For citation purposes: Kolar GR, Elrick MM, Yosten GLC. G protein-coupled receptor signaling: Implications for the treatment of diabetes and its complications. OA Evidence-Based Medicine 2014 Jan 18;2(1):2.

Review

 
Treatment

G protein-coupled receptor signaling: Implications for the treatment of diabetes and its complications.

G Kolar1, M Elrick1, G Yosten1*
 

Authors affiliations

(1) Saint Louis University School of Medicine, Saint Louis, Missouri, USA

* Corresponding author Email: gyosten@slu.edu

Abstract

Introduction

G protein coupled receptors (GPCRs) represent the most abundant receptor family encoded by the human genome, and are the targets of a large percentage of drugs currently prescribed in the United States. Recently, several GPCRs have been identified as potential therapeutic targets for the treatment of diabetes and diabetes-associated complications, including retinopathy, nephropathy, and neuropathy.

Conclusion

In this review, we will discuss GPCR structure and signalling cascades, as well as highlight GPCR-based therapeutics that are currently prescribed or are in clinical trials to combat diabetes and its complications, a disease which now affects over 347 million patients worldwide.

Introduction

Diabetes is a multi-factorial disease process with a complex aetiology involving insulin resistance, aberrations in glucose homeostasis, lipid metabolism, and mitochondrial function, as well as inflammation and pancreatic beta cell toxicity[1,2,3] Both type 1 and type 2 diabetes are associated with the development of multiple microvascular complications including retinopathies, nephropathies, and neuropathies, which can lead to blindness, kidney disease and failure, and loss of feeling or function of the lower extremities, sometimes requiring amputation of one or more limbs[4]. The underlying causes of diabetes-associated microvascular dysfunction are not fully understood, but likely involve aberrations in multiple cellular processes, including nutrient metabolism and mitochondrial function, as well as intracellular signalling mechanisms and enhanced inflammation. Although dysfunctional insulin signalling often is implicated in the aetiology of diabetes-associated complications, many of these cellular activities may be modulated by G-protein coupled receptor (GPCR) signalling as well. Consequently, GPCRs may prove to be effective targets for the treatment of diabetes and its complications. The aim of this review was to discuss the Implications for the treatment of diabetes and its complications of G protein-coupled receptor signalling.

Discussion

The authors have referenced some of their own studies in this review. The protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed.

GPCR Structure and Signalling

GPCRs are the most abundant receptor family encoded by the human genome, and, accordingly, are the targets of a large percentage (~30%) of pharmaceuticals currently prescribed in the United States[5]. All GPCRs share basic structural features including seven transmembrane domains, three extracellular and three intracellular loops, and conserved cysteine residues in the second extracellular loop which may play a role in the formation of the ligand binding pocket[6,7]. With a few notable exceptions, the N terminal region of GPCRs are extracellular and may function in ligand specificity, while the C terminal cytoplasmic tail may play a role in GPCR signalling, including association with G protein Receptor Kinases (GRKs)[8].

GPCRs are categorized based on homology into six classes; however, most small peptide hormones that signal via a GPCR, such as glucagon and GLP-1, interact with either Class A (Rhodopsin-Like) or Class B (Secretin-Like) GPCRs. The “classical” signalling pathways initiated by activation of these Class A and B receptors have been very well described and include a complex series of steps, including dissociation of G proteins, GTP hydrolysis, and re-association of the G protein trimer[6,7]. This traditional GPCR signalling often involves stimulation or inhibition of adenylate cyclase by Gas or Gai, respectively (Figure 1). Adenylate cyclase activation triggers cAMP formation, cAMP binds to the regulatory subunits of PKA (PKAr) and a consequent allosteric change leads to release of the PKA catalytic subunits (PKAc)[9]. PKAc then phosphorylates downstream targets, and is a key player in the regulation of metabolic enzymes and activation of transcription factors.

Classical and Non-Traditional GPCR-Mediated Signaling Cascades. Activation of GPCRs coupled to Gαi leads to an inhibition of adenyl cyclase (AC) activity, resulting in reduced intracellular levels of cyclic AMP (cAMP). Activation of GPCRs coupled to Gαs leads to stimulation of AC activity, resulting in increased protein kinase A (PKA) activity, and downstream signaling events, including alterations in gene transcription. Alternatively, dissociation of Gαs can lead to activation of IKK (IkB kinase) through an unknown mechanism (dotted green arrow). IKK in turn phosphorylates IkB (inhibitor of kappa B), leading to the proteosomal degradation of IkB and dissociation of the IkB-NFkB-PKA complex. NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells) then translocates to the nucleus to act as a transcription factor, while PKA has additional downstream effects.

In the last several years, multiple reports have been published on the possibility of cAMP-independent activation of PKAc (Figure 1). In 1997, Zhong et al. (10) were the first to characterize a novel signalling pathway with cAMP-independent activation of PKAc in rabbit lung cytosol extract as well as mouse and human lymphocytes. They showed that while they were able to measure increased PKAc phosphorylation as a result of LPS treatment, they were unable to detect an elevation in cAMP. An eloquent set of pharmacological experiments demonstrated that a portion of intracellular PKAc (but not PKAr) was bound to the NFkB-IkB complex and that degradation of IkB with NFkB inducers led to the release and activation of PKAc. These same NFkB-IkB-PKAc isolated complexes were insensitive to increases in cAMP, and increased cAMP levels did not lead to increased PKAc activation. Since then, there have been several reports in the literature linking GPCRs with cAMP-independent PKAc activation. Dulin et al.[11] reported that two separate vasoactive peptides, endothelin-1 (ET1) and angiotensin II, upon GPCR binding, induced cAMP-independent PKAc activation. Their data complemented Zhong et al.[10] by demonstrating the NFkB-IkB complex bound to PKAc, rendering it inactive by blocking its ATP binding site. Ubiquitination and subsequent proteosomal degradation of IkB resulted in release of both PKAc and NFkB, followed by immediate phosphorylation and activation of NFkB by PKAc. Additionally, Vinciguerra et al.[12] reported that principal cells of the cortical collecting duct in the mammalian kidney, when stimulated, showed an increase in ouabain binding sites and an increase in PKAc that was prevented by PKA inhibitors. No increase in cAMP was observed, and PKAc activation was prevented by inhibiting the proteasome. Gambaryan et al.[13] observed a similar PKA-dependent, cAMP-independent phenomenon in human platelets, which serves as a novel inhibitory feedback signalling mechanism for preventing undesired platelet activation. Thrombin, signalling through a non-traditional GPCR[14], activated PKAc associated with an NFkB-IkB complex without measurable increases in cAMP.

Chemokines and classic chemoattractants are examples of other known ligands that signal through seven-transmembrane receptors, triggering degradation of IkB and activation of NFkB-dependent transcription[15]. For example, the chemokine fractalkine binds the GPCR CXCR3 and signals through the heterotrimeric G protein Gai, phosphoinositide 3-kinase (PI3-kinase), phosphoinositide-dependent kinase 1 (PDK1), Akt, NIK, IKK and finally NF-kB[16]. Phophorylation of Akt through the phosphorylation of IKK, can result in degradation of IkB by the proteosome and release of NFkB[17]. Therefore any ligand that signals through a GPCR to stimulate PI3K and subsequently Akt could potentially intersect with the NFkB-IkB-PKAc complex.

Clearly GPCR-mediated signalling is more complex than originally realized, and multiple non-traditional GPCR signalling pathways exist. For example, another possible mechanism for cAMP-independent protein kinase A activation is through the heterotrimeric G protein Ga13. Niu et al.,18 demonstrated that Ga13, AKAP110, PKAr, and PKAc can form a complex, and Ga13-induced release of PKAc from the AKAP110-PKAr complex results in cAMP-independent PKA activation. Additional alternative signalling mechanisms likely exist, and represent potential targets that can be manipulated for the treatment of diabetes and its complications.

GPCRs as Therapeutic Targets in Diabetes

The pharmaceutical therapeutic options for diabetes have traditionally included both injectable insulin regimens as well as oral agents. Insulin therapy has been the mainstay treatment of type 1 diabetes. Exogenous insulin treatment lowers blood glucose levels but must be administered to approximate physiologic insulin delivery requiring careful dosing, attention to pharmacokinetics, and current state of health. Though many formulations exist (regular, intermediate, and long-acting insulin) from either human or animal species with a variety of absorption rates and concentrations, the daily use of these products can be difficult requiring substantial empirical adjustment. Significant side effects can include hypoglycaemia, insulin allergy, antibody-mediated insulin resistance, and local lipodystrophy at injection sites[19].

Oral agents are typically first line therapy in type 2 diabetics and commonly used drugs include sulfonylureas (Glipizide, Gliburide) and biguanides (e.g. Metformin). Sulfonylureas stimulate insulin secretion from the beta cells of the pancreas through an ATP-dependent potassium channel and therefore require the function of these cells. A major complication of this approach is the possibility of developing hypoglycaemia due to increased insulin release. Biguanides increase insulin sensitivity and glucose uptake and decrease gluconeogenesis. Because they do not affect the output of insulin, do not require functional pancreatic beta cells and therefore are useful in type 2 and type 1 diabetics where they can be used in combination with insulin therapy. A side benefit in some patients desiring weight loss is anorexia, but side effects can include abdominal pain, nausea, and diarrhoea[19].

In addition to insulin itself, which signals via a tyrosine kinase receptor, several new therapies for diabetes and diabetic complications target GPCRs (Table 1). In many cases, therapies targeting GPCRs require once or twice daily dosage regimens. While in some cases clinical trials have indicated utility as monotherapy, addition of these agents to sulfonylureas or metformin offer advantages. These include GLP-1 based agonists, the related DPP-4 antagonists[20], bromocriptine, serotonin agonists, and, more recently, GPR40 agonists and selective endothelin-A receptor antagonists. The GLP-1 agonists and DPP4 inhibitors currently represent the most well-developed of therapies based on GPCRs for diabetes. GLP-1 (glucagon like peptide 1) is an incretin hormone that is released from the gut after a meal. GLP-1 stimulates insulin secretion, inhibits glucagon secretion, and may stimulate islet proliferation and cytoprotection through an interaction with its receptor, GLP1R[21,22]. While its effect on the pancreatic beta cell is direct, its effect on alpha cells and glucagon secretion may be either direct or indirect [23,24,25].

Table 1

Examples of GPCR-Based Therapeutics for the Treatment of Diabetes and its Complications

In 1992 it was suggested that GLP-1 might be a therapeutic target in type 2 diabetes[26] and the first GLP-1-based pharmaceutical came to market in 2005. Several strategies aimed at the GLP-1 receptor have been used to circumvent the otherwise short half-life of GLP-1 (usually 1-2 minutes) that is the result of inactivation by the DPP4 enzyme[27]. One of these strategies was to use a mimetic from the Gila monster called exendin-4 that shows 53% homology to GLP-1 and binds the receptor with the same affinity as the human homologue[28,29]. It is resistant to DPP4 and has a half-life of 30 minutes (intravenous administration) or 2-3 hours (sub-cutaneous administration). A synthetic form called exenatide or Byetta (Amylin/Eli Lilly) was shown to reduce body weight and HbA1c levels when administered twice daily subcutaneously with metformin, a sulphonylurea, or both[30,31,32]. The use of exenatide is approved by the FDA as both a monotherapy and in combination with other hypoglycemic agents. Though well tolerated overall, the predominate side effects include nausea during the beginning of treatment (~40% of patients) and hypoglycaemia when used with sulfonylureas (30% of patients). When combined with metformin, hypoglycaemia occurs with a similar frequency as when metformin is given alone[30,33]. Antibodies can be formed against exenatide in as many as 38% of treated patients. However in the vast majority these are low-titer with no clinical consequences[34]. The half-life of exenatide also has been modified using extension of the carboxy-terminus, conjugation to albumin, or containment within polymer microspheres, which have given rise to once daily and once weekly forms[20].

Efforts to extend the half-life of GLP-1 agonists also have included modifications of the native GLP-1 structure itself for resistance to DPP4 activity. Liraglutide (Novo Nordisk) was developed to include an attached C16 fatty and a Lys28Arg substitution allowing the molecule to bind albumin protecting it from DPP4 and renal clearance. It also has a slower absorption rate with a half-life of 12 hours after subcutaneous administration, resulting in once daily dosing (35). HbA1c levels and body weight were reduced in clinical trials. The most common side effect is nausea (~10%)[36,37,38,39]. Several other GLP-1 agonists have had varying success and have entered phase 3 clinical trials (albiglutide, dulaglutide, semaglutide, lixisenatide). In addition, combination therapies utilizing GLP-1 agonists and insulin are also currently in phase 3 clinical trials [iDegLira (combined insulin degludec and liraglutide); LixiLan (combined lixisenatide and insulin glargine)].

DPP4 inhibitors prolong endogenous GLP-1 concentrations that are typically observed after a meal and increase fasting levels of GLP-1. This results in the same type of augmentation of insulin and inhibition of glucagon secretion observed with GLP-1 agonists[20,40]. Several DPP4 inhibitors have been approved by the FDA as adjuvant treatment for diabetes, including alogliptin (Xanthine based compound), saxagliptin (substrate like inhibitor), and sitagliptin (non-substrate like inhibitor)[41,42,43]. However, DPP4 also is involved in suppressing tissue invasion/metastasis in certain cancers, including non-small cell carcinoma in the lung and colon cancer[44,45]. Both DPP4 and GLP-1-based therapies have been at the center of an academic debate [46,47,48,49] over the risk of pancreatitis and pancreatic cancer associated with incretin-based therapies. Reviews of current therapies by the European Medicines Agency and the Food and Drug Administration have not altered recommendations at this time[50,51]. There have been recent calls for efforts to investigate the possible risks by the American Diabetes Association and The Endocrine Society as of mid-2013[51,53].

Free fatty acids stimulate insulin secretion, a process that operates not only through the formation of long-chain CoA esters[54] that modulate beta cell ion channels and exocytosis, but also through the activation of islet GPCR signalling by lipids themselves [55,56,57]. One such receptor, GPR40 (free fatty acid receptor 1 or FFAR1), is expressed in pancreatic beta cells as well as in brain, omental adipocytes, and endocrine cells of GI mucosa. Activation by medium- or long-chained free fatty acids leads to insulin secretion in a glucose-dependent manner[20,58]. A loss of function mutation in the GPR40 gene is found in 0.75% of healthy subjects and is associated with obesity and impaired insulin secretion[59]. GPR40 is not likely to be involved in beta-cell lipotoxicity under high fat diet conditions but may be involved in the adaption of islets to insulin resistance[60,61,62]. Because of its intestinal expression and because of a lack of incretin responses in GPR40 knockout mice, GPR40 has been linked to incretin responses to free fatty acids[63]. A large number of GPR40 agonists are being developed. TAK-875 (fasiglifam, Takeda Pharmaceutical Company) was developed as an oral agent and was shown in rats to enhance glucose dependent insulin secretion and improve postprandial and fasting hyperglycemia [64]. In these studies there was a low risk of hypoglycaemia and no evidence of beta cell toxicity. In a human phase 2 clinical trial, TAK-875 monotherapy reduced HbA1c significantly compared to placebo without an increase in hypoglycaemic events, substantiating the utility in targeting FFAR1 for the treatment of type 2 diabetes [65]. However, a phase 3 clinical trial of TAK-875 was voluntarily terminated in December 2013 due to concerns related to liver safety [66].

The D2 dopamine receptor is also a GPCR. Bromocriptine (a sympatholytic) targets this receptor and was approved recently for the treatment of type 2 diabetes when given once daily within 2 hours of awakening [67]. It is thought that low hypothalamic dopamine levels and excessive sympathetic tone in the CNS alter the metabolic state so that it resembles the changes that occur in mammalian species that undergo hibernation. As in type 2 diabetics, these animals switch to a state of insulin resistance in muscle and liver along with accelerated hepatic glucose production and gluconeogenesis, hyperglycaemia, adipocyte insulin resistance, increased lipolysis, enhanced fat oxidation with increased plasma free fatty acids and triglycerides along with obesity [68,69,70,71]. Endogenous dopaminergic and serotonergic rhythms in the SCN and VMH are involved in the transition to this state and an insulin sensitive state [68]. A modified, oral form of bromocriptine (bromocriptine mesylate, Cycloset) is rapidly dissolved and absorbed within 30 min. Hepatic first pass metabolism is high (leaving 5-10% of ingested dose) with a biliary elimination half-life of 6 hours [72,73,74,75]. Phase 2 and phase 3 clinical trials have shown improvement in HbA1c, plasma triglycerides, and free fatty acid concentrations when given both as monotherapy and in combination with oral hypoglycemic agents [72,77,78].There is evidence from cardiovascular safety trials that Cycloset may improve major adverse cardiovascular outcomes (myocardial infarction, stroke, death) in type 2 diabetics by 40% [77].

A promising new therapeutic for the treatment of diabetes-associated microvascular complications currently in clinical trials is synthetic C-peptide or C-peptide conjugates [78]. C-peptide, or Connecting Peptide, is part of the insulin prohormone, and for many years was thought to be biologically inert and to have little physiological significance beyond its role in the proper folding of insulin. It is now known that C-peptide plays a protective role in the microvasculature [79,80], likely through an interaction with the previously orphaned GPCR, GPR146 [81]. In type 1 diabetic patients, higher levels of endogenous C-peptide correlated with a significant reduction in the incidence of retinopathy, neuropathy, and nephropathy [82]. Importantly, administration of exogenous C-peptide was shown to at least partially reverse microvascular dysfunction in diabetic humans with mild to undetectable side effects [80]. Cebix recently completed a phase 1/2 clinical trial evaluating Ersatta, a long-acting C-peptide agonist, in type 1 diabetic patients. The results of this study were favourable in terms of safety and improvements in neuropathy, and a phase 2b trial currently is underway [78].

Conclusion

GPCRs are abundantly expressed in the pancreatic islets and may play an important role in normal glucose homeostasis and microvascular function. Although many of the current therapies for diabetes and its complications target tyrosine kinase receptors (insulin) or ion channels (sulfonylureas), several GPCRs, including the GLP-1 receptor, D2 receptor, and the C-peptide receptor (GPR146), may provide novel targets for the treatment of this disease. At least 293 different GPCRs are expressed by pancreatic islets[83], and thus future studies may reveal even more targets for the development of GPCR-based therapeutics.

Conflict of interests

None declared.

Competing interests

None declared

References

1-Taylor R. Type 2 diabetes: etiology and reversibility. Diabetes Care. 2013 Apr;36(4):1047-1055.

2-Van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011 Jan;91(1):79-118.

3-Henriksen EJ, Diamond-Stanic MK, Marchionne EM. Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med. 2011 Sep 1;51(5):993-999.

4-Bowden DW, Cox AJ, Freedman BI, Hugenschmidt CE, Wagenknecht LE, Herrington D, Agarwal S, Register TD, Maldjian JA, Ng MC, Hsu FC, Langefeld CD, Williamson JD, Carr JJ. Review of the Diabetes Heart Study (DHS) family of studies: a comprehensively examined sample for genetic and epidemiological studies of type 2 diabetes and its complications. Rev Diabet Stud. 2010;7(3):188-201.

5-Williams C, Hill SJ. GPCR signaling: understanding the pathway to successful drug discovery. Methods Mol Biol. 2009;552:39-50.

6-Collins S, Lohse MJ, O’Dowd B, Caron MG, Lefkowitz RJ. Structure and regulation of G protein-coupled receptors: the beta 2-adrenergic receptor as a model. Vitam Horm. 1991;46:1-39.

7-Lefkowitz RJ. Seven transmembrane receptors: something old, something new. 2007;190:9-19.

8-Ribas C, Penela P, Murga C, Salcedo A, Garcia-Hoz C, Jurado-Pueyo M, Aymerich I, Mayor F Jr. The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling. Biochim Biophys Acta. 2007 Apr;1768(4):913-922.

9-Taylor SS, Zhang P, Steichen JM, Keshwani MM, Kornev AP. PKA: lessons learned after twenty years. Biochim Biophys Acta. 2013 Jul;1834(7):1271-8.

10-Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell. 1997,89:413-24.

11-Dulin NO, Niu J, Browning DD, Ye RD, Voyno-Yasenetskaya T. Cyclic AMP-independent activation of protein kinase A by vasoactive peptides. J Biol Chem. 2001 Jun 15;276(24):20827-30.

12-Vinciguerra M, Deschênes G, Hasler U, Mordasini D, Rousselot M, Doucet A, Vandewalle A, Martin PY, Féraille E. Intracellular Na+ controls cell surface

expression of Na,K-ATPase via a cAMP-independent PKA pathway in mammalian kidney collecting duct cells. Mol Biol Cell. 2003 Jul;14(7):2677-88.

13-Gambaryan S, Kobsar A, Rukoyatkina N, Herterich S, Geiger J, Smolenski A, Lohmann SM, Walter U. Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase A from an NFkappaB-IkappaB complex. J Biol Chem. 2010, 285:18352-63.

14-Cirino G, Severino B. Thrombin receptors and their antagonists: an update on

the patent literature. Expert Opin Ther Pat. 2010 Jul;20(7):875-84. Ye RD. Regulation of nuclear factor kappaB activation by G-protein-coupled

receptors. J Leukoc Biol. 2001 Dec;70(6):839-48.

15-Ye RD. Regulation of nuclear factor kappaB activation by G-protein-coupled receptors. J Leukoc Biol. 2001 Dec;70(6):839-48.

16-Chandrasekar B, Mummidi S, Perla RP, Bysani S, Dulin NO, Liu F, Melby PC.

Fractalkine (CX3CL1) stimulated by nuclear factor kappaB (NF-kappaB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway. Biochem J. 2003 Jul 15;373(Pt 2):547-58.

17-Bai D, Ueno L, Vogt PK. Akt-mediated regulation of NFkappaB and the

essentialness of NFkappaB for the oncogenicity of PI3K and Akt. Int J Cancer.

15;125(12):2863-70.

18-Niu J, Vaiskunaite R, Suzuki N, Kozasa T, Carr DW, Dulin N, Voyno-Yasenetskaya TA. Interaction of heterotrimeric G13 protein with an A-kinase-anchoring protein 110 (AKAP110) mediates cAMP-independent PKA activation. Curr Biol. 2001 Oct 30;11(21):1686-90.

19-Orland MJ. “Diabetes Mellitus and Related Disorders” in The Washington Manual of Medical Therapeutics. 29th ed. Carey CF, Lee HH, and Woeltje KF eds. Lippincott-Raven:Philadelphia pages 396-411.

20-Ahren B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nature Rev Drug Discovery. 2009;8:369.

21-Ahrén B. Glucagon-like peptide-1 (GLP1): a gut hormone of potential interest in the treatment of diabetes. Bioassays. 1998;20:642–651.

22-Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165.

23-Dunning BE, Foley J, Ahrén B. Alpha-cell function in health and disease: influence of GLP1. Diabetologia. 2005;48:1700–1713.

24-Heller RS, Kieffer TJ, Habener JF. Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas. Diabetes. 1997;46:785–791.

25-Tornehave D, Kristensen P, Rømer J, Knudsen LB, Heller RS. Expression of the GLP1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem. 2008 Sep;56(9):841-51.

26-Gutniak MK, Svartberg J, Hellström PM, Holst JJ, Adner N, Ahrén B. Antidiabetogenic effect of glucagon- like peptide-1 (7–36) amide in normal subjects and patients with diabetes mellitus. J Intern Med. 2001 Jul;250(1):81-7.

27-Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes. 1998;47:1663–1670.

28-Ahrén B. Exenatide: a novel treatment of type 2 diabetes. Therapy. 2005;2:207–222.

29-Ahrén B. GLP1-based therapy of type 2 diabetes. GLP1 mimetics and DPP-IV inhibitors. Curr Diabetes Rep. 2007;7:340–347.

30-Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004 Nov;27(11):2628-35.

31-DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005 May;28(5):1092-100.

32-Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005 May;28(5):1083-91.

33-Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Wintle ME, Maggs DG. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008 Jan;24(1):275-86.

34-Pratley RE, Gilbert M. Targeting incretins in type 2 diabetes: role of GLP1 receptor agonists and DPP-4 inhibitors. Rev Diabet Stud. 2008;5:73–94.

35-Madsen K, Knudsen LB, Agersoe H, Nielsen PF, Thøgersen H, Wilken M, Johansen NL. Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness. J Med Chem. 2007 Nov 29;50(24):6126-32.

36-Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, Hale PM, Zdravkovic M, Bode B; LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono):a randomized 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009 Feb 7;373(9662):473-81.

37-Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring M, Matthews DR; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, glimepiride, and placebo- all in combination with metformin in type 2 diabetes mellitus (LEAD-2 Met). Diabetes Care. 2009 Jan;32(1):84-90.

38-Marre M, Shaw J, Brändle M, Bebakar WM, Kamaruddin NA, Strand J, Zdravkovic M, Le Thi TD, Colagiuri S; LEAD-1 SU study group. Liraglutide, a once daily human GLP1 analog, added to a sulfonylurea (SU) offers significantly better glycemic control compared with rosiglitazone and SU: combination therapy in subjects with type 2 diabetes. Diabet Med. 2009 Mar;26(3):268-78.

39-Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, Zdravkovic M, Ravn GM, Simó R; Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study Group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009 Oct;52(10):2046-55.

40-Ahrén B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert Opin Emerg Drugs. 2008;13:593–607.

41-Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007 Sep;9(5):733-45.

42-Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naïve patients with type 2 diabetes.Diabetes Obes Metab. 2008 May;10(5):376-86.

43-Deacon CF. Drug profile: Alogliptin, a potent and selective dipeptidyl peptidase-IV inhibitor for the treatment of type 2 diabetes. Curr Opin Invest Drugs. 2008;9: 402–413.

44-Wesley UV, Tiwari S, Houghton AN. Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells. Int J Cancer. 2004 May 10;109(6):855-66.

45-Masur K, Schwartz F, Entschladen F, Niggemann B, Zaenker K. DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regulatory Peptides. 2006;137(3):147–55.

46-Butler PC, Elashoff M, Elashoff R, and Gale EAM. A Critical Analysis of the Cliical Use of Incretin-Based Therapies: Are the GLP-1 therapies safe? Diabetes Care. 2013;36:2118-2125.

47-Nauck MA. A Critical Analysis of the Clinical Use of Incretin-Based Therapies: The benefits by far outweight the potential risks. Diabetes Care. 2013;36:2126-2132.

48-Cohen D. Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed? Brittish Medical Journal. 2013;346:f3680.

49-Moses A. Novo Nordisk Replies to BMJ investigation on incretins and pancreatic damage. British Medical Journal. 2013;347:f4386.

50-European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes. EMA. European Medicines Agency Sciences Medicines Health. March 26, 2013. http:www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/03/news_detail_001753.jsp&,mid=WC0b01ac058004d5c1

51-Brooks M. FDA Sides with EMA on Incretin Diabetes Drugs. Medscape Medical News. August 1 2013. http:www.medscape.com/viewarticle/808830

52-American Diabetes Association Calls for Independent Review of Incretin Therapy. American Diabetes Association. June 10, 2013. http:finance.yahoo.com/news/american-diabetes-association-calls-independent-195409306.html

53-Society Joins Call for Review of Incretin-based Therapy for Diabetes Mellitus. The Endocrine Society. June 18, 2013. https:www.endocrine.org/~/media/endosociety/Files/Advocacy%20and%20Outreach/Position%20Statements/2013/Incretin%20statement%2018%20JUN%2013.pdf

54-Corkey BE, Deeney JT, Yaney GC, Tornheim K, Prentki M. The role of long-chain fatty acyl-CoA esters in cell signal transduction. J Nutr. 2000 Feb;130(2S Suppl):299S-304S.

55-Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B. A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun. 2003 Feb 7;301(2):406-10.

56-Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, Komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M. Free fatty acids regulate insulin secretion from pancreatic cells through GPR40. Nature. 2003 Mar 13;422(6928):173-6.

57-Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR Jr, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem. 2003 Mar 28;278(13):11303-11.

58-Gromada J. The free fatty acid receptor GPR40 generates excitement in pancreatic -cells. Endocrinology. 2008;147:672–673.

59-Vettor R, Granzotto M, De Stefani D, Trevellin E, Rossato M, Farina MG, Milan

G, Pilon C, Nigro A, Federspil G, Vigneri R, Vitiello L, Rizzuto R, Baratta R, Frittitta L. Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization. J Clin Endocrinol Metab. 2008 Sep;93(9):3541-50.

60-Kebede M, Alquier T, Latour MG, Semache M, Tremblay C, Poitout V. The fatty-acid receptor GPR40 plays a role in insulin secretion in vivo after high-fat feeding. Diabetes. 2008 Sep;57(9):2432-7.

61-Zhang Y, Xu M, Zhang S, Yan L, Yang C, Lu W, Li Y, Cheng H. The role of G protein-coupled receptor 40 in lipoapoptosis in mouse cell line NIT-1. J Mol Endocrinol. 2007 Jun;38(6):651-61.

62-Wu P, Yang L, Shen X. The relationship between GPR40 and lipotoxicity of the pancreatic beta cells as well as the effect of pioglitazone. Biochem Biophys Res Commun. 2010;403(1):36-39.

63-Edfalk S, Steneberg P, Edlund H. GPR40 is expressed in enteroendocrine cells and mediates FFA stimulation of incretin secretion. Diabetes. 2008 Sep;57(9):2280-7.

64-Tsuiihata Y, Ito R, Suzuki M, Harada A, Negoro N, Yasuma T, Momose Y and Takeuchi K. 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. The Journal of Pharmacology and Experimental Therapeutics. 2011;339:228-237.

65-Burant CF, Viswanathan P, Marcinak J, Cao C, Vakilynejad M, Xie B, and Leifke E. Tak-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. The Lancet. 2012;379 (9824):1403-1411.

66-Takeda Pharmacuetical Company. Takeda Announces Termination of Fasiflifam (TAK-875) Development. Press Release. December 27, 2013. www.takeda.com/news/2013/201311227_6117.html.

67-DeFronzo RA. Bromocriptine: A Sympatholytic, D2-dopamine Agonist for the Treatment of Type 2 Diabetes. Diabetes Care. 2011;34(4):789-794.

68-Cincotta AH. Hypothalamic role in the insulin resistance syndrome. In Insulin Resistance Syndrome. Hansen B, Shaffrir E, Eds. London, Taylor and Francis, 2002, p. 271–312.

69-Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “prog- ress”? Am J Hum Genet 1962;14:353–362.

70-DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173–194.

71-Reaven GM. Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes. 1988;37:1595–1607.

72-Cincotta AH, Meier AH, Cincotta Jr M. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin Investig Drugs. 1999;8:1683–1707.

73-Parkes D. Drug therapy: bromocriptine. N Engl J Med. 1979;301:873–878.

74-Maurer G, Schreier E, Delaborde S, Loosli HR, Nufer R, Shukla AP. Fate and disposition of bromocriptine in animals and man. I: structure elucidation of the metabolites. Eur J Drug Metab Pharmacokinet. 1982;7:281–292.

75-Maurer G, Schreier E, Delaborde S, Nufer R, Shukla AP. Fate and disposition of bromocriptine in animals and man. II: Absorption, elimination and metabolism. Eur J Drug Metab Pharmacokinet. 1983;8:51–62.

76-Pijl H, Ohashi S, Matsuda M, Miyazaki Y, Mahankali A, Kumar V, Pipek R, Iozzo P, Lancaster JL, Cincotta AH, DeFronzo RA. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care. 2000 Aug;23(8):1154-61.

77-Gaziano JM, Cincotta AH, O'Connor CM, Ezrokhi M, Rutty D, Ma ZJ, Scranton RE. Randomized clinical trial of quick- release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care. 2010 Jul;33(7):1503-8.

78-Cebix Press Release. Cebix Announces Positive Results of ERSATTA Phase 1/2 Trial in Peripheral Neuropathy. October 16, 2012. http:www.cebix.com/index.php/news/article/cebix-announces-positive-results-of-ersatta-phase-1-2-trial-in-peripheral-n.

79-Ido Y, Vindigni A, Chang K, Stramm L, Chance R, Heath WF, DiMarchi RD, Di Cera E, Williamson JR. Prevention of vascular and neural dysfunction in diabetic rats by C-peptide. Sciene. 1997;277:563-566.

80-Wahren J, Kallas A, Sima AAF. The clinical potential of C-peptide replacement in Type 1 diabetes. Diabetes. 2012;61:761-772.

81-Yosten GLC, Kolar GR, Redlinger LJ, Samson WK. Evidence for an interaction between proinsulin C-peptide and GPR146. J Endocrinol. 2013 Jul 11;218(2):B1-8.

82-Bo S, Gentile L, Castiglione A, Prandi V, Canil S, Ghigo E, Ciccone G. C-peptide and the risk for incident complications and mortality in type 2 diabetic patients: a retrospective cohort study after a 14-year follow-up. European Journal of Endocrinology. 2012;167(2):1730-1780.

83-Amisten S, Salehi A, Rorsman P, Jones PM, Persaud SJ. An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans. Pharmacol Ther. 2013 Sep;139(3):359-391.

    Licensee to OAPL (UK) 2014. Creative Commons Attribution License (CC-BY)

    Examples of GPCR-Based Therapeutics for the Treatment of Diabetes and its Complications

    Compound Name

    Trade Name(s)

    GPCR Targeted

    Clinical Utility

    Status

    References

    Exenatide

    Byetta, Bydureon

    GLP1R

    Incretin mimetic; enhances insulin release

    Currently Prescribed

    28-34

    Liraglutide

    Victoza

    GLP1R

    Incretin mimetic; enhances insulin release

    Currently Prescribed

    29; 36-39

    Alogliptin

    Nesina

    GLP1R (indirect)

    DPP4 inhibitor; enhances endogenous GLP-1 levels

    Currently Prescribed

    40, 43, 45

    Bromocriptine

    Cycloset

    D2R

    Dopamine agonist; reduces HbA1C and serum lipids

    Currently Prescribed

    72-77

    C-peptide

    Ersatta

    CpepR

    May reverse diabetic neuropathy

    Phase 2b Clinical Trials

    78-82

     

    Keywords