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.

Background: Distinguishing diabetic nephropathy (DN) from non-diabetic kidney disease (NDKD) in patients with diabetes remains clinically challenging, particularly when renal biopsy is not routinely performed. We aimed to identify clinical predictors of biopsy-proven NDKD. Methods: We conducted a retrospective cohort study of patients with type 2 diabetes who underwent native kidney biopsy at a tertiary referral center. Patients were classified as DN alone, mixed DN with NDKD, or pure NDKD. Baseline clinical and laboratory variables were analyzed. Logistic regression models were used to identify factors associated with NDKD. Results: Among 664 patients, 18.7% had DN alone, 27.0% had mixed lesions, and 54.3% had pure NDKD. In multivariable analysis, higher HbA1c, lower body mass index, lower low-density lipoprotein cholesterol, and higher urine albumin-to-creatinine ratio were independently associated with NDKD. For pure NDKD, lower HbA1c, lower serum albumin, lower body mass index, higher IgA levels, and absence of hypertension were significant predictors. Conclusions: NDKD is common among patients with diabetes undergoing biopsy and can be partially predicted using routinely available clinical parameters. These findings may aid in identifying patients who could benefit from timely renal biopsy and individualized management.