Treatment of type 2 diabetes with incretin-based therapies.

Department of Endocrinology, Hvidovre Hospital and University of Copenhagen, 2650 Hvidovre, Denmark.
The Lancet (Impact Factor: 39.21). 10/2008; 373(9662):438-9. DOI: 10.1016/S0140-6736(08)61247-7
Source: PubMed
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) is a promising target for diabetes mellitus (DM) therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4). We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM) Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD) simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD), solvent accessible surface (SAS), mean square deviation (MSD), Gyrate, total energy, root mean square fluctuation (RMSF), matrices of smallest distance of residues, database of secondary structure assignment (DSSP), cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists.
    Evidence-based complementary and alternative medicine : eCAM. 01/2014; 2014:385120.
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    ABSTRACT: Nowadays pharmacological therapy to limit obesity has reached a critical stage: not only have Authorities limited the use of antiobesity drugs due to their proven inefficacy and dangerous side effects, but bariatric surgery has delivered better results. At present, when the number of obese subjects is growing exponentially worldwide and more and more pathological mechanisms inducing fat accumulation have been discovered, no drugs are available to help patients and physicians to limit one the most dreadful causes of death. Following the failures of promising drugs as sibutramine and rimonabant, many companies stopped to invest in the field of obesity pharmacotherapy. At the same time, leading Authorities have started to require more solid evidence before providing authorization for these drugs to enter the market. This review aims at revising the failed promises of antiobesity drugs and describing the few potential future candidates in order to shed some light in the still uncertain field of antiobesity drugs. It also provides a critical contribution to the ongoing debate among scientists, clinicians, patients and Authorities on the possibility to treat obesity with pharmacological drugs.
    Endocrine 05/2013; · 1.42 Impact Factor
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    ABSTRACT: G protein-coupled receptors (GPCRs) constitute a large family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and cellular responses. GPCR are involved in a wide variety of physiological processes, including in the neuroendocrine system. GPCR are also involved in many diseases and are the target of 30% of marketed medicinal drugs. Whereas the majority of the GPCR-targeting drugs have proved their therapeutic benefit, some of them were associated with undesired effects. We develop two examples of used drugs whose therapeutic benefits are tarnished by carcinogenesis risks. The chronic administration of glucagon-like peptide-1 (GLP-1) analogs widely used to treat type-2 diabetes was associated with an increased risk of pancreatic or thyroid cancers. The long-term treatment with the estrogen antagonist tamoxifen, developed to target breast cancer overexpressing estrogen receptors ER, presents agonist activity on the G protein-coupled estrogen receptor which is associated with an increased incidence of endometrial cancer and breast cancer resistance to hormonotherapy. We point out and discuss the need of pharmacological studies to understand and overcome the undesired effects associated with the chronic administration of GPCR ligands. In fact, biological effects triggered by GPCR often result from the activation of multiple intracellular signaling pathways. Deciphering which signaling networks are engaged following GPCR activation appears to be primordial to unveil their contribution in the physiological and physiopathological processes. The development of biased agonists to elucidate the role of the different signaling mechanisms mediated by GPCR activation will allow the generation of new therapeutic agents with improved efficacy and reduced side effects. In this regard, the identification of GLP-1R biased ligands promoting insulin secretion without inducing pro-tumoral effects would offer therapeutic benefit.
    Frontiers in Endocrinology 01/2013; 4:50.