GPCR targets in type 2 diabetes

Chapter 18

GPCR targets in type 2 diabetes Patricio Atanes and Shanta J. Persaud Department of Diabetes, Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom

18.1 Introduction Diabetes is the fastest growing health crisis of our generation. There are currently approximately 425 million people with diabetes worldwide, a figure that has more than doubled in the past 20 years (Cho et al., 2018). Although much effort has been expended in attempting to reduce the incidence of diabetes, it is predicted that it will continue to grow at an alarming rate such that 642 million people will have diabetes by 2040 (Ogurtsova et al., 2017). Around 90% of people with diabetes have type 2 diabetes (T2D), a condition where hyperglycemia occurs because of insensitivity of cells to insulin, and insufficient insulin secretion from islet b-cells to compensate for this insulin resistance. The remainder have type 1 diabetes (T1D), which arises as a consequence of autoimmune destruction of insulin-secreting b-cells. A diagnosis of diabetes involves not only careful self-management but also chronic administration of a range of glucose lowering therapies for T2D and injections of insulin for individuals with T1D (de Groot et al., 2016). A late diagnosis or poorly controlled glycemia can lead to devastating complications that are associated with increased morbidity, disability, and mortality (Papatheodorou et al., 2016). The main complications arising from prolonged hyperglycemia in both T1D and T2D are cardiovascular disease, neuropathy, nephropathy, and retinopathy and these can lead to coronary artery disease, heart attack, stroke, atherosclerosis, amputation, end stage renal disease, and blindness (Forbes and Cooper, 2013). It is, therefore, essential that people with diabetes are diagnosed early and given appropriate therapies to maintain their blood glucose levels within an acceptable range of approximately 4e7 mM, which will reduce the risk of developing these deleterious and costly complications. A combination of genetic predisposition, sedentary lifestyle and obesity are the main factors that contribute to the onset of T2D (Wu et al., 2014). Lifestyle modifications to ameliorate the pathophysiological irregularities of insulin resistance and b-cell dysfunction are recommended before the initiation of pharmacotherapy, but only a minority of people with T2D are able to appropriately regulate their glucose levels with refined lifestyle habits alone (Delahanty et al., 2013). Success of intervention is determined by the amount of glycated haemoglobin (HbA1c) present in red blood cells, which is usually less than 6% in non-diabetic individuals but can reach >12% under conditions of poorly controlled diabetes. If it is not possible to reduce HbA1c levels to
7% by modifications to diet and exercise, therapeutic agents are introduced to normalize glycemia, and thus, reduce the risk of diabetic complications. Current drug therapies for T2D that are prescribed worldwide have four major modes of action, all of which decrease blood glucose levels (Tahrani et al., 2016; Kahn et al., 2014): increase insulin secretion (sulphonylureas, glinides, GLP-1 analogs, DPP4 inhibitors), increase insulin sensitivity (biguanides, thiazolidinediones), increase glucose excretion (SGLT2 inhibitors), and delay carbohydrate digestion (a-glucosidase inhibitors). These therapeutic approaches have improved the quality of life of millions of diabetic patients over the last 7 decades, starting with sulphonylureas in the 1950s and most recently with SGLT2 inhibitors in the past few years (Kahn et al., 2014). In addition, less commonly used T2D therapies include the dopamine agonist bromocriptine, and the amylin analog, pramlintide. Given that GPCRs are highly druggable entities, with at least one-third of current drugs in clinical use acting at these receptors (Persaud, 2017; Sriram and Insel, 2018), it is perhaps unexpected that very few of the therapies used for T2D directly regulate GPCR activity. This chapter reviews the current GPCR-based therapies for T2D, and provides information on potential future candidates that have arisen through GPCR research in insulin-secreting b-cells or insulin target tissues, and on GPCR ligands that are undergoing clinical trials. We also provide a future perspective on GPCR-based T2D therapeutic approaches, emphasizing the importance of refining and discovering new ways to treat T2D to improve the quality of life of individuals with diabetes.

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TABLE 18.1 GPCR-targeted therapies in current clinical use for type 2 diabetes. Therapy

Average HbA1c reduction

Mode of delivery

Main mode of action

Other beneficial effects

GLP-1 analogs

1%e1.5%

Subcutaneous injection

Activation of b-cell GLP-1 receptors; increased cAMP and insulin secretion

Delayed gastric emptying, decreased food intake, decreased glucagon secretion

DPP4 inhibitors

0.5%e1%

Oral

Increased endogenous GLP-1; activation of b-cell GLP-1 receptors; increased cAMP and insulin secretion

Decreased glucagon secretion

Bromocriptine

0.4%e0.8%

Oral

Activation of central D2 receptors; reset dopamine circadian rhythms leading to increased insulin sensitivity

Reduced cardiovascular event rates

Pramlintide

0.7%

Subcutaneous injection; coadministered with insulin

Activation of RAMP complex; decreased glucagon secretion

Delayed gastric emptying, decreased food intake

There are only three therapies for type 2 diabetes that directly activate GPCRs, and the DPP4 inhibitors have indirect GPCR-activating effects through increases in the endogenous GPCR ligand GLP-1. GLP-1 analogs are more widely prescribed than bromocriptine and pramlintide and are very effective at lowering HbA1c levels. The main disadvantage of GLP-1 analog use is that they must be administered by subcutaneous injection, as does pramlintide, while DPP4 inhibitors and bromocriptine are taken orally.

18.2 GPCRs as targets for current diabetes therapies GPCRs are the largest and most diverse group of cell surface receptors, acting to transduce signals from extracellular stimuli (Rosenbaum et al., 2009). Their specialized ligand-receptor interactions provide exclusive sites for high-affinity drug binding, which has led to GPCRs being targeted for a wide range of conditions including hypertension, asthma, depression, insomnia, and stomach ulcers (Latek et al., 2012; Sriram and Insel, 2018). However, considering that over 300 non-olfactory GPCRs have been identified (Vassilatis et al., 2003), it is surprising that receptors for GLP-1, dopamine, and amylin are the only GPCR-based therapies in current clinical use for T2D, highlighting the requirement for additional research with other promising GPCRs to underpin new therapies to treat T2D and its complications. This section will review the currently used GPCR pharmacotherapies for T2D, with information on their mechanisms of action, signaling pathways and functional effects to improve blood glucose levels in T2D diabetes. The key information is summarized in Table 18.1.

18.3 GLP-1 analog activation of GLP-1 receptors The incretin system plays an essential role in communicating food content of the gastrointestinal tract to islet b-cells and it was established over 50 years ago that plasma insulin levels were substantially higher when a fixed dose of glucose was delivered directly to the upper jejunum rather than intravenously (McIntyre et al., 1964). It is now apparent that GLP-1 secretion from the ileum and colon in response to food intake accounts for approximately 70% of all secreted insulin following nutrient consumption (Garber, 2011). GLP-1 that is released from the distal gastrointestinal tract travels in the circulation to islets where it has glucose lowering effects by stimulating insulin secretion from b-cells and inhibiting glucagon secretion from a-cells (Drucker, 2018). The observations that GLP-1 secretion is diminished in T2D patients (Holst et al., 2011), that its infusion in T2D individuals potentiated insulin secretion and improved glucose tolerance (Holst and Gromada, 2004), while the other intestinal-derived incretindglucose-dependent insulinotropic peptide (GIP)dwas not effective (Nauck et al., 1993), led to the development of GLP-1 analogs to treat T2D. The native GLP-1 peptide was not suitable as a therapeutic as it is readily degraded by dipeptidyl peptidase-4 (DPP4), which limits its half-life to less than 2 min. However, long-acting analogs of GLP-1, which are DPP4-resistant but maintain agonist activity at GLP-1 receptors, have proven to be very effective in treating T2D in the last 10e15 years. In particular, exenatide (Cvetkovic and Plosker, 2007) and liraglutide (Neumiller and Campbell, 2009), which are injectable synthetic GLP-1 variants with half-lives of over 2 h, have excellent glucose lowering profiles and they have the added advantage that they also act centrally to reduce food intake (Drucker, 2018). Exenatide (Byetta), a synthetic version of the naturally occurring peptide exendin-4, was approved in 2005 for treatment of T2D. It is 53% identical to GLP-1 but resistant to DPP4 cleavage, due to substitution of the glycine residue at position two of the N-terminus with alanine. In 2015, a review of the first decade of clinical use of exenatide products indicated that they had been used by more than two million people, in 80 countries worldwide (Hemler). Liraglutide (Victoza) was approved for the treatment of T2D in 2009 and since then it has been prescribed to over one million people in 95 countries (Plainsboro). It has approximately 97% sequence homology to native GLP-1 and its reduced susceptibility to

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enzymatic degradation is conferred by the attachment of palmitic acid to a lysine residue via a glutamate spacer, which allows its binding to plasma albumin. The anorexigenic effect of GLP-1 analogs complements their insulin secretagogue activity, as weight reduction improves insulin sensitivity. In fact, liraglutide is so effective at inducing weight loss that it is now being marketed as a medication for weight management (Mehta et al., 2017). Islet GLP-1 receptors may also be activated in T2D through the use of orally available DPP4 inhibitors such as vildagliptin (Galvus) and sitagliptin (Januvia), which block the proteolytic action of DPP4, thus, increasing the level of endogenous GLP-1 (Persaud, 2017). GLP-1 and its analogs activate the GLP-1 receptor, which is an archetypal component of the class B subfamily of GPCRs (Miller et al., 2014). GLP-1 receptors are widely expressed in islet b-cells, cells of the gastrointestinal tract, cardiomyocytes, vascular smooth muscle cells, and hypothalamic nuclei. The GLP-1 receptor predominantly signals through Gas to raise intracellular cAMP levels through increasing adenylate cyclase activity (Wheeler et al., 1993), although there are also reports of signaling via Gai, Gao, and Gaq/11 (Montrose-Rafizadeh et al., 1999; Baggio and Drucker, 2007), and G-protein-independent signaling, via recruitment of regulatory b-arrestin proteins (Sonoda et al., 2008). The mechanisms of action of GLP-1 and its analogs at islets go beyond an exclusive effect of potentiating glucosestimulated insulin secretion, with additional reported effects of increased insulin expression, reduced b-cell apoptosis and elevated b-cell proliferation (Drucker, 2018), all of which are beneficial in maintaining functional b-cell mass. Some disadvantages have been reported for exenatide, liraglutide and DPP4 inhibitors, including acute pancreatitis, kidney failure, bile duct, and gall bladder diseases (Faillie et al., 2016), and inflammatory bowel disease (Timofte et al., 2013; Filippatos et al., 2014; Abrahami et al., 2018), but the incidence of these adverse events is relatively low, and thus, they are still attractive treatment options.

18.4 Bromocriptine activation of dopamine D2 receptors Dopamine plays a central role in the regulation of appetite, with dopamine D2 receptors being associated with regulation of food reward and obesity (Kalra et al., 2011), and D2 receptor knockout mice show reductions in food intake and weight gain via hypothalamic leptin signaling (Kim et al., 2010). It is, therefore, perhaps counterintuitive that a D2 receptor agonist should be used to treat T2D, as it might be predicted that this would exacerbate obesity-induced hyperglycemia through enhanced food intake. However, it has been suggested that dopamine deficiency in obesity and the consequent reduction in dopamine-activated reward circuits may promote pathological eating (Baik, 2013), so that exogenous provision of a dopamine agonist could reset this balance. In addition, there is evidence of disrupted circadian rhythms and reduced dopaminergic tone in the morning in individuals with T2D and obesity (Luo et al., 1999) and it has been proposed that this contributes to insulin resistance and elevated hepatic glucose output (Shivaprasad and Kalra, 2011). The potent D2 receptor agonist bromocriptine (Cycloset) was approved by the U.S. Food and Drug Administration (FDA) as a T2D therapy in 2009 (Mikhail, 2011; Mahajan, 2009), and it is the only T2D therapy in clinical use that has a primary mode of action in the central nervous system. It is administered in the morning as a once-daily tablet with a quickrelease formulation, providing maximum plasma concentrations within 1 h of ingestion (Defronzo, 2011). Its mode of action has not been fully established, but it is thought to act at hypothalamic D2 receptors to reset dopamine circadian rhythms to improve insulin sensitivity (Mikhail, 2011; Shivaprasad and Kalra, 2011). D2 receptors are members of the class A subfamily of GPCRs (Kasai et al., 2018), and they are widely expressed in the central nervous system. They couple to Gai to inhibit adenylate cyclase and reduce intracellular cAMP levels, and they also activate protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) through Gb/g (Pivonello et al., 2007). There is also peripheral expression of D2 receptors, and this may explain the reduced cardiovascular risk profile of bromocriptine (Shivaprasad and Kalra, 2011). However, the observations that dopamine increases human b-cell apoptosis and decreases b-cell proliferation, while a D2 receptor antagonist has the opposite effect (Sakano et al., 2016), suggest that long-term use of bromocriptine may be associated with declining b-cell function and this is something that should be monitored in individuals receiving this drug. Some adverse effects have been reported for bromocriptine, including nausea, vomiting, loss of appetite, headache, and allergy (Roe et al., 2015), but it is not associated with weight gain or hypoglycemia, which are the disadvantages of some T2D therapies such as sulphonylureas.

18.5 Pramlintide activation of calcitonin/RAMP receptors Islet amyloid polypeptide (IAPP), also known as amylin, is stored in islet b-cells and it is cosecreted with insulin when blood glucose levels rise. It plays a physiological role in maintaining normoglycemia by delaying gastric emptying, suppressing glucagon secretion from islet a-cells and through its central anorexigenic effects to reduce food intake (Ludvik et al., 1997). Its levels are reduced in T2D (Pullman et al., 2006), suggesting that delivery of exogenous amylin could be a

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therapeutic option for T2D. However, aggregation of amylin into amyloid deposits in b-cells is a relatively common feature in T2D, and these amyloid fibrils trigger the inflammasome protein complex to secrete IL-1b, which stimulates islet apoptosis (Marzban, 2015). Amylin is, therefore, not an appropriate therapy for T2D as its administration could lead to deposition of amyloid plaques in islets, resulting in b-cell dysfunction and death. Human and rat amylin are both composed of 37 amino acids and they differ by only six amino acid residues (Nanga et al., 2008), but rat amylin is neither toxic nor amyloidogenic, so rats do not develop amyloid deposits. The maintained solubility of rat amylin, even at high concentrations, has been exploited therapeutically by the development of a human amylin analog that has three proline substitutions at positions 25, 28, and 29, identical to rat amylin at these residues. This synthetic analog, called pramlintide (Symlin), does not self-aggregate, but maintains the beneficial gluco-regulatory effects of amylin. It was approved by the FDA in 2004 for use in both type 1 and 2 diabetic individuals who were being treated with mealtime insulin alone or a combination of insulin and metformin and/or a sulphonylurea (Ryan et al., 2009). Pramlintide is used as an adjunct to mealtime insulin and it reduces postprandial glucose levels by slowing gastric emptying, inhibiting inappropriate secretion of glucagon, and inducing satiety to promote weight loss (Edelman et al., 2008; Schmitz et al., 2004; Pullman et al., 2006). The capacity of pramlintide to reduce food intake compensates for the weight-inducing effects of the coadministered insulin, and the use of pramlintide with insulin in T2D therapy is associated with weight loss of approximately 1.5 kg, which will contribute to the improved glucose homeostasis seen with this therapeutic combination (Hollander et al., 2004; Pullman et al., 2006). Amylin belongs to the calcitonin family of peptides and it transduces its effects via the calcitonin GPCR. Activation of this receptor by amylin requires the GPCR to associate with members of the receptor activity-modifying proteins (RAMPs), which can form heterogenic networks with GPCRs to modulate their expression and pharmacology (Poyner et al., 2002). Complexes of the calcitonin receptor interacting with RAMPs one to three are known as AMY1, AMY2, and AMY3 respectively, and all three receptors signal via Gas to raise intracellular cAMP levels through increasing adenylate cyclase activity (Lee et al., 2016). The weight regulating effects of pramlintide have been exploited in the development of a dual amylin/calcitonin receptor agonist, KBP-089, as a prospective antiobesity therapy. The weight loss and glucose normalizing effects of KBP-089 in rats fed a high-fat diet are promising (Gydesen et al., 2017), and suggest that this peptide has therapeutic potential. There are few disadvantages to pramlintide use: it must be delivered by subcutaneous injection, but as it is used in combination with insulin, those treated with pramlintide must have prior experience of insulin injections. The most commonly reported adverse effects associated with pramlintide use are nausea, headache, anorexia, vomiting, and abdominal pain, although these occur more often at the start of therapy and are usually mild to moderate (Ryan et al., 2005).

18.6 GPCRs expressed by islets and other metabolically active tissues: potential targets for novel diabetes therapies The prevalence of T2D has increased considerably in the past few decades and this has led to new glucose lowering strategies to drive glucose excretion, improve insulin sensitivity or stimulate insulin release and b-cell mass (Tahrani et al., 2016). As outlined above, one of the most recent families of therapies in clinical use for T2D is stable GLP-1 analogs, which act at islet GLP-1 receptors to potentiate glucose-induced insulin secretion and promote b-cell survival (Drucker, 2018). The effectiveness of GLP-1 analogs and the widespread use of GPCR ligands as pharmacotherapies for other conditions has resulted in substantial interest in targeting other GPCRs to treat T2D. To date, the focus has largely been on the other intestinal-derived incretin, GIP, and on agonists of the long chain fatty acid receptor FFAR1 (GPR40) or the novel cannabinoid receptor GPR119 (Persaud, 2017). However, our observations that islets isolated from human organ donors express nearly 300 GPCRs (Amisten et al., 2013) make it clear that there is a vast untapped potential for therapies targeting islet GPCRs to increase their functional mass. Similarly, we have also identified that human subcutaneous adipose tissue expresses 163 GPCRs (Amisten et al., 2015) and our unpublished data indicate that human skeletal muscle cells express 215 GPCRs. The abundance of GPCRs in islets and insulin-sensitive tissues, the majority of which have not been explored functionally, highlights the importance of carrying out further investigation in this field to develop novel and refined GPCR-targeted therapies for T2D. The plasma glucose concentration is maintained between 4 and 7 mM by the coordinated function of islet b-cells to secrete insulin and the action of insulin at skeletal muscle, adipose tissue, and liver for glucose uptake, utilization, and storage (Triplitt, 2012), together with an intricate modulatory neuro-hormonal system (Sprague and Arbelaez, 2011). Glucose is the predominant metabolic source employed by the central nervous system, which can autonomously regulate glucose uptake by the high-affinity GLUT-1 transporter (Mergenthaler et al., 2013). Conversely, skeletal muscle and adipose tissue require insulin for translocation of GLUT-4 transporters to the cell surface to allow glucose uptake into

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myocytes and adipocytes. They use glucose as their primary metabolic fuel in the absorptive phase, leading to its consumption or storage as glycogen in the muscle, or as fat in the adipose tissue, and free fatty acids or ketones are used as the primary energy source during periods of hypoinsulinemia (Alemany, 2011). Glucose enters liver hepatocytes via low affinity, insulin-independent GLUT-2 transporters and excess glucose is stored as glycogen. Adding more layers of complexity to this finely balanced system, while intestinal absorption elevates blood glucose levels in the absorptive state, periods of hypoglycemia do not occur in the absence of food intake because glucose levels are maintained by glycogenolysis in liver and muscle, and gluconeogenesis in liver and kidney, in the postabsorptive state (Bano, 2013). It is, therefore, clear that mechanisms that improve insulin secretion and/or insulin action will counteract the impairments in whole body glucose homeostasis that occur in T2D, and therapies that regulate GPCR function in metabolically active cells should have excellent potential for development as drug candidates. The tissues and cells that are most appropriate for GPCR-targeted therapies to normalize blood glucose levels are shown in Fig. 18.1.

FIGURE 18.1 Key targets of GPCR ligands to regulate glucose homeostasis. The figure shows the tissues and cells that are most appropriate for GPCR-targeted therapies to normalize blood glucose levels. In particular, GPCRs that increase insulin secretion and maintain or expand b-cell mass will ensure sufficient insulin levels to compensate for insulin resistance. GPCRs that increase glucose uptake into adipose tissue and skeletal muscle will also reduce hyperglycemia, as will those that promote glycogen storage and inhibit glycogenolysis and gluconeogenesis in the liver. Additional GPCR targets include those in gastrointestinal enteroendocrine cells to induce secretion of incretin hormones, the hypothalamus to decrease food intake and the gastrointestinal tract to reduce peak increases in glucose after food intake. In addition, some GPCRs may be targets to reduce diabetic complications, such as diabetic nephropathy. *Insulin stimulates lipogenesis but a successful T2D therapy should not induce lipid storage, which contributes to weight gain; increased lipolysis would be beneficial. **Inhibition of glucagon secretion will reduce glycogenolysis and gluconeogenesis, but glucagon receptor agonists are being investigated for coagonist therapy with GLP-1 analogs.

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FIGURE 18.2 Signaling downstream of GPCRs in the regulation of insulin secretion and action. The figure shows the key signal transduction pathways downstream of GPCR activation by their cognate ligands, which results in alterations in cell function. All GPCRs undergo conformational changes following ligand binding and this allows the Ga subunits of the heterotrimeric GTP-binding proteins to exchange GDP for GTP and dissociate from the Gbg dimer. The GTP-bound Ga subunits can activate (Gas) or inhibit (Gai/o) adenylate cyclase (AC) to regulate intracellular cAMP levels, while Gaq/11 activates phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5 bisphosphate (PIP2) to the second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (IP3). IP3 stimulates mobilization of Ca2þ from the endoplasmic reticulum, which activates the calciumcalmodulin-dependent protein kinases (CaMK), while cAMP and DAG activate the protein kinases A and C (PKA and PKC), respectively. Activation of these kinases results in phosphorylation of intracellular proteins on serine and threonine residues and this can lead to acute signaling, such as exocytotic release of insulin and GLP-1 from b-cells and enteroendocrine cells, or longer term signaling through alterations in gene expression. Ligands that activate GPCRs coupled to Ga12/13 regulate actin cytoskeletal remodelling while the Gbg dimers downstream of these receptors can activate phosphatidylinositol 3-kinase (PI3K) to generate phosphatidylinositol 3,4,5 trisphosphate, which signals via activation of protein kinase B (Akt). Akt is a key kinase downstream of insulin signaling in insulin-sensitive cells and it has short term effects to stimulate GLUT4 translocation in fat and muscle and longer term effects to drive fuel storage via changes in gene expression.

The following section provides a nonexhaustive overview of key GPCRs expressed by cells involved in the regulation of glucose homeostasis, explaining their functional effects and signal transduction mechanisms that they use, and evaluating the opportunities for development of novel therapies for T2D. The key pathways through which GPCR ligands can modify function of b-cells or insulin-sensitive cells are summarized in Fig. 18.2.

18.7 Receptors for gut-derived peptides Nutrient delivery to specialized enteroendocrine cells of the gastrointestinal tract acts as a stimulant for secretion of several peptides that contribute to glucose homeostasis. GLP-1 released from L-cells in the ileum and colon has been harnessed for therapeutic use, as described above, but other peptides that are released from the specialized I-, K- and L-cells are also implicated in the regulation of blood glucose levels.

18.7.1 Cholecystokinin receptors Cholecystokinin (CCK) is secreted from the duodenal I-cells postprandially and it promotes gallbladder contraction, stimulates insulin secretion, delays gastric emptying, and induces satiety (Adamska et al., 2014). CCK activates two distinct subtypes of CCK receptors: CCK1R and CCK2R (Berna and Jensen, 2007), which are distributed in the gastrointestinal tract, pancreas, kidney, gallbladder, and nervous system, explaining the widespread effects of this hormone after food intake (Wank, 1995). The primary transduction mechanism for CCK1R is via Gaq/11, but it may also have secondary signaling via

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Gas and Ga13, while CCK2R exclusively signals via Gaq/11 (Tripathi et al., 2015). Mutations or polymorphisms in the CCK receptors have been implicated in predisposition to obesity and T2D. For example, the V125I-CCK2R polymorphism in T2D patients is associated with enhanced glucagon secretion (Marchal-Victorion et al., 2002), which will exacerbate hyperglycemia as a consequence of glucagon-mediated gluconeogenesis and glycogenolysis. In addition, a V365I-CCK1R mutation identified in an obese patient was associated with reduced phospholipase C (PLC) activation, and it was proposed that this could be responsible for impaired CCK-induced satiety (Marchal-Victorion et al., 2002). A recent approach to exploiting the glucoregulatory effects of CCK is the use of enzymatically stable CCK peptide analogs, which cause weight loss and improved glucose tolerance (Pathak et al., 2018). In addition, a combination therapy of an exenatide analog (AC3174) and a CCK1R agonist has led to metabolic improvement in obese rodents (Trevaskis et al., 2015). Other CCK combination therapies are under consideration, including its association with GLP-1, GIP, leptin, and amylin (Pathak et al., 2018), which could lead to the development of novel and effective therapeutic approaches for obesity and T2D.

18.7.2 Glucose-dependent insulinotropic peptide receptor Glucose-dependent insulinotropic peptide (GIP) is released from the duodenal K-cells after food intake. It has multiple glucose lowering effects, by stimulating insulin secretion (Chia et al., 2014), inhibiting hepatic glycogenolysis (Hartmann et al., 1986), increasing glucose uptake into the skeletal myocytes (Snook et al., 2015) and stimulating lipoprotein lipase activity (Eckel et al., 1979) and triacylglycerol synthesis (Asmar, 2011) in adipocytes. It exerts its effects through the GIP receptor, a class B GPCR whose principal signaling is through coupling to Gas, although recent reports indicate that it can also signal via other regulatory proteins such as arrestins (Abdullah et al., 2016). GIP levels are diminished in people with T2D, but targeting GIP receptors with stable GIP analogs, as has been done with the GLP-1 analogs, is not a suitable therapeutic approach since there is an impaired insulinotropic response to GIP in T2D (Nauck et al., 1993), and the stimulatory effects of GIP on glucagon secretion (Chia et al., 2014) also mitigate against the use of GIP receptor agonists to treat T2D. However, there has recently been a reappraisal of the therapeutic utility of GIP receptor agonists when used in combination with GLP-1 analogs, and a phase two trial in patients with T2D indicated that once weekly delivery of LY3298176, a dual GIP/GLP-1 receptor agonist, led to dose-dependent reduction in HbA1c and weight (Frias et al., 2018). In contrast to the use of GIP receptor agonists, observations that deletion of GIP receptors in mice protects against obesity and insulin resistance (Miyawaki et al., 2002), and that reduced GIP secretion has similar beneficial effects (Nasteska et al., 2014), have led to the proposal that GIP receptor antagonists should be considered as a novel class of antidiabetic drugs to improve fasting and postprandial glycemia. However, no studies using GIP receptor antagonists have so far been performed in patients with T2D (Gasbjerg et al., 2018).

18.7.3 PYY receptors Peptide tyrosine-tyrosine (PYY) is released from enteroendocrine L-cells after food intake and it has both beneficial and detrimental effects on glucose homeostasis. Thus, it acts centrally to reduce food intake, leading to weight loss and improved sensitivity, and it delays gastric emptying, decreases b-cell apoptosis and stimulates b-cell proliferation, but it also has direct inhibitory effects on insulin secretion (Persaud and Bewick, 2014, Franklin et al., 2018). Full length PYY has 36 amino acids, but a truncated peptide, PYY3-36, is the major circulating form. Both of these peptides have physiological effects through the activation of members of the NPY GPCR family (Y1, Y2, Y4, and Y5), all of which couple to Gai to inhibit cAMP generation, and there is also evidence of Gaq coupling to drive diacylglycerol accumulation and PKC activation (Karlsson and Ahren, 1996; Persaud and Bewick, 2014, Franklin et al., 2018). PYY1-36 is equally effective at all four receptor subtypes while PYY3-36 preferentially activates Y2 receptors, which are responsible for the anorectic effects of PYY, and it has also been shown that Y2 receptor activation indirectly increases insulin secretion through the stimulation of GLP-1 release (Chandarana et al., 2013). Human and mouse islets express Y1 and Y4 receptors that transduce the effects of PYY to protect against apoptosis and stimulate b-cell proliferation, but these receptors are also responsible for PYY inhibitory effects on insulin secretion. Furthermore, although PYY3-36 induces satiety via activation of Y2 receptors, full length PYY increases food intake through the activation of central Y1 receptors. Therefore, ligands that selectively activate Y1 receptors would be useful in maintaining b-cell mass, but these ligands would also be expected to inhibit insulin secretion and elevate weight gain (unless peripherally restricted agonists were used). Given these drawbacks, it seems unlikely that Y1 receptor agonists will be developed to treat T2D, but targeting Y2 receptors to promote satiety and indirectly potentiate glucose-stimulated insulin secretion may be a sensible therapeutic strategy.

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18.8 Receptors for islet hormones Islets are three-dimensional clusters of endocrine cells that respond in a paracrine or autocrine manner to locally secreted insulin, glucagon, and somatostatin. Insulin mediates its effects through activation of a receptor tyrosine kinase while glucagon and somatostatin are GPCR agonists.

18.8.1 Glucagon receptor When blood glucose levels are low, glucagon secreted from islet a-cells drives hepatic gluconeogenesis and glycogenolysis, and it also stimulates lipolysis in adipocytes and hepatocytes, all of which provide the necessary fuel for maintenance of activity in the absence of food intake (Roder et al., 2016). The glucagon receptor is a Class B GPCR that is coupled to cAMP generation through Gas, although there is also evidence for additional signaling mediated by Gaq/11 and Gai/o proteins (Xu and Xie, 2009). It has been reported that elevated plasma levels of glucagon contribute to the increased hepatic glucose release observed in patients with T2D (Haedersdal et al., 2018). The most likely source of this glucagon is islet a-cells, but the observation that hyperglucagonemia occurs in pancreatectomized patients suggests that the excess glucagon observed in T2D is not solely a-cell-derived (Lund et al., 2016). An obvious therapeutic approach is to inhibit glucagon action, and it is well accepted that glucagon receptor inhibition decreases hyperglycemia in animal models of T2D (Kim et al., 2012a) and patients with T2D (Kelly et al., 2015), an amelioration in glycemic levels that results mainly from diminished hepatic glucose production. However, a phase II clinical trial using the glucagon receptor antagonist LY2409021 indicated that although it was effective in reducing blood glucose levels it displayed undesirable adverse effects, including significant hepatic fat accumulation, hypertension, and weight gain (Guzman et al., 2017), and development of other glucagon receptor antagonists has been curtailed because of similar contraindications (Christensen et al., 2011). Another approach being considered is combinatory therapies using glucagon receptor agonists rather than antagonists. For example, use of glucagon/GLP-1 receptor coagonists could harness the effects of both receptors to reduce food intake and stimulate insulin secretion, and GLP-1 receptor activation would counteract the hyperglycemic effect of glucagon (Soni, 2016). In addition, glucagon/GIP/GLP-1 receptor triagonists have also been proposed, to exploit the beneficial effects of the incretin system in conjunction with glucagon to develop a refined T2D pharmacotherapy (Capozzi et al., 2018).

18.8.2 Somatostatin receptor Somatostatin (SST) is secreted from islet d-cells in response to elevated blood glucose levels and it acts in a paracrine manner to suppress insulin and glucagon secretion (Marco et al., 1983), and it also has autocrine effects to inhibit its own secretion (Ballian et al., 2006). Islets express high levels of RGS16, a member of the regulator of G-protein signaling (RGS) family, which has been implicated in limiting the inhibitory effects of SST on insulin secretion (Vivot et al., 2016). In addition, RGS16 is thought to act as a nutrient sensor in the liver to inhibit fatty acid oxidation (Pashkov et al., 2011), so increased activity of this GPCR regulatory protein could be useful in maintaining insulin secretion and action. RGS proteins have been less studied than GPCRs as targets for treating diseases, but an RGS4 inhibitor has shown encouraging effects to ameliorate akinesia and bradykinesia in an animal model of Parkinson’s disease (Blazer et al., 2015), suggesting the therapeutic potential of this family of proteins. It is too early to determine whether activation of RGS16 could be used to improve glucose homeostasis in T2D, and careful titration would be required to prevent hepatic steatosis, but the recent inclusion of RGS proteins in the IUPHAR database of drug targets (Sjogren, 2017) suggests that they may be promising future candidates. The biological effects of SST are mediated by SST1-5 receptors, all of which are coupled to Gai/o to inhibit adenylate cyclase activity, thereby, decreasing intracellular cAMP levels. In addition, secondary transduction mechanisms via Gaq/11 or G-protein-independent cascades have been identified (Rai et al., 2015; Theodoropoulou and Stalla, 2013). One of the most studied receptors in SST biology is SST2R, a subtype that is highly expressed in both human and mouse islets (Amisten et al., 2017) where it is localized to a- and b-cells (Kailey et al., 2012). SST2R antagonists might be useful in T2D to relieve inhibition of insulin secretion by SST, but the main interest in these drugs has been to block SST-mediated reduction in glucagon, which is accentuated during hypoglycemia and impairs the capacity of glucagon to stimulate gluconeogenesis and glycogenolysis. The SST2R antagonist PRL-2903 can restore glucagon secretion in an autoimmune rat model of T1D (Karimian et al., 2013) and streptozotocin-induced diabetic rats (Yue et al., 2012) to prevent insulininduced hypoglycemia. SST is also secreted by the hypothalamus and it acts at anterior pituitary somatotrophs to inhibit growth hormone secretion and thus reduce circulating IGF-1 levels. IGF-1 has been implicated in the development

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of diabetic retinopathy, so the long-acting SST analog octreotide has been used in clinical trials to determine whether it may be effective in arresting the progression of diabetic retinopathy. However, neither trial showed beneficial effects of octreotide (Simo-Servat et al., 2018), and since SST has inhibitory effects on insulin secretion, the use of a systemic longacting SST analog could worsen hyperglycemia in T2D.

18.9 Neurotransmitter receptors Glucose homeostasis is regulated by sympathetic and parasympathetic neurotransmitters that are released from neurons innervating islets and insulin-sensitive tissues, and nonadrenergic, noncholinergic neurotransmitters may also be involved in the fine tuning of blood glucose levels.

18.9.1 Muscarinic receptors The GPCR family of muscarinic receptors consists of five members (M1-M5), all of which have a widespread tissue distribution and respond to the natural ligand acetylcholine (Ishii and Kurachi, 2006). M1, M3, and M5 receptors couple to Gaq/11, and M2 and M4 receptors signal via Gai/o (Haga, 2013), and there is also evidence of G-protein-independent muscarinic signaling pathways (Kong et al., 2010). It has long been known that cholinergic agonists directly potentiate glucose-induced insulin secretion in a PKC-dependent manner (Persaud et al., 1991), and it has now been established that islet b-cells express M3 receptors that are coupled to Gaq/11 to transduce elevations in intracellular Ca2þ and PKC activation. These receptors also signal via Src tyrosine kinases to activate NALCN sodium channels and via b-arrestin coupling to activate PKD1, and they are inactivated by RGS4 (Kong and Tobin, 2011). Inhibition of M3 receptors by antidepressant drugs is associated with an increased risk of development of T2D, as M3 antagonists decrease glucoseinduced insulin release (Tran et al., 2017). Consistent with this, mice, in which M3 receptors have been specifically deleted in islet b-cells, show reduced insulin secretion and impaired glucose tolerance, while obese mice overexpressing b-cell M3 receptors were protected against insulin resistance and hyperglycemia (Gautam et al., 2006). Although M3 agonists appear to be an attractive therapeutic option for treating T2D, it is unlikely that progress will be made unless highly selective M3 agonist compounds are developed that can be targeted directly to islet b-cells to prevent off-target effects at widely expressed M3 receptors.

18.9.2 Adrenergic a2 receptors The sympathetic neurotransmitter noradrenaline plays a key role in elevating blood glucose levels, by direct effects at islet b- and a-cells to inhibit insulin secretion and stimulate glucagon secretion, respectively, and by promoting adipocyte lipolysis (Hoffman, 2007). These counterregulatory responses are essential to prevent hypoglycemia, but elevated sympathetic tone has been associated with impaired glucose tolerance and increased risk of developing T2D and its associated complications (Fagerholm et al., 2011). Noradrenaline signals via adrenergic receptors, which are categorized into a1, a2, and b subgroups according to their sequence and preferred associated G-protein: a1 receptors primarily couple to Gaq/11, a2 to Gai/o, and b to Gas (Riddy et al., 2018). The a2 receptor subfamily, predominantly a2A, has been implicated in glucose control. Thus, clinical association studies have discovered that genetic variations in a2A, in particular rs553668, are associated with increased a2A receptor expression, impaired glucose-induced insulin secretion and higher risk of T2D (Rosengren et al., 2010). In addition, mice with b-cell-specific a2A-adrenoceptor overexpression had impaired glucose tolerance and marked hyperglycemic responses to the a2-adrenoceptor agonist brimonidine (Devedjian et al., 2000), while a2A knockout mice showed a clear improvement in glucose tolerance (Savontaus et al., 2008), confirming the benefit of antagonizing a2 receptor activity to prevent hyperglycemia. Thus, a2A-adrenoceptor antagonist therapy may be beneficial to regulate insulin secretion and glucose tolerance. However, the extensive expression of a2 receptors and their critical role in many physiological processes, including feedback inhibition of noradrenaline release at prejunctional terminals, mitigates against the widespread use of a2 antagonists.

18.9.3 5-HT receptors Serotonin, also known as 5-hydroxytryptamine (5-HT), is a key neurotransmitter that orchestrates a vast array of physiological and pathophysiological pathways, including mood, emotion, sleep, social behavior, appetite, and digestion (Charnay and Leger, 2010). Serotonin is the endogenous agonist of 5-HT receptors, which are classified into seven

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subfamilies based on their pharmacological properties: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F and 5-HT5A receptors signal via Gai/o; 5-HT2A, 5-HT2B, 5-HT2C receptors are linked to Gaq/11 and 5-HT4, 5-HT6 and 5-HT7 receptors transduce their effects through Gas (McCorvy and Roth, 2015). On the other hand, 5-HT₃ receptors belong to the Cys-loop superfamily of ligand-gated ion channels (Barnes et al., 2009), differing in structure and function from the rest of the 5-HT receptor subfamilies classified as GPCRs. Serotonin is co-released with insulin (Almaca et al., 2016) and its levels are up-regulated under conditions of metabolic challenge such as pregnancy, where placental lactogen increases serotonin synthesis (Schraenen et al., 2010), and enhanced activation of 5-HT2B and 5-HT3 receptors stimulates b-cell proliferation and insulin secretion, respectively (OharaImaizumi et al., 2013). Any disruption of this complex balance during pregnancy can predispose to the development of gestational diabetes. In addition to this, the 5-HT2A receptor antagonist sarpogrelate has shown beneficial effects in reducing HbA1c levels in diabetic kidney disease (Yang et al., 2017), increased expression of 5-HT1D inhibited somatostatin signaling (Mota et al., 1995), and activation of 5-HT1F receptors reduced glucagon secretion in diabetic mice (Almaca et al., 2016). Furthermore, 5-HT2C knockout in mice exacerbates obesity-induced weight gain and glucose intolerance (Wade et al., 2008). The onset of obesity caused by 5-HT2C deletion and the expression of 5-HT2C receptors by the hypothalamic anorexigenic POMC neurons (Shukla et al., 2015) suggest that 5-HT2C agonists could be important in promoting weight loss and improving insulin sensitivity, and in 2012, lorcaserin, a highly selective 5-HT2C against was approved by the FDA to treat obesity (Yanovski and Yanovski, 2014). Treatment with lorcaserin is associated with significantly decreased fasting glucose and HbA1c in addition to its effects on weight loss (Shukla et al., 2015), validating targeting of 5-HT2C receptors to regulate glucose homeostasis.

18.9.4 Melatonin receptors Melatonin is a 5-HT derivative that is secreted from the pineal gland to entrain circadian rhythms. It acts via MT1 and MT2, both of which couple to Gai/o to inhibit cAMP accumulation and MT1 receptors can also activate PLC through Gaq/11 (Brydon et al., 1999). Human islets mainly express MT1 receptors, with much lower expression of MT2 (Ramracheya et al., 2008), and in isolated human islets melatonin stimulates insulin secretion while having inhibitory effects in rodent islets (Picinato et al., 2002; Ramracheya et al., 2008). The data with human islets support melatonin having insulin secretagogue effects via MT1 receptors under normal circumstances. However, the rs10830963 variant of MT2 receptors, which is associated with increased risk of T2D (Lyssenko et al., 2009), leads to up-regulation of this receptor on b-cells (Tuomi et al., 2016) and this could alter the balance of melatonin signaling such that the MT2-Gai/o coupling takes precedence over that of MT1-Gaq/11 signaling (Persaud and Jones, 2016). MT2 receptor antagonists may, therefore, be useful in normalizing glucose homeostasis in those individuals with the rs10830963 risk variant, but they are unlikely to be of therapeutic relevance to the general population with T2D, who have very low levels of islet MT2 receptor expression.

18.10 Fatty acid receptors Free fatty acids (FFAs) are an important energy source for most tissues, playing a pivotal role in the modulation of whole body fuel homeostasis (Van Harmelen et al., 1999). Thus, when blood glucose levels are low, FFAs are used as fuel by cells and are converted into glucose in the liver, and when glucose levels are high they are stored as triacylglycerols. Fatty acids are characterized as short, medium or long-chain, depending on the number of carbon atoms that the chains possess, and these are recognized selectively by four main GPCRs: FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120) (Hara et al., 2013).

18.10.1 FFAR1 FFAR1, signals primarily via Gaq/11 (Burant, 2013), but there is also evidence that it can signal secondarily via Gas (Hauge et al., 2015) or Gai/o (Schroder et al., 2011), displaying more physiological heterogeneity than originally described. Its activation by long chain fatty acids enhances glucose-induced insulin secretion through elevation in intracellular Ca2þ levels (Burant, 2013), and human SNPs in the FFAR1 gene (His211Arg and Gly180Ser) have been associated with loss of function mutations and impaired insulin secretory capacity (Ogawa et al., 2005; Vettor et al., 2008). FFAR1 agonists have been developed as potential therapeutic agents for the treatment of T2D, some of them reaching Phase II or III in recent clinical trials (Persaud, 2017). In particular, fasiglifam (TAK-875), has proved to be effective in lowering HbA1c levels without the risk of hypoglycemia, by promoting both GLP-1 and insulin secretion

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(Tsujihata et al., 2011; Burant, 2013). However, the increased levels of hepatotoxicity that were identified during phase III clinical trials led Takeda to announce the voluntary termination of its TAK-875 program due to concerns about liver safety. It was later reported that the hepatotoxicity resulted from formation of TAK-875AG and TAK-875CoA in hepatocytes and the inhibition of hepatic transporters and mitochondrial respiration (Otieno et al., 2018). Despite the setback with TAK-875 the next generation of FFAR1 agonists, including SAR1, DS-1558, LY2922470, P11187, SHR0534 appear to demonstrate an appropriate balance between lipophilicity and activity and several pharmaceutical companies are continuing to pursue development of these drugs for the treatment of T2D (Li et al., 2016; Eleazu et al., 2018). However, long-term exposure of b-cells to long chain fatty acids such as palmitate is known to impair insulin secretion and trigger apoptosis due to lipotoxicity (Morgan, 2009), so it has been speculated that FFAR1 antagonists may be of beneficial therapy (Li et al., 2018), although the main efforts are currently focused on using synthetic FFAR1 agonists.

18.10.2 FFAR2/3 Short chain fatty acids (SCFAs) represent the predominant product of fermentation of nondigestible carbohydrates and fiber in the colon (Byrne et al., 2015). They play a key role in balancing redox production in the anaerobic environment of the gastrointestinal tract, but they can also enter the general circulation after reabsorption in hepatic, portal, or peripheral blood (Morrison and Preston, 2016). SCFAs have chains composed of two to six carbon atoms (C2-6), with C2-4 (acetate, propionate, and butyrate) showing agonist activity at FFAR2 (GPR43) and FFAR3 (GPR41) (Priyadarshini et al., 2016). The dominant transduction mechanism for FFAR2 is via Gaq/11-mediated stimulation of PLC activity, but there are additional reports confirming secondary signaling via Gai/o and arrestins (Alvarez-Curto and Milligan, 2016). On the other hand, FFAR3 signaling is predominantly through Gai/o, but this receptor has been reported to form heteromers with FFAR2, affecting b-arrestin-2 recruitment (Tolhurst et al., 2012; Lee et al., 2013; Ang et al., 2018). SCFAs stimulate GLP-1 secretion from L-cells via activation of FFAR2 and its coupling to Gaq/11 (Tolhurst et al., 2012), and the elevation in GLP-1 levels may be responsible for the improved glucose homeostasis observed with intake of high fiber diets (Canfora et al., 2015). Consistent with this, FFAR2 knockout mice exhibited decreased SCFA-induced GLP-1 release and impaired glucose tolerance (Tolhurst et al., 2012). An involvement of FFAR3 in the release of GLP-1 has also been implicated through the observation that AR420626, an allosteric FFAR3 compound, is at least as efficacious as a FFAR2-selective agonist in stimulating GLP-1 secretion (Nohr et al., 2013), and GLP-1 release was reduced in primary enteroendocrine cells derived from Ffar3 knockout mice (Samuel et al., 2008; Tolhurst et al., 2012). Thus, FFAR2 and FFAR3 appear to act as co-sensors of SCFA signals in enteroendocrine cells (Nohr et al., 2013), adding more weight to the idea of FFAR2/FFAR3 heteromers being a functional unit, at least in the gastrointestinal tract. Despite this, the effects of SCFAs on insulin secretion differ depending on the receptor activated, with FFAR2 activation potentiating insulin secretion while FFAR3 activation is associated with reduced insulin secretion (Priyadarshini et al., 2016). The observation that the SCFA propionate directly increases insulin secretion from isolated human islets (Pingitore et al., 2017) suggests that there is translational potential in targeting FFAR2 to improve glucose homeostasis, and it indicates that the glucose lowering effects of SCFAs are not only mediated by GLP-1 secretion. However, the therapeutic capabilities of these SCFAs is still at an early stage, and further progress in this area is dependent on the design of selective, potent agonists of FFAR2 and FFAR3.

18.10.3 FFAR4 FFAR4 is a class A GPCR that is activated by the u-3 long chain fatty acids a-linolenic acid, palmitoleic acid and docosahexaenoic acid (Burns and Moniri, 2010; Talukdar et al., 2011). Its primary transduction mechanism is via Gaq/11, leading to PLC-mediated elevations in intracellular Ca2þ and activation of ERK and Akt signaling cascades, but secondary signaling through b-arrestin-2 and Gai/o have also been proposed (Li et al., 2015; Stone et al., 2014). FFAR4 shows widespread cellular expression including in the gastrointestinal tract, brain, adipose tissue, liver, and islet d-cells, and it has been implicated in diverse processes including increased GLP-1 secretion, alteration of food preference, insulin sensitization, antiinflammation, and inhibition of ghrelin and somatostatin secretion (Alvarez-Curto and Milligan, 2016). In addition, genetic studies focusing on the FFAR4 variants rs116454156 (Vestmar et al., 2016) and rs17108973 (Vallee Marcotte et al., 2017) have demonstrated that FFAR4 dysfunction is associated with insulin resistance and obesity, supporting FFAR4 as a target to develop pharmacotherapies to treat T2D and its complications. A range of FFAR4 agonists, including TUG-891, GW-9508, NCG-21, and GSK137647A, have been synthesized as potential T2D therapies (Li et al., 2015). These compounds have shown promising effects to reduce inflammation in obese

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mice and improve insulin sensitivity and glucose tolerance. However, chronic activation of FFAR4 is associated with reduced receptor functionality (Li et al., 2015), which has limited tractability of this receptor as a therapeutic target.

18.11 Taste receptors The five taste categories of salty, sour, umami, sweet, and bitter contribute to distinct patterns of food appeal and biased consumption, some of which may lead to an elevated predisposition to metabolic impairment and progression to obesity and diabetes (Bertoli et al., 2014). Salty and sour tastes are transduced by alterations in ion channel activities, while the other three tastes are sensed by activation of TAS1 and TAS2 GPCRs that are expressed in taste receptor cells.

18.11.1 TAS1R2/3 The ability to identify sweet substances is thought to have been an evolutionary mechanism to ensure appropriate intake of dietary carbohydrates of high nutritional value, but the satisfaction obtained from recognizing sweet food is likely to have contributed to the obesity epidemic. Both natural and synthetic sweet substances are detected by TAS1R2 and TAS1R3 sweet taste receptors, which form heterodimers that are coupled to a specialized G-protein composed of an a-gustducin subunit linked to bg subunits (Neiers et al., 2016; Rother et al., 2018). Receptor activation leads to PLC-mediated Ca2þ mobilization and cell depolarization via the opening of TRPM5 ion channels. TAS1R2/3 subunits are expressed in the gastrointestinal tract and islet b-cells, where sweet substances, including nonnutritive sweeteners, cause increased GLP-1 and insulin secretion, respectively. Agents that stimulate GLP-1 and insulin release are capable of improving glucose homeostasis, as described earlier, but the observation that obese mice lacking TAS1R2 and TAS1R3 have reduced adiposity (Simon et al., 2014) suggests that these receptors are coupled to weight gain. It has, therefore, been suggested that sweet inhibitors could be used to treat T2D (Neiers et al., 2016), but there is currently very little evidence to support the development of such compounds.

18.11.2 TAS2R Bitterness is a key taste that is important in determining food approval or exclusion, and it has a protective function in allowing us to avoid potentially toxic substances (Gaudette and Pickering, 2013). The receptors responsible for processing the bitter taste are encoded by the TAS2R gene family, with TAS2R38 being the most studied GPCR from this subfamily due to its ability to recognize the bitter compounds phenylthiocarbamide and 6-n-propylthiouracil (Risso et al., 2016). TAS2R38 is widely expressed in the body, including in the gastrointestinal tract, lung, liver, pancreas, and brain (Choi et al., 2016). The gene encoding this receptor possesses two major haplotypes (PAV, or “taster ” and AVI, or “nontaster”), shaped by the effect of three SNPs (rs714598, rs1726866, rs10246939) that regulate the individual differences in the perceived bitterness of TAS2R38 agonists (Risso et al., 2018), and subjects carrying the AVI/AVI homozygote haplotype of TAS2R38 have a higher frequency of obesity (Ortega et al., 2016). GLP-1 secretion is increased by bitter ligands, and this is associated with improved glucose tolerance in obese mice (Kok et al., 2018). However, development of “bitter” therapies for T2D may not be an appropriate therapeutic route as patient adherence to bitter tasting drugs is likely to be low, and these receptors are unlikely to be an attractive approach unless palatable TAS2R ligands are developed.

18.12 Other GPCRs as potential targets for T2D therapy There are over 300 nonsensory GPCRs in addition to the receptor families described above and some of these have promising functional effects that support investigation of whether they have utility for treating T2D and its complications. An overview of some of the key receptors is provided here.

18.12.1 GPR56 Adhesion GPCRs differ from other GPCRs in that they have an extended extracellular N-terminal domain that is linked to the C-terminus by a GPCR autoproteolysis-inducing domain (Hamann et al., 2015). Although adhesion GPCRs are the second largest GPCR subfamily, they are relatively poorly studied as most of the receptors are orphans. However, the identification that the extracellular matrix protein collagen III is an endogenous agonist of the adhesion GPCR GPR56 has led to interest in the physiological function of this receptor. It is reported to couple to Gaq/11 (Little et al., 2004) to increase intracellular Ca2þ through PLC activation and Ga12/13 (Iguchi et al., 2008) to activate Rho-associated protein

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kinase. It is highly expressed in several regions of the central nervous system (Piao et al., 2004) and in metabolically active peripheral tissues such as skeletal muscle, liver, adipose tissue, and pancreas, where it is the most abundantly expressed islet GPCR (Amisten, 2016; White et al., 2014; Amisten et al., 2017; Olaniru et al., 2018). This distribution pattern has led to the hypothesis that GPR56 is involved in regulating food intake, energy homeostasis, and islet function. Deletion of GPR56 in nondiabetic, nonobese mice is not associated with significant changes in weight or glucose tolerance (Olaniru et al., 2018), suggesting that the receptor is not essential for regulating food intake or glucose homeostasis under normal conditions. Activation of GPR56 by collagen III potentiates glucose-stimulated insulin release and protects islets from apoptosis induced by inflammatory cytokines (Olaniru et al., 2018; Duner et al., 2016). These findings, in addition to the close correlation between reduced insulin release and reduced levels of GPR56 in human islets from T2D donors (Duner et al., 2016), suggest that GPR56 may have a role as a drug target for T2D. The GPCR autoproteolysis-inducing domain of GPR56 could be suitable for development of a novel T2D drug as it is a unique structural feature of adhesion GPCRs, and the use of biased ligands could lead to selective activation of GPR56 (Olaniru and Persaud, 2018). Given that islet GPR56 expression is reduced in T2D, success in this area would also be dependent on sufficient endogenous GPR56 being present in islets to transduce the prosecretory and antiapoptotic effects of any available activating ligands.

18.12.2 GPR91 (SUCNR1) One of the main intermediates of the mitochondrial Krebs cycle is succinate, which acts as a substrate for succinate dehydrogenase. Succinate also acts extracellularly as a ligand for GPR91 (Peti-Peterdi, 2010), a receptor that is expressed in kidney, liver, heart, fat, retinal cells, and several other tissues (de Castro Fonseca et al., 2016). The dominant transduction mechanism for GPR91 is via Gai/o, leading to inhibition of adenylate cyclase, but there are additional reports confirming secondary signaling via Gaq/11 and independent signaling mechanisms via arrestins, internalizing the receptor upon stimulation (Geubelle et al., 2017). Local accumulation of succinate in diabetic mouse kidneys leads to activation of GPR91 and subsequent renin release, which contributes to the onset of hypertension (Toma et al., 2008). In addition, GPR91 activation in diabetic mice leads to increased phosphorylation of ERK1/2, which is associated with the development of tubulo-interstitial fibrosis in diabetic nephropathy and diabetes-induced hypertension (Robben et al., 2009). GPR91 has also been reported to have diabetes-related consequences in other organs. For example, its activation in macrophages is associated with infiltration and inflammation of the adipose tissue in obesity (van Diepen et al., 2017), in agreement with the observation that this receptor is highly expressed in adipocytes and its deletion leads to leanness (McCreath et al., 2015). In addition, it has recently been reported that succinate, via GPR91 activation, contributes to bone dysregulation in T2D (Guo et al., 2017), providing further confirmation of the deleterious downstream effects of GPR91 activation. GPR91 has been proposed as a possible therapeutic target in T2D and associated complications (Ariza et al., 2012), but it may be more appropriate to reduce extracellular succinate levels rather than developing GPR91 antagonists.

18.12.3 GPR119 GPR119 is a class A GPCR that is activated by lipid metabolites, including lysophosphatidylethanolamine, oleoylethanolamide, palmitoylethanolamide and oleoylethylamide (Yang et al., 2018). It is expressed primarily in islet b-cells and in the K- and L-cells of the gastrointestinal tract (Overton et al., 2008), and it has been strongly implicated in the regulation of energy balance and body weight (Godlewski et al., 2009). Its primary transduction mechanism relies on Gas coupling, leading to increased cAMP levels, although it is reported to have secondary signal transduction by Gai, Gaq, and b-arrestin recruitment (Yang et al., 2018). In agreement with Gas signaling, GPR119 activation promotes glucose-stimulated insulin secretion from b-cells and GIP, GLP-1, and PYY release from enteroendocrine cells (Hansen et al., 2012). Many GPR119 agonists, including GSK1292263, MBX-2982, DS-8500a, APD668, and BMS-903452, have been synthesized and assessed in clinical trials in the last decade (Ritter et al., 2016). However, none of these compounds has moved forward to phase II trials due to lack of efficacy or pharmacodynamic and pharmacokinetic limitations (Yang et al., 2018). It has recently become apparent that glucose tolerance and insulin secretory responsiveness are not impaired in b-cellspecific GPR119 knockout mice (Panaro et al., 2017), implying that this receptor does not play an essential role in regulating insulin secretion and these observations may explain the dearth of pharmacodynamic and pharmacokinetic efficacy of GPR119 agonists in clinical trials conducted so far. Refined synthetic variants of GPR119 agonists (Yang et al., 2018) and combinatory therapies with other current T2D treatments, such as metformin (Al-Barazanji et al., 2015), are the subject of

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ongoing research, and long-term studies are required to better understand if targeting enteroendocrine cell GPR119 can be transferred into a T2D pharmacotherapy.

18.12.4 GPR131 (TGR5) Bile acids are cholesterol derivatives that are essential in the digestion and absorption of dietary fats (Staels and Fonseca, 2009). It is now apparent that bile acids can act as ligands at the nuclear farnesoid X receptor (FXR) and the GPCR GPR131 (TGR5), in addition to their direct emulsifying action (Duboc et al., 2014). GPR131 is ubiquitously expressed (Malhi and Camilleri, 2017) and it signals via Gas to generate cAMP, leading to regulation of important signaling pathways, including NF-kB, Akt, and ERK (Guo et al., 2016). Activation of GPR131 by bile acids stimulates GLP-1 secretion, most likely by elevation in the intracellular ATP/ADP ratio and a consequent increase in intracellular Ca2þ levels (Thomas et al., 2009). In addition, GPR131 deletion in obese mice resulted in impaired glucose tolerance, while GPR131 overexpression led to increased GLP-1 and insulin secretion and improved glucose tolerance (Thomas et al., 2009). Consistent with GPR131 activation being involved in appropriate regulation of blood glucose levels, the GPR131 activator WB403 reduced hyperglycemia and preserved b-cell mass in mice with T2D (Zheng et al., 2015). INT-767, a dual FXR and GPR131 agonist (Baghdasaryan et al., 2011), has been reported to up-regulate GPR131, elevate GLP-1 secretion and improve hepatic glucose and lipid metabolism in obese mice (Pathak et al., 2017), and it also protects against nephropathy in diabetic mice (Wang et al., 2018). All of these observations suggest that pharmacotherapies activating GPR131 may constitute a potential strategy for the treatment of T2D and its associated metabolic disorders, and it has been suggested that an intestine-specific GPR131 agonist would be most appropriate to circumvent the increase in gallbladder volume that may occur with a systemic agonist (Shapiro et al., 2018).

18.12.5 GPR142 L-tryptophan is an essential amino acid that is required for protein and serotonin biosynthesis (Palego et al., 2016). It is also a ligand for GPR142, which is expressed by enteroendocrine cells and b-cells, and it is coupled to Gaq to increase incretin and insulin secretion (Wang et al., 2016). GPR142 also improves glucose disposal in mice, and it has been suggested that GPR142 agonists may be effective therapies for the treatment of T2D (Toda et al., 2013). However, although these findings look very promising, a recent report has indicated that GPR142 deletion and a GPR142 antagonist protect against arthritis, most likely through decreased production of inflammatory cytokines (Murakoshi et al., 2017), suggesting that the development of GPR142 agonists may be contraindicated by their possible proinflammatory effects.

18.12.6 GPR146 The A and B chains of insulin are connected by a connecting peptide (C-peptide), which is cleaved during insulin biosynthesis and secreted in equimolar amounts. It has long been thought that C-peptide has biological activity rather than merely being a by-product of insulin prohormone processing (Hills and Brunskill, 2008) and GPR146 was identified as a receptor for this peptide by deductive ligand-receptor matching strategies (Yosten et al., 2013). GPR146 activation leads to signaling via several intracellular cascades, including PLC activation, nitric oxide formation, and increased Naþ/Kþ-ATPase activity (Hills and Brunskill, 2008). C-peptide has been proposed as an endogenous antioxidant that reduces hyperglycemia-induced apoptosis of vascular endothelial cells (Cifarelli et al., 2011), and thus it may be beneficial in limiting microvascular complications of diabetes (Wahren, 2017). Delivery of a pegylated, longacting form of human C-peptide, CBX129801, to cynomolgus monkeys indicated that it was well-tolerated (Naas et al., 2015) and it improved vibration perception threshold in patients with peripheral neuropathy in a phase II clinical trial (Wahren et al., 2016). However, it has not yet been established that CBX129801 acts via GPR146, which is still considered to be an orphan receptor by IUPHAR.

18.13 Orphan GPCRs The endogenous ligands of more than 150 GPCRs have not been identified yet, providing an additional source of novel therapeutic targets (Ngo et al., 2016). However, there are obviously challenges for exploiting orphan receptors in the absence of known agonists, but their roles in metabolic regulation can be identified from altered expression levels in T2D and diabetic complications, and alterations in fuel homeostasis following deletion or overexpression of selective orphan GPCRs.

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18.13.1 GPRC5A GPRC5A is a retinoic acid-inducible receptor that is highly expressed in lungs and at lower levels in many organs, including kidney, colon, prostate, testis, ovary, gastrointestinal tract, and spinal cord (Zhou et al., 2016). Although retinoic acid promotes expression of GPRC5A, this vitamin A derivative is not a direct ligand of the receptor. The main reported functions of GPRC5A are related to cancer (Zhou et al., 2016), but it has recently been implicated in protection against renal diabetic complications following observations that it is downregulated in the glomeruli of patients with diabetic nephropathy and its deletion in diabetic mice resulted in glomerular injury (Ma et al., 2018). Mechanistically, GPRC5A silencing in kidney podocytes led to activation of TGF-b signaling and up-regulation of genes involved in glomerular basement membrane thickening (Ma et al., 2018). It is, therefore, possible that activation of GPRC5A signaling could protect against the development of diabetic nephropathy, but, as for all orphan GPCRs, the absence of identity of its endogenous ligand and the lack of evidence that it couples to G-proteins mean that this receptor cannot currently be targeted therapeutically (Zhou and Rigoutsos, 2014).

18.13.2 GPRC5B GPRC5B is another retinoic acid-inducible receptor that is highly expressed in human and mouse islets (Soni et al., 2013), brain (Robbins et al., 2002; Kurabayashi et al., 2013), and white adipose tissue (Kim et al., 2012b), tissues that are highly important in metabolic function. It is up-regulated in islets from donors with T2D (Soni et al., 2013), its deletion in mice triggers glucose intolerance (Kim et al., 2012b), its down-regulation in islets increases insulin secretion (Soni et al., 2013) and its overexpression promotes b-cell apoptosis, most likely through activation of the TGF-b and IFNg signaling pathways (Atanes et al., 2018). These observations suggest that targeted pharmacological inhibition of GPRC5B with a selective antagonist might provide a novel therapy for T2D, but progress in this area will require identification of the native GPCR5B ligand and understanding of the receptor binding site for development of synthetic antagonists.

18.14 Future perspectives T2D is an escalating pandemic, affecting approximately 400 million people worldwide, many of whom go on to develop severe macrovascular and microvascular complications. This chronic condition dictates a huge social and economic burden, with healthcare costs increasing worldwide every year. Appropriate glycemic regulation is essential to limit diabetic complications, but restoration of euglycemic levels is rarely achievable regardless of the range of glucose-lowering drugs currently available. It is well-known that b-cell dysfunction is central in the pathogenesis of T2D, so understanding the intrinsic mechanisms related to islet function and dysfunction is an essential foundation underpinning much of the research on identifying and characterizing novel therapies for T2D. Human islets express nearly 300 GPCRs and some of these have been investigated as druggable targets for therapeutic intervention in T2D through their effects to promote b-cell survival and/or improve insulin secretory capacity (Persaud, 2017). In addition, insulin-sensitive tissues also express hundreds of GPCRs, but to date, the main success in terms of GPCR therapy for T2D is limited to the replacement of endogenous GLP-1 with GLP-1 analogs or inhibition of its degradation with DPP4 inhibitors, with lesser widespread use of bromocriptine and pramlintide.

18.15 Limitations to development of GPCR therapies for T2D Considering that at least one-third of all drugs in current clinical use regulate GPCR activity (Latek et al., 2012; Sriram and Insel, 2018) it makes sense that some of the GPCRs expressed by islets and insulin-sensitive tissues could be targeted for appropriate regulation of glucose homeostasis. However, despite promising data for some GPCRs that have been summarized in the preceding sections, several limitations have restricted the development of novel therapies for T2D.

18.15.1 Translation from animal models to man Animals, in particular mice, are often employed as surrogates for understanding the etiology and progression of human disease, and our knowledge of the effects of GPCR ligands in rodents and functional consequences of GPCR deletion has informed progress in understanding the roles of particular GPCRs in glucose homeostasis. However, sometimes observations made in rodents are not translatable into a human context. For example, identification of GPCRs expressed by

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human and mouse islets has indicated that species differences exist in islet GPCR expression and function (Amisten et al., 2017). In addition, the beneficial effects of GLP-1 analogs on rodent b-cell mass have not been observed in humans (Drucker, 2013) and the effects of nonnutritional sweeteners, agonists for TAS1R2/3, on gastrointestinal bacterial populations in rodents has so far not been replicated in human studies (Rother et al., 2018).

18.15.2 Deorphanization Without knowledge of endogenous agonists it is difficult to make progress with developing ligands targeting orphan receptors, even if they appear to have potential for improving glucose homeostasis or reducing diabetic complications. The adhesion receptor GPR97 is an orphan receptor, but it was identified a few years ago as the target of beclomethasone, an inhaled steroid that has been used for long-term management of asthma for nearly 50 years (Gupte et al., 2012). Strategies using reverse and forward pharmacology should be refined to unveil the pharmacology of prospective glucose lowering candidates, and deorphanization approaches such as the PRESTO-Tango system can be used to identify the GPCR target of prospective T2D therapeutic candidates that interact with orphan GPCRs (Kroeze et al., 2015).

18.15.3 Off-target effects Many GPCRs show widespread expression, and so even if activation or inhibition of a particular GPCR promotes insulin secretion, improves insulin sensitivity or protects against progression of diabetic complications, it is difficult to limit ligand delivery to specific cell types. This may lead to off-target effects where adverse outcomes arise because of activation or inhibition of the same receptor in other tissues. In some cases, this can be circumvented by direct delivery of the drug to the site of action, such as the inhalation delivery of b-adrenergic receptor agonists for the treatment of asthma, but this is not possible for GPCR therapies for diabetes. Therefore, the prudent approach is to focus on GPCRs that show limited expression, to tissues that are involved in regulation of glucose homeostasis. A good example of a GPCR in this category is the GLP-1 receptor, which is highly expressed in the pancreas, gastrointestinal tract, and hypothalamus, all of which contribute to its glucose lowering and satiety effects.

18.15.4 GPCR selectivity If a GPCR with limited tissue expression and capacity to regulate blood glucose levels is identified, it is important that the compounds used to regulate its activity have high selectivity for that particular GPCR, with limited and low potency effects at other GPCRs. The native agonist is often a useful starting point for development of high affinity, selective synthetic ligands, which have a sufficiently long half-life in vivo to produce the required signaling, with minimal adverse effects.

18.16 Future development of GPCR-based therapies for T2D As mentioned above, the success rate of developing GPCR therapies for T2D has been very limited and almost all of the preclinical studies have failed to transform into novel therapies. However, Table 18.2 indicates some GPCR ligands that generated promising data in clinical trials and these may provide the basis for the development of refined therapies for T2D that do not have unacceptable side-effects associated with their use. Future progress requires a strategic approach to maximize the opportunity of normalizing glycemia while minimizing unwanted contraindications of the GPCR ligands. In particular, focus should be on GPCR ligands that have beneficial action at islets and additional glucose lowering capacity through central effects to induce satiety or peripheral effects at insulin-sensitive tissues and the gastrointestinal tract, as indicated in Fig. 18.1. In addition, meaningful progress requires availability of more information on GPCR expression by particular tissues and agonist binding sites of GPCRs of interest, which will allow prediction of hits using bioinformatics databases and preliminary analysis during early drug discovery stages with high-throughput technologies to increase understanding of their pharmacological profiles. The use of improved deorphanization strategies, preclinical models with predictive clinical efficacy, refined synthetic compounds, tissue-specific knockout models, combination therapies, and implementation of advances in pharmacology (e.g. dimerization/oligomerization, allosterism, biased signaling) will also allow us to better understand GPCR pharmacology to underpin novel therapies to treat T2D and its complications. Attention should also be focused on improved understanding of proteins that regulate the duration and amplitude of GPCR signaling, such as RGS proteins and GPCR kinases, as these may also prove to be tractable therapeutic targets.

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TABLE 18.2 GPCR ligands used in clinical trials for type 2 diabetes. Receptor

Ligand

Highest phase

Beneficial effects

Limitations

FFAR1

TAK-875: Agonist

III

Increased GLP-1 and insulin secretion

Hepatotoxicity

GPR119

DS 8500: Agonist PSN821: Agonist

II

Increased incretin and insulin secretion

Insufficient efficacy

Glucagon

LY2409021: Antagonist MK-0893: Antagonist

II

Decreased hepatic glycogenolysis and gluconeogenesis

Hepatic fat accumulation, weight gain

GLP-1/ glucagon

LY2944876: Agonist MK-8521: Agonist

II

Increased insulin secretion and decreased food intake

N/A

Ligands for FFAR1, GPR119, and glucagon receptors have shown promising effects in phase 2 and 3 clinical trials, but adverse effects or insufficient efficacy has precluded further development of these compounds. Nonetheless, the beneficial effects of targeting these receptors suggests that modified ligands may have future potential and the effects of the joint GLP-1/glucagon receptor agonists are encouraging, with no reports of contraindications so far.

References Abdullah, N., Beg, M., Soares, D., Dittman, J.S., Mcgraw, T.E., 2016. Downregulation of a GPCR by beta-arrestin2-mediated switch from an endosomal to a TGN recycling pathway. Cell Rep. 17, 2966e2978. Abrahami, D., Douros, A., Yin, H., Yu, O.H.Y., Renoux, C., Bitton, A., Azoulay, L., 2018. Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study. BMJ 360, k872. Adamska, E., Ostrowska, L., Gorska, M., Kretowski, A., 2014. The role of gastrointestinal hormones in the pathogenesis of obesity and type 2 diabetes. Prz. Gastroenterol. 9, 69e76. Al-Barazanji, K., Mcnulty, J., Binz, J., Generaux, C., Benson, W., Young, A., Chen, L., 2015. Synergistic effects of a GPR119 agonist with metformin on weight loss in diet-induced obese mice. J. Pharmacol. Exp. Ther. 353, 496e504. Alemany, M., 2011. Utilization of dietary glucose in the metabolic syndrome. Nutr. Metab. 8, 74. Almaca, J., Molina, J., Menegaz, D., Pronin, A.N., Tamayo, A., Slepak, V., Berggren, P.O., Caicedo, A., 2016. Human beta cells produce and release serotonin to inhibit glucagon secretion from alpha cells. Cell Rep. 17, 3281e3291. Alvarez-Curto, E., Milligan, G., 2016. Metabolism meets immunity: the role of free fatty acid receptors in the immune system. Biochem. Pharmacol. 114, 3e13. Amisten, S., 2016. Quantification of the mRNA expression of G protein-coupled receptors in human adipose tissue. Methods Cell Biol. 132, 73e105. Amisten, S., Atanes, P., Hawkes, R., Ruz-Maldonado, I., Liu, B., Parandeh, F., Zhao, M., Huang, G.C., Salehi, A., Persaud, S.J., 2017. A comparative analysis of human and mouse islet G-protein coupled receptor expression. Sci. Rep. 7, 46600. Amisten, S., Neville, M., Hawkes, R., Persaud, S.J., Karpe, F., Salehi, A., 2015. An atlas of G-protein coupled receptor expression and function in human subcutaneous adipose tissue. Pharmacol. Ther. 146, 61e93. Amisten, S., Salehi, A., Rorsman, P., Jones, P.M., Persaud, S.J., 2013. An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans. Pharmacol. Ther. 139, 359e391. Ang, Z., Xiong, D., Wu, M., Ding, J.L., 2018. FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing. FASEB J. 32, 289e303. Ariza, A.C., Deen, P.M., Robben, J.H., 2012. The succinate receptor as a novel therapeutic target for oxidative and metabolic stress-related conditions. Front. Endocrinol. (Lausanne) 3, 22. Asmar, M., 2011. New physiological effects of the incretin hormones GLP-1 and GIP. Dan. Med. Bull. 58, B4248. Atanes, P., Ruz-Maldonado, I., Hawkes, R., Liu, B., Persaud, S.J., Amisten, S., 2018. Identifying signalling pathways regulated by GPRC5B in beta-cells by CRISPR-cas9-mediated genome editing. Cell. Physiol. Biochem. 45, 656e666. Baggio, L.L., Drucker, D.J., 2007. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131e2157. Baghdasaryan, A., Claudel, T., Gumhold, J., Silbert, D., Adorini, L., Roda, A., Vecchiotti, S., Gonzalez, F.J., Schoonjans, K., Strazzabosco, M., Fickert, P., Trauner, M., 2011. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO3 output. Hepatology 54, 1303e1312. Baik, J.H., 2013. Dopamine signaling in reward-related behaviors. Front. Neural Circuits 7, 152. Ballian, N., Brunicardi, F.C., Wang, X.P., 2006. Somatostatin and its receptors in the development of the endocrine pancreas. Pancreas 33, 1e12. Bano, G., 2013. Glucose homeostasis, obesity and diabetes. Best Pract. Res. Clin. Obstet. Gynaecol. 27, 715e726. Barnes, N.M., Hales, T.G., Lummis, S.C., Peters, J.A., 2009. The 5-HT3 receptorethe relationship between structure and function. Neuropharmacology 56, 273e284. Berna, M.J., Jensen, R.T., 2007. Role of CCK/gastrin receptors in gastrointestinal/metabolic diseases and results of human studies using gastrin/CCK receptor agonists/antagonists in these diseases. Curr. Top. Med. Chem. 7, 1211e1231.

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Bertoli, S., Laureati, M., Battezzati, A., Bergamaschi, V., Cereda, E., Spadafranca, A., Vignati, L., Pagliarini, E., 2014. Taste sensitivity, nutritional status and metabolic syndrome: implication in weight loss dietary interventions. World J. Diabetes 5, 717e723. Blazer, L.L., Storaska, A.J., Jutkiewicz, E.M., Turner, E.M., Calcagno, M., Wade, S.M., Wang, Q., Huang, X.P., Traynor, J.R., Husbands, S.M., Morari, M., Neubig, R.R., 2015. Selectivity and anti-Parkinson’s potential of thiadiazolidinone RGS4 inhibitors. ACS Chem. Neurosci. 6, 911e919. Brydon, L., Roka, F., Petit, L., De Coppet, P., Tissot, M., Barrett, P., Morgan, P.J., Nanoff, C., Strosberg, A.D., Jockers, R., 1999. Dual signaling of human Mel1a melatonin receptors via G(i2), G(i3), and G(q/11) proteins. Mol. Endocrinol. 13, 2025e2038. Burant, C.F., 2013. Activation of GPR40 as a therapeutic target for the treatment of type 2 diabetes. Diabetes Care 36 (Suppl. 2), S175eS179. Burns, R.N., Moniri, N.H., 2010. Agonism with the omega-3 fatty acids alpha-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor. Biochem. Biophys. Res. Commun. 396, 1030e1035. Byrne, C.S., Chambers, E.S., Morrison, D.J., Frost, G., 2015. The role of short chain fatty acids in appetite regulation and energy homeostasis. Int. J. Obes. 39, 1331e1338. Canfora, E.E., Jocken, J.W., Blaak, E.E., 2015. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat. Rev. Endocrinol. 11, 577e591. Capozzi, M.E., Dimarchi, R.D., Tschop, M.H., Finan, B., Campbell, J.E., 2018. Targeting the incretin/glucagon system with triagonists to treat diabetes. Endocr. Rev. 39, 719e738. Chandarana, K., Gelegen, C., Irvine, E.E., Choudhury, A.I., Amouyal, C., Andreelli, F., Withers, D.J., Batterham, R.L., 2013. Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance. Mol. Metab. 2, 142e152. Charnay, Y., Leger, L., 2010. Brain serotonergic circuitries. Dialogues Clin. Neurosci. 12, 471e487. Chia, C.W., Odetunde, J.O., Kim, W., Carlson, O.D., Ferrucci, L., Egan, J.M., 2014. GIP contributes to islet trihormonal abnormalities in type 2 diabetes. J. Clin. Endocrinol. Metab. 99, 2477e2485. Cho, N.H., Shaw, J.E., Karuranga, S., Huang, Y., Fernandes, J.D.D., Ohlrogge, A.W., Malanda, B., 2018. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res. Clin. Pract. 138, 271e281. Choi, J.H., Lee, J., Choi, I.J., Kim, Y.W., Ryu, K.W., Kim, J., 2016. Genetic variation in the TAS2R38 bitter taste receptor and gastric cancer risk in Koreans. Sci. Rep. 6, 26904. Christensen, M., Bagger, J.I., Vilsboll, T., Knop, F.K., 2011. The alpha-cell as target for type 2 diabetes therapy. Rev. Diabet. Stud. 8, 369e381. Cifarelli, V., Geng, X., Styche, A., Lakomy, R., Trucco, M., Luppi, P., 2011. C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells. Diabetologia 54, 2702e2712. Cvetkovic, R.S., Plosker, G.L., 2007. Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea). Drugs 67, 935e954. De Castro Fonseca, M., Aguiar, C.J., Da Rocha Franco, J.A., Gingold, R.N., Leite, M.F., 2016. GPR91: expanding the frontiers of Krebs cycle intermediates. Cell Commun. Signal. 14, 3. De Groot, M., Golden, S.H., Wagner, J., 2016. Psychological conditions in adults with diabetes. Am. Psychol. 71, 552e562. Defronzo, R.A., 2011. Bromocriptine: a sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes. Diabetes Care 34, 789e794. Delahanty, L.M., Peyrot, M., Shrader, P.J., Williamson, D.A., Meigs, J.B., Nathan, D.M., Group, D.P.P.R., 2013. Pretreatment, psychological, and behavioral predictors of weight outcomes among lifestyle intervention participants in the Diabetes Prevention Program (DPP). Diabetes Care 36, 34e40. Devedjian, J.C., Pujol, A., Cayla, C., George, M., Casellas, A., Paris, H., Bosch, F., 2000. Transgenic mice overexpressing alpha2A-adrenoceptors in pancreatic beta-cells show altered regulation of glucose homeostasis. Diabetologia 43, 899e906. Drucker, D.J., 2013. Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes 62, 3316e3323. Drucker, D.J., 2018. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metabol. 27, 740e756. Duboc, H., Tache, Y., Hofmann, A.F., 2014. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig. Liver Dis. 46, 302e312. Duner, P., Al-Amily, I.M., Soni, A., Asplund, O., Safi, F., Storm, P., Groop, L., Amisten, S., Salehi, A., 2016. Adhesion G protein-coupled receptor G1 (ADGRG1/GPR56) and pancreatic beta-cell function. J. Clin. Endocrinol. Metab. 101, 4637e4645. Eckel, R.H., Fujimoto, W.Y., Brunzell, J.D., 1979. Gastric inhibitory polypeptide enhanced lipoprotein lipase activity in cultured preadipocytes. Diabetes 28, 1141e1142. Edelman, S., Maier, H., Wilhelm, K., 2008. Pramlintide in the treatment of diabetes mellitus. BioDrugs 22, 375e386. Eleazu, C., Charles, A., Eleazu, K., Achi, N., 2018. Free fatty acid receptor 1 as a novel therapeutic target for type 2 diabetes mellitus-current status. Chem. Biol. Interact. 289, 32e39. Fagerholm, V., Haaparanta, M., Scheinin, M., 2011. alpha2-adrenoceptor regulation of blood glucose homeostasis. Basic Clin. Pharmacol. Toxicol. 108, 365e370. Faillie, J.L., Yu, O.H., Yin, H., Hillaire-Buys, D., Barkun, A., Azoulay, L., 2016. Association of bile duct and gallbladder diseases with the use of incretinbased drugs in patients with type 2 diabetes mellitus. JAMA Intern. Med. 176, 1474e1481. Filippatos, T.D., Panagiotopoulou, T.V., Elisaf, M.S., 2014. Adverse effects of GLP-1 receptor agonists. Rev. Diabet. Stud. 11, 202e230. Forbes, J.M., Cooper, M.E., 2013. Mechanisms of diabetic complications. Physiol. Rev. 93, 137e188. Franklin, Z.J., Tsakmaki, A., Fonseca Pedro, P., King, A.J., Huang, G.C., Persaud, S.J., Bewick, G.A., 2018. Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta-cell mass. Diabetes Obes. Metab. 20, 599e609.

GPCR targets in type 2 diabetes Chapter | 18

385

Frias, J.P., Nauck, M.A., Van, J., Kutner, M.E., Cui, X., Benson, C., Urva, S., Gimeno, R.E., Milicevic, Z., Robons, D., Haupt, A., 2018. The Lancet. https://doi.org/10.1016/S0140-6736(18)32260-8. Garber, A.J., 2011. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care 34 (Suppl. 2), S279eS284. Gasbjerg, L.S., Gabe, M.B.N., Hartmann, B., Christensen, M.B., Knop, F.K., Holst, J.J., Rosenkilde, M.M., 2018. Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti-diabetic agents. Peptides 100, 173e181. Gaudette, N.J., Pickering, G.J., 2013. Modifying bitterness in functional food systems. Crit. Rev. Food Sci. Nutr. 53, 464e481. Gautam, D., Han, S.J., Hamdan, F.F., Jeon, J., Li, B., Li, J.H., Cui, Y., Mears, D., Lu, H., Deng, C., Heard, T., Wess, J., 2006. A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metabol. 3, 449e461. Geubelle, P., Gilissen, J., Dilly, S., Poma, L., Dupuis, N., Laschet, C., Abboud, D., Inoue, A., Jouret, F., Pirotte, B., Hanson, J., 2017. Identification and pharmacological characterization of succinate receptor agonists. Br. J. Pharmacol. 174, 796e808. Godlewski, G., Offertaler, L., Wagner, J.A., Kunos, G., 2009. Receptors for acylethanolamides-GPR55 and GPR119. Prostag. Other Lipid Mediat. 89, 105e111. Guo, C., Chen, W.D., Wang, Y.D., 2016. TGR5, not only a metabolic regulator. Front. Physiol. 7, 646. Guo, Y., Xie, C., Li, X., Yang, J., Yu, T., Zhang, R., Zhang, T., Saxena, D., Snyder, M., Wu, Y., Li, X., 2017. Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis. Nat. Commun. 8, 15621. Gupte, J., Swaminath, G., Danao, J., Tian, H., Li, Y., Wu, X., 2012. Signaling property study of adhesion G-protein-coupled receptors. FEBS Lett. 586, 1214e1219. Guzman, C.B., Zhang, X.M., Liu, R., Regev, A., Shankar, S., Garhyan, P., Pillai, S.G., Kazda, C., Chalasani, N., Hardy, T.A., 2017. Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes Obes. Metab. 19, 1521e1528. Gydesen, S., Hjuler, S.T., Freving, Z., Andreassen, K.V., Sonne, N., Hellgren, L.I., Karsdal, M.A., Henriksen, K., 2017. A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference. Br. J. Pharmacol. 174, 591e602. Haedersdal, S., Lund, A., Knop, F.K., Vilsboll, T., 2018. The role of glucagon in the pathophysiology and treatment of type 2 diabetes. Mayo Clin. Proc. 93, 217e239. Haga, T., 2013. Molecular properties of muscarinic acetylcholine receptors. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 89, 226e256. Hamann, J., Aust, G., Arac, D., Engel, F.B., Formstone, C., Fredriksson, R., Hall, R.A., Harty, B.L., Kirchhoff, C., Knapp, B., Krishnan, A., Liebscher, I., Lin, H.H., Martinelli, D.C., Monk, K.R., Peeters, M.C., Piao, X., Promel, S., Schoneberg, T., Schwartz, T.W., Singer, K., Stacey, M., Ushkaryov, Y.A., Vallon, M., Wolfrum, U., Wright, M.W., Xu, L., Langenhan, T., Schioth, H.B., 2015. International union of basic and clinical pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol. Rev. 67, 338e367. Hansen, H.S., Rosenkilde, M.M., Holst, J.J., Schwartz, T.W., 2012. GPR119 as a fat sensor. Trends Pharmacol. Sci. 33, 374e381. Hara, T., Kimura, I., Inoue, D., Ichimura, A., Hirasawa, A., 2013. Free fatty acid receptors and their role in regulation of energy metabolism. Rev. Physiol. Biochem. Pharmacol. 164, 77e116. Hartmann, H., Ebert, R., Creutzfeldt, W., 1986. Insulin-dependent inhibition of hepatic glycogenolysis by gastric inhibitory polypeptide (GIP) in perfused rat liver. Diabetologia 29, 112e114. Hauge, M., Vestmar, M.A., Husted, A.S., Ekberg, J.P., Wright, M.J., DI Salvo, J., Weinglass, A.B., Engelstoft, M.S., Madsen, A.N., Luckmann, M., Miller, M.W., Trujillo, M.E., Frimurer, T.M., Holst, B., Howard, A.D., Schwartz, T.W., 2015. GPR40 (FFAR1) e combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo. Mol. Metab. 4, 3e14. Hemler, M, Celebrating 10 Years of Exenatide: The First GLP-1 RA Treatment Option. https://www.astrazeneca-us.com/media/blogs/2015/Celebrating10-Years-of-Exenatide-The-First-GLP-1-RA-Treatment-Option-08271015.html. Hills, C.E., Brunskill, N.J., 2008. Intracellular signalling by C-peptide. Exp. Diabetes Res. 2008, 635158. Hoffman, R.P., 2007. Sympathetic mechanisms of hypoglycemic counterregulation. Curr. Diabetes Rev. 3, 185e193. Hollander, P., Maggs, D.G., Ruggles, J.A., Fineman, M., Shen, L., Kolterman, O.G., Weyer, C., 2004. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes. Res. 12, 661e668. Holst, J.J., Gromada, J., 2004. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am. J. Physiol. Endocrinol. Metab. 287, E199eE206. Holst, J.J., Knop, F.K., Vilsboll, T., Krarup, T., Madsbad, S., 2011. Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes. Diabetes Care 34 (Suppl. 2), S251eS257. Iguchi, T., Sakata, K., Yoshizaki, K., Tago, K., Mizuno, N., Itoh, H., 2008. Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a G alpha 12/13 and Rho pathway. J. Biol. Chem. 283, 14469e14478. Ishii, M., Kurachi, Y., 2006. Muscarinic acetylcholine receptors. Curr. Pharmaceut. Des. 12, 3573e3581. Kahn, S.E., Cooper, M.E., Del Prato, S., 2014. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 383, 1068e1083. Kailey, B., Van De Bunt, M., Cheley, S., Johnson, P.R., Macdonald, P.E., Gloyn, A.L., Rorsman, P., Braun, M., 2012. SSTR2 is the functionally dominant somatostatin receptor in human pancreatic beta- and alpha-cells. Am. J. Physiol. Endocrinol. Metab. 303, E1107eE1116. Kalra, S., Kalra, B., Agrawal, N., Kumar, S., 2011. Dopamine: the forgotten felon in type 2 diabetes. Recent Pat. Endocr. Metab. Immune Drug Discov. 5, 61e65.

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Karimian, N., Qin, T., Liang, T., Osundiji, M., Huang, Y., Teich, T., Riddell, M.C., Cattral, M.S., Coy, D.H., Vranic, M., Gaisano, H.Y., 2013. Somatostatin receptor type 2 antagonism improves glucagon counterregulation in biobreeding diabetic rats. Diabetes 62, 2968e2977. Karlsson, S., Ahren, B., 1996. A role for islet peptide YY in the regulation of insulin secretion. Acta Physiol. Scand. 157, 305e306. Kasai, R.S., Ito, S.V., Awane, R.M., Fujiwara, T.K., Kusumi, A., 2018. The class-A GPCR dopamine D2 receptor forms transient dimers stabilized by agonists: detection by single-molecule tracking. Cell Biochem. Biophys. 76, 29e37. Kelly, R.P., Garhyan, P., Raddad, E., Fu, H., Lim, C.N., Prince, M.J., Pinaire, J.A., Loh, M.T., Deeg, M.A., 2015. Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes. Metab. 17, 414e422. Kim, K.S., Yoon, Y.R., Lee, H.J., Yoon, S., Kim, S.Y., Shin, S.W., An, J.J., Kim, M.S., Choi, S.Y., Sun, W., Baik, J.H., 2010. Enhanced hypothalamic leptin signaling in mice lacking dopamine D2 receptors. J. Biol. Chem. 285, 8905e8917. Kim, W.D., Lee, Y.H., Kim, M.H., Jung, S.Y., Son, W.C., Yoon, S.J., Lee, B.W., 2012a. Human monoclonal antibodies against glucagon receptor improve glucose homeostasis by suppression of hepatic glucose output in diet-induced obese mice. PLoS One 7, e50954. Kim, Y.J., Sano, T., Nabetani, T., Asano, Y., Hirabayashi, Y., 2012b. GPRC5B activates obesity-associated inflammatory signaling in adipocytes. Sci. Signal. 5, ra85. Kok, B.P., Galmozzi, A., Littlejohn, N.K., Albert, V., Godio, C., Kim, W., Kim, S.M., Bland, J.S., Grayson, N., Fang, M., Meyerhof, W., Siuzdak, G., Srinivasan, S., Behrens, M., Saez, E., 2018. Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefits. Mol. Metab. 16, 76e87. Kong, K.C., Butcher, A.J., Mcwilliams, P., Jones, D., Wess, J., Hamdan, F.F., Werry, T., Rosethorne, E.M., Charlton, S.J., Munson, S.E., Cragg, H.A., Smart, A.D., Tobin, A.B., 2010. M3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1. Proc. Natl. Acad. Sci. U.S.A. 107, 21181e21186. Kong, K.C., Tobin, A.B., 2011. The role of M3-muscarinic receptor signaling in insulin secretion. Commun. Integr. Biol. 4, 489e491. Kroeze, W.K., Sassano, M.F., Huang, X.P., Lansu, K., Mccorvy, J.D., Giguere, P.M., Sciaky, N., Roth, B.L., 2015. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 22, 362e369. Kurabayashi, N., Nguyen, M.D., Sanada, K., 2013. The G protein-coupled receptor GPRC5B contributes to neurogenesis in the developing mouse neocortex. Development 140, 4335e4346. Latek, D., Modzelewska, A., Trzaskowski, B., Palczewski, K., Filipek, S., 2012. G protein-coupled receptors–recent advances. Acta Biochim. Pol. 59, 515e529. Lee, S.M., Hay, D.L., Pioszak, A.A., 2016. Calcitonin and amylin receptor peptide interaction mechanisms. INSIGHTS INTO PEPTIDE-BINDING MODES AND ALLOSTERIC MODULATION OF THE CALCITONIN RECEPTOR BY RECEPTOR ACTIVITY-MODIFYING PROTEINS. J. Biol. Chem. 291, 16416. Lee, S.U., In, H.J., Kwon, M.S., Park, B.O., Jo, M., Kim, M.O., Cho, S., Lee, S., Lee, H.J., Kwak, Y.S., Kim, S., 2013. beta-arrestin 2 mediates G proteincoupled receptor 43 signals to nuclear factor-kappaB. Biol. Pharm. Bull. 36, 1754e1759. Li, A., Li, Y., Du, L., 2015. Biological characteristics and agonists of GPR120 (FFAR4) receptor: the present status of research. Future Med. Chem. 7, 1457e1468. Li, Z., Qiu, Q., Geng, X., Yang, J., Huang, W., Qian, H., 2016. Free fatty acid receptor agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II clinical development. Expert Opin. Investig. Drugs 25, 871e890. Li, Z., Xu, X., Huang, W., Qian, H., 2018. Free fatty acid receptor 1 (FFAR1) as an emerging therapeutic target for type 2 diabetes mellitus: recent progress and prevailing challenges. Med. Res. Rev. 38, 381e425. Little, K.D., Hemler, M.E., Stipp, C.S., 2004. Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Galpha q/11 association. Mol. Biol. Cell 15, 2375e2387. Ludvik, B., Kautzky-Willer, A., Prager, R., Thomaseth, K., Pacini, G., 1997. Amylin: history and overview. Diabet. Med. 14 (Suppl. 2), S9eS13. Lund, A., Bagger, J.I., Wewer Albrechtsen, N.J., Christensen, M., Grondahl, M., Hartmann, B., Mathiesen, E.R., Hansen, C.P., Storkholm, J.H., Van Hall, G., Rehfeld, J.F., Hornburg, D., Meissner, F., Mann, M., Larsen, S., Holst, J.J., Vilsboll, T., Knop, F.K., 2016. Evidence of extrapancreatic glucagon secretion in man. Diabetes 65, 585e597. Luo, S., Luo, J., Cincotta, A.H., 1999. Chronic ventromedial hypothalamic infusion of norepinephrine and serotonin promotes insulin resistance and glucose intolerance. Neuroendocrinology 70, 460e465. Lyssenko, V., Nagorny, C.L., Erdos, M.R., Wierup, N., Jonsson, A., Spegel, P., Bugliani, M., Saxena, R., Fex, M., Pulizzi, N., Isomaa, B., Tuomi, T., Nilsson, P., Kuusisto, J., Tuomilehto, J., Boehnke, M., Altshuler, D., Sundler, F., Eriksson, J.G., Jackson, A.U., Laakso, M., Marchetti, P., Watanabe, R.M., Mulder, H., Groop, L., 2009. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat. Genet. 41, 82e88. Ma, X., Schwarz, A., Sevilla, S.Z., Levin, A., Hultenby, K., Wernerson, A., Lal, M., Patrakka, J., 2018. Depletion of Gprc5a promotes development of diabetic nephropathy. J. Am. Soc. Nephrol. 29, 1679e1689. Mahajan, R., 2009. Bromocriptine mesylate: FDA-approved novel treatment for type-2 diabetes. Indian J. Pharmacol. 41, 197e198. Malhi, H., Camilleri, M., 2017. Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases. Curr. Opin. Pharmacol. 37, 80e86. Marchal-Victorion, S., Vionnet, N., Escrieut, C., Dematos, F., Dina, C., Dufresne, M., Vaysse, N., Pradayrol, L., Froguel, P., Fourmy, D., 2002. Genetic, pharmacological and functional analysis of cholecystokinin-1 and cholecystokinin-2 receptor polymorphism in type 2 diabetes and obese patients. Pharmacogenetics 12, 23e30. Marco, J., Correas, I., Zulueta, M.A., Vincent, E., Coy, D.H., Comaru-Schally, A.M., Schally, A.V., Rodriguez-Arnao, M.D., Gomez-Pan, A., 1983. Inhibitory effect of somatostatin-28 on pancreatic polypeptide, glucagon and insulin secretion in normal man. Horm. Metab. Res. 15, 363e366.

GPCR targets in type 2 diabetes Chapter | 18

387

Marzban, L., 2015. New insights into the mechanisms of islet inflammation in type 2 diabetes. Diabetes 64, 1094e1096. Mccorvy, J.D., Roth, B.L., 2015. Structure and function of serotonin G protein-coupled receptors. Pharmacol. Ther. 150, 129e142. Mccreath, K.J., Espada, S., Galvez, B.G., Benito, M., De Molina, A., Sepulveda, P., Cervera, A.M., 2015. Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity. Diabetes 64, 1154e1167. Mcintyre, N., Holdsworth, C.D., Turner, D.S., 1964. New interpretation of oral glucose tolerance. Lancet 2, 20e21. Mehta, A., Marso, S.P., Neeland, I.J., 2017. Liraglutide for weight management: a critical review of the evidence. Obes. Sci. Pract. 3, 3e14. Mergenthaler, P., Lindauer, U., Dienel, G.A., Meisel, A., 2013. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 36, 587e597. Mikhail, N., 2011. Quick-release bromocriptine for treatment of type 2 diabetes. Curr. Drug Deliv. 8, 511e516. Miller, L.J., Sexton, P.M., Dong, M., Harikumar, K.G., 2014. The class B G-protein-coupled GLP-1 receptor: an important target for the treatment of type2 diabetes mellitus. Int. J. Obes. Suppl. (4), S9eS13. Miyawaki, K., Yamada, Y., Ban, N., Ihara, Y., Tsukiyama, K., Zhou, H., Fujimoto, S., Oku, A., Tsuda, K., Toyokuni, S., Hiai, H., Mizunoya, W., Fushiki, T., Holst, J.J., Makino, M., Tashita, A., Kobara, Y., Tsubamoto, Y., Jinnouchi, T., Jomori, T., Seino, Y., 2002. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. 8, 738e742. Montrose-Rafizadeh, C., Avdonin, P., Garant, M.J., Rodgers, B.D., Kole, S., Yang, H., Levine, M.A., Schwindinger, W., Bernier, M., 1999. Pancreatic glucagon-like peptide-1 receptor couples to multiple G proteins and activates mitogen-activated protein kinase pathways in Chinese hamster ovary cells. Endocrinology 140, 1132e1140. Morgan, N.G., 2009. Fatty acids and beta-cell toxicity. Curr. Opin. Clin. Nutr. Metab. Care 12, 117e122. Morrison, D.J., Preston, T., 2016. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microb. 7, 189e200. Mota, A., Bento, A., Penalva, A., Pombo, M., Dieguez, C., 1995. Role of the serotonin receptor subtype 5-HT1D on basal and stimulated growth hormone secretion. J. Clin. Endocrinol. Metab. 80, 1973e1977. Murakoshi, M., Kuwabara, H., Nagasaki, M., Xiong, Y.M., Reagan, J.D., Maeda, H., Nara, F., 2017. Discovery and pharmacological effects of a novel GPR142 antagonist. J. Recept. Signal Transduct. Res. 37, 290e296. Naas, D., Morris, T., Kousba, A., Mazzoni, M., 2015. A 9-month toxicity and toxicokinetic assessment of subcutaneous pegylated human C-peptide (CBX129801) in cynomolgus monkeys. Int. J. Toxicol. 34, 318e324. Nanga, R.P., Brender, J.R., Xu, J., Veglia, G., Ramamoorthy, A., 2008. Structures of rat and human islet amyloid polypeptide IAPP(1-19) in micelles by NMR spectroscopy. Biochemistry 47, 12689e12697. Nasteska, D., Harada, N., Suzuki, K., Yamane, S., Hamasaki, A., Joo, E., Iwasaki, K., Shibue, K., Harada, T., Inagaki, N., 2014. Chronic reduction of GIP secretion alleviates obesity and insulin resistance under high-fat diet conditions. Diabetes 63, 2332e2343. Nauck, M.A., Heimesaat, M.M., Orskov, C., Holst, J.J., Ebert, R., Creutzfeldt, W., 1993. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Investig. 91, 301e307. Neiers, F., Canivenc-Lavier, M.C., Briand, L., 2016. What does diabetes “taste” like? Curr. Diabetes Rep. 16, 49. Neumiller, J.J., Campbell, R.K., 2009. Liraglutide: a once-daily incretin mimetic for the treatment of type 2 diabetes mellitus. Ann. Pharmacother. 43, 1433e1444. Ngo, T., Kufareva, I., Coleman, J., Graham, R.M., Abagyan, R., Smith, N.J., 2016. Identifying ligands at orphan GPCRs: current status using structurebased approaches. Br. J. Pharmacol. 173, 2934e2951. Nohr, M.K., Pedersen, M.H., Gille, A., Egerod, K.L., Engelstoft, M.S., Husted, A.S., Sichlau, R.M., Grunddal, K.V., Poulsen, S.S., Han, S., Jones, R.M., Offermanns, S., Schwartz, T.W., 2013. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154, 3552e3564. Ogawa, T., Hirose, H., Miyashita, K., Saito, I., Saruta, T., 2005. GPR40 gene Arg211His polymorphism may contribute to the variation of insulin secretory capacity in Japanese men. Metabolism 54, 296e299. Ogurtsova, K., Da Rocha Fernandes, J.D., Huang, Y., Linnenkamp, U., Guariguata, L., Cho, N.H., Cavan, D., Shaw, J.E., Makaroff, L.E., 2017. IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract. 128, 40e50. Ohara-Imaizumi, M., Kim, H., Yoshida, M., Fujiwara, T., Aoyagi, K., Toyofuku, Y., Nakamichi, Y., Nishiwaki, C., Okamura, T., Uchida, T., Fujitani, Y., Akagawa, K., Kakei, M., Watada, H., German, M.S., Nagamatsu, S., 2013. Serotonin regulates glucose-stimulated insulin secretion from pancreatic beta cells during pregnancy. Proc. Natl. Acad. Sci. U.S.A. 110, 19420e19425. Olaniru, O.E., Persaud, S.J., 2018. Identifying novel therapeutic targets for diabetes through improved understanding of islet adhesion receptors. Curr. Opin. Pharmacol. 43, 27e33. Olaniru, O.E., Pingitore, A., Giera, S., Piao, X., Castanera Gonzalez, R., Jones, P.M., Persaud, S.J., 2018. The adhesion receptor GPR56 is activated by extracellular matrix collagen III to improve beta-cell function. Cell. Mol. Life Sci. 75, 4007e4019. Ortega, F.J., Aguera, Z., Sabater, M., Moreno-Navarrete, J.M., Alonso-Ledesma, I., Xifra, G., Botas, P., Delgado, E., Jimenez-Murcia, S., FernandezGarcia, J.C., Tinahones, F.J., Banos, R.M., Botella, C., De La Torre, R., Fruhbeck, G., Rodriguez, A., Estivill, X., Casanueva, F., Ricart, W., Fernandez-Aranda, F., Fernandez-Real, J.M., 2016. Genetic variations of the bitter taste receptor TAS2R38 are associated with obesity and impact on single immune traits. Mol. Nutr. Food Res. 60, 1673e1683. Otieno, M.A., Snoeys, J., Lam, W., Ghosh, A., Player, M.R., Pocai, A., Salter, R., Simic, D., Skaggs, H., Singh, B., Lim, H.K., 2018. Fasiglifam (TAK875): mechanistic investigation and retrospective identification of hazards for drug induced liver injury. Toxicol. Sci. 163, 374e384.

388 PART | III GPCRs in disease and targeted drug discovery

Overton, H.A., Fyfe, M.C., Reynet, C., 2008. GPR119, a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity. Br. J. Pharmacol. 153 (Suppl. 1), S76eS81. Palego, L., Betti, L., Rossi, A., Giannaccini, G., 2016. Tryptophan biochemistry: structural, nutritional, metabolic, and medical aspects in humans. J. Amino Acids 2016, 8952520. Panaro, B.L., Flock, G.B., Campbell, J.E., Beaudry, J.L., Cao, X., Drucker, D.J., 2017. Beta-cell inactivation of Gpr119 unmasks incretin dependence of GPR119-mediated glucoregulation. Diabetes 66, 1626e1635. Papatheodorou, K., Papanas, N., Banach, M., Papazoglou, D., Edmonds, M., 2016. Complications of diabetes 2016. J. Diabetes Res 2016, 6989453. Pashkov, V., Huang, J., Parameswara, V.K., Kedzierski, W., Kurrasch, D.M., Tall, G.G., Esser, V., Gerard, R.D., Uyeda, K., Towle, H.C., Wilkie, T.M., 2011. Regulator of G protein signaling (RGS16) inhibits hepatic fatty acid oxidation in a carbohydrate response element-binding protein (ChREBP)dependent manner. J. Biol. Chem. 286, 15116e15125. Pathak, P., Liu, H., Boehme, S., Xie, C., Krausz, K.W., Gonzalez, F., Chiang, J.Y.L., 2017. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J. Biol. Chem. 292, 11055e11069. Pathak, V., Flatt, P.R., Irwin, N., 2018. Cholecystokinin (CCK) and related adjunct peptide therapies for the treatment of obesity and type 2 diabetes. Peptides 100, 229e235. Persaud, S., 2017. Islet G-protein coupled receptors: therapeutic potential for diabetes. Curr. Opin. Pharmacol. 37, 24e28. Persaud, S.J., Bewick, G.A., 2014. Peptide YY: more than just an appetite regulator. Diabetologia 57, 1762e1769. Persaud, S.J., Jones, P.M., 2016. A wake-up call for type 2 diabetes? N. Engl. J. Med. 375, 1090e1092. Persaud, S.J., Jones, P.M., Howell, S.L., 1991. Activation of protein kinase C is essential for sustained insulin secretion in response to cholinergic stimulation. Biochim. Biophys. Acta 1091, 120e122. Peti-Peterdi, J., 2010. High glucose and renin release: the role of succinate and GPR91. Kidney Int. 78, 1214e1217. Piao, X., Hill, R.S., Bodell, A., Chang, B.S., Basel-Vanagaite, L., Straussberg, R., Dobyns, W.B., Qasrawi, B., Winter, R.M., Innes, A.M., Voit, T., Ross, M.E., Michaud, J.L., Descarie, J.C., Barkovich, A.J., Walsh, C.A., 2004. G protein-coupled receptor-dependent development of human frontal cortex. Science 303, 2033e2036. Picinato, M.C., Haber, E.P., Cipolla-Neto, J., Curi, R., De Oliveira Carvalho, C.R., Carpinelli, A.R., 2002. Melatonin inhibits insulin secretion and decreases PKA levels without interfering with glucose metabolism in rat pancreatic islets. J. Pineal Res. 33, 156e160. Pingitore, A., Chambers, E.S., Hill, T., Maldonado, I.R., Liu, B., Bewick, G., Morrison, D.J., Preston, T., Wallis, G.A., Tedford, C., Castanera Gonzalez, R., Huang, G.C., Choudhary, P., Frost, G., Persaud, S.J., 2017. The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro. Diabetes Obes. Metab. 19, 257e265. Pivonello, R., Ferone, D., Lombardi, G., Colao, A., Lamberts, S.W., Hofland, L.J., 2007. Novel insights in dopamine receptor physiology. Eur. J. Endocrinol. 156 (Suppl. 1), S13eS21. Plainsboro, NJ. VictozaÒ (liraglutide) is Approved in the US as the Only Type 2 Diabetes Treatment Indicated to Reduce the Risk of Three Major Adverse Cardiovascular Events. http://press.novonordisk-us.com/2017-08-25-Victoza-R-liraglutide-is-approved-in-the-US-as-the-only-type-2diabetes-treatment-indicated-to-reduce-the-risk-of-three-major-adverse-cardiovascular-events. Poyner, D.R., Sexton, P.M., Marshall, I., Smith, D.M., Quirion, R., Born, W., Muff, R., Fischer, J.A., Foord, S.M., 2002. International union of pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol. Rev. 54, 233e246. Priyadarshini, M., Wicksteed, B., Schiltz, G.E., Gilchrist, A., Layden, B.T., 2016. SCFA receptors in pancreatic beta cells: novel diabetes targets? Trends Endocrinol. Metabol. 27, 653e664. Pullman, J., Darsow, T., Frias, J.P., 2006. Pramlintide in the management of insulin-using patients with type 2 and type 1 diabetes. Vasc. Health Risk Manag. 2, 203e212. Rai, U., Thrimawithana, T.R., Valery, C., Young, S.A., 2015. Therapeutic uses of somatostatin and its analogues: current view and potential applications. Pharmacol. Ther. 152, 98e110. Ramracheya, R.D., Muller, D.S., Squires, P.E., Brereton, H., Sugden, D., Huang, G.C., Amiel, S.A., Jones, P.M., Persaud, S.J., 2008. Function and expression of melatonin receptors on human pancreatic islets. J. Pineal Res. 44, 273e279. Riddy, D.M., Delerive, P., Summers, R.J., Sexton, P.M., Langmead, C.J., 2018. G protein-coupled receptors targeting insulin resistance, obesity, and type 2 diabetes mellitus. Pharmacol. Rev. 70, 39e67. Risso, D., Sainz, E., Morini, G., Tofanelli, S., Drayna, D., 2018. Taste perception of Antidesma bunius fruit and its relationships to bitter taste receptor gene haplotypes. Chem. Senses 43, 463e468. Risso, D.S., Mezzavilla, M., Pagani, L., Robino, A., Morini, G., Tofanelli, S., Carrai, M., Campa, D., Barale, R., Caradonna, F., Gasparini, P., Luiselli, D., Wooding, S., Drayna, D., 2016. Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosal. Sci. Rep. 6, 25506. Ritter, K., Buning, C., Halland, N., Poverlein, C., Schwink, L., 2016. G protein-coupled receptor 119 (GPR119) agonists for the treatment of diabetes: recent progress and prevailing challenges. J. Med. Chem. 59, 3579e3592. Robben, J.H., Fenton, R.A., Vargas, S.L., Schweer, H., Peti-Peterdi, J., Deen, P.M., Milligan, G., 2009. Localization of the succinate receptor in the distal nephron and its signaling in polarized MDCK cells. Kidney Int. 76, 1258e1267. Robbins, M.J., Charles, K.J., Harrison, D.C., Pangalos, M.N., 2002. Localisation of the GPRC5B receptor in the rat brain and spinal cord. Brain Res. Mol. Brain Res. 106, 136e144. Roder, P.V., Wu, B., Liu, Y., Han, W., 2016. Pancreatic regulation of glucose homeostasis. Exp. Mol. Med. 48, e219.

GPCR targets in type 2 diabetes Chapter | 18

389

Roe, E.D., Chamarthi, B., Raskin, P., 2015. Impact of bromocriptine-QR therapy on glycemic control and daily insulin requirement in type 2 diabetes mellitus subjects whose dysglycemia is poorly controlled on high-dose insulin: a pilot study. J Diabetes Res. 2015, 834903. Rosenbaum, D.M., Rasmussen, S.G., Kobilka, B.K., 2009. The structure and function of G-protein-coupled receptors. Nature 459, 356e363. Rosengren, A.H., Jokubka, R., Tojjar, D., Granhall, C., Hansson, O., Li, D.Q., Nagaraj, V., Reinbothe, T.M., Tuncel, J., Eliasson, L., Groop, L., Rorsman, P., Salehi, A., Lyssenko, V., Luthman, H., Renstrom, E., 2010. Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 327, 217e220. Rother, K.I., Conway, E.M., Sylvetsky, A.C., 2018. How non-nutritive sweeteners influence hormones and health. Trends Endocrinol. Metabol. 29, 455e467. Ryan, G., Briscoe, T.A., Jobe, L., 2009. Review of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes. Drug Des. Dev. Ther. 2, 203e214. Ryan, G.J., Jobe, L.J., Martin, R., 2005. Pramlintide in the treatment of type 1 and type 2 diabetes mellitus. Clin. Ther. 27, 1500e1512. Sakano, D., Choi, S., Kataoka, M., Shiraki, N., Uesugi, M., Kume, K., Kume, S., 2016. Dopamine D2 receptor-mediated regulation of pancreatic beta cell mass. Stem Cell Reports 7, 95e109. Samuel, B.S., Shaito, A., Motoike, T., Rey, F.E., Backhed, F., Manchester, J.K., Hammer, R.E., Williams, S.C., Crowley, J., Yanagisawa, M., Gordon, J.I., 2008. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. U.S.A. 105, 16767e16772. Savontaus, E., Fagerholm, V., Rahkonen, O., Scheinin, M., 2008. Reduced blood glucose levels, increased insulin levels and improved glucose tolerance in alpha2A-adrenoceptor knockout mice. Eur. J. Pharmacol. 578, 359e364. Schmitz, O., Brock, B., Rungby, J., 2004. Amylin agonists: a novel approach in the treatment of diabetes. Diabetes 53 (Suppl. 3), S233eS238. Schraenen, A., Lemaire, K., De Faudeur, G., Hendrickx, N., Granvik, M., Van Lommel, L., Mallet, J., Vodjdani, G., Gilon, P., Binart, N., In’t Veld, P., Schuit, F., 2010. Placental lactogens induce serotonin biosynthesis in a subset of mouse beta cells during pregnancy. Diabetologia 53, 2589e2599. Schroder, R., Schmidt, J., Blattermann, S., Peters, L., Janssen, N., Grundmann, M., Seemann, W., Kaufel, D., Merten, N., Drewke, C., Gomeza, J., Milligan, G., Mohr, K., Kostenis, E., 2011. Applying label-free dynamic mass redistribution technology to frame signaling of G protein-coupled receptors noninvasively in living cells. Nat. Protoc. 6, 1748e1760. Shapiro, H., Kolodziejczyk, A.A., Halstuch, D., Elinav, E., 2018. Bile acids in glucose metabolism in health and disease. J. Exp. Med. 215, 383e396. Shivaprasad, C., Kalra, S., 2011. Bromocriptine in type 2 diabetes mellitus. Indian J. Endocrinol. Metab. 15, S17eS24. Shukla, A.P., Kumar, R.B., Aronne, L.J., 2015. Lorcaserin Hcl for the treatment of obesity. Expert Opin. Pharmacother. 16, 2531e2538. Simo-Servat, O., Hernandez, C., Simo, R., 2018. Somatostatin and diabetic retinopathy: an evolving story. Endocrine 60, 1e3. Simon, B.R., Learman, B.S., Parlee, S.D., Scheller, E.L., Mori, H., Cawthorn, W.P., Ning, X., Krishnan, V., Ma, Y.L., Tyrberg, B., Macdougald, O.A., 2014. Sweet taste receptor deficient mice have decreased adiposity and increased bone mass. PLoS One 9, e86454. Sjogren, B., 2017. The evolution of regulators of G protein signalling proteins as drug targets e 20 years in the making: IUPHAR review 21. Br. J. Pharmacol. 174, 427e437. Snook, L.A., Nelson, E.M., Dyck, D.J., Wright, D.C., Holloway, G.P., 2015. Glucose-dependent insulinotropic polypeptide directly induces glucose transport in rat skeletal muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R295eR303. Soni, A., Amisten, S., Rorsman, P., Salehi, A., 2013. GPRC5B a putative glutamate-receptor candidate is negative modulator of insulin secretion. Biochem. Biophys. Res. Commun. 441, 643e648. Soni, H., 2016. Peptide-based GLP-1/glucagon co-agonists: a double-edged sword to combat diabesity. Med. Hypotheses 95, 5e9. Sonoda, N., Imamura, T., Yoshizaki, T., Babendure, J.L., Lu, J.C., Olefsky, J.M., 2008. Beta-arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic beta cells. Proc. Natl. Acad. Sci. U.S.A. 105, 6614e6619. Sprague, J.E., Arbelaez, A.M., 2011. Glucose counterregulatory responses to hypoglycemia. Pediatr. Endocrinol. Rev. 9, 463e473 quiz 474-5. Sriram, K., Insel, P.A., 2018. G protein-coupled receptors as targets for approved drugs: how many targets and how many drugs? Mol. Pharmacol. 93, 251e258. Staels, B., Fonseca, V.A., 2009. Bile acids and metabolic regulation: mechanisms and clinical responses to bile acid sequestration. Diabetes Care 32 (Suppl. 2), S237eS245. Stone, V.M., Dhayal, S., Brocklehurst, K.J., Lenaghan, C., Sorhede Winzell, M., Hammar, M., Xu, X., Smith, D.M., Morgan, N.G., 2014. GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia 57, 1182e1191. Tahrani, A.A., Barnett, A.H., Bailey, C.J., 2016. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 12, 566e592. Talukdar, S., Olefsky, J.M., Osborn, O., 2011. Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol. Sci. 32, 543e550. Theodoropoulou, M., Stalla, G.K., 2013. Somatostatin receptors: from signaling to clinical practice. Front. Neuroendocrinol. 34, 228e252. Thomas, C., Gioiello, A., Noriega, L., Strehle, A., Oury, J., Rizzo, G., Macchiarulo, A., Yamamoto, H., Mataki, C., Pruzanski, M., Pellicciari, R., Auwerx, J., Schoonjans, K., 2009. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metabol. 10, 167e177. Timofte, L., Stratmann, B., Quester, W., Bojita, M.T., Tschoepe, D., 2013. Liraglutide and DPP-4 inhibitors e side effects comparative clinical study. Clujul Med. 86, 111e113. Toda, N., Hao, X., Ogawa, Y., Oda, K., Yu, M., Fu, Z., Chen, Y., Kim, Y., Lizarzaburu, M., Lively, S., Lawlis, S., Murakoshi, M., Nara, F., Watanabe, N., Reagan, J.D., Tian, H., Fu, A., Motani, A., Liu, Q., Lin, Y.J., Zhuang, R., Xiong, Y., Fan, P., Medina, J., Li, L., Izumi, M.,

390 PART | III GPCRs in disease and targeted drug discovery

Okuyama, R., Shibuya, S., 2013. Potent and orally bioavailable GPR142 agonists as novel insulin secretagogues for the treatment of type 2 diabetes. ACS Med. Chem. Lett. 4, 790e794. Tolhurst, G., Heffron, H., Lam, Y.S., Parker, H.E., Habib, A.M., Diakogiannaki, E., Cameron, J., Grosse, J., Reimann, F., Gribble, F.M., 2012. Shortchain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61, 364e371. Toma, I., Kang, J.J., Sipos, A., Vargas, S., Bansal, E., Hanner, F., Meer, E., Peti-Peterdi, J., 2008. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J. Clin. Investig. 118, 2526e2534. Tran, Y.H., Schuiling-Veninga, C.C.M., Bergman, J.E.H., Groen, H., Wilffert, B., 2017. Impact of muscarinic M3 receptor antagonism on the risk of type 2 diabetes in antidepressant-treated patients: a case-controlled study. CNS Drugs 31, 483e493. Trevaskis, J.L., Sun, C., Athanacio, J., D’souza, L., Samant, M., Tatarkiewicz, K., Griffin, P.S., Wittmer, C., Wang, Y., Teng, C.H., Forood, B., Parkes, D.G., Roth, J.D., 2015. Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents. Diabetes Obes. Metab. 17, 61e73. Tripathi, S., Flobak, A., Chawla, K., Baudot, A., Bruland, T., Thommesen, L., Kuiper, M., Laegreid, A., 2015. The gastrin and cholecystokinin receptors mediated signaling network: a scaffold for data analysis and new hypotheses on regulatory mechanisms. BMC Syst. Biol. 9, 40. Triplitt, C.L., 2012. Examining the mechanisms of glucose regulation. Am. J. Manag. Care 18, S4eS10. Tsujihata, Y., Ito, R., Suzuki, M., Harada, A., Negoro, N., Yasuma, T., Momose, Y., Takeuchi, K., 2011. TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats. J. Pharmacol. Exp. Ther. 339, 228e237. Tuomi, T., Nagorny, C.L.F., Singh, P., Bennet, H., Yu, Q., Alenkvist, I., Isomaa, B., Ostman, B., Soderstrom, J., Pesonen, A.K., Martikainen, S., Raikkonen, K., Forsen, T., Hakaste, L., Almgren, P., Storm, P., Asplund, O., Shcherbina, L., Fex, M., Fadista, J., Tengholm, A., Wierup, N., Groop, L., Mulder, H., 2016. Increased melatonin signaling is a risk factor for type 2 diabetes. Cell Metabol. 23, 1067e1077. Vallee Marcotte, B., Cormier, H., Rudkowska, I., Lemieux, S., Couture, P., Vohl, M.C., 2017. Polymorphisms in FFAR4 (GPR120) gene modulate insulin levels and sensitivity after fish oil supplementation. J. Personalized Med. 7. Van Diepen, J.A., Robben, J.H., Hooiveld, G.J., Carmone, C., Alsady, M., Boutens, L., Bekkenkamp-Grovenstein, M., Hijmans, A., Engelke, U.F.H., Wevers, R.A., Netea, M.G., Tack, C.J., Stienstra, R., Deen, P.M.T., 2017. SUCNR1-mediated chemotaxis of macrophages aggravates obesityinduced inflammation and diabetes. Diabetologia 60, 1304e1313. Van Harmelen, V., Reynisdottir, S., Cianflone, K., Degerman, E., Hoffstedt, J., Nilsell, K., Sniderman, A., Arner, P., 1999. Mechanisms involved in the regulation of free fatty acid release from isolated human fat cells by acylation-stimulating protein and insulin. J. Biol. Chem. 274, 18243e18251. Vassilatis, D.K., Hohmann, J.G., Zeng, H., Li, F., Ranchalis, J.E., Mortrud, M.T., Brown, A., Rodriguez, S.S., Weller, J.R., Wright, A.C., Bergmann, J.E., Gaitanaris, G.A., 2003. The G protein-coupled receptor repertoires of human and mouse. Proc. Natl. Acad. Sci. U.S.A. 100, 4903e4908. Vestmar, M.A., Andersson, E.A., Christensen, C.R., Hauge, M., Glumer, C., Linneberg, A., Witte, D.R., Jorgensen, M.E., Christensen, C., Brandslund, I., Lauritzen, T., Pedersen, O., Holst, B., Grarup, N., Schwartz, T.W., Hansen, T., 2016. Functional and genetic epidemiological characterisation of the FFAR4 (GPR120) p.R270H variant in the Danish population. J. Med. Genet. 53, 616e623. Vettor, R., Granzotto, M., DE Stefani, D., Trevellin, E., Rossato, M., Farina, M.G., Milan, G., Pilon, C., Nigro, A., Federspil, G., Vigneri, R., Vitiello, L., Rizzuto, R., Baratta, R., Frittitta, L., 2008. Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization. J. Clin. Endocrinol. Metab. 93, 3541e3550. Vivot, K., Moulle, V.S., Zarrouki, B., Tremblay, C., Mancini, A.D., Maachi, H., Ghislain, J., Poitout, V., 2016. The regulator of G-protein signaling RGS16 promotes insulin secretion and beta-cell proliferation in rodent and human islets. Mol. Metab. 5, 988e996. Wade, J.M., Juneja, P., Mackay, A.W., Graham, J., Havel, P.J., Tecott, L.H., Goulding, E.H., 2008. Synergistic impairment of glucose homeostasis in ob/ ob mice lacking functional serotonin 2C receptors. Endocrinology 149, 955e961. Wahren, J., 2017. C-peptide and the pathophysiology of microvascular complications of diabetes. J. Intern. Med. 281, 3e6. Wahren, J., Foyt, H., Daniels, M., Arezzo, J.C., 2016. Long-acting C-peptide and neuropathy in type 1 diabetes: a 12-month clinical trial. Diabetes Care 39, 596e602. Wang, J., Carrillo, J.J., Lin, H.V., 2016. GPR142 agonists stimulate glucose-dependent insulin secretion via gq-dependent signaling. PLoS One 11, e0154452. Wang, X.X., Wang, D., Luo, Y., Myakala, K., Dobrinskikh, E., Rosenberg, A.Z., Levi, J., Kopp, J.B., Field, A., Hill, A., Lucia, S., Qiu, L., Jiang, T., Peng, Y., Orlicky, D., Garcia, G., Herman-Edelstein, M., D’agati, V., Henriksen, K., Adorini, L., Pruzanski, M., Xie, C., Krausz, K.W., Gonzalez, F.J., Ranjit, S., Dvornikov, A., Gratton, E., Levi, M., 2018. FXR/TGR5 dual agonist prevents progression of nephropathy in diabetes and obesity. J. Am. Soc. Nephrol. 29, 118e137. Wank, S.A., 1995. Cholecystokinin receptors. Am. J. Physiol. 269, G628eG646. Wheeler, M.B., Lu, M., Dillon, J.S., Leng, X.H., Chen, C., Boyd 3rd, A.E., 1993. Functional expression of the rat glucagon-like peptide-I receptor, evidence for coupling to both adenylyl cyclase and phospholipase-C. Endocrinology 133, 57e62. White, J.P., Wrann, C.D., Rao, R.R., Nair, S.K., Jedrychowski, M.P., You, J.S., Martinez-Redondo, V., Gygi, S.P., Ruas, J.L., Hornberger, T.A., Wu, Z., Glass, D.J., Piao, X., Spiegelman, B.M., 2014. G protein-coupled receptor 56 regulates mechanical overload-induced muscle hypertrophy. Proc. Natl. Acad. Sci. U.S.A. 111, 15756e15761. Wu, Y., Ding, Y., Tanaka, Y., Zhang, W., 2014. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention. Int. J. Med. Sci. 11, 1185e1200. Xu, Y., Xie, X., 2009. Glucagon receptor mediates calcium signaling by coupling to G alpha q/11 and G alpha i/o in HEK293 cells. J. Recept. Signal Transduct. Res. 29, 318e325.

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Yang, J.W., Kim, H.S., Choi, Y.W., Kim, Y.M., Kang, K.W., 2018. Therapeutic application of GPR119 ligands in metabolic disorders. Diabetes Obes. Metab. 20, 257e269. Yang, Y., Huang, H., Xu, Z., Duan, J.K., 2017. Serotonin and its receptor as a new antioxidant therapeutic target for diabetic kidney disease. J. Diabetes Res. 2017, 7680576. Yanovski, S.Z., Yanovski, J.A., 2014. Long-term drug treatment for obesity: a systematic and clinical review. J. Am. Med. Assoc. 311, 74e86. Yosten, G.L., Kolar, G.R., Redlinger, L.J., Samson, W.K., 2013. Evidence for an interaction between proinsulin C-peptide and GPR146. J. Endocrinol. 218, B1eB8. Yue, J.T., Burdett, E., Coy, D.H., Giacca, A., Efendic, S., Vranic, M., 2012. Somatostatin receptor type 2 antagonism improves glucagon and corticosterone counterregulatory responses to hypoglycemia in streptozotocin-induced diabetic rats. Diabetes 61, 197e207. Zheng, C., Zhou, W., Wang, T., You, P., Zhao, Y., Yang, Y., Wang, X., Luo, J., Chen, Y., Liu, M., Chen, H., 2015. A novel TGR5 activator WB403 promotes GLP-1 secretion and preserves pancreatic beta-cells in type 2 diabetic mice. PLoS One 10, e0134051. Zhou, H., Rigoutsos, I., 2014. The emerging roles of GPRC5A in diseases. Oncoscience 1, 765e776. Zhou, H., Telonis, A.G., Jing, Y., Xia, N.L., Biederman, L., Jimbo, M., Blanco, F., Londin, E., Brody, J.R., Rigoutsos, I., 2016. GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR. Cell Death Dis. 7, e2294.