TAK-875 is a novel, orally available, selective GPR40 agonist. TAK-875 exhibits potent agonist activity and high binding affinity to the human GPR40 receptor with Ki of 38 nM. TAK-875 enhanced glucose-induced insulin secretion in a glucose-dependent manner in both human and rat islets. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity. TAK-875 significantly improved glycaemic control in patients with type 2 diabetes with minimum risk of hypoglycaemia.
|Source||Br J Pharmacol (2013). Figure 3. TAK-875|
|Cell Lines||ZL rats|
|Incubation Time||120 min|
|Results||TAK-875 significantly enhanced insulin secretion before a glucose load (P ≤ 0.01) and tended to augment it at 10 min after glucose load, while metformin showed a trend towards reduce insulin release at 10 min|
|Cell lines||INS-1 832/13 cells|
|Preparation method||Measurement of Caspase 3/7 Activity. INS-1 832/13 cells were suspended in RPMI medium containing 11 mM glucose and the supplements described above. These cells were seeded at a density of 2 × 104 cells/well in a 96-well black plate coated with poly-D-lysine (BD BioCoat), and 1% BSA and 0.1% DMSO alone (control), palmitic acid (62.5, 125, 250, 500, and 1000 μM), oleic acid (62.5, 125, 250, 500, and 1000 μM), or TAK-875 (6.25, 12.5, 25, 50, and 100 μM) was added to the plate with 1% BSA and 0.1% DMSO, followed by culture for 72 h. After the culture, caspase 3/7 activity was measured with the Apo-one homogeneous caspase 3/7 assay (Promega, Madison, WI) according to the manufacturer's instructions. Fluorescence intensity was measured at an excitation of 485 nm and an emission at 535 nm.|
|Concentrations||6.25, 12.5, 25, 50, and 100 μM|
|Incubation time||72 h|
|Animal models||Oral Glucose Tolerance Test and Effects on Fasting Normoglycemia and Hyperglycemia with N-STZ-1.5 rats|
|Dosages||10 and 30 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 100 mg/mL|
The effects of TAK-875, a selective G protein-coupled receptor 40/free fatty acid 1 agonist, on insulin and glucagon secretion in isolated rat and human islets.
Yashiro H, et al. J Pharmacol Exp Ther. 2012 Feb;340(2):483-9. PMID: 22106100.
TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats.
Tsujihata Y, et al. J Pharmacol Exp Ther. 2011 Oct;339(1):228-37. PMID: 21752941.
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