TABLE 1

Summary of published GPCRs involved in the development and progression of β-cell dysfunction, insulin resistance, obesity, and type 2 diabetes mellitus

Nomenclature as described in “The Concise Guide to Pharmacology 2015/16” (Alexander et al., 2015).

GPCREndogenous Ligand(s)FamilyG Protein CouplingCompounds AvailableExpression Profile(Patho)physiologic EffectsReferences
α1A-ARNoradrenalineAGαq/11A61603Pancreatic β-cells, liver, muscle, and heartDirect and indirect influence on glucose metabolismCheng et al. (2012)
DabuzalgronPiascik and Perez (2001)
OxymetazolineWier and Morgan (2003)
Evans et al. (2011)
Beak et al. (2017)
Willis et al. (2016)
α2A-ARNoradrenalineAGαi/oIdazoxanPancreatic α- and β-cellsActivation on α-cells increases glucagon secretion, and on β-cells decreases insulin secretionGonzalez-Manchon et al. (1989)
MK-912Limbird (1988)
Ortiz-Alonso et al. (1991); Ostenson et al. (1988)
Rosengren et al. (2010)
β2-ARAdrenaline, noradrenalineAGαsBRL37344Widely expressedVasodilation, increased insulin secretion from β-cells in the pancreas and directly by stimulating insulin-independent glucose uptake in skeletal muscleNevzorova et al. (2002, 2006)
Clenbuterol
Dehvari et al. (2012)
Sato et al. (2014)
Evans et al. (2010)
β3-ARNoradrenalineAGαi/oBRL26830Bladder, heart, gastrointestinal tract, adipose tissueImprovement in insulin sensitivity is related to downregulation of TNF-α expressionArch et al. (1984, 2008))
GαsBRL35135Emorine et al. (1989)
BRL37344Ghorbani et al. (2012)
L755507Michel and Gravas (2016)
MirabegronNedergaard and Cannon (2014)
SolabegronRoth Flach et al. (2013)
BLT1/2RLeukotriene B4AGαq/11 Gαi/oImmune cells, endothelial cellsInsulin resistance in hepatocytes and myocytesLi et al. (2015b)
Spite et al. (2011)
Yokomizo et al. (2001)
CB1RAnandamide,AGαi/oJD5037Pancreatic β-cells, brainStimulation of food intakeGruden et al. (2016)
2-AGRimonabantJourdan et al. (2014)
CCK1RCCKAGαq/11Pancreatic β-cells, gastrointestinal tract, pancreasStimulation of exocrine pancreatic and gall bladder contractionAhrén et al. (2000)
CCR2CCL2, CCL7, CCL8, CCL11, CCL13AGαi/oCCX140-BImmune cellsObesity-induced insulin resistance by macrophage proinflammatory activityde Zeeuw et al. (2015)
CenicrivirocGutierrez et al. (2011)
NOX-E36Kawano et al. (2016)
Lefebvre et al. (2016)
Menne et al. (2017)
Sullivan et al. (2013a,b)
Weisberg et al. (2006)
EP3RProstaglandin E2AGαq/11DG-041Brain, kidneyNegatively regulates glucose and hormone-stimulated insulin secretionCeddia et al. 2016
Gαi/oKimple et al. (2013)
Neuman and Kimple (2013)
FFAR1 (GPR40)MCFAs (C9–C22): linoleic acidAGαi/oCompound 15iPancreatic β-cells, enteroendocrine cells, brain, liver, muscle, omental adipocytes, islet α-cellsIndirect release of GLP-1 from intestinal endocrine cells; insulin secretion from pancreatic β-cellsBlad et al. (2012)
Gαq/11GW9508Defossa and Wagner (2014)
GαsLY2881835Houthuijzen (2016)
LY2922470Husted et al. (2017)
TAK-875Mancini and Poitout (2013, 2015)
Bindels et al. (2013); McKenzie et al. (2015)
Thorburn et al. (2014)
FFAR2 (GPR43)SCFAs (C2–C7): formate, acetate, propionate, butyrate, pentanoateAGαi/o Gαq/112-Methylacrylic acidPancreatic β-cells, innate immune cells, enteroendocrine cells, gut epithelium, white adipose tissue, spleen, bone marrowG protein bias, inhibition of lipolysis, immune function, insulin-mediated fat accumulation, control of body energyBlad et al. (2012)
AZ1729 (PAM)Bolognini et al. (2016)
Compound 34Husted et al. (2017)
Compound 4Bindels et al. (2013); McKenzie et al. (2015)
Compound 58Smith et al. (2011)
Thorburn et al. (2014)
FFAR3 (GPR41)SCFAs (C3–C7): formate, acetate, propionate, butyrate, pentanoateAGαi/oPancreatic β-cells, adipocytes, enteroendocrine cells, brain, lung, immune cellsAnti-inflammation, involved in energy expenditure and metabolic regulation; activation causes release of leptinHusted et al. (2017)
Inoue et al. (2014)
Thorburn et al. (2014)
Ulven (2012)
FFAR4 (GPR120)Long-chain unsaturated fatty acids (C14–C18): docosahexaeonic acidAGαq/11Compound APancreatic β-cells, enteroendocrine cells, macrophagesStimulation of GLP-1 secretion, involvement of G protein–dependent and independent pathways, proinflammationHirasawa et al. (2005)
GW9508Houthuijzen (2016)
Husted et al. (2017)
Im (2016)
Konno et al. (2015)
Li et al. (2015a)
Oh et al. (2010)
Stone et al. (2014)
Ulven and Christiansen (2015)
GCGRGlucagonBGαsPancreatic β-cells, hepatocytesStimulates hepatic glucose outputKieffer et al. (1996)
GHSR-1aGhrelinAGαq/11Pancreatic β-cells, widely expressedStimulates ghrelin secretionDezaki et al. (2008)
Gαi/o Gα12/13
GIPRGIPBGαsPancreatic β-cells, adipocytes, small intestine, stomach, adrenal cortex, lung, pituitary, heart, testis, bone, brainStimulates GLP-1 secretion, inhibits gastric emptying, induces adipocyte differentiationFlatt (2008)
GLP-1RGLP-1-(7–36)BGαsAlbiglutidePancreatic β-cells, brain, heart, kidney, gastrointestinal tractSatiety, inhibits gastric emptying, inhibits glucagon secretionDonnelly (2012)
GLP-1-(7–37)DulaglutideGraaf et al. (2016)
ExenatideMeier (2012)
LiraglutideSecher et al. (2014)
SemaglutideSisley et al. (2014)
Taspoglutide
GPER (GPR30)17β-estradiol (E2)AGαi/oICI 182, 780Pancreatic β-cells, placenta, lung, liver, prostate, ovary, brainPromotes insulin production, β-cell survival and adipogenesisBalhuizen et al. (2010)
GαsTamoxifenDavis et al. (2014)
RaloxifeneDennis et al. (2009, 2011)
G-1Kumar et al. (2011)
G15Sharma et al. (2013, 2017)
G36Wang et al. (2016)
GPR21AGαqMacrophages, brain, heartCoordinates macrophage proinflammatory activity in the context of obesity-induced insulin resistanceGardner et al. (2012)
Osborn et al. (2012)
GPR27AGαq/11Pancreatic β-cellsPositive insulin promoter and glucose-stimulated insulin secretionKu et al. (2012)
GPR35Kynurenic acid, pamoic acid, kysophosphatidic acidAGαi/oMonocytes, neutrophils, gastrointestinal tract, peripheral nervous tissue, mast cellsIndirect release of GLP-1MacKenzie et al. (2011)
Maravillas-Montero et al. (2015)
Shore and Reggio (2015)
GPR54 (KiSS1R)KisspeptinAGαq/11Pancreatic β-cells, brain, blood vessels, placentaInhibition of tumor growthPopa et al. (2008)
GPR55LysophosphatidylinositolAGαq/11 Gα12/13BrainEnergy homeostasis through the regulation of food intake, fuel storage in adipocytes, gut motility, and insulin secretionLiu et al. (2015a)
Meadows et al. (2015)
Ross (2009)
Simcocks et al. (2014)
GPR68Proton sensing (pH 6–7.6)AGαi/o Gαq/11Lorazepam, Ogerin (PAM)Widely expressedControls pancreatic β-cell response to acidic microenvironmentChandra et al. (2016)
Huang et al. (2015b)
GPR82AGastrointestinal glands, gall bladder, and pancreasInfluences food intake, energy, and body weight balanceEngel et al. (2011)
GPR84MCFAs (C9–C14): capric acid, 6-n-octylaminouracilAGαi/oCompound 1Immune cells, adipocytes, macrophagesObesity-induced insulin resistance by macrophage proinflammatory activityBlad et al. (2012)
Suzuki et al. (2013)
Talukdar et al. (2011)
Thorburn et al. (2014)
Wang et al. (2006)
GPR119Lipid aminesAGαsGSK2041706Pancreatic β-cells, enteroendocrine cells, brainCauses release of GLP-1 and GIPChu et al. (2008)
GSK1292263Release of insulin from pancreatic β-cellsHansen et al. (2012)
MBX2982Ritter et al. (2016)
PSN821Yang et al. (2016)
GPR132Long-chain n-acyl amides, pH, commensal metabolitesAGαsCompound 1Macrophages, adipose tissue, skeletal muscleInvolved in the cell cycle and promotes chemotaxis and proliferationCohen et al. (2015)
Gα13Shehata et al. (2015)
GPR142AGαqCLP-3094Exclusively pancreatic β-cellsStimulates insulin secretion under conditions of high blood glucoseDu et al. (2012)
Compound 33Lizarzaburu et al. (2012)
Toda et al. (2013)
Yu et al. (2013)
GPRC5BCGα12/13Pancreatic β-cellsIncreased expression contributes to reduced insulin secretion and β-cell viabilityKim et al. (2012)
Kurabayashi et al. (2013)
Soni et al. (2013)
GPRC6AL-ArginineCGαqCompound 7Pancreatic β-cellsIncreased pancreatic β-cell proliferation, and insulin release from pancreatic isletsDi Nisio et al. (2017)
L-LysineCompound 34bJørgensen et al. (2017)
L-OrnithinePi et al. (2008, 2011, 2016)
OsteocalcinJohansson et al. (2015)
Rueda et al. (2016)
Smajilovic et al. (2013)
HCA2 (GPR109A)SCFAs (C4–C8): butyrate, nicotinic acidAGαi/oGSK256073Adipocytes, neutrophils, macrophages, intestinal epithelial cellsIntracellular triglyceride lipolysis in adipocytes; activation causes unwanted flushing side effect, activation may cause insulin resistance in skeletal muscleDobbins et al. (2013, 2015)
Thorburn et al. (2014)
Wanders and Judd (2011)
M3RAcetylcholine, cholineAGαq/11Pancreatic β-cells, widely expressedEnhanced glucose-stimulated insulin secretion from pancreatic β-cellsGautam et al. (2008)
MT1/2RMelatoninAGαi/o Gαq/11Pancreatic α- and β-cellsInhibition of glucose-stimulated insulin secretion, involvement in sleep/wake cycleJockers et al. (2016)
Tuomi et al. (2016)
Lane et al. (2016)
P2Y14R (GPR105)UDP and UDP-glucoseAGαi/oPancreatic β-cells, smooth muscle, lungInsulin secretion from pancreatic β-cellsAbbracchio et al. (2003)
Carter et al. (2009)
Fricks et al. (2008)
Meister et al. (2014)
Xu et al. (2012)
PAC1RPACAPBGαsPancreatic β-cells, widely expressedStimulation of glucagon and adrenaline secretionHarmar et al. (2012)
Moody et al. (2011)
SUCNR1 (GPR91)SuccinateAGαi/o Gαq/11Compound 5 gAdipose tissue, kidney, nervous system, dendritic cells, liver, spleenHypertensive effects, activation of renin angiotensin systemCarmone et al. (2015)
Littlewood-Evans et al. (2016)
McCreath et al. (2015)
Rubic et al. (2008)
Van den Bossche et al. (2017)
van Diepen et al. (2017)
VPAC2RVIP and PACAPBGαsPancreatic β-cells, widely expressedStimulation of glucagon and adrenaline secretion, vasodilationHarmar et al. (2012)
Moody et al. (2011)
Y1RNPYAGαi/oPancreatic β-cells, widely expressedVasoconstrictionBrothers and Wahlestedt (2010)