Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101966


Historical Background

In 1906, it was first identified that the pancreas could be stimulated by factors from the gut to aid in removal of nutrients, and porcine small intestinal extract was used to treat diabetic patients (Graaf et al. 2016). In 1928, it was demonstrated that injection of secretin extracted from the small intestinal mucosa displays a hypoglycemic effect that is mediated through the pancreas (Creutzfeldt 2005). In the 1960s, it was shown that orally administered glucose induces a much stronger insulin response than that induced by intravenously administered glucose, despite the similar resulting plasma glucose levels – this was termed the “incretin effect” (Creutzfeldt 2005; Graaf et al. 2016). Gastric inhibitory peptide (GIP) was the first incretin hormone to be discovered in 1975, which is produced by K cells of the small intestine (Creutzfeldt 2005). It was then observed in 1981 that antibodies against GIP did not abolish the incretin effect, which led to the discovery of glucagon-like peptide-1 (GLP-1) in the translational products of mRNAs isolated from pancreatic islets of anglerfish (Shields 1981; Graaf et al. 2016). Subsequently, it was shown that hamster and human preproglucagon cDNAs encode GLP-1 and -2, but only GLP-1 possessed the incretin activity (Graaf et al. 2016).


Promoting metabolic homeostasis in humans is essential to ensure that sufficient energy (in the form of adenosine triphosphate (ATP)) is provided to all biological processes (Voet and Voet 2011). After nutrient ingestion, pancreatic islet beta-cells produce insulin (Aronoff et al. 2004). Insulin promotes peripheral uptake of nutrients (carbohydrates, fats, and amino acids) from the bloodstream into various tissues such as skeletal muscle and fat (Aronoff et al. 2004; Voet and Voet 2011). Insulin secretion is a biphasic event: first phase insulin secretion involves islet beta-cells rapidly secreting already synthesized insulin during the first few minutes after these cells “sense” blood glucose concentrations of 5 mM or above, and second phase insulin secretion involves a prolonged response (lasting a few hours) whereby the islet beta-cells have to synthesize and secrete insulin; hence, this phase results in a steady secretion of insulin but there is a lower concentration of it in the blood compared to the first phase (Wang and Thurmond 2009; Voet and Voet 2011). Glucagon hormone, which is produced by pancreatic alpha-cells when blood glucose levels become too low, promotes gluconeogenesis in the liver to raise the blood glucose levels (Aronoff et al. 2004). Insulin and glucagon are pivotal for maintaining metabolic homeostasis – the activity of both hormones are reciprocally correlated in order to achieve normoglycemia (Aronoff et al. 2004; Voet and Voet 2011). However, it has been elucidated that other hormones are also crucial for metabolic homeostasis. The discovery of the incretin effect lead to the identification of two gut hormones possessing incretin activity: GLP-1 and GIP (Graaf et al. 2016). GLP-1 is a 30-amino acid long gastrointestinal incretin hormone, which is produced by enteroendocrine L-cells (located mainly in the distal ileum and colon) in response to postprandial nutrient loads (Holst 2007). It has been established that incretin hormones play a major role in metabolic homeostasis by augmenting insulin secretion from islet-beta cells: The general consensus in the literature is that the incretin effect accounts for 60–70% of insulin secretion after glucose ingestion (Salehi et al. 2012). GIP and GLP-1 account for approximately 60 and 40% of the incretin effect, respectively (Goldstein and Wieland 2007). Islet beta-cells can produce and secrete insulin without the presence of these hormones as long blood glucose levels are 5 mM or higher (Voet and Voet 2011; Salehi et al. 2012). GLP-1 is produced by alternative processing of the preproglucagon gene product (Graaf et al. 2016). The preproglucagon gene is located on chromosome 2 (2q36-q37) and spans approximately 9.4 kb consisting of six exons and five introns, and exons 2 to 5 encode the protein products with biological function: Glucagon is encoded in exon 3, and exons 4 and 5 encode GLP-1 and -2, respectively (Kim and Egan 2008). The main target for GLP-1 is the pancreatic islet cells but this hormone also modulates the activity of other organs (Holst 2007). The ability of GLP-1 to augment insulin production in response to postprandial nutrient loads is its best characterized and most-studied physiological effect, and is a source of interest from a clinical perspective given the role of GLP-1 analogues (liraglutide and exenatide) in treatment of type 2 diabetes (Holst 2007; Thompson and Kanamarlapudi 2013). GLP-1 exerts its actions by binding to its receptor (GLP-1R) on the surface of target cells (Thompson and Kanamarlapudi 2013; Graaf et al. 2016).

GLP-1 Synthesis, Composition, and Processing

The preproglucagon gene is transcribed to mRNA and then translated to form the protein product proglucagon, which is then cleaved in pancreatic alpha-cells, gut endocrine L-cells, and neurons in the caudal brainstem and hypothalamus (Graaf et al. 2016). The signal peptide of the preproglucagon gene product (180 amino acid residues) is cleaved to form proglucagon (160 amino acid residues) in all of these tissues (Graaf et al. 2016). In intestinal L-cells, proglucagon is posttranslationally processed by prohormone convertase 1/3 to produce GLP-1 (consisting of amino acid residues 72-108 of proglucagon), glicentin, oxyntomodulin, and GLP-2, which all have biological activity (Fig. 1) (Holst 2007; Thompson and Kanamarlapudi 2013). GLP-1 is also produced in a similar manner in the central nervous system. However, prohormone convertase 2 processes proglucagon in islet alpha-cells to produce glucagon, which consists of amino acid residues 33-61 of proglucagon (Holst 2007; Donath and Burcelin 2013).
GLP-1, Fig. 1

Proglucagon is processed differently in different tissues to form the desired products. Proglucagon undergoes alternative processing by prohormone convertase enzymes in islet alpha-cells and L-cells of the gut/neurons to produce the desired products. Only the biologically active products are shown and only GLP-1 activity is discussed in this review (this figure and information in its legend are adapted from Holst (2007), Donath and Burcelin (2013), Thompson and Kanamarlapudi (2013))

The glycine located at the C-terminal of GLP-1 is converted to an amide to increase its intracellular stability, forming GLP-1 (1-36 amide) (Holst 2007). Prior to secretion, the amino terminal is cleaved to produce GLP-1 with its C-terminal Arg amidated (7-36 amide) and GLP-1 without its C-terminal amidated (7-37): Approximately 80% of GLP-1 is released into the bloodstream as GLP-1 (7-36 amide), and the other 20% is released as GLP-1 (7-37) (Thompson and Kanamarlapudi 2013). Both GLP-1 (7-36 amide) and GLP-1 (7-37) have similar affinity for the GLP-1R and also display similar potency (Thompson and Kanamarlapudi 2013). However, there is evidence that GLP-1 (7-36 amide) is more stable in circulation (Graaf et al. 2016). Both forms of GLP-1 present in the bloodstream are approximately 50% homologous with glucagon (Brubaker and Drucker 2002).

GLP-1 Secretion, Levels, and Regulation

There is a directly proportional relationship between the levels of GLP-1 in the blood and levels of nutrients exposed to L-cells (Wang et al. 2015). Originally, GLP-1 secretion by L-cells was thought to be dependent on glucose; however, studies have demonstrated that GLP-1 secretion is greater after ingestion of a mixed meal (carbohydrates, fats, and proteins) in comparison to just glucose ingestion (Ahlkvist et al. 2012). This demonstrates that fats, proteins, and glucose interact synergistically to promote GLP-1 secretion. There is also evidence that fats and proteins can induce GLP-1 secretion in a glucose-independent manner (Wang et al. 2015). Food ingestion also increases transcription of the gene encoding GLP-1 in L-cells (Meloni et al. 2013). Fasting plasma levels of GLP-1 are approximately 5-15pM and postprandial levels rise to 40-60pM (Padidela et al. 2009; Thompson and Kanamarlapudi 2013). The GLP-1 response occurs within 15 min after food ingestion and peaks after approximately 30 min (Wang and Thurmond 2009; Dailey and Moran 2013; Wang et al. 2015). Why the GLP-1 response is so rapid remains currently elusive but it is thought that L-cells in the upper jejunum and the vagal nerve are likely involved (Holst 2007). However, the response is later than the “first phase” stimulation of insulin secretion suggesting that neuronal signals which generate insulin release do not influence GLP-1 levels (Holst 2007; Thompson and Kanamarlapudi 2013). After secretion, GLP-1 has a short half-life in the blood of just 1–2 min (Holst 2007). The main enzyme involved in GLP-1 degradation is dipeptidyl peptidase-4 (DPP-IV), which cleaves the first two N-terminal residues from GLP-1 (7-36 amide) and GLP-1 (7-37) to produce GLP-1 (9-36 amide) and GLP-1 (9-37), respectively (Holst 2007; Graaf et al. 2016). After exposing to DPP-IV, both forms of GLP-1 become either inactive or act as an antagonist for GLP-1R (Holst 2007). Exendin-4, which is found in the saliva of the Gila monster lizard, also acts as an agonist to the GLP-1R (Thompson and Kanamarlapudi 2013). Exenatide (a synthetic version of Exendin-4) and liraglutide (a DPP-IV resistant GLP-1) are currently in use as drugs for type 2 diabetes (Thompson and Kanamarlapudi 2013). Strikingly, only 15% of the active GLP-1 reaches the portal vein prior to the liver, as the inactivation via DPP-IV is so rapid (Holst 2007; Thompson and Kanamarlapudi 2013). Consequently, it has been postulated that approximately 85% of GLP-1 in circulation exists in the inactive forms (Thompson and Kanamarlapudi 2013). From a bioenergetics point of view, the GLP-1 response is wasteful in terms of ATP expenditure (ATP is required for GLP-1 synthesis) as most of the GLP-1 is inactivated before it reaches its target tissues (Voet and Voet 2011; Thompson and Kanamarlapudi 2013). It is unclear why the GLP-1 response is so inefficient, but recent evidence suggests that the inactive forms of GLP-1 have insulin-like actions on the heart, vasculature, and liver (Sharma et al. 2013). Therefore, it is possible that the inactive forms of GLP-1 may act via novel signaling pathways to promote these effects.

GLP-1 Targets and Effects

The actions of GLP-1 are primarily mediated through its receptor GLP-1R, which is a G-protein coupled receptor (GPCR) (Thompson and Kanamarlapudi 2013). GLP-1R is expressed in the pancreas (in islet alpha- and beta-cells), cardiovascular system, gastrointestinal tract (GIT), lung, kidney, and in the peripheral and central nervous system (Holst 2007; Graaf et al. 2016). In all of these tissue types, GLP-1 mediates its effect by binding to GLP-1R, but the signaling pathways are different as GLP-1R is coupled to a range of varying downstream signaling pathways in different tissues, each of which can impact on the physiologic response elicited by receptor activation (Holst 2007).
  1. 1.

    It is generally accepted that the main function of GLP-1 is to act as an incretin hormone and augment insulin secretion from islet beta-cells (Meloni et al. 2013). GLP-1 does not stimulate insulin secretion at low glucose levels; hence, the insulinotropic activity of GLP-1 is dependent on high levels of glucose in the blood (Graaf et al. 2016). GLP-1 also reduces blood glucose levels by indirectly inhibiting glucagon secretion from islet alpha-cells due to its insulinotropic activity, and GLP-1 also directly suppresses glucagon secretion via currently unknown mechanisms (Donath and Burcelin 2013). Figure 2 summarizes how GLP-1 binding to GLP-1R promotes the incretin effect.

  2. 2.

    In the GIT, GLP-1 decreases gastric motility and inhibits postprandial gastric acid secretion (Dailey and Moran 2013). GLP-1 also inhibits smooth muscle activity in the small intestine resulting in an overall reduced digestion of nutrients from the GIT, and additionally GLP-1 inhibits meal-induced pancreatic secretion (Holst 2007). The effects of GLP-1 on the GIT result in a less rapid uptake of nutrients into the bloodstream; this then results in a more steady influx of nutrients into the bloodstream preventing hyperglycemia and the need for an excessive and rapid insulin response (Holst 2007; Graaf et al. 2016). GLP-1 has also been shown to have a negative effect on appetite (Graaf et al. 2016). It is possible that GLP-1’s effect on appetite could be due to its negative regulation of gut motility; however, there is continuing emerging evidence that GLP-1 has direct effects on specific neurons in the hypothalamus (Dailey and Moran 2013). GLP-1 is expressed in neurons of the brainstem, and GLP-1R is present in the hypothalamic areas that control energy homeostasis and food intake, including the arcuate nucleus, paraventricular nucleus, and dorsomedial nucleus (Holst 2007; Graaf et al. 2016). Studies have shown that central injections of GLP-1 induce satiety even in the absence of food in the GIT and when gastric empting has been inhibited; thus, GLP-1 can induce satiety via its effects on neurons in the caudal brainstem (Holst 2007; Dailey and Moran 2013; Graaf et al. 2016). It seems reasonable to assume that GLP-1 does indeed reduce appetite in order to allow for the body to process already ingested nutrients and stop any possibility of hyperglycemia by ingesting further nutrients.

  3. 3.

    GLP-1R is expressed on multiple cell types in the cardiovascular system such as vascular smooth muscle, cardiomyocytes, endocardium, and coronary endothelium/smooth muscle in humans (Graaf et al. 2016). Intravenous administration of GLP-1 in animal models has had a variety of beneficial effects on the cardiovascular system: improved left ventricular contractility, increased functional recovery and cardiomyocyte viability, reduced myocardial infarction, reduced atherosclerotic lesions, and decreased hypertension (Holst 2007; Graaf et al. 2016). In humans, studies of recombinant native GLP-1 have demonstrated multiple cardiovascular benefits such as reduced arrhythmias, improved left ventricular function, and improved endothelial function, in both diabetic and non-diabetic subjects (Graaf et al. 2016). Multiple studies on animal models have revealed that GLP-1 infusion has increased heart rate, blood pressure, and glucose uptake by the heart (Holst 2007; Graaf et al. 2016). This suggests that GLP-1 has direct effects on the heart.

  4. 4.

    Studies have demonstrated that GLP-1 also plays a role in the immune system. GLP-1R mRNA has been discovered in multiple immune cell types in mice: macrophages, Treg cells, thymocytes, splenocytes, bone marrow-derived cells, natural killer cells, etc. (Graaf et al. 2016). When GLP-1 analogues were administered to patients with psoriasis this led to a reduced psoriasis area and decreased cytokine secretion from natural killer cells (Graaf et al. 2016). High-fat diet-fed mice treated with exendin-4 had decreased mRNA levels of certain pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) (Graaf et al. 2016). When pancreatic islets were transplanted into nonobese diabetic mice from a type 1 diabetic animal model, GLP-1 administration boosted the number of lymphocytes secreting transforming growth factor-beta 1 (TGF-β1) and decreased the number of interferon (IFN)-γ secreting lymphocytes, and these mice also had a delayed onset of diabetes (Graaf et al. 2016). From these observations, it seems that GLP-1 likely has a negative regulatory role in the immune system.

  5. 5.

    A study in 2004 demonstrated that GLP-1 modulates kidney function: GLP-1 infusion into healthy and obese subjects enhanced sodium excretion, urinary secretion, and glomerular filtration rate (Graaf et al. 2016). Rats treated with exendin-4 displayed improved renal function as well as reduced inflammation, fibrosis, and proteinuria in the kidney (Graaf et al. 2016). These observations imply that GLP-1 enhances kidney function and has a protective effect on the kidney.

  6. 6.

    GLP-1 has also been reported to have an effect on the nervous system. GLP-1 or exendin-4 infusion into the lateral ventricles of mice decreased endogenous levels of amyloid beta protein (a protein associated with the pathogenesis of Alzheimer’s disease), and additionally, infusion of GLP-1 and exendin-4 into rat hippocampus neurons prevented amyloid beta protein-induced cell death (Graaf et al. 2016). Infusion of GLP-1 into intracerebroventricular tissue resulted in enhanced synaptic plasticity in the hippocampus and also completely reversed impairment in long-term potentiation caused by subsequent injection of amyloid beta protein (Holst 2007; Graaf et al. 2016). In Parkinson’s disease, nigrostriatal neurons (GLP-1R is present on these neurons) are lost (Graaf et al. 2016). This implies that dysfunction of this receptor may play a role in the pathogenesis of Parkinson’s disease, or that there could be future therapeutic options involving modulation of this receptor to delay or prevent the onset of the disease. GLP-1 or exendin-4 infusion into primary neurons from rat cerebral cortical tissues supported cell viability during hypoxic injury, and exendin-4 has also protected against apoptosis and maintained viability in NSC19 neuronal cells when they have been undergoing H2O2-induced oxidative stress (Graaf et al. 2016). From these observations it seems that GLP-1 has neuroprotective and neurotropic effects.

  7. 7.

    Given that GLP-1 activity is responsible for much of the postprandial insulin released (Holst 2007; Thompson and Kanamarlapudi 2013; Graaf et al. 2016), it can be argued that this hormone indirectly effects other tissues such as skeletal muscle, adipose tissue, and the liver through the insulin secretion it induces – insulin can be thought of as the “second messenger” of GLP-1. Insulin induces increased glucose uptake and storage into adipose tissue, skeletal muscle, and cardiac muscle by inducing translocation of GLUT4 to the cell membrane which promotes glucose uptake from circulation (Voet and Voet 2011; Thompson and Kanamarlapudi 2013). Insulin also promotes glycogen synthesis in the liver and inhibits gluconeogenesis, as well as promoting fat storage in adipocytes by promoting fat uptake into these cells from circulation (Voet and Voet 2011; Thompson and Kanamarlapudi 2013). Interestingly, there is continuing emerging evidence that GLP-1 has direct effects on the liver, adipose tissue, and skeletal muscle despite the absence of GLP-1R on these tissues (Holst 2007; Graaf et al. 2016). Experiments on rat hepatocytes have shown that GLP-1 can indeed bind to these cells’ membranes, and this has resulted in enhanced inhibition of gluconeogenesis and promotion of glycogen synthesis after insulin release (Graaf et al. 2016). GLP-1 has also been shown to exert insulin-like effects on skeletal muscle tissue by promoting glycogen synthesis and inhibiting glycogen phosphorylase activity in strips of human skeletal muscle – similar findings were obtained when incubating L6 myotubes with GLP-1, which resulted in enhanced insulin-stimulated glycogen synthesis (Holst 2007). There is evidence that GLP-1 acts synergistically with insulin on adipocytes, as increased basal and acute insulin-stimulated glucose uptake was observed in fully differentiated 3T3-L1 adipocytes upon administration of GLP-1 and exendin-4 (Holst 2007; Voet and Voet 2011; Graaf et al. 2016). Contradictory to these observations, several studies have failed to provide any evidence that GLP-1 enhances insulin sensitivity in humans (Holst 2007). Hence, it is currently unclear whether or not GLP-1 enhances the insulin effect on adipocytes, liver, and skeletal muscle. If GLP-1 does indeed augment the effect of insulin on these tissues then it must do so by a currently unidentified receptor.

  8. 8.
    The effect of GLP-1 on the lung is not well understood but is an area of ongoing research (Holst 2007; Graaf et al. 2016). However, GLP-1 has been shown to enhance macromolecule secretion from neuroendocrine cells in the lungs (Holst 2007). Figure 3 summarizes GLP-1’s targets and effects.
    GLP-1, Fig. 2

    A summary of the processes resulting in insulin secretion in islet beta-cells. Glucose transporter 2 (GLUT2) is an insulin-insensitive glucose transporter which allows glucose to enter islet beta-cells. When glucose concentration in circulation is 5 mM or higher, glucokinase initiates glucose catabolism. This leads to an increase in the cell’s ATP/ADP ratio which leads to closure of ATP-sensitive potassium channels, causing membrane depolarization (due to potassium becoming sequestered in the cell) and subsequent calcium influx. The resulting calcium influx then triggers insulin secretion. The binding of GLP-1 to GLP-1R enhances glucose-stimulated insulin secretion by initiating cAMP production by adenylyl cyclase which, in turn, activates protein kinase A (PKA) and exchanges protein directly activated by cAMP (Epac). PKA and Epac further induce potassium channel closure which indirectly assists with extracellular calcium influx, and Epac also promotes release of calcium from the endoplasmic reticulum. There is also evidence that PKA increases the permeability of calcium channels to allow for a faster influx of calcium. The now raised calcium levels further promote exocytosis of insulin vesicles. GLP-1R activation also induces transcription of the preproinsulin, glucokinase, and GLUT2 genes allowing for further insulin production, glucose catabolism, and glucose uptake, respectively, via activation of the pancreatic duodenal homeobox-1 (PDX-1) transcription factor and its translocation to the nucleus. PDX-1 activation also induces transcription of genes involved in proliferation, neogenesis, and apoptotic resistance. In addition, the lipolytic actions of GLP-1R activation are thought to provide the mitochondria with more metabolic fuel to further raise the ATP/ADP ratio, which is needed for both phases of insulin secretion (this figure and information in its legend are adapted from: Brissova et al. (2002); Holst (2007); Wang and Thurmond (2009); Voet and Voet (2011); Meloni et al. (2013); Graaf et al. (2016))

    GLP-1, Fig. 3

    A summary of the effects that GLP-1 has on various organs after it has been released from the L-cells in the gut in response to nutrient ingestion. Organs highlighted in blue have not been shown to express GLP-1R, but GLP-1 has been shown to have insulin-like effects on these tissues in experimental settings – it is however correct to state that GLP-1 does have indirect action on these organs in humans as it is an incretin hormone. GLP-1R mRNA has been shown to be expressed in immune cells, and GLP-1 modulates immune system (highlighted in red) activity in experimental settings (this figure and information in its legend are adapted from: Holst (2007); Donath and Burcelin (2013); Meloni et al. (2013); Thompson and Kanamarlapudi (2013); Graaf et al. (2016))


GLP-1 Analogues and Diabetes

The incretin effect is greatly diminished in individuals with type 2 diabetes – GLP-1 and GIP account for <20% of the insulin release after glucose ingestion in patients (Holst 2007). Whether or not GLP-1 levels are reduced in type 2 diabetes has been a matter of debate (Meier and Nauck 2010; Thompson and Kanamarlapudi 2013). The current consensus in the literature is that GLP-1 levels are normal in type 2 diabetic patients and its action is not severely impaired, but the action of GIP is (Holst 2007; Meier and Nauck 2010; Thompson and Kanamarlapudi 2013). Administration of GLP-1 analogues (exenatide and liraglutide) to type 2 diabetic patients improves glycemic control by augmenting insulin secretion and dampening glucagon secretion, as well as delaying gastric emptying (Holst 2007; Graaf et al. 2016). Exenatide and liraglutide mimic endogenous GLP-1 activity by binding to GLP-1R on various tissues, but these analogues are resistant to DPP-IV degradation (Graaf et al. 2016). Exenatide has a half-life of 3.4–4 h, and liraglutide has a half-life of 11–13 h; hence, these GLP-1 analogues vastly prolong the GLP-1 response promoting normoglycemia in type 2 diabetic patients during fasting and after nutrient ingestion (Thompson and Kanamarlapudi 2013). In addition, these analogues also induce weight loss and reduce daily insulin requirements in type 2 diabetic patients (Graaf et al. 2016). Adverse effects have been reported with the use of GLP-1 analogues, and the most common are dyspepsia and nausea, which usually subside after continuous administration (Thompson and Kanamarlapudi 2013).


This review has discussed the discovery, synthesis, regulation, targets, and effects of GLP-1. GLP-1 is secreted by L-cells in the GIT after nutrient ingestion and is produced by alternative processing of proglucagon (Wang et al. 2015). A variety of tissues express GLP-1R, and the binding of GLP-1 to its receptor GLP-1R induces the desired biological response (Graaf et al. 2016). GLP-1 has a short half-life in circulation of 1–2 min as it is degraded by DPP-IV enzymes (Holst 2007). GLP-1 plays a pivotal role in metabolic homeostasis by: augmenting insulin secretion from islet beta-cells, inhibiting glucagon secretion from islet alpha-cells, and delaying gastric emptying (Holst 2007; Meloni et al. 2013; Graaf et al. 2016). The DPP-IV resistant GLP-1 analogues are currently used to treat type 2 diabetes by promoting normoglycemia. A better understanding of the interaction of GLP-1 and GLP-1 analogues with GLP-1R and the subsequent intracellular effects are an area of ongoing research, which aims to produce more efficacious drugs to treat type 2 diabetes and obesity (Holst 2007; Graaf et al. 2016). Studies have demonstrated that GLP-1 has beneficial effects on the nervous, renal, and cardiovascular systems which implies that future research examining GLP-1 could lead to new therapeutic options to treat disorders of all these systems (Graaf et al. 2016).


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Life Science 1, School of MedicineSwansea UniversitySwanseaUK