Search

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]

: We recently showed that bitter melon-derived triterpenoids (BMTs) activate AMPK and increase GLUT4 translocation to the plasma membrane in vitro, and improve glucose disposal in insulin resistant models in vivo. Here we interrogated the mechanism by which these novel compounds activate AMPK, a leading anti-diabetic drug target. BMTs did not activate AMPK directly in an allosteric manner as AMP or the Abbott compound (A-769662) does, nor did they activate AMPK by inhibiting cellular respiration like many commonly used anti-diabetic medications. BMTs increased AMPK activity in both L6 myotubes and LKB1-deficient HeLa cells by 20–35%. Incubation with the CaMKKβ inhibitor, STO-609, completely attenuated this effect suggesting a key role for CaMKKβ in this activation. Incubation of L6 myotubes with the calcium chelator EGTA-AM did not alter this activation suggesting that the BMT-dependent activation was Ca2+-independent. We therefore propose that CaMKKβ is a key upstream kinase for BMT-induced activation of AMPK. [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]