To‐Pang Chen

Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, FABP4 mRNA, and SREBP1 mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.

Everolimus, which inhibits mTOR kinase activity and is clinically used in graft rejection treatment, may have a two-sided influence on metabolic syndrome; its role in obesity and hyperglycemic in animals and humans, however, has been explored insufficiently. This study further determined how continual everolimus treatment affects glucose homeostasis and body weight control in C57BL6/J mice with obesity. An obesity mouse model was developed by administering a high-fat diet (HFD) to C57BL6/J mice over 12 weeks. The experimental group, while continuing their HFD consumption, were administered everolimus daily for 8 weeks. Metabolic parameters, glucose tolerance, fatty liver score, endocrine profile, insulin sensitivity index (ISI), insulin resistance (IR) index, and Akt phosphorylation, GLUT4, TNF-α, and IL-1 levels were measured in vivo. Compared with the control group, the everolimus group gained less body weight and had smaller adipocytes and lower fat pad weight; triglyceride (serum and hepatic), patatin-like phospholipase domain-containing 3, and fatty acid synthase levels; fatty liver scores; and glucose tolerance test values-all despite consuming more food. However, the everolimus group exhibited decreased ISI and muscle Akt phosphorylation and GLUT4 expression as well as impaired glucose tolerance and serum TNF-α and IL-1β levels-even when insulin levels were high. In conclusion, continual everolimus treatment may lead to diabetes with glucose intolerance and IR.

OBJECTIVE: Proton pump inhibitors' (PPIs) widespread use raises concerns about bone health, renal outcomes, and iron deficiency anaemia (IDA). We aim to address these concerns via comprehensive matching. METHODS: Using TriNetX 1:1 propensity score matching (PSM), we compared PPI and histamine-2 receptor antagonist (H2RA) users in terms of renal outcomes (eg, estimated glomerular filtration rate and chronic kidney disease (CKD) stages), bone health (osteoporosis and fractures), and IDA (International Classification of Diseases codes and laboratory values). RESULTS: After 1:1 PSM, 126 155 matched patients (mean age 59 years, estimated glomerular filtration rate (eGFR) 84-86 mL/min/1.732 m²) with fewer comorbidities (24% diabetes, 18% ischaemic heart disease, 11% heart failure, 11% nicotine dependence, 4% osteoporosis) were included. After follow-up, patients in the PPI group had a significantly lower mean eGFR compared with those in the H2RA group (75.74 ± 37.56 vs 78.60 ± 35.23 mL/min/1.732 m², p<0.001). The PPI group also demonstrated significantly increased risk of CKD progression, with HR of 1.137 (95% CI 1.120 to 1.154) for stage 3a, 1.260 (95% CI 1.235 to 1.286) for stage 3b, 1.316 (95% CI 1.288 to 1.345) for stage 4, and 1.785 (95% CI 1.718 to 1.854) for stage 5. In addition, PPI users exhibited higher risks of osteoporosis (HR 1.119, 95% CI 1.071 to 1.169) and major bone fractures (HR 1.153, 95% CI 1.110 to 1.198). The risk of IDA was also significantly elevated in the PPI group (HR 1.761, 95% CI 1.691 to 1.835). Findings were consistent across all subgroups and regions. CONCLUSION: In this large matched cohort, PPI use was associated with higher risks of CKD, osteoporosis, fractures, and IDA. Clinicians should monitor long-term PPI users for these potential adverse effects.