TAK-875, an Orally Available GPR40/FFA1 Agonist Enhances Glucose-Dependent Insulin Secretion and Improves Both Postprandial and Fasting Hyperglycemia in Type 2 Diabetic Rats

Metabolic Disease Drug Discovery Unit,Takeda Pharmaceutical Company Limited, Osaka, Japan.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 07/2011; 339(1):228-37. DOI: 10.1124/jpet.111.183772
Source: PubMed


G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. 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. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. 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 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.

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    • "GPR40 is highly expressed in pancreatic b cells and is activated by the binding of medium-or long-chain free fatty acids, which augments glucose-stimulated insulin secretion [13] . The novel mechanism of action of fasiglifam potentiates the activity of GPR40, thus stimulating insulin secretion only at elevated blood glucose concen- trations [12, 14]. In contrast, insulin secretagogues, such as glinides and sulfonylureas, stimulate insulin secretion even at low blood glucose concentrations [7], which can lead to hypoglycemia. "
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    ABSTRACT: Introduction Approximately one-third of patients with type 2 diabetes mellitus (T2DM) have concurrent renal impairment. There are limited therapeutic options for these patients. Fasiglifam is a G protein-coupled receptor 40 agonist that was under investigation for the treatment of T2DM. The objective of this study was to evaluate the potential effect of renal impairment on the pharmacokinetics and safety of a single dose of fasiglifam and its metabolite M-1. Methods This was a phase I, open-label, parallel-group study. Subjects with varying degrees of renal function received a single oral dose of fasiglifam 50 mg. Blood and urine samples were collected through 168 h postdose. Study endpoints were pharmacokinetic and safety variables. Results Fifty-three subjects were enrolled. Mean fasiglifam plasma concentrations were higher in subjects with mild renal impairment compared with other groups, but within each renal function cohort, plasma concentrations tended to decrease with decreasing renal function. Regression analyses indicated that fasiglifam exposure decreased and M-1 exposure increased with decreasing renal function. Predicted exposure values at about the midpoint of creatinine clearance for each renal impairment group differed by up to 21 % (fasiglifam) and 87 % (M-1) from that of the normal renal function group. Hemodialysis had no effect on fasiglifam or M-1 exposure. Fasiglifam renal clearance (CLR) was not affected, but M-1 CLR decreased with increasing impairment. No incidences of hypoglycemia were reported during the study. Conclusion Varying renal function status did not have a significant impact on the clearance of fasiglifam in this study.
    Full-text · Article · Nov 2014 · Drugs in R & D
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    • "TAK-875 augmented insulin secretion under high-glucose conditions in the rat pancreatic beta cell line INS1 833/14 (24) and human pancreatic islets (25) but did not affect glucagon secretion in humans (25), in accordance with the observations in humans by our group and others (9–11). TAK-875 significantly improved glycemic control with the augmentation of insulin secretion in diabetic rat models such as Wistar fatty rats (23) and Zucker diabetic fatty rats (24). "
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    ABSTRACT: Free fatty acids (FFAs) play a pivotal role in metabolic control and cell signaling processes in various tissues. In particular, FFAs are known to augment glucose-stimulated insulin secretion by pancreatic beta cells, where fatty acid-derived metabolites, such as long-chain fatty acyl-CoAs, are believed to act as crucial effectors. Recently, G-protein-coupled receptor 40 (GPR40), a receptor for long-chain fatty acids, was reported to be highly expressed in pancreatic beta cells and involved in the regulation of insulin secretion. Hence, GPR40 is considered to be a potential therapeutic target for the treatment of diabetes. In this review, we summarize the identification and gene expression patterns of GPR40 and its role in glucose metabolism. We also discuss the potential application of GPR40 as a therapeutic target.
    Full-text · Article · Sep 2014 · Frontiers in Endocrinology
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    • "Crucially, although these effects were comparable to current sulfonylurea treatments, Fasiglifam was associated with markedly less side effects, with no significant increases in body weight and a reduced concomitant incidence of hypoglycemia (32–36). This is consistent with pre-clinical data demonstrating that Fasiglifam improved fasting hyperglycemia and glucose tolerance and augmented GSIS in diabetic rat models, with no hypoglycemia observed in normoglycemic rats (31). No changes in insulin resistance have been reported in response to Fasiglifam treatment (37, 38) and Fasiglifam had no effect on glucagon secretion in isolated human islets and did not alter glucagon levels in T2D patients (39). "
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    ABSTRACT: Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for free fatty acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long-chain FFA receptor, FFA1, improved glycemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss, and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programs within industry and academia aimed at improving the safety and effectiveness of these potential treatments.
    Full-text · Article · Aug 2014 · Frontiers in Endocrinology
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