GPR40: A therapeutic target for mediating insulin secretion

Feng, Xiaobing; Leng, Jing; Xie, Zhen; Li, Shuanglei; Zhao, Wei; Tang, Qianli

doi:10.3892/ijmm.2012.1142

Cited by 49 publications

(32 citation statements)

References 91 publications

(90 reference statements)

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“…GPR40, a G protein-coupled receptor also called FFA1, is expressed abundantly in the pancreatic β-cells and serves as receptor for long-chain FFAs 30 . It has been shown that activation of GPR40 by long-chain FFAs leads to an enhanced β-cell response to glucose in the secretion of insulin 31 .…”

Section: Discussionmentioning

confidence: 99%

GPR40/FFA1 and neutral sphingomyelinase are involved in palmitate-boosted inflammatory response of microvascular endothelial cells to LPS

Jin

et al. 2015

Atherosclerosis

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Objectives Increased levels of both saturated fatty acids (SFAs) and lipopolysaccharide (LPS) are associated with type 2 diabetes. However, it remains largely unknown how SFAs interact with LPS to regulate inflammatory responses in microvascular endothelial cells (MIC ECs) that are critically involved in atherosclerosis as a diabetic complication. In this study, we compared the effects of LPS, palmitic acid (PA), the most abundant saturated fatty acid, or the combination of LPS and PA on interleukin (IL)-6 expression by MIC ECs and explored the underlying mechanisms. Methods Human cardiac MIC ECs were treated with LPS, PA and LPS plus PA and the regulatory pathways including receptors, signal transduction, transcription and post-transcription, and sphingolipid metabolism for IL-6 expression were investigated. Results G protein-coupled receptor (GPR)40 or free fatty acid receptor 1 (FFA1), but not toll-like receptor 4, was involved in PA-stimulated IL-6 expression. PA not only stimulated IL-6 expression by itself, but also remarkably enhanced LPS-stimulated IL-6 expression via a cooperative stimulation on mitogen-activated protein kinase and nuclear factor kappa B signaling pathways, and both transcriptional and post-transcriptional activation. Furthermore, PA induced a robust neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis that was involved in PA-augmented IL-6 upregulation. Conclusion PA boosted inflammatory response of microvascular endothelial cells to LPS via GPR40 and nSMase.

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Section: Discussionmentioning

confidence: 99%

GPR40/FFA1 and neutral sphingomyelinase are involved in palmitate-boosted inflammatory response of microvascular endothelial cells to LPS

Jin

et al. 2015

Atherosclerosis

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“…Meanwhile, free fatty acids have also been reported to stimulate insulin secretion in a glucose-dependent manner by activation of GPR40 (free fatty acid receptor 1 or FFAR1) [154–156]. Thus, several GPR40 agonists are being developed such as TAK-875, which was shown both in rodents and humans to enhance insulin secretion and promote glucose control [155, 157].…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

Shi²,

West

et al. 2017

Journal of Cardiovascular Pharmacology

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Summary Diabetes is a major risk factor for the development of heart failure. One of the hallmarks of diabetes is insulin resistance associated with hyperinsulinemia. The literature shows that insulin and adrenergic signaling is intimately linked to each other; however, whether and how insulin may modulate cardiac adrenergic signaling and cardiac function remains unknown. Notably, recent studies have revealed that insulin receptor and β2 adrenergic receptor (β2AR) forms a membrane complex in animal hearts, bringing together the direct contact between two receptor signaling systems, and forming an integrated and dynamic network. Moreover, insulin can drive cardiac adrenergic desensitization via PKA and GRK phosphorylation of the β2AR, which compromises adrenergic regulation of cardiac contractile function. In this review, we will explore the current state of knowledge linking insulin and GPCR signaling, especially βAR signaling in the heart, with emphasis on molecular insights regarding its role in diabetic cardiomyopathy (DCM).

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“…In fact a number of small molecule agonists have been shown to modulate glucose stimulated insulin secretion. Different GPR40 agonists such as GW9508, TAK-875, AS2575959, AMG837 and phenyl propanoic acid derivatives have shown increased insulin secretion in both insulinoma cells and/or in animal models [16-20]. Among these agonists, TAK-875 has been shown to prevent β-cells dysfunction [21] in animal model of diabetes and improves glycemic control in T2DM patients [22,23].…”

Section: Introductionmentioning

confidence: 99%

CNX-011-67, a novel GPR40 agonist, enhances glucose responsiveness, insulin secretion and islet insulin content in n-STZ rats and in islets from type 2 diabetic patients

Venkategowda

Verma

Oommen

et al. 2014

BMC Pharmacol Toxicol

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BackgroundGPR40 is a G-protein coupled receptor regulating free fatty acid induced and also glucose induced insulin secretion. We generated neonatally-streptozotocin-treated female rats (n-STZ) and treated them with CNX-011-67, a GPR40 agonist to examine the role of GPR40 in modulation of glucose metabolism, insulin secretion and content.MethodsFemale n-STZ animals were orally administered with CNX-011-67 (15 mg/kg body weight, twice daily) or with vehicle for 8 weeks (n = 8 per group). Glucose tolerance in treated animals and insulin secretion, islet insulin content and gene expression in isolated islets were determined. Islets from type 2 diabetic mellitus (T2DM) patients were treated with different concentrations of glucose in presence or absence of CNX-011-67 and insulin secretion was measured.ResultsTreatment of n-STZ rats with GPR40 agonist CNX-011-67 enhanced insulin secretion in response to oral glucose load on day 0 and this response persisted during the treatment period. The treatment also produced a ‘memory effect’ during which insulin secretion in response to oral glucose load remained enhanced, for a week, even in absence of the agonist. Activation of GPR40 enhanced responsiveness of islets to glucose and increased glucose induced insulin secretion and islet insulin content. An increase in islet mRNA expression of GCK, PDX1, insulin and PC was also observed. Acute treatment of islets from n-STZ rats with GPR40 agonist enhanced cellular ATP content. Activation of GPR40 enhanced mitochondrial calcium level in NIT-1 insulinoma cells. CNX-011-67 increased insulin secretion in islets from T2DM patients which were non-responsive to increased glucose concentrationConclusionsOur data provide evidence that activation of GPR40 with CNX-011-67 stimulates glucose metabolism, enhances glucose responsiveness, increases insulin secretion and content and that pharmacological activation of GPR40 will prove beneficial for treatment of T2DM.

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GPR40: A therapeutic target for mediating insulin secretion

Cited by 49 publications

References 91 publications

GPR40/FFA1 and neutral sphingomyelinase are involved in palmitate-boosted inflammatory response of microvascular endothelial cells to LPS

GPR40/FFA1 and neutral sphingomyelinase are involved in palmitate-boosted inflammatory response of microvascular endothelial cells to LPS

Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

CNX-011-67, a novel GPR40 agonist, enhances glucose responsiveness, insulin secretion and islet insulin content in n-STZ rats and in islets from type 2 diabetic patients

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