Article Figures & Data
Figures
- Fig. 1.
Pathology of T2DM. β-cell dysfunction occurs following insult from increased FFA levels, obesity, insulin resistance, and inflammation. Initially the β-cell compensates by increasing the release of insulin; however, over time this compensatory mechanism fails and reduction in β-cell mass is evident. The loss of β-cell mass occurs from cellular degranulation, resulting in an increase in glucagon from α-cells and a decrease in insulin secretion. The reduced plasma insulin results in an increase in glucose levels. Glucose-sensitive tissues, including skeletal muscle and adipocytes, are unable to accommodate the increased glucose concentration. Increased fat accumulation in adipocytes also leads to an increase in proinflammatory cytokine release and increased lipolysis. A further release of FFAs stimulates the liver to increase glucose production. Persistent glucose release preserves the hyperglycemic environment, leading ultimately to T2DM.
- Fig. 2.
Inflammation and insulin resistance. Under normal conditions, tissue-resident M2 macrophages surround adipocytes and secrete anti-inflammatory mediators, including IL-4 and IL-13, maintaining an insulin-sensitive environment. Increased levels of nutrients, including fat, FFAs, and proinflammatory mediators, result in adipocyte hypertrophy, lipolysis, and ER stress. In addition, further release of proinflammatory mediators, including IL-6, IL-10, and CCL2 (MCP-1), results in transition, differentiation, and polarization of the tissue-resident M2 macrophages into M1 proinflammatory macrophages. Furthermore, recruitment and differentiation of circulating peripheral blood monocytes result in an increase in the proinflammatory milieu. Other metabolic tissues, including the liver and skeletal muscle, are also susceptible to the increased levels of cytokine production, ER stress, and macrophage recruitment, resulting in an increase in glucose production, fueling the hyperglycemic state further.
- Fig. 3.
Venn diagram illustrating GPCRs, as described in Table 1, involved in the development and/or progression of β-cell dysfunction, insulin resistance, and obesity-induced T2DM. Some overlap between these two groups exists, which will continue to expand with our increased understanding of these receptors and the disease pathophysiology. The number of targets illustrated perhaps reflects focus on β-cell function over the past 20–30 years.
- Fig. 4.
Schematic diagram of a pancreatic β-cell illustrating GPCR-involved β-cell dysfunction, insulin resistance, and obesity-induced T2DM and the signaling pathways of downstream G protein activation. Typically, insulin secretion occurs when glucose is taken up into the cell, which increases the ATP/ADP ratio. This change causes a reduction in the ATP-regulated K+ channel activity. The increased levels of K+ within the cell cause depolarization of the cellular membrane, which in turn causes opening of voltage-dependent Ca2+ channels. This influx of Ca2+ causes the exocytosis of insulin from insulin-storing secretory granules. Phosphorylation of the insulin receptor by phospholipase C and activation of the serine/threonine kinase pathway enhance glucose uptake into the relevant tissues. The involvement of GPCRs causes an increase in the level of insulin exocytosis either via the stimulation of the Gαs signaling pathway, which causes an increase in protein kinase A, or via the Gαq signaling pathway, which causes an increase in both PKC and intracellular Ca2+ concentrations. The levels of insulin secretion can be inhibited by the Gβγ subunit complex, inhibiting the voltage-dependent Ca2+ channel activity. GPCRs can also cause an increase in the gene transcription of multiple proinflammatory genes and increased chemotaxis via activation of IKK-β, JNK, and NF-κB signaling pathways.
Tables
- 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).
GPCR Endogenous Ligand(s) Family G Protein Coupling Compounds Available Expression Profile (Patho)physiologic Effects References α1A-AR Noradrenaline A Gαq/11 A61603 Pancreatic β-cells, liver, muscle, and heart Direct and indirect influence on glucose metabolism Cheng et al. (2012) Dabuzalgron Piascik and Perez (2001) Oxymetazoline Wier and Morgan (2003) Evans et al. (2011) Beak et al. (2017) Willis et al. (2016) α2A-AR Noradrenaline A Gαi/o Idazoxan Pancreatic α- and β-cells Activation on α-cells increases glucagon secretion, and on β-cells decreases insulin secretion Gonzalez-Manchon et al. (1989) MK-912 Limbird (1988) Ortiz-Alonso et al. (1991); Ostenson et al. (1988) Rosengren et al. (2010) β2-AR Adrenaline, noradrenaline A Gαs BRL37344 Widely expressed Vasodilation, increased insulin secretion from β-cells in the pancreas and directly by stimulating insulin-independent glucose uptake in skeletal muscle Nevzorova et al. (2002, 2006) Clenbuterol Dehvari et al. (2012) Sato et al. (2014) Evans et al. (2010) β3-AR Noradrenaline A Gαi/o BRL26830 Bladder, heart, gastrointestinal tract, adipose tissue Improvement in insulin sensitivity is related to downregulation of TNF-α expression Arch et al. (1984, 2008)) Gαs BRL35135 Emorine et al. (1989) BRL37344 Ghorbani et al. (2012) L755507 Michel and Gravas (2016) Mirabegron Nedergaard and Cannon (2014) Solabegron Roth Flach et al. (2013) BLT1/2R Leukotriene B4 A Gαq/11 Gαi/o Immune cells, endothelial cells Insulin resistance in hepatocytes and myocytes Li et al. (2015b) Spite et al. (2011) Yokomizo et al. (2001) CB1R Anandamide, A Gαi/o JD5037 Pancreatic β-cells, brain Stimulation of food intake Gruden et al. (2016) 2-AG Rimonabant Jourdan et al. (2014) CCK1R CCK A Gαq/11 Pancreatic β-cells, gastrointestinal tract, pancreas Stimulation of exocrine pancreatic and gall bladder contraction Ahrén et al. (2000) CCR2 CCL2, CCL7, CCL8, CCL11, CCL13 A Gαi/o CCX140-B Immune cells Obesity-induced insulin resistance by macrophage proinflammatory activity de Zeeuw et al. (2015) Cenicriviroc Gutierrez et al. (2011) NOX-E36 Kawano et al. (2016) Lefebvre et al. (2016) Menne et al. (2017) Sullivan et al. (2013a,b) Weisberg et al. (2006) EP3R Prostaglandin E2 A Gαq/11 DG-041 Brain, kidney Negatively regulates glucose and hormone-stimulated insulin secretion Ceddia et al. 2016 Gαi/o Kimple et al. (2013) Neuman and Kimple (2013) FFAR1 (GPR40) MCFAs (C9–C22): linoleic acid A Gαi/o Compound 15i Pancreatic β-cells, enteroendocrine cells, brain, liver, muscle, omental adipocytes, islet α-cells Indirect release of GLP-1 from intestinal endocrine cells; insulin secretion from pancreatic β-cells Blad et al. (2012) Gαq/11 GW9508 Defossa and Wagner (2014) Gαs LY2881835 Houthuijzen (2016) LY2922470 Husted et al. (2017) TAK-875 Mancini 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, pentanoate A Gαi/o Gαq/11 2-Methylacrylic acid Pancreatic β-cells, innate immune cells, enteroendocrine cells, gut epithelium, white adipose tissue, spleen, bone marrow G protein bias, inhibition of lipolysis, immune function, insulin-mediated fat accumulation, control of body energy Blad et al. (2012) AZ1729 (PAM) Bolognini et al. (2016) Compound 34 Husted et al. (2017) Compound 4 Bindels et al. (2013); McKenzie et al. (2015) Compound 58 Smith et al. (2011) Thorburn et al. (2014) FFAR3 (GPR41) SCFAs (C3–C7): formate, acetate, propionate, butyrate, pentanoate A Gαi/o Pancreatic β-cells, adipocytes, enteroendocrine cells, brain, lung, immune cells Anti-inflammation, involved in energy expenditure and metabolic regulation; activation causes release of leptin Husted et al. (2017) Inoue et al. (2014) Thorburn et al. (2014) Ulven (2012) FFAR4 (GPR120) Long-chain unsaturated fatty acids (C14–C18): docosahexaeonic acid A Gαq/11 Compound A Pancreatic β-cells, enteroendocrine cells, macrophages Stimulation of GLP-1 secretion, involvement of G protein–dependent and independent pathways, proinflammation Hirasawa et al. (2005) GW9508 Houthuijzen (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) GCGR Glucagon B Gαs Pancreatic β-cells, hepatocytes Stimulates hepatic glucose output Kieffer et al. (1996) GHSR-1a Ghrelin A Gαq/11 Pancreatic β-cells, widely expressed Stimulates ghrelin secretion Dezaki et al. (2008) Gαi/o Gα12/13 GIPR GIP B Gαs Pancreatic β-cells, adipocytes, small intestine, stomach, adrenal cortex, lung, pituitary, heart, testis, bone, brain Stimulates GLP-1 secretion, inhibits gastric emptying, induces adipocyte differentiation Flatt (2008) GLP-1R GLP-1-(7–36) B Gαs Albiglutide Pancreatic β-cells, brain, heart, kidney, gastrointestinal tract Satiety, inhibits gastric emptying, inhibits glucagon secretion Donnelly (2012) GLP-1-(7–37) Dulaglutide Graaf et al. (2016) Exenatide Meier (2012) Liraglutide Secher et al. (2014) Semaglutide Sisley et al. (2014) Taspoglutide GPER (GPR30) 17β-estradiol (E2) A Gαi/o ICI 182, 780 Pancreatic β-cells, placenta, lung, liver, prostate, ovary, brain Promotes insulin production, β-cell survival and adipogenesis Balhuizen et al. (2010) Gαs Tamoxifen Davis et al. (2014) Raloxifene Dennis et al. (2009, 2011) G-1 Kumar et al. (2011) G15 Sharma et al. (2013, 2017) G36 Wang et al. (2016) GPR21 A Gαq Macrophages, brain, heart Coordinates macrophage proinflammatory activity in the context of obesity-induced insulin resistance Gardner et al. (2012) Osborn et al. (2012) GPR27 A Gαq/11 Pancreatic β-cells Positive insulin promoter and glucose-stimulated insulin secretion Ku et al. (2012) GPR35 Kynurenic acid, pamoic acid, kysophosphatidic acid A Gαi/o Monocytes, neutrophils, gastrointestinal tract, peripheral nervous tissue, mast cells Indirect release of GLP-1 MacKenzie et al. (2011) Maravillas-Montero et al. (2015) Shore and Reggio (2015) GPR54 (KiSS1R) Kisspeptin A Gαq/11 Pancreatic β-cells, brain, blood vessels, placenta Inhibition of tumor growth Popa et al. (2008) GPR55 Lysophosphatidylinositol A Gαq/11 Gα12/13 Brain Energy homeostasis through the regulation of food intake, fuel storage in adipocytes, gut motility, and insulin secretion Liu et al. (2015a) Meadows et al. (2015) Ross (2009) Simcocks et al. (2014) GPR68 Proton sensing (pH 6–7.6) A Gαi/o Gαq/11 Lorazepam, Ogerin (PAM) Widely expressed Controls pancreatic β-cell response to acidic microenvironment Chandra et al. (2016) Huang et al. (2015b) GPR82 A Gastrointestinal glands, gall bladder, and pancreas Influences food intake, energy, and body weight balance Engel et al. (2011) GPR84 MCFAs (C9–C14): capric acid, 6-n-octylaminouracil A Gαi/o Compound 1 Immune cells, adipocytes, macrophages Obesity-induced insulin resistance by macrophage proinflammatory activity Blad et al. (2012) Suzuki et al. (2013) Talukdar et al. (2011) Thorburn et al. (2014) Wang et al. (2006) GPR119 Lipid amines A Gαs GSK2041706 Pancreatic β-cells, enteroendocrine cells, brain Causes release of GLP-1 and GIP Chu et al. (2008) GSK1292263 Release of insulin from pancreatic β-cells Hansen et al. (2012) MBX2982 Ritter et al. (2016) PSN821 Yang et al. (2016) GPR132 Long-chain n-acyl amides, pH, commensal metabolites A Gαs Compound 1 Macrophages, adipose tissue, skeletal muscle Involved in the cell cycle and promotes chemotaxis and proliferation Cohen et al. (2015) Gα13 Shehata et al. (2015) GPR142 A Gαq CLP-3094 Exclusively pancreatic β-cells Stimulates insulin secretion under conditions of high blood glucose Du et al. (2012) Compound 33 Lizarzaburu et al. (2012) Toda et al. (2013) Yu et al. (2013) GPRC5B C Gα12/13 Pancreatic β-cells Increased expression contributes to reduced insulin secretion and β-cell viability Kim et al. (2012) Kurabayashi et al. (2013) Soni et al. (2013) GPRC6A L-Arginine C Gαq Compound 7 Pancreatic β-cells Increased pancreatic β-cell proliferation, and insulin release from pancreatic islets Di Nisio et al. (2017) L-Lysine Compound 34b Jørgensen et al. (2017) L-Ornithine Pi et al. (2008, 2011, 2016) Osteocalcin Johansson et al. (2015) Rueda et al. (2016) Smajilovic et al. (2013) HCA2 (GPR109A) SCFAs (C4–C8): butyrate, nicotinic acid A Gαi/o GSK256073 Adipocytes, neutrophils, macrophages, intestinal epithelial cells Intracellular triglyceride lipolysis in adipocytes; activation causes unwanted flushing side effect, activation may cause insulin resistance in skeletal muscle Dobbins et al. (2013, 2015) Thorburn et al. (2014) Wanders and Judd (2011) M3R Acetylcholine, choline A Gαq/11 Pancreatic β-cells, widely expressed Enhanced glucose-stimulated insulin secretion from pancreatic β-cells Gautam et al. (2008) MT1/2R Melatonin A Gαi/o Gαq/11 Pancreatic α- and β-cells Inhibition of glucose-stimulated insulin secretion, involvement in sleep/wake cycle Jockers et al. (2016) Tuomi et al. (2016) Lane et al. (2016) P2Y14R (GPR105) UDP and UDP-glucose A Gαi/o Pancreatic β-cells, smooth muscle, lung Insulin secretion from pancreatic β-cells Abbracchio et al. (2003) Carter et al. (2009) Fricks et al. (2008) Meister et al. (2014) Xu et al. (2012) PAC1R PACAP B Gαs Pancreatic β-cells, widely expressed Stimulation of glucagon and adrenaline secretion Harmar et al. (2012) Moody et al. (2011) SUCNR1 (GPR91) Succinate A Gαi/o Gαq/11 Compound 5 g Adipose tissue, kidney, nervous system, dendritic cells, liver, spleen Hypertensive effects, activation of renin angiotensin system Carmone 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) VPAC2R VIP and PACAP B Gαs Pancreatic β-cells, widely expressed Stimulation of glucagon and adrenaline secretion, vasodilation Harmar et al. (2012) Moody et al. (2011) Y1R NPY A Gαi/o Pancreatic β-cells, widely expressed Vasoconstriction Brothers and Wahlestedt (2010)
