Daily Endocrinology Research Analysis

UNLABELLED: Diabetic kidney disease (DKD) progression involves intricate interactions among senescence, oxidative stress, inflammation, and fibrosis. This study systematically investigates the regulatory role and molecular mechanisms of NUAK1 in DKD pathogenesis. Bioinformatics analysis of Gene Expression Omnibus data sets identified NUAK1 as a differentially expressed gene, validated in human kidney proximal tubule epithelial (HK-2) cells, high-fat diet and streptozotocin-induced DKD mice, d-galactose-induced senescent mice, and human peripheral blood mononuclear cells. Functional studies demonstrated that NUAK1 inhibition via siRNA knockdown, pharmacological inhibitors, or kidney tubule-targeted adeno-associated virus serotype carrying shRNA against NUAK1 delivery attenuated reactive oxygen species-tumor protein 53 (ROS/P53) axis-mediated renal tubular senescence, oxidative stress, inflammation, and fibrosis in vitro and in vivo. Mechanistically, chromatin immunoprecipitation quantitative PCR revealed that transcription factor ETS1 directly binds to the NUAK1 promoter, driving its transcriptional activation in DKD. Furthermore, molecular docking and dynamics simulations identified Asiatic acid (AA) as a potent NUAK1 inhibitor, with a stable binding affinity. AA suppressed NUAK1 expression and downstream pathological processes, ameliorating renal injury in DKD models. These findings elucidate the role and regulatory mechanisms of NUAK1 in modulating ROS/P53 axis-driven tubular senescence and oxidative stress, providing a theoretical basis for structure optimization in drug development targeting NUAK1. ARTICLE HIGHLIGHTS: Mechanisms linking renal tubular senescence to diabetic kidney disease (DKD) progression remain poorly understood. Systematic elucidation of the regulatory role of NUAK1 in the pathogenesis of DKD and its regulatory mechanisms is provided. NUAK1 is upregulated in DKD, promoting senescence via reactive oxygen species-tumor protein 53 under transcriptional activation by E26 transformation-specific 1, while Asiatic acid (AA) directly binds NUAK1 to suppress these pathological processes. NUAK1 emerges as a therapeutic target for DKD, and AA provides a natural scaffold for NUAK1 inhibitor development, offering a strategy to combat diabetes-related renal decline.

OBJECTIVE: Overweight and obesity are prevalent in type 1 diabetes and contribute to cardiovascular risk. Tirzepatide, a gastric inhibitory polypeptide and glucagon-like peptide 1 receptor coagonist, has not been studied in type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a 12-week, phase 2, double-blind, placebo-controlled trial in adults with type 1 diabetes and BMI >30 kg/m2. Participants were randomized to once-weekly subcutaneous tirzepatide (2.5 mg for 4 weeks, 5.0 mg for 8 weeks) or placebo. The primary end point was change in body weight at 12 weeks. RESULTS: Twenty-two of 24 adults with type 1 diabetes completed the study. After 12 weeks, the mean change in weight was -10.3 kg (95% CI -12.8 to -7.7 kg) in the tirzepatide group and -0.7 kg (95% CI -1.4 to 2.8 kg) in the placebo group, with an estimated treatment difference of -8.7 kg (95% CI -12.0 to -5.5 kg; P < 0.0001), representing 8.8% weight loss. In the tirzepatide group, 100% and 45% of participants experienced weight loss of ≥5% and ≥10% respectively, compared with 9% and 0% in the placebo group. Tirzepatide improved HbA1c (mean difference -0.4% [95% CI -0.7 to 0.0%] vs. placebo; P = 0.05) and reduced total daily insulin dose (-24.2 units/day tirzepatide and -0.3 units/day placebo; difference from baseline vs. placebo -35.1% [95% CI -46.5 to -21.3%; P = 0.0002]). There were no significant adverse events in either group. CONCLUSIONS: Among adults with type 1 diabetes and obesity, tirzepatide was superior to placebo for weight loss over 12 weeks.

BACKGROUND: Checkpoint inhibitor-associated autoimmune diabetes (CIADM) is a rare but life-altering complication of immune checkpoint inhibitor (ICI) therapy. Biomarkers that predict type 1 diabetes (T1D) are unreliable for CIADM. AIM: To identify biomarkers for prediction of CIADM. METHODS: From our prospective biobank, 14 CIADM patients who had metastatic melanoma treated with anti-PD-1 ± anti-CTLA4 were identified. Controls were selected from the same biobank, matched 2:1. Pre-treatment, on-ICI and post-CIADM serum and peripheral blood mononuclear cells (PBMCs) were analysed. Serum was analysed for T1D autoantibodies, C-peptide, glucose and cytokines. PBMCs were profiled using flow cytometry. Pancreatic volume was measured using CT volumetry. RESUTLS: Before treatment, CIADM patients had smaller pancreatic volume (27% reduction, p=0.044) and higher anti-GAD antibody titres (median 2.9 versus 0, p=0.01). They had significantly higher baseline proportions of Th17 helper cells (p=0.03), higher CD4+ central memory cells (p=0.04) and lower naïve CD4+ cells (p=0.01). With ICI treatment, greater declines in pancreatic volume were seen in CIADM patients (p<0.0001). Activated CD4+ subsets increased significantly in CIADM and controls with immune-related adverse effects (IRAE) but not controls without IRAE. Using only pre-treatment results, pancreatic volume, anti-GAD antibody titre and baseline immune flow profile were highly predictive of CIADM development, with an area under the curve (AUC) of >0.96. CONCLUSIONS: People who develop CIADM are immunologically predisposed and have antecedent pancreatic and immunological changes that accurately predict disease with excellent sensitivity. These biomarkers could be used to guide ICI use, particularly when planning treatment for low-risk tumours. FUNDING: JEG is supported by NHMRC Investigator grant 2033228. AMM by NHMRC Investigator grant2009476 and GVL by NHMRC Investigator grant 2007839.