alpha-linolenic-acid and Diabetes-Mellitus--Type-2

GPR40, also known as free fatty acid receptor 1 (FFAR1), is a member of G protein-coupled receptors (GPCR) family and has emerged as an attractive target for the treatment of type 2 diabetes mellitus. So far, most of the synthetic GPR40 agonists, including several drug candidates discontinued in clinical trials, were derived from the phenylpropionic acid scaffold. For discovering novel GPR40 agonists with diverse chemical structures, a series of phenylpropiolic acid derivatives were designed, synthesized, and evaluated under a battery of bioassays. Compound 9, the most potent compound in this series, exhibited submicromolar agonist activity and similar agonistic efficacy compared to that of TAK-875. In addition, compound 9 was able to dose-dependently amplify glucose-stimulated insulin secretion (GSIS) in pancreatic β-cell line MIN6, which could be reversed by a selective GPR40 antagonist GW1100. In addition, compound 9 was found to have potent glucose-lowering effects during an oral glucose tolerance test in normal C57BL/6 mice.

Topics: Animals; Cell Line; Diabetes Mellitus, Type 2; Drug Design; Glucose; Glucose Tolerance Test; HEK293 Cells; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Phenylpropionates; Receptors, G-Protein-Coupled

The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Drug Discovery; Glucose Tolerance Test; Hypoglycemic Agents; Ligands; Lipids; Mice; Mice, Inbred C57BL; Models, Molecular; Phenylpropionates; Receptors, G-Protein-Coupled; Structure-Activity Relationship

GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

Topics: Biphenyl Compounds; Cell Survival; Cinnamates; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; HEK293 Cells; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Phenylpropionates; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Thiazolidinediones are insulin sensitizing drugs that target the peroxisome proliferator-activated receptor (PPAR) gamma. An n-hexane extract of the flowers of Echinacea purpurea was found to activate PPARgamma without stimulating adipocyte differentiation. Bioassay-guided fractionations yielded five alkamides, of which one was new, and three fatty acids that all activated PPARgamma. The new alkamide hexadeca-2E,9Z,12Z,14E-tetraenoic acid isobutylamide (5) was identified by analysis of spectroscopic data and found to activate PPARgamma with no concurrent stimulation of adipocyte differentiation. Compound 5 was further shown to increase insulin-stimulated glucose uptake. The data suggest that flowers of E. purpurea contain compounds with potential to manage insulin resistance and type 2 diabetes.

Topics: 3T3-L1 Cells; Animals; Denmark; Diabetes Mellitus, Type 2; Echinacea; Fatty Acids, Unsaturated; Flowers; Glucose; Insulin Resistance; Mice; Plants, Medicinal; PPAR gamma