Lack of <scp>GPR40</scp>/<scp>FFAR<sub>1</sub></scp> does not induce diabetes even under insulin resistance condition

Kae, Matsuda-Nagasumi; Takami-Esaki, R.; Iwachidow, K.; Yasuhara, Yoshitaka; Tanaka, Hideyuki; Ogi, Kazuhiro; Nakata, Mitsugu; Yano, Takashi; Hinuma, Shuji; Taketomi, Shigehisa; Odaka, Hiroyuki; Kaisho, Yoshihiko

doi:10.1111/dom.12065

Cited by 18 publications

(16 citation statements)

References 36 publications

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“…As reported previously, transgenic mice overexpressing human FFAR1 (hFFAR1) in pancreatic β cells exhibit improved glucose excursion and increased insulin secretion during the oral glucose tolerance test (OGTT) and develop resistance to high-fat diet-induced glucose intolerance [3], whereas FFAR1-deficient mice show impaired or unaffected GSIS [4], [5] and absence of insulin and incretin secretion in response to FFAs [6]. These studies clearly identify FFAR1 as an attractive therapeutic target for type 2 diabetes (T2DM).…”

Section: Introductionmentioning

confidence: 80%

A Novel Antidiabetic Drug, Fasiglifam/TAK-875, Acts as an Ago-Allosteric Modulator of FFAR1

et al. 2013

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Selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist fasiglifam (TAK-875), an antidiabetic drug under phase 3 development, potentiates insulin secretion in a glucose-dependent manner by activating FFAR1 expressed in pancreatic β cells. Although fasiglifam significantly improved glycemic control in type 2 diabetes patients with a minimum risk of hypoglycemia in a phase 2 study, the precise mechanisms of its potent pharmacological effects are not fully understood. Here we demonstrate that fasiglifam acts as an ago-allosteric modulator with a partial agonistic activity for FFAR1. In both Ca2+ influx and insulin secretion assays using cell lines and mouse islets, fasiglifam showed positive cooperativity with the FFAR1 ligand γ-linolenic acid (γ-LA). Augmentation of glucose-induced insulin secretion by fasiglifam, γ-LA, or their combination was completely abolished in pancreatic islets of FFAR1-knockout mice. In diabetic rats, the insulinotropic effect of fasiglifam was suppressed by pharmacological reduction of plasma free fatty acid (FFA) levels using a lipolysis inhibitor, suggesting that fasiglifam potentiates insulin release in conjunction with plasma FFAs in vivo. Point mutations of FFAR1 differentially affected Ca2+ influx activities of fasiglifam and γ-LA, further indicating that these agonists may bind to distinct binding sites. Our results strongly suggest that fasiglifam is an ago-allosteric modulator of FFAR1 that exerts its effects by acting cooperatively with endogenous plasma FFAs in human patients as well as diabetic animals. These findings contribute to our understanding of fasiglifam as an attractive antidiabetic drug with a novel mechanism of action.

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Section: Introductionmentioning

confidence: 80%

A Novel Antidiabetic Drug, Fasiglifam/TAK-875, Acts as an Ago-Allosteric Modulator of FFAR1

et al. 2013

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“…11 More than 50% of the augmentation of insulin secretion by FA is considered to be mediated by FFAR1, based on genetic and pharmacological suppression of FFAR1 signaling, while the remainder is considered to require intracellular metabolism of FA. 15 Further studies are necessary to determine whether FFAR1 is primarily activated by 20-HETE or by FA in beta cells, since the reduction in GSIS in the absence of added FA has been noted in some, 16 but not in others, 17,18 studies when FFAR1 signaling is inhibited in mice in vivo and isolated islets in vitro. FFAR1 activation also increases intracellular calcium ([Ca 2+ ] i ) by releasing calcium from the endoplasmic reticulum (ER) through inositol triphosphate (IP3) receptor.…”

Section: How Do Fa and Lipid Metabolites Support Gsis?mentioning

confidence: 99%

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Imai

Cousins

Liu

et al. 2019

Annals of the New York Academy of Sciences

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Obesity is the major contributing factor for the increased prevalence of type 2 diabetes (T2D) in recent years. Sustained positive influx of lipids is considered to be a precipitating factor for beta cell dysfunction and serves as a connection between obesity and T2D. Importantly, fatty acids (FA), a key building block of lipids, are a double‐edged sword for beta cells. FA acutely increase glucose‐stimulated insulin secretion through cell‐surface receptor and intracellular pathways. However, chronic exposure to FA, combined with elevated glucose, impair the viability and function of beta cells in vitro and in animal models of obesity (glucolipotoxicity), providing an experimental basis for the propensity of beta cell demise under obesity in humans. To better understand the two‐sided relationship between lipids and beta cells, we present a current view of acute and chronic handling of lipids by beta cells and implications for beta cell function and health. We also discuss an emerging role for lipid droplets (LD) in the dynamic regulation of lipid metabolism in beta cells and insulin secretion, along with a potential role for LD under nutritional stress in beta cells, and incorporate recent advancement in the field of lipid droplet biology.

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“…Global knockout GPR120 and GPR40 mice were crossbred to generate DKO mice. For analysis of K‐cell number and gene expression in K cells, DKO mice were crossbred with GIP‐green fluorescent protein (GFP) knock‐in (GIP‐GFP) mice in which visualization and isolation of K cells can be achieved.…”

Section: Methodsmentioning

confidence: 99%

Free fatty acid receptors, G protein‐coupled receptor 120 and G protein‐coupled receptor 40, are essential for oil‐induced gastric inhibitory polypeptide secretion

Sankoda

Harada

Kato

et al. 2019

J of Diabetes Invest

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Aims/IntroductionIncretin hormone glucose‐dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) plays a key role in high‐fat diet‐induced obesity and insulin resistance. GIP is strongly secreted from enteroendocrine K cells by oil ingestion. G protein‐coupled receptor (GPR)120 and GPR40 are two major receptors for long chain fatty acids, and are expressed in enteroendocrine K cells. In the present study, we investigated the effect of the two receptors on oil‐induced GIP secretion using GPR120‐ and GPR40‐double knockout (DKO) mice.Materials and MethodsGlobal knockout mice of GPR120 and GPR40 were crossbred to generate DKO mice. Oral glucose tolerance test and oral corn oil tolerance test were carried out. For analysis of the number of K cells and gene expression in K cells, DKO mice were crossbred with GIP‐green fluorescent protein knock‐in mice in which visualization and isolation of K cells can be achieved.ResultsDouble knockout mice showed normal glucose‐induced GIP secretion, but no GIP secretion by oil. We then investigated the number of K cells and gene characteristics in K cells isolated from GIP‐green fluorescent protein knock‐in mice. Deficiency of both receptors did not affect the number of K cells in the small intestine or expression of GIP messenger ribonucleic acid in K cells. Furthermore, there was no significant difference in the expression of the genes associated with lipid absorption or GIP secretion in K cells between wild‐type and DKO mice.ConclusionsOil‐induced GIP secretion is triggered by the two major fatty acid receptors, GPR120 and GPR40, without changing K‐cell number or K‐cell characteristics.

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Lack of GPR40/FFAR₁ does not induce diabetes even under insulin resistance condition

Cited by 18 publications

References 36 publications

A Novel Antidiabetic Drug, Fasiglifam/TAK-875, Acts as an Ago-Allosteric Modulator of FFAR1

A Novel Antidiabetic Drug, Fasiglifam/TAK-875, Acts as an Ago-Allosteric Modulator of FFAR1

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Free fatty acid receptors, G protein‐coupled receptor 120 and G protein‐coupled receptor 40, are essential for oil‐induced gastric inhibitory polypeptide secretion

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Lack of GPR40/FFAR1 does not induce diabetes even under insulin resistance condition

Cited by 18 publications

References 36 publications

A Novel Antidiabetic Drug, Fasiglifam/TAK-875, Acts as an Ago-Allosteric Modulator of FFAR1

A Novel Antidiabetic Drug, Fasiglifam/TAK-875, Acts as an Ago-Allosteric Modulator of FFAR1

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Free fatty acid receptors, G protein‐coupled receptor 120 and G protein‐coupled receptor 40, are essential for oil‐induced gastric inhibitory polypeptide secretion

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Lack of GPR40/FFAR₁ does not induce diabetes even under insulin resistance condition