Aim: Hormone pulsatility is an important aspect of the hypothalamic-pituitary-adrenal (HPA) axis in health and disease. We use the properties of simple mathematical models to determine whether hormone pulsatility reflects the presence of a time delay in the production of hormones and/or is related to the impulsive nature of hormone secretion. Methods: The predictions of two models for HPA pulsatility are compared. The first model assumes pulsatility arises because of a time delay in the synthesis of glucocorticoids (GCs). The second model suggests that pulsatility reflects the impulsive nature of hormone secretion. The generation of oscillations by the second mechanism does not require a time delay. Results: The time delay for the synthesis of GC (0–10 minutes) may not be long enough to account for the oscillations in adrenocorticotrophin (ACTH) and GC observed with constant corticotrophin-releasing hormone (CRH) infusion in rats. A simple mechanism for hormone release, illustrated using an integrate-and-fire mechanism, reproduces the observed hormone pulsatility. Conclusions: The water solubility of CRH and ACTH draws attention to the role played by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in the calcium-dependent exocytosis of peptide hormones. Abnormalities in SNARE proteins are anticipated to cause changes in the amplitude modulation of ACTH and CRH hormone pulses. In mice, a mutation in a SNARE protein causes abnormalities in the HPA axis. Mutations in SNARE proteins occur in many neurodegenerative and neuropsychiatric diseases. Abnormalities in HPA function also occur in these disorders. The identification of SNARE protein mutations in exosomes in serum and cerebrospinal fluid in humans may make it possible to determine whether there exists a causal relationship between an SNARE protein mutation and abnormalities in the HPA axis in this patient group.

Aim: This study aimed to evaluate and compare the therapeutic effects of resmetirom, semaglutide, and obeticholic acid (OCA) on non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and fibrosis progression across three distinct metabolic dysfunction-associated steatohepatitis (MASH) models. A secondary objective was to assess model-specific variations in drug efficacy to inform future preclinical model selection for MASH research. Methods: The Gubra-Amylin NASH (GAN) diet-induced obesity (DIO)-MASH model was induced by the GAN diet in C57BL/6 mice for 24 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. The ob/ob-MASH model was induced by the GAN diet in ob/ob mice for 6 weeks, followed by semaglutide and resmetirom treatment for 4 weeks. GAN-carbon tetrachloride (CCL4) MASH model was induced by 10 weeks of GAN diet and followed by 4 weeks of CCL4 in C57BL/6 mice, resmetirom and OCA were given in the last 4 weeks. Body weights, serum biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids], histopathological NAS scores, fibrosis staging, and α-smooth muscle actin (α-SMA) expression were analyzed. Results: In the GAN DIO-MASH model, both semaglutide and resmetirom reduced NAS significantly, and resmetirom but not semaglutide reduced α-SMA expression. In the ob/ob MASH model, treatment with semaglutide and resmetirom reduced NAS. Semaglutide significantly reduced α-SMA expression. In the GAN-CCL4 MASH model, both resmetirom and OCA significantly reduced MASH progression, resmetirom reduced liver fibrosis and α-SMA expression while OCA reduced α-SMA expression only. Conclusions: Resmetirom, semaglutide, and OCA exhibited model-dependent efficacy in attenuating MASH progression. Although all agents improved the NAS, their antifibrotic effects diverged significantly: resmetirom demonstrated pan-model efficacy, semaglutide selectively reduced α-SMA expression in leptin-deficient models, and OCA showed minimal impact on fibrosis biomarkers. These observations highlight the critical importance of preclinical model selection for MASH therapeutic development, particularly when assessing fibrosis-targeted interventions.

Aim: Metabolic syndrome (MetS) is associated with chronic conditions, including type 2 diabetes mellitus (T2DM) and cardiovascular disorders. New markers are needed for the early detection and successful treatment of MetS, especially in patients with T2DM. The serum uric acid-to-creatinine ratio (UCR) and waist-to-height ratio (WHR) are novel markers in various chronic metabolic disorders. We aimed to compare WHR, UCR, and other metabolic and laboratory markers in T2DM patients with and without MetS. Methods: Patients with T2DM who visited the outpatient clinics of our institution were enrolled in the study. Total diabetic subjects were 239 of which 180 were in MetS group while 59 were in without MetS group. Data from both study groups were compared. Results: The serum UCR in the MetS and control groups was 6.3 ± 2.1 and 5.8 ± 1.6, respectively (p = 0.04). The WHR in the MetS and control groups was 0.65 (0.47–0.87) and 0.62 (0.35–0.84), respectively (p < 0.001). Significant positive correlations were observed between UCR and triglycerides (r = 0.17, p = 0.009), waist circumference (r = 0.13, p = 0.046), hip circumference (r = 0.18, p = 0.006), BMI (r = 0.2, p = 0.002), and GFR (r = 0.4, p < 0.001). Similarly, significant positive correlations were noted between WHR and systolic blood pressure (r = 0.12, p = 0.049), weight (r = 0.5, p < 0.001), BMI (r = 0.7, p < 0.001), and UCR (r = 0.12, p = 0.047). In the ROC analysis, the sensitivity and specificity of WHR (when higher than 0.64) in detecting MetS were 72% and 54%, respectively (AUC: 0.69, p < 0.001, 95% CI: 0.61–0.77). Conclusions: We propose that WHR and UCR could be valuable tools for the early detection of MetS in patients with T2DM. The ease and low cost of evaluating WHR and UCR make them practical markers for monitoring and diagnosing MetS.