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Despite major investment by pharmaceutical companies in conventional drug discovery pipelines, development of new drugs has failed to keep up with the increasing incidence of many diseases, including type 2 diabetes (T2D). Drug repurposing, where existing drugs are applied to a new indication, is gaining momentum as a successful approach to overcome the bottlenecks commonly encountered with conventional approaches. Repurposing takes advantage of available information on the molecular pharmacology of clinical agents to drastically shorten drug development timelines. This review discusses recent advances in the discovery of new antidiabetic agents using repurposing strategies. [ABSTRACT FROM AUTHOR]

The present study investigated the role of dietary cholesterol and fat in the development of nonalcoholic fatty liver disease, a common liver disease in metabolic disorders. Mice were fed a diet of regular chow (CH), chow supplemented with 0.2% w/w cholesterol (CHC), high fat (HF, 45kcal%) or HF with cholesterol (HFC) for 17weeks. While both HF and HFC groups displayed hepatic steatosis and metabolic syndrome, only HFC group developed the phenotype of liver injury, as indicated by an increase in plasma level of alanine transaminase (ALT, by 50-80%). There were ~2-fold increases in mRNA expression of tumor necrosis factor α, interleukin 1β and monocyte chemotactic protein 1 in the liver of HFC-fed mice (vs. HF) but no endoplasmic reticulum stress or oxidative stress was observed. Furthermore, cholesterol suppressed HF-induced increase of peroxisome proliferator-activated receptor γ coactivator 1α and mitochondrial transcription factor A expression and blunted fatty acid oxidation. Interestingly, after switching HFC to HF diet for 5weeks, the increases in plasma ALT and liver inflammatory markers were abolished but the blunted of mitochondrial function remained. These findings suggest that cholesterol plays a critical role in the conversion of a simple fatty liver toward nonalcoholic steatohepatitis possibly by activation of inflammatory pathways together with retarded mitochondrial function. [ABSTRACT FROM AUTHOR]

Hepatic steatosis is often associated with insulin resistance as a hallmark of the metabolic syndrome in the liver. The present study investigated the effects of PPARα activation induced by fenofibrate (FB) on the relationship of insulin resistance and hepatic steatosis in mice fed a high-fat (HF) diet, which increases lipid influx into the liver. Mice were fed HF diet to induce insulin resistance and hepatic steatosis with or without FB. FB activated PPARα and ameliorated HF diet-induced glucose intolerance and hepatic insulin resistance without altering either hepatic steatosis or inflammation signaling (JNK or IKK). Interestingly, FB treatment simultaneously increased fatty acid (FA) synthesis (50%) and oxidation (66%, both p < 0.01) into intermediate lipid metabolites, suggesting a FA oxidation-synthesis cycling in operation. Associated with these effects, diacylglycerols (DAGs) were sequestered within the lipid droplet/ER compartment, thus reducing their deposition in the cellular membrane, which is known to impair insulin signal transduction. These findings suggest that the reduction in membrane DAGs (rather than total hepatic steatosis) may be critical for the protection by fenofibrate-induced PPARα activation against hepatic insulin resistance induced by dietary fat. [ABSTRACT FROM AUTHOR]

Abstract: Reducing lipid accumulation in insulin target tissues is critical for the treatment of type 2 diabetes. This study aimed to develop a biochemical assay in cells for high throughput (HTP) screening of anti-diabetic drugs by reducing lipid accumulation via different mechanisms. We designed a new method to extract triglyceride (TG) with KOH to allow biochemical quantification of TGs for HTP screening in 3T3-L1 cells. This new method was validated for its biochemical properties with identical results of TG obtained with or without KOH (r 2 =0.9978, p <0.001) and a fourfold improvement in TG extraction recovery rate (88–95%, p <0.001) as compared to the conventional chloroform/methanol extraction (12–18%). The ability of this phenotype screening to capture potential anti-diabetic drugs was verified by pharmacological agents well known to alter lipid accumulation by different mechanisms including AMPK activators, fatty acid synthesis inhibitors, PPARγ activator and several lipogenic substrates. To further demonstrate the application of this screening tool for discovery of new anti-diabetic drugs, we screened >200 new candidates selected from Chinese medicine and identified 49 compounds from different classes which reduced TG content by >50% at 1μM or >75% at 10μM. Finally, we tested two selected leads (albiflorin and oxymatrine) in vivo and confirmed their efficacy in reducing visceral adiposity, glucose intolerance and hepatic steatosis in high fat-fed or high fructose-fed mice. Our results indicate that screening for the efficacy on lipid accumulation in cells by biochemical quantification of TGs with KOH extraction is an effective tool for the identification of new anti-diabetic compounds. [Copyright &y& Elsevier]

• We aimed to establish an M1 subdivision for personalized prognosis prediction and treatment planning for mNPC. • M1 subdivision demonstrated superior discrimination and clinical utility. • The novel M1 staging strategy provides a refined approach for prognostic prediction and treatment planning. To meet the demand for personalized treatment, effective stratification of patients with metastatic nasopharyngeal carcinoma (mNPC) is essential. Hence, our study aimed to establish an M1 subdivision for prognostic prediction and treatment planning in patients with mNPC. This study included 1239 patients with mNPC from three medical centers divided into the synchronous mNPC cohort (smNPC, n = 556) to establish an M1 stage subdivision and the metachronous mNPC cohort (mmNPC, n = 683) to validate this subdivision. The primary endpoint was overall survival. Univariate and multivariate Cox analyses identified covariates for the decision-tree model, proposing an M1 subdivision. Model performance was evaluated using time-dependent receiver operating characteristic curves, Harrell's concordance index, calibration plots, and decision curve analyses. The proposed M1 subdivisions were M1a (≤5 metastatic lesions), M1b (>5 metastatic lesions + absent liver metastases), and M1c (>5 metastatic lesions + existing liver metastases) with median OS of 34, 22, and 13 months, respectively (p < 0.001). This M1 subdivision demonstrated superior discrimination (C-index = 0.698; 3-year AUC = 0.707) and clinical utility over those of existing staging systems. Calibration curves exhibited satisfactory agreement between predictions and actual observations. Internal and mmNPC cohort validation confirmed the robustness. Survival benefits from local metastatic treatment were observed in M1a, while immunotherapy improved survival in patients with M1b and M1c disease. This novel M1 staging strategy provides a refined approach for prognostic prediction and treatment planning in patients with mNPC, emphasizing the potential benefits of local and immunotherapeutic interventions based on individualized risk stratification. [ABSTRACT FROM AUTHOR]