

Associations between metabolic score for visceral fat and the risk of cardiovascular disease and all-cause mortality among populations with different glucose tolerance statuses.

AIMS: To investigate the associations between metabolic score for visceral fat (METS-VF) and clinical outcomes among populations with different glucose tolerance statuses. METHODS: We analysed 6827 participants aged ≥ 40 years with different glucose tolerance statuses from a cohort study. The associations between METS-VF and cardiovascular disease (CVD) events and all-cause mortality were assessed using Cox regression, restricted cubic spline and receiver operating characteristic curves. RESULTS: During a follow-up of 5.00 years, there were 338 CVD events and 307 subjects experienced all-cause death. The METS-VF quartile (Quartile 4 versus 1) was significantly related to CVD events [adjusted HRs and 95% CIs: 5.75 (2.67-12.42), 2.80 (1.76-4.48), and 3.31 (1.28-8.54) for subjects with normal glucose tolerance, prediabetes and diabetes, respectively] and all-cause mortality [adjusted HRs and 95% CIs: 2.80 (1.43-5.49), 4.15 (2.45-7.01), and 4.03 (1.72-9.42), respectively]. Restricted cubic spline suggested a dose-response association of METS-VF with the risk of CVD events and all-cause mortality. The area under curve for CVD events and all-cause mortality was higher for METS-VF than for the other obesity and IR indexes in subjects with different glucose tolerance statuses. CONCLUSIONS: The METS-VF was associated with an increased risk of CVD events and all-cause mortality and could be used as a predictive index of the risk of CVD events and all-cause mortality among populations with different glucose tolerance statuses.

LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis.

Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB-/- bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.

ED visits for drug-related poisoning in the United States, 2007.

BACKGROUND: Fatal drug-related poisoning has been well described. However, death data only show the tip of the iceberg of drug-related poisoning as a public health problem. Using the 2007 Nationwide Emergency Department Sample, this study described the characteristics of emergency department visits for drug-related poisoning in the United States. METHODS: Any ED visit that had an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of 960-979 was defined as a drug-related poisoning case. Intentionality of poisoning was determined by E-codes. Weighted estimates of ED visits were calculated by patient and hospital characteristics, intentionality of poisoning, and selected drug classes. Population rates by sex, age, urban/rural classification, median household income in patient's zip code, and hospital region were calculated. RESULTS: An estimated 699 123 (95% confidence interval, 666 529-731 717) ED visits for drug-related poisoning occurred in 2007. Children 0 to 5 years old had the highest rate for unintentional poisoning (male, 237 per 100 000; female, 218 per 100 000). The rate of drug-related poisoning in rural areas (684 per 100 000) was 3 times higher than the rates in other areas. Psychotropic agents and analgesics were responsible for 43.7% of all drug-related poisoning. Women 18 to 20 years old had the highest ED visit rate for suicidal poisoning (245 per 100 000). The estimated ED charges were $1 394 051 262, and 41.1% were paid by Medicaid and Medicare. CONCLUSION: Antidepressants and analgesics were responsible for nearly 44% of ED visits for drug-related poisoning in the United States. Interventions and future research should target prescription opioids, rural areas, children 0 to 5 years old for unintentional drug-related poisoning, and female ages 12 to 24 years for suicidal drug-related poisoning.