ABSTRACT
BACKGROUND: The molecular mechanisms underlying nonalcoholic fatty liver disease (NAFLD) remain to be fully elucidated. Ubiquitin specific protease 13 (USP13) is a critical participant in inflammation-related signaling pathways, which are linked to NAFLD. Herein, the roles of USP13 in NAFLD and the underlying mechanisms were investigated. METHODS: L02 cells and mouse primary hepatocytes were subjected to free fatty acid (FFA) to establish an in vitro model reflective of NAFLD. To prepare in vivo model of NAFLD, mice fed a high-fat diet (HFD) for 16 weeks and leptin-deficient (ob/ob) mice were used. USP13 overexpression and knockout (KO) strategies were employed to study the function of USP13 in NAFLD in mice. RESULTS: The expression of USP13 was markedly decreased in both in vitro and in vivo models of NAFLD. USP13 overexpression evidently inhibited lipid accumulation and inflammation in FFA-treated L02 cells in vitro. Consistently, the in vivo experiments showed that USP13 overexpression ameliorated hepatic steatosis and metabolic disorders in HFD-fed mice, while its deficiency led to contrary outcomes. Additionally, inflammation was similarly attenuated by USP13 overexpression and aggravated by its deficiency in HFD-fed mice. Notably, overexpressing of USP13 also markedly alleviated hepatic steatosis and inflammation in ob/ob mice. Mechanistically, USP13 bound to transforming growth factor ß-activated kinase 1 (TAK1) and inhibited K63 ubiquitination and phosphorylation of TAK1, thereby dampening downstream inflammatory pathways and promoting insulin signaling pathways. Inhibition of TAK1 activation reversed the exacerbation of NAFLD caused by USP13 deficiency in mice. CONCLUSIONS: Our findings indicate the protective role of USP13 in NAFLD progression through its interaction with TAK1 and inhibition the ubiquitination and phosphorylation of TAK1. Targeting the USP13-TAK1 axis emerges as a promising therapeutic strategy for NAFLD treatment.
Subject(s)
Diet, High-Fat , MAP Kinase Kinase Kinases , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease , Ubiquitin-Specific Proteases , Animals , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , MAP Kinase Kinase Kinases/metabolism , Ubiquitin-Specific Proteases/metabolism , Humans , Male , Enzyme Activation , Inflammation/pathology , Mice, Knockout , Mice , Hepatocytes/metabolism , Cell Line , UbiquitinationSubject(s)
Diabetes Mellitus, Type 2 , Glucagon-Like Peptides , Hypoglycemic Agents , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/blood , Retrospective Studies , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/adverse effects , Glucagon-Like Peptides/administration & dosage , Glucagon-Like Peptides/adverse effects , Glucagon-Like Peptides/therapeutic use , Female , Male , Injections, Subcutaneous , Middle Aged , Product Surveillance, Postmarketing , Aged , Treatment Outcome , Blood Glucose/drug effects , Blood Glucose/metabolism , Glycated Hemoglobin/analysis , Glycated Hemoglobin/drug effects , Glycated Hemoglobin/metabolism , Drug Administration ScheduleABSTRACT
BACKGROUND: There is limited evidence on the safety of sodium-glucose co-transporter-2 inhibitor (SGLT2i) use in the real world of China. We conducted this two-center, retrospective study to assess the incidence rate and risk factors of Dapagliflozin-associated DK/DKA among patients with type 2 diabetes mellitus (T2DM) in China. RESEARCH DESIGN AND METHODS: Patients with T2DM treated with Dapagliflozin in Shanghai General Hospital were included in this retrospective analysis. Univariate and multivariate logistic regression was performed, and odds ratio (OR) and 95% confidence interval (CI) were calculated to identify the influencing factors associated with the occurrence of DK/DKA. RESULTS: A total of 1985 T2DM patients received Dapagliflozin for the first time were included. The prevalence of DK and DKA was 2.47% and 0.35%, respectively. Multivariate logistic regression identified age <45 years [OR = 2.99, 95% CI (1.45-6.17)], concomitant use of Acarbose [OR = 2.18, 95% CI (1.06-3.38)], Metformin [OR = 1.84, 95% CI (1.01-3.38)], and Insulin [OR = 1.93, 95% CI (1.02-3.66)] as participating factors for DK/DKA. The 1:4 matched subset sensitivity analysis further confirmed the risk factors of Dapagliflozin-associated DK/DKA. CONCLUSIONS: Age less than 45 years, concomitant use of Acarbose and insulin were risk factors for Dapagliflozin-associated DK/DKA. Clinicians should watch out for high-risk features among patients with SGLT2i prescription.
Subject(s)
Benzhydryl Compounds , Diabetes Mellitus, Type 2 , Diabetic Ketoacidosis , Glucosides , Sodium-Glucose Transporter 2 Inhibitors , Humans , Middle Aged , Diabetic Ketoacidosis/chemically induced , Diabetic Ketoacidosis/epidemiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Retrospective Studies , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Acarbose , China/epidemiology , Risk Factors , InsulinABSTRACT
Objective: The purpose of this study was to determine the relation between the lipid accumulation product index (LAPI) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: Herein, 931 patients were enrolled and their data were collected. Then the interrelation between LAPI and DKD was assessed using multivariate logistic regression analyses (LRAs) and by a restricted cubic spline (RCS). Results: In total, 931 participants (352 females and 579 males) aged 55 years on average were included in the study. After adjusting for several confounders, the odds ratio for DKD was increased evidently in the third LAPI tertile compared with that in the first LAPI tertile. In addition, the RCS revealed a positive interrelation between LAPI and DKD. In the subgroup analyses, age, sex, hyperlipidemia, hypertension, and HbA1c did not significantly interact with LAPI. Conclusions: LAPI was higher in the DKD group than in the no-DKD group, and LAPI is positively linked with DKD, which may have potential value to diagnose DKD in clinical practice.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Hypertension , Lipid Accumulation Product , Female , Male , Humans , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/etiology , Odds RatioABSTRACT
Objective: Patients with type 2 diabetes have a high risk of non-alcoholic fatty liver disease (NAFLD) and related liver fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated efficacy in improving NAFLD, while their effectiveness on liver fibrosis is limited in type 2 diabetic patients. Materials/Methods: A prospective cohort study was performed in type 2 diabetic patients. The study subjects were divided into two groups based on the use of liraglutide or not, and propensity score matching (PSM) was also conducted. After 12 months follow-up, liver fibrosis was assessed by NAFLD fibrosis score (NFS) fibrosis-4 (FIB-4), and liver stiffness measurement (LSM). The association between liraglutide use and liver fibrosis was analyzed by multivariable linear regression. Results: In the current study, a total of 1,765 type 2 diabetic patients were enrolled. 262 patients were liraglutide user and 1,503 were nouser. After 12 months follow-up, liraglutide use tended to be associated with reduced prevalence of advanced fibrosis (3.1% vs. 6.1%, P = 0.218). After adjustment for confounding factors, multivariable linear regression revealed that liraglutide use was negatively associated with decreased NFS (ß= -0.34, P = 0.043), FIB4 (ß= -0.26, P = 0.044) and LSM (ß= -4.95, P = 0.007) in type 2 diabetics. The results after PSM were similar to those before PSM. Conclusions: Liraglutide treatment is associated with decreased liver fibrosis in type 2 diabetic subjects.
