Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Li, Zheng; Xue, Xu; Huang, Wenlong; Qian, Hai

doi:10.1002/med.21441

Cited by 69 publications

(41 citation statements)

References 179 publications

(441 reference statements)

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“…FFAR1 is also expressed intestinal L and K cells, which secrete incretin hormones such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) ( 31 ), suggested that FFAR1 regulate FFA-induced insulin secretion from beta-cells directly and indirectly by regulation of incretin secretion. Therefore, many pharmaceutical companies and academic institutes are undertaking development of FFAR1 agonists such as Tak-875, LY2881835, and AMG-837 ( 32 ). Tak-875 reduced glycemia in diabetic patients but not in normoglycemic people without diabetes and progressed to phase III clinical trials ( 33 ).…”

Section: Fatty Acids and Lipotoxicitymentioning

confidence: 99%

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Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes

et al. 2018

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Type 2 diabetes is caused by chronic insulin resistance and progressive decline in beta-cell function. Optimal beta-cell function and mass is essential for glucose homeostasis and beta-cell impairment leads to the development of diabetes. Elevated levels of circulating fatty acids (FAs) and disturbances in lipid metabolism regulation are associated with obesity, and they are major factors influencing the increase in the incidence of type 2 diabetes. Chronic free FA (FFA) treatment induces insulin resistance and beta-cell dysfunction; therefore, reduction of elevated plasma FFA levels might be an important therapeutic target in obesity and type 2 diabetes. Lipid signals via receptors, and intracellular mechanisms are involved in FFA-induced apoptosis. In this paper, we discuss lipid actions in beta cells, including effects on metabolic pathways and stress responses, to help further understand the molecular mechanisms of lipotoxicity-induced type 2 diabetes.

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Section: Fatty Acids and Lipotoxicitymentioning

confidence: 99%

“…However, the development was discontinued because of hepatotoxicity ( 34 ). Recently, some agonist such as P11187, LY2922470, and SHR0534 are currently in phase I clinical trials ( 32 ).…”

Section: Fatty Acids and Lipotoxicitymentioning

confidence: 99%

Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes

et al. 2018

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“…The GPR40/FFA1 receptor, a G-protein-coupled receptor (GPCR), couples predominantly with the Gq/11 protein, promoting phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate into diacylglycerol and inositol 1,4,5-triphosphate (Ghislain and Poitout, 2017). This, in turn, increases intracellular Ca 21 concentrations (Li et al, 2018). Medium-to-long chain fatty acids activate intracellular Ca 21 responses in GPR40-expressing cells, demonstrating that they are natural GPR40 ligands (Briscoe et al, 2003;Itoh et al, 2003;Kotarsky et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity

Ueno

Ito

Abe

et al. 2019

J Pharmacol Exp Ther

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The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca 21 signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/-) mice. Treatment with SCO-267 activated Gq signaling in both high-and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/mice, indicating a GPR40dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

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“…[ 5,33,34 ] Many FFA1 agonists are widely studied in type 2 diabetes, which is highly correlated with NAFLD. [ 35–37 ] Furthermore, the role of FFA1 in hepatic steatosis and fibrosis had also been reported. [ 10,11 ] In previous studies, we found HWL‐088 exerted stronger hypoglycemic effect than TAK‐875, the most advanced candidate of FFA1 agonists.…”

Section: Discussionmentioning

confidence: 99%

HWL-088, a new and highly effective FFA1/PPARδ dual agonist, attenuates nonalcoholic steatohepatitis by regulating lipid metabolism, inflammation and fibrosis

Zhou

Deng

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Nonalcoholic fatty liver (NAFLD), a chronic progressive liver disease, is highly correlated with pathoglycemia, dyslipidemia and oxidative stress. The free fatty acid receptor 1 (FFA1) agonists have been reported to improve liver steatosis and fibrosis, and the peroxisome proliferator-activated receptor d (PPARd) plays a synergistic role with FFA1 in energy metabolism and fibrosis. HWL-088, a PPARd/FFA1 dual agonist, exerts better glucose-lowering effects than the representative FFA1 agonist TAK-875. However, the ability of HWL-088 to protect NAFLD was unknown. This study aimed to discover a new strategy for the treatment of NAFLD. Methods The methionine-and choline-deficient diet (MCD)-induced Nonalcoholic steatohepatitis (NASH) model was constructed to evaluate the effects of HWL-088. Key findings Administration of HWL-088 exerted multiple benefits on glucose control, lipid metabolism and fatty liver. Further mechanism research indicated that HWL-088 promotes lipid metabolism by decreasing lipogenesis and increasing lipolysis. Moreover, HWL-088 attenuates NASH by regulating the expression levels of genes related to inflammation, fibrosis and oxidative stress. Conclusions These positive results indicated that PPARd/FFA1 dual agonist HWL-088 might be a potential candidate to improve multiple pathogenesis of NASH.

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Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Cited by 69 publications

References 179 publications

Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes

Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes

SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity

HWL-088, a new and highly effective FFA1/PPARδ dual agonist, attenuates nonalcoholic steatohepatitis by regulating lipid metabolism, inflammation and fibrosis

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