The incidence of type 2 diabetes in developed countries is increasing yearly with a significant negative impact on patient quality of life and an enormous burden on the healthcare system. Current biguanide and thiazolidinedione treatments for type 2 diabetes have a number of clinical limitations, the most serious long-term limitation being the eventual need for insulin replacement therapy (Table 1). Since 2007, drugs targeting the glucagon-like peptide-1 (GLP-1) receptor have been marketed for the treatment of type 2 diabetes. These drugs have enjoyed a great deal of success even though our underlying understanding of the mechanisms for their pleiotropic effects remain poorly characterized even while major pharmaceutical companies actively pursue small molecule alternatives. Coupling of the GLP-1 receptor to more than one signalling pathway (pleiotropic signalling) can result in ligand-dependent signalling bias and for a peptide receptor such as the GLP-1 receptor this can be exaggerated with the use of small molecule agonists. Better consideration of receptor signalling pleiotropy will be necessary for future drug development. This is particularly important given the recent failure of taspoglutide, the report of increased risk of pancreatitis associated with GLP-1 mimetics and the observed clinical differences between liraglutide, exenatide and the newly developed long-acting exenatide long acting release, albiglutide and dulaglutide. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2014.171.issue-5 Abbreviations ADP, adenosine diphosphate; ANS, autonomic nervous system; ATP, adenosine triphosphate; Bad, Bcl-2-associated death promoter; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding protein; DPPIV, dipeptidyl peptidase IV; EGF-R1, epidermal growth factor receptor; Epac2, exchange protein directly activated by cAMP 2; GCGR, glucagon receptor; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; GLP-2, glucagon-like peptide-2; GPCR, G protein-coupled receptor; GRK, G protein-coupled receptor kinase; GSIS, glucose stimulated insulin secretion; ICV, introcerebroventricular; KATP, ATP sensitive potassium channel (potassium inwardly-rectifying channel, subfamily J); MAPK, mitogen activated protein kinase; NFAT, nuclear factor of activated T-cells; PACAP, pituitary adenylate cyclase activating polypeptide; PDX-1, pancreatic-duodenum homeobox-1; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; Rab3A, Ras-associated protein 3A; Rap1, Ras-proximate-1; Rim2, regulating synaptic membrane exocytosis 2; SNAP25, synaptosomal-associated protein 25; T2DM, type 2 diabetes mellitus; VDCC, voltage-dependant calcium channel; VIP, vasoactive intestinal peptide The incretin effectThe observation that oral glucose administration results in significantly higher pancreatic insulin secretion compared with intravenous dosing...

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Acaudina molpadioides has been long used as traditional medicinal resources and reported to demonstrate various important bioactivities such as anticoagulation, antithrombosis, anti-hyperglycemia and anticancer. However, its lipid lowering activity is yet to be fully explored. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that enhances the lysosomal degradation of hepatic low density lipoprotein receptor (LDLR) resulting in excessive accumulation of the plasma levels of LDL-cholesterols (LDL-C) which subsequently accelerate atherosclerosis. In the present study, A. molpadioides fractions were subjected to promoter-reporter luciferase assay to determine its role as PCSK9 inhibitors. It was found both fractions (EFA and EFB) reduced the transcriptional activity of PCSK9 promoter. Among the seven 5′end deletion constructs of PCSK9 promoter, fragments D1 (−1,711/−94), D3 (−709/−94) and D4 (−440/−94), were suppressed in the presence of both fractions whereas D2 (−1,214/−94), and, D6 (−351/−94) as well as D7 (−335/−94) were inhibited only by EFA and EFB, respectively. Further transcription factor binding sites prediction using MatInspector software discovered various potential cis -regulatory elements namely, PPAR, KLFs, RBPJ-kappa and SREBP that may potentially be involved in ameliorating the transcriptional activity of PCSK9. Immunofluorescence staining was used to evaluate the effects of both fractions on LDL-C and LDLR. Results showed that levels of LDL-C uptake in EFA-treated cells were 69.1% followed by EFB at 32.6%, as compared to untreated control after 24 h treatment. The LDLR protein distribution was induced by 62.41% and 32.2%, which corresponded to an increase in LDL-C uptake in both EFA and EFB treatment, respectively. Hence, the inhibition of PCSK9 by bioactive compounds in EFA and EFB could be another promising therapeutic agent in reducing the cholesterol levels and atherosclerosis by targeting PCSK9.