InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Endocrinology and Metabolism » "Treatment of Type 2 Diabetes", book edited by Colleen Croniger, ISBN 978-953-51-2032-2, Published: April 1, 2015 under CC BY 3.0 license. © The Author(s).

Chapter 11

Incretin System in the Pathogenesis of Type 2 Diabetes and the Role of Incretin Based Therapies in the Management of Type 2 Diabetes

By Ayse Nur Torun and Derun Taner Ertugrul
DOI: 10.5772/59241

Article top


Post-translational processing of proglucagon peptide in pancreas, intestine and brain (GRPP: Glicentin related polypeptide, IP-1: intervening peptide 1).
Figure 1. Post-translational processing of proglucagon peptide in pancreas, intestine and brain (GRPP: Glicentin related polypeptide, IP-1: intervening peptide 1).
The wnt pathway and the role of GLP-1 on wnt pathway (APC:adenomatosis polyposis coli, CK-1: casein kinase 1, pERK: phosphorylated extracellular signal-regulated kinase, GSK-3β: glycogene synthase kinase 3β, β-cat:beta catenin, TCF-7: T cell like factor 7) (A and B: Inactive wnt pathway, C: Activation of wnt pathway by a wnt ligand, D: Activation of wnt pathway by GLP-1).
Figure 2. The wnt pathway and the role of GLP-1 on wnt pathway (APC:adenomatosis polyposis coli, CK-1: casein kinase 1, pERK: phosphorylated extracellular signal-regulated kinase, GSK-3β: glycogene synthase kinase 3β, β-cat:beta catenin, TCF-7: T cell like factor 7) (A and B: Inactive wnt pathway, C: Activation of wnt pathway by a wnt ligand, D: Activation of wnt pathway by GLP-1).

Incretin System in the Pathogenesis of Type 2 Diabetes and the Role of Incretin Based Therapies in the Management of Type 2 Diabetes

Ayse Nur Torun1 and Derun Taner Ertugrul2

1. Introduction

Discovery of incretin hormones and their role on glucose metabolism and pathogenesis of type 2 diabetes mellitus (T2 DM) are current interests of diabetology. Incretin hormones are secreted from intestinal endocrine cells in response to food ingestion and potentiate pancreatic insulin secretion when compared with iv glucose administration. Since malfunction of incretin hormones has been found to have role in T2 DM pathogenesis, incretin based therapies have been developed. Incretin effect, incretine hormones, functions, their role in pathogenesis of T2 DM and management of T2 DM with incretin-based drugs are discussed in this chapter.

2. Incretin effect, incretin hormones, secretion and functions

2.1. The incretin effect

Pancreas secrete insulin in response to the food content in the gastrointestinal lumen. Endocrine pancreas senses food ingestion via incretin hormones, nerve inputs and substrates to secrete insulin. This chain of secretion which starts with food ingestion and result with insulin secretion by endocrine pancreas is called enteroinsulinar axis [1, 2]. The first definition of incretin effect depend on the fact that, much more insulin secretion is induced by oral glucose than with iv glucose administration. So two-to three fold augmented insulin response to oral glucose compared with iv glucose is known as the incretin effect [3].

A duodenal exctract has been found to reduce glucosuria first in early 20th century before the discovery of this phenomenon. The elements of the incretin effect were recognised much more before their insulinotropic effects. Glucagon like insulinotropic peptide (GIP) is the first, which was discovered in 1973 by its inhibitory effect on gastric acid secretion and insulinotropic effect was defined later. This discovery was followed by the definiton of another intestinal peptide called glucagon like peptide 1 (GLP-1) ten years later. Discovery of incretin system, and its pathogenetic role in T2 DM caused an important evolution in pathogenesis and management of diabetes. This discovery pointed the role of gastrointestinal system and derived peptides on insulin secretion and glucose metabolism, which has not been taken into account for a very long time.

Postprandial rate of insulin secretion is assumed to be solely affected by the stimulatory effect of incretin hormones, and the role of gastrointestinal motility seems not to be accounted. Passage rate of the ingested foods through the gastrointestinal tract directly affects the secretion rate, secretion amount and the type of incretin hormone [4-6]. These mentioned gastrointestinal motility dependent events play an important role on postprandial glucose homeostasis. Effect of gastrointestinal motor function on glucose metabolism, pathogenesis of diabetes and glycemic regulation still need to be further evaluated.

2.2. Incretin hormones

There are two incretin hormones known to function on postprandial insulin secretion, which called GIP and GLP-1. Their malfunction and malsecretion have been shown to have role in the pathogenesis of T2 DM.

GIP is a large peptide hormone which is processed from a larger prohormone. Expression of GIP is widely distributed in the body, but the functions are not well understood at these locations. GIP is secreted from enteroendocrine, so called K cells, which predominantly located in the proximal duodenal mucosa but may be seen anywhere in the entire intestinal mucosa [7].

The other incretine hormone GLP-1 is derived from proglucagon peptide. Proglucagon gene is dominantly expressed in pancreatic alpha cells, brain stem and distal intestinal mucosal endocrine, so called L cells [8]. Posttranslational processing of proglucagon peptide differ between pancreatic alpha, brain and intestinal cells, resulting with different endproducts [9-10]. Proglucagon peptide contains two proglucagon peptides named glicentin and major proglucagon fragment. Pancreas contains these two proglucagon peptides in one molecule and secrete glucagon along with major proglukagon fragment. Pancreas processes glicentin to glicentin related pancreatic polypeptide (GRPP), glucagon, and intervening peptide 1 (IP-1), while major proglucagon fragment is not further processed in pancreas. Intestinal L cells secrete these two glucagon like peptide seperately. Unlike alpha cells, intestinal cells have the ability to process major proglucagon fragment to GLP-1, GLP-2 and IP-2. Glicentin is not cleaved or partly cleaved into GRPP and oxyntomodulin in the intestinal cells [Figure 1].


Figure 1.

Post-translational processing of proglucagon peptide in pancreas, intestine and brain (GRPP: Glicentin related polypeptide, IP-1: intervening peptide 1).

Mechanism of organ spesific posttranslational progulcagon processing is not fully determined. Several factors have been defined to have role in organ spesific processing. Transcription factor named pax6 and the other novel regulator is β-catenin, which is the major effector in Wnt signalisation system are among these regulators. T cell factor 4 (TCF-4 or known as TCF7L2) has been discovered to mediate the Wnt pathway, and shown to induce proglucagon gene expression to produce GLP-1 in the intestinal endocrine cells, but not in alpha cells [11, 12]. Later a TCF-4 gene polymorphism has been found to be involved in susceptibity to T2 DM. This is an important evidence which proved a link between disrupted incretin effect and development of T2 DM.

Active forms of GLP-1 are GLP-1 (7-36) and GLP-1 (7-37). Lower than %25 of total amount of active form secretion leaves intestine, then 40-50% of this degraded in the liver. In conclusion a very low amount of active GLP-1 reaches into the systemic circulation [13, 14]. GLP-1 (7-36) is cleaved by dipeptidylpeptidase 4 (DPP-4) to GLP-1 (9-36). This enzyme is highly expressed in the brush border of the enterocytes and also in the endothelial cells of the enteric vasculature [15]. Inactive GLP-1 (9-36) and active GLP-1 (7-36) are also degraded by neutral endopeptidase 24.11 (NEP 24,11) to form another inactive form named GLP-1 (28-36) [16]. Although GLP-1 (9-36) and GLP-1 (28-36) are known as inactive forms, it has been shown that they may be as beneficial as their active counterparts on glucose metabolism [17, 18]. Active GLP-1 and its metabolites are cleared from kidneys [19].

Both incretin hormones has been shown to be important in food induced insulin secretion but their potency and molar secretion amounts differ. GIP is secreted into the circulation 10-fold higher amount than GLP-1, but the potency of GLP-1 exceeds GIP [20].

2.3. Incretin hormone secretion and regulation of secretion

Both incretin hormones are secreted from gastrointestinal endocrine cells response to food ingestion. Although it is very low in amount, incretins are also has been shown to secreted during fasting [21]. Proximal intestinal cells secrete GIP, while GLP-1 is secreted from distal ileal and colonic L cells. It is the amount of ingested foods and the gastric emptying rate which effect the type of incretin hormone secreted [22, 23]. For example small amounts of food and a rapid gastric emptying induce GIP secretion, while slow gastric emptying and large complex food portions induce GLP-1 secretion. The exact mechanism of how food components induce the selective secretion of incretin hormones are still not clear. Elements of glucose transport system, such as sodium glucose transporter 1 (SGLT-1) and G protein coupled long chain fatty acid receptors on L cells has been shown to mediate the pathways which induce enteric endocrine cells to secrete incretin hormones in a selective manner [24, 25]. In conclusion incretin hormone levels are very low during fasting state, they are secreted in response to ingested glucose and lipids. Food ingestion is the trigger which starts enteroinsulinar axis result with insulin secretion from pancreatic β-cells. Although neuronal pathways modulate insulin secretion, neuronal pathways do not have role in the induction of enteroinsulinar axis, since GLP-1 does not increase during cephalic phase of insulin secretion [26].

2.4. Functions of incretin hormones

The incretin GIP shows its actions via a G protein coupled membrane receptor which belongs to the secretin-glucagon receptor family [27, 28]. The other incretin GLP-1 also shows its effects on target cells via a G protein coupled GLP-1 receptor (GLP-1R), which is widely expressed in the body unlike limited secretion sites of GLP-1 [29]. Only one type GLP-1R has been defined in the body, and the organ spesific effects of GLP-1 is believed to be determined by the difference in the glycosilation of the receptor. Wide distribution of the receptor such as endocrine pancreas, brain, heart, gastrointestinal system and kidney, is responsible for the extrapancreatic and extraintestinal effects of the peptide.

Because GIP has been reported to be nearly not affected in diabetic patients, and there is a clear evidence of diminished GLP-1 secretion in T2 DM, this chapter will mention GLP-1 as a representative of incretine hormones [30, 31].

  1. Effects of GLP-1 on β-cells:

    It has been shown that GLP-1 has insulinomimetic, insulinotropic and insulinotrophic effects, which mean insulin-like, insulin secretory and regenerative and proliferative effects respectively.

    Insulin-like effect of GLP-1 has been shown in several studies, in which GLP-1 inhbibited hepatic glucose output [32, 33]. The mechanisms of inhibition of hepatic glucose output and involving receptors need to be clarified, since hepatocytes do not express GLP-1R.

    Insulin secretion is potentiated by GLP-1 only in the presence of glucose. This effect starts with the interaction between the GLP-1 and its G protein coupled membrane receptor. GLP-1 induces insulin secretion only in the presence of glucose in the β-cell [34]. GLP-1 and glucose both increase intracellular cAMP levels sinergistically, then cAMP induces protein kinase A (PKA) and cAMP regulated guanine nucleotide exchange factor II (cAMP-GEF II), also known as Epac2. These two system induce β-cells to secrete insulin by several mechanisms. Closure of ATP sensitive potassium channel and activation of calcium channels both cause depolarisation of β-cell, and then insulin secretion occurs. Both calcium derived from intracellular stores and extracellular space contribute in increase in intracellular calcium levels. Increase in intracellular calcium further stimulate insulin secretion via granule exocytosis. The latter calcium dependent insulin secretion may contribute to >70 % of overall GLP-1 induced insulin secretion. Induction of insulin secretion is not the only effect of GLP-1 on β-cells. Insulin gene promoter region which is mediated with PKA and possibly mitogen activated protein (MAP) kinase pathway are also modulated by GLP-1 [35]. Pancreatic duodenal homeobox-1 (PDX-1), which is a key regulator of developing pancreas, and essential for β-cell growth and insulin gene transcription in adulthood, has been shown to be regulated by GLP-1 [36]. Intracellular glucose concentration depends on the function of glucose transporter system, predominantly GLUT-2, and β-cells sense the presence of high glucose levels by the action of the enzyme glucokinase. These two effectors modulate insulin secretion and GLP-1 upregulates the transcription of glucose transporter and glucokinase genes [37].

    Research on carcinogenesis and embryogenesis revealed an important intracellular signaling pathway named wnt. Insulinotropic, pancreatic and extrapanceratic insulinomimetic effects of GLP-1 and possibly its metabolites, has shown to be mediated by the activation of wnt pathway. Role of GLP-1 metabolites and GLP-1R in the induction of wnt pathway are not clear [38]. The pathway starts with a wnt ligand and LRP5/6-frizzled receptor complex interaction. The cytosolic effector of pathway is β-catenin (β-cat) and is tightly regulated by a phophorylation-destruction complex. This complex is formed by glycogene synthase kinase 3β (GSK-3β), casein kinase 1 (CK-1), axin/conductin, adenomatosis poliposis coli (APC), and phosphorylated extracellular signal-regulated kinase (pERK) [Figure 2]. When the receptor complex is stimulated by a wnt ligand, phosphorylation complex which stimulate the degredation of β-cat by phosphorylation is disrupted. So β-cat escapes from phosphorylation and remains free. Free β-cat then enter to the nucleus and make complex with nuclear coactivator transcription factor named TCF-7. This β-cat-TCF-7 complex induce the target gene expression. Effector β-cat is degraded due to phosphorylation when the receptor is not stimulated. TCF-7 remain free when β-cat does not reach into the nucleus and free TCF-7 regulates the repression of target genes. The most attractive function of GLP-1 is its insulinotrophic effect, which means a regenerative effect on β-cells and progenitor cells of pancreas [39]. Regeneration of β-cells is maintained by stimulation of β-cell proliferation and differentiation of ductal epithelial progenitor cells into β-cells by GLP-1 [40-44]. GLP-1 increases free β-cat in β-cells, which then induce wnt pathway to show its insulinotrophic effects and decreasing glucotoxicity on β-cells. Anti-apoptotic effect of GLP-1 on β-cells has been currently defined and may be a promising cure for diabetes [45]. Oxidative stress, which play role in β-cell death is another possible target of GLP-1. Thioredoxin (TRX), the thiol oxidoreductase is an important intracellular anti-oxidant. The function of TRX is downregulated by a binding protein, called TRX binding protein-2 (TBP-2). This binding protein has been shown to induce β-cell apoptosis, by increasing intracellular oxidative stress. Intracellular levels of TBP-2 closely correlate with blood glucose level [46, 47]. Several studies have found that GLP-1 decreases TBP-2 levels, which in turn increases intracellular TRX and decreases oxidative stress, and further β-cell damage [47, 48].


Figure 2.

The wnt pathway and the role of GLP-1 on wnt pathway (APC:adenomatosis polyposis coli, CK-1: casein kinase 1, pERK: phosphorylated extracellular signal-regulated kinase, GSK-3β: glycogene synthase kinase 3β, β-cat:beta catenin, TCF-7: T cell like factor 7) (A and B: Inactive wnt pathway, C: Activation of wnt pathway by a wnt ligand, D: Activation of wnt pathway by GLP-1).

  1. Effects of GLP-1 on alpha cells:

    Glucagon plays an important role in pathogenesis of T2 DM. Glucagon hypersecretion has been shown during both fasting and postprandial states in patients with diabetes [49]. GLP-1 decrease glucagon secretion. The exact mechanism of this inhibition is not yet elucidated, but the most possible mechanism is the induction of pancreatic somatostatin secretion, which inhibit the glucagon secretion by paracrine manner [50, 51].

  2. Effects of GLP-1 on gastrointestinal system:

    Gastrointestinal system has a central role in nutrient metabolism with its absorption and endocrine functions. GLP-1 inhibits gastrointestinal system motility, gastrin induced gastric acid and exocrine pancreatic secretions, which lead to a physiological malabsorption state [52, 53]. This malabsorbtive state contributes to alleviation of postprandial glucose excursions in diabetic patients.

  3. Effects of GLP-1 on central nervous system and satiety:

    Low levels of GLP-1 in the systemic circulation may not reach to the central nervous system, but it has been shown that GLP-1 mediated vagal stimulation may play role in decreased gastrointestinal motility. The effect of GLP-1 on vagal afferent sensorial neurons may be a local effect, which in turn these afferent neurons transmit the inputs to solitary tract nucleus, then inhibit the gastrointestinal motility [54, 55]. GLP-1 decreases food intake by inducing satiety. Hypotalamic satiety centers, predominantly arcuate nucleus has been shown to express GLP-1 receptors. But the exact mechanism of how peripheral GLP-1 stimulate these central receptors is not yet elucidated.

  4. Pleitropic effects of GLP-1

    Nontraditional (pleitropic) effects of GLP-1 and its metabolites is an evolving area of research. Wide expression of GLP-1R mediate the widespread action of the peptide. Insulin like effects of GLP-1 has been shown in heart and vasculature. Since cardiovascular diseases are the major contributor of mortality and morbidity in patients with T2 DM, scientific concerns about cardiovascular effects of GLP-1 and based therapies are growing. Preclinical and clinical studies revealed several cardioprotective effects of GLP-1. There are two possible mechanism of action of GLP-1 on cardivascular system, one via GLP-1R, and the other one is receptor-independent [56]. Preliminary cinical studies show that GLP-1 decreases post-ischemic left ventricular dysfunction in patients with coronary heart disease [57, 58].

    Invitro studies revealed that GLP-1 improves endothelial dysfunction via decreasing TNF-α, PAI-1 and cellular adhesion molecules [59]. But these observations need to be suggested by clinical studies.

    A study with an insulin resistant patient population showed that GLP-1 increases renal sodium and fluid excretion, which is oppose to the mechanism of hypertension in T2 DM [60]. This finding raise the possible blood pressure lowering and renoprotective effect of GLP-1 and based thearpies. Improved endothelial function and anti-oxidant effects of GLP-1 may be another contributory effect in their renoprotective action.

    Favorable effects on lipids is another important metabolic action of GLP-1. Preliminary studies reveal that GLP-1 decreases triglyceride, apo B-48 and cholesterol levels [61].

    GLP-1 is proposed to be a new therapeutic option for neurodegenerative diseases with its neuroprotective effects which has been shown in animal studies [62].

3. Contribution of incretin system in the pathogenesis of diabetes

Diabetes is the state of compromised insulin secretion which resulted with hyperglycemia. Incretin effect is reduced or almost absent in T2 DM [63]. Although the secretion of GIP is nearly normal, its insulinotropic effect has been shown to be lost in T2 DM [27]. Secretion of GLP-1 is decreased in contrast to GIP, but its favorable effects on endocrine pancreas and extrapanceratic sites are preserved in T2 DM [20, 64]. In conclusion, detoriation of both the effect and secretion of incretin hormones are involved in the pathogenesis of T2 DM. It is not clear wheter the detoriation of incretin effect is a primary defect in the pathogenesis of diabetes or not. Studies suggest that incretin hormone detoriation is a secondary defect during progression of diabetes. Another important fact is the restoration of insulin secretion with GLP-1 replacement is possible and improve hyperglycemia [65, 66].

There are several mechanisms of action of GLP-1 in T2 DM. The first one is the augmentation of glucose induced insulin secretion, resulting with improvement in hyperglycemia. Near-normal improvement in β-cell response to glucose, improvement in the first phase insulin secretion and completely normalisation of second phase insulin secretion by GLP-1 has been exactly defined [67]. Although the induction of insulin secretion is lost during chronic GLP-1 administration, glucose lowering action with maintained insulin levels tend do persist. Reduction in glucagon secretion is another mechanism of antiglycemic effect of GLP-1 [68]. Administration of GLP-1 delays gastric emptying significantly, and results with reduced postprandial glucose levels [69, 70]. The latter mechanism seems to be lost in chronic fashion. Based upon these mentioned antiglycemic effects of GLP-1, several pharmacological agents are developed for the treatment of diabetes, which will be talked about elswhere in this chapter.

4. Incretin based therapies and their role in the management of type 2 diabetes

Effects of incretin hormones on glucose metabolism and contribution of incretins in the pathogenesis of T2 DM, make these hormones ideal therapeutical targets. Decrease in apetite, reduction of body weight, improvement in insulin secretion and delay in gastric emptying are among several favorable effects of GLP-1 infusion [71]. Rapid degradation of bioactive GLP-1 by DPP-4 shortens half life, and limits anti-diabetic effects of GLP-1 [73]. Two treatment strategies has been developed to overcome this problem, first to develop DPP-4 resistant GLP-1 analogs, and the second to inhibit the degrading enzyme DPP-4. These two groups of medications will be discussed in detail.

4.1. Dipeptydyl peptidase-4 inhibitors

These oral agents are approved for treatment of diabetes whose hyperglycemia do not improve with monotherapy with sullphonylurea, tiazolidinedione and metformin or their dual combinations. They exert their effects by inhibiting the enzyme which cleaves the incretins and increase GIP and GLP-1 levels. Sitagliptin, saxagliptin, linagliptin and alogliptin are available in US, and vildagliptin is used in outside US. They have the advantage of being weight neutral and do not cause hypoglycemia except for combinations with sulphonylureas. They have been shown to be effective and safe when combined with sulphonylurea, tiazolidinedione or metformin in patients with T2 DM [73]. Usual dose of sitagliptin is 100 mg once daily, and renal dysfunction necessitate dose reduction (50 mg for patients who have glomerular filtration rate 50 mL/min and 25 mg for patients with <30 mL/min) [74]. Saxagliptin is used 2.5-5 mg once a day and the dose should be reduced to 2.5 mg for moderate renal insufficiency. It is also an effective agent in combinations like sitagliptin [75, 76]. Vildagliptin is used 50 mg twice daily in T2 DM. Dose adjustment is not necessary in mild renal insufficency, 50 mg daily dose is suggested in case of modarate and severe renal dysfunction. Linagliptin is used 5 mg daily, and it differs from other DPP-4 inhibitors with its completely hepatic elimination, which makes it possible to use in renal dysfunction. Efficacy and safety of linagliptin have been proven in monotherapy and combination studies [78-80]. Alogliptin is used 25 mg daily and dose adjustment is necessary in renal dysfunction. It has similar efficacy and safety profiles with other DPP-4 inhibitors [80].

All of the members of DPP-4 inhibitors seem to have similar efficacy, but their enzymatic affinity may be different [81, 82]. Their side effects include headache, increased risk of nasopharyngitis, urinary tract infection, and skin reactions [83]. There are reports about hepatic dysfunction with alogliptin and vildagliptin. Although the incidence of pancreatitis is not increased, a population based data suggested an increased frequency of hospitalisation for pancreatitis among sitagliptin users [84]. There is concern about whether DPP-IV inhibitors cause panceratic cancer development or not, but a causal relationship has not been established yet.

Cardiovascular safety of DPP-4 inhibitors is the matter of concern, since cardiovascular diseases are the most common cause of death in T2 DM patient population and there are several antidiabetic drugs which have been withdrawn from marketing due to their cardivascular safety problems. In a study which cardiovascular events was an endpoint, saxagliptine and metformin showed similar cardiovascular safety pattern, but patients in saxagliptin group hospitalised more frequently for heart failure when compared with metformin group [85]. Two other studies showed that neither alogliptin, nor sitagliptin have beneficial or adverse cardiovascular effects in short term use [86, 87]. Although these studies showed increased or decreased risks for cardiovascular events with DPP-4 inhibitors in short term use, their long term cardiovascular safety need to be further evaluated in long term clinical trials.

4.2. GLP-1 receptor agonists

There are two approved synthetic GLP-1R agonist molecules in the marketing. First one is Exenatide and the second one is Liraglutide. They are approved for T2 DM as an add-on drug for patients whom glycemic regulation is failed with one or two oral anti-diabetic medication [88]. Lower hypoglycemia risk is an important advantage of these molecules, which make them an excellent choice of therapy in patients whom hypoglycemia is of concern. Although they are as effective as other older anti-diabetic agents in comparison trials, data about their long term safety, effects on mortality and weight reduction is lacking [89]. Their effects on weight reduction has been proven by several studies, in which weight reducion was a secondary endpoint [90].

4.3. Exenatide

It is the synthetic analog of GLP-1, and it naturally occurs in the saliva of Gila monster (Heloderma spectum) as Exendin-4. It has 53% aminoacid homology with original GLP-1 molecule and has a long half-life beacuse of its resitance to DPP-4 mediated degradation. It is approved for T2 DM, as single or an add-on agent with other oral anti-diabetics in US. It can be combined with all of the oral anti-diabetics except for DPP-4 inhibitors.

It binds to GLP-1R and shows insulinotropic effects of GLP-1 on β-cells in the presence of glucose. It slows gastric emptying, lowers plasma glucose levels and reduces weight by inducing satiety like GLP-1 [91, 92]. Insulinotrophic effects has been shown in animal models [93, 94].

Beneficial effects on hyperglycemia, weight reduction, lipids and blood pressure has been shown with clinical trials, which has less than 30 weeks of duration [71, 95-99]. Exenatide reduces a1c levels by aproximately 1%, has lower hypoglycemia risk and hypoglycemia risk is increased with concurrent use of sulphonylurea. Exenatide causes a significant weight loss, which seems independent from its nausea inducing effect. Of note, patients experience nause lose more weight compared with patients who do not have [83, 100]. Preceding type of of drug is another important factor on weight loss during exenatide use. Patients using metformin show much more weight loss when compared with patients using sulphonylurea and tiazolidinedions [100-103].

The most common side effect of exenatide is gastrointestinal, predominantly nausea and rarely vomitting, which wane with ongoing therapy. Starting with 5 mcg and increasing the dose after one month to 10 mcg help to overcome nausea. Although risk of pancreatitis among patients who use incretin based drugs has been shown to be similar to the diabetic patients who do not use incretin based therapy, hospitalisation for acute pancreatitis may be increased [84, 104-106]. Insulinotrophic effects of GLP-1 raised concerns about the possibilty of pancreatic cancer and neuroendocrine tumor risk among patients using incretin-based therapies [107-110]. There is no data which prove or unprove these issues, so it is suggested to monitor patients for possible adverse effects affecting pancreas [111]. Although acute renal failure following exenatide use has been reported, it is difficult to prove direct relationship with exenatide use and renal failure in this patient population, which is prone to develop acute renal failure because of concurrent use of nephrotoxic drugs and underlying diabetic nephropathy [112]. Exenatide is conraindicated in severe renal impairment (creatinine clearance below 30 mL/min), and close follow up for serum creatinine is suggested when initiating therapy and after the dose titration from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min. Gastroparesis and history of past acute pancretitis are the other contraindications for exenatide use.

Although Exendin-4 is a GLP-1R analog, it shares a %53 homology with human GLP-1, which leads to development of anti-exendin antibody. It has been shown that anti-exenatide antibody development occur in about %40-57 of treated group [103, 113]. In one study the frequency of anti-exenatide antibody was reported to be more than %70 at the end of 24 weeks, and %40 of these antibody positive patients did not show further a1c reduction [114].. Although these mentioned studies have some limitations, ineffectiveness of exenatide due to blocking antibodies in long term use is possible.

The usual administarion schedule is starting with 5 mcg sc twice a day within 1 hours before breakfast and diner, and titration to 10 mcg twice a day 1 month later. Exenatide once weekly sc formulation is also available in US and Europe, and efficacy on hyperglycemia has been shown [115]. There are studies which compare the efficacy of daily and weekly formulations of exenatide. The improvement in a1c level seem to be better achieved with weekly formulation when compared with daily formulation, with similar body weight reduction [116, 117].

4.4. Liraglutide

Liraglutide is a GLP-1 analog which is produced by a recombinant DNA technology. Substitution of lysine at position 34 by arginine, and attachment of palmitic acid side chain to lysine group at position 26 of original GLP-1 produce liraglutide. The lipid side chain lead to formation of a non-covalent bond with albumin, which in turn slows degredation of the molecule, allowing it to be used once a day sc. Liraglutide shares 97% aminoacid homology with GLP-1.

Clinical indications are similar with exenatide. Once daily administration of 0.6 mg sc for one week reduce gastrointestinal side effects. The dose should be increased to 1.2 mg once daily for one week, and to 1.8 mg once daily if blood glucose remains above the goals [118]. Liraglutide monotherapy and comibination with one or two oral agents are efficacous in reducing blood glucose and a1c, causing significant weight reduction compared with placebo, glimepride and sitagliptin [119-121].

Nausea, vomiting and diarrhea are the most common adverse events [119]. The relationship between liraglutide use and pancreatitis is controversial. Animal studies have shown a relationship between liraglutide use and benign and mallignant parafollicular C-cell tumors [122]. It may be a species specific effect and GLP-1R expression of human C-cell has been shown to be very low [122]. Short term human studies did not show any elevation in calcitonin levels with liraglutide, but this issue need further evaluation, since it takes a long time for a mallignant transformation. Liraglutide is not recommended for use in patients who have medullary thyroid carcinoma or a related syndrome, or a family history of these diseases.

4.5. Is one GLP-1 receptor agonist superior to the other?

In a 26 week trial comparing the effects of liraglutide and exenatide showed a beter glycemic control with liraglutide compared with exenatide, with similar weight loss and adverse effects [123]. In another study the effects of both analogs on hyperglycemia was similar, with slightly better weight reduction in liraglutide group [124]. One potential superiority of liraglutide to exenatide may be its molecular homology to GLP-1, which is not associated with development of blocking antibodies causing drug ineffectiveness during chronic use.

Besides their beneficial effects like weight reduction and low frequency of hypoglycemia, long-term safety data, effect on diabetic macro and microvascular complications and mortality of these GLP-1R analogs are still lacking.

5. Summary

The role of comperatively older drugs such as insulin, insulin secretagogues, metformin, thiazolidinediones and alpha glucosidase inhbitors in the management of diabetes are familiar aspects of diabetes therapy. These medications target insulin secretion, insulin sensitivity and glucose absorption, which may be intrepreted as having limited targets in the pathogenesis of diabetes. Definition of incretin hormones and their role on β-cell function and survival are the new aspects of the pathogenesis of diabetes, and management of hyperglycemia. Besides the novelty of incretin based therapies in the management of diabetes, their roles on β-cell function and regeneration, which are really promising effects for an anti-diabetic agent are so interesting and need to be observed in long term clinical practice. Possible effects of these drugs that is associated with their pleitropic effects, which have been shown in invitro studies on diabetes related complications are the new era in diabetology. In our opinion the role of incretin besed therapies in the progression of diabetes and diabetic complications will be determined in the future, although fovarable or not.


1 - Creutzfeldt W. Entero-insular axis and diabetes mellitus. Horm Metab Res. 1992; Suppl 26:13-18.
2 - Unger RH and Eisentraut AM. Entero-insular axis. Arch Intern Med. 1969;123: 261-5.
3 - Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, and Creutzfeldt W. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin EndocrinolMetab. 1986;63: 492-8.
4 - Horowitz M, Edelbroek MA, Wishart JM, Straathof JV. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia. 1993;36:857-62.
5 - Jones KL, Horowitz M, Carney BI, Wishart JM, Guha S, Green L. Gastric emptying in early noninsulin-dependent diabetes mellitus. Journal of Nuclear Medicine. 1996;37:1643-8.
6 - Gonlachanvit S, Hsu CW, Boden GH, Knight LC, Maurer AH, Fisher RS, et al. Effect of altering gastric emptying on postprandial plasma glucose concentrations following a physiologic meal in type-II diabetic patients. Digestive Diseases and Sciences. 2003;48:488-97.
7 - Mortensen K, Christensen LL, Holst JJ, and Orskov C. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul Pept. 2003;114:189-96.
8 - Mojsov S, Heinrich G, Wilson IB, Ravazzola M, Orci L, and Habener JF. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem. 1986;261:11880-9.
9 - Holst JJ, Bersani M, Johnsen AH, Kofod H, Hartmann B, Orskov C. Proglucagon processing in porcine and human pancreas. J Biol Chem. 1994;269:18827-33.
10 - Orskov C, Holst JJ, Knuhtsen S, Baldissera FG, Poulsen SS, Nielsen OV. Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas. Endocrinology. 1986;119:1467-75.
11 - Trinh DK, Zhang K, Hossain M, Brubaker PL, Drucker DJ. Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium. Diabetes. 2003; 52:425-33.
12 - Yi F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3. 2005;J Biol Chem. 280:1457-64.
13 - Hansen L, Hartmann B, Bisgaard T, Mineo H, Jorgensen PN, Holst JJ. Somatostatin restrains the secretion of glucagon-like peptide-1 and 2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab. 2000;278:E1010-E1018.
14 - Deacon CF, Pridal L, Klarskov L, Olesen M, Holst JJ. Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am J Physiol Endocrinol Metab. 1996;271:E458-E464.
15 - Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology.1999;140:5356-63.
16 - Hupe-Sodmann K, McGregor GP, Bridenbaugh R, Göke R, Göke B, Thole H, et al. Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7-36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regul Pept. 1995; 58:149-56.
17 - Ban K, Kim KH, Cho CK, Sauve M, Diamandis EP, Backx PH, et al. Glucagon-like peptide (GLP)-1(9-36)amide-mediated cytoprotection is blocked by exendin(9-39) yet does not require the known GLP-1 receptor. Endocrinology. 2010;151:1520-31.
18 - Liu Z, Stanojevic V, Brindamour LJ, Habener JF. GLP1-derived nonapeptide GLP1(28-36)amide protects pancreatic β-cells from glucolipotoxicity. J Endocrinol. 2012;213:143-54.
19 - Meier JJ, Nauck MA, Kranz D, Holst JJ, Deacon CF, Gaeckler D, Schmidt WE, Gallwitz B. Secretion, degradation, elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53:654-62.
20 - Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R,Creutzfeldt W. 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 Invest. 1993;91: 301-7.
21 - Mari A, Sallas WM, He YL, Watson C, Ligueros-Saylan M, Dunning BE, et al. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed –cell function in patients with type 2 diabetes. J Clin Endocrinol Metab. 2005;90:4888-94.
22 - Vilsboll T, Krarup T, Sonne J, Madsbad S, Volund A, Juul AG, Holst JJ. Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol Metab. 2003;88: 2706-13.
23 - Miholic J, Orskov C, Holst JJ, Kotzerke J, Meyer HJ. Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), reactive hypoglycemia after total gastrectomy. Dig Dis Sci. 1991;36:1361-70.
24 - Gribble FM, Williams L, Simpson AK, Reimann F. A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line. Diabetes. 2003;52:1147-54.
25 - Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005;11: 90-4.
26 - Hansen L, Lampert S, Mineo H, Holst JJ. Neural regulation of glucagon-like peptide-1 secretion in pigs. Am J Physiol Endocrinol Metab. 2004;287:E939-E947.
27 - Vilsboll T, Krarup T, Madsbad S, and Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia. 2002;45:1111-9.
28 - Mayo KE, Miller LJ, Bataille D, Dalle S, Goke B, Thorens B, et al. The glucagon receptor family. Pharmacol Rev. 2003;55:167-94.
29 - Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett. 1995;358:219-24.
30 - Krarup T. Immunoreactive gastric inhibitory polypeptide. Endocr Rev. 1988;9:122-34.
31 - Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86: 3717-23.
32 - Egan JM, Meneilly GS, Habener JF, Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab. 2002;87:3768-73.
33 - Elahi D, Egan JM, Shannon RP, Meneilly GS, Khatri A, Habener JF, et al. GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide. Obesity (Silver Spring). 2008;16:1501-9.
34 - Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287:E199-E206.
35 - Kemp DM, Habener JF. Insulinotropic hormone glucagon-like peptide 1 (GLP-1) activation of insulin gene promoter inhibited by p38 mitogen-activated protein kinase. Endocrinology. 2001;142:1179-87.
36 - Li Y, Cao X, Li LX, Brubaker PL, Edlund H, Drucker DJ. Cell Pdx1 expression is essential for the glucoregulatory, proliferative, cytoprotective actions of glucagon-like peptide-1. Diabetes.2005;54: 482-91.
37 - Buteau J, Roduit R, Susini S, Prentki M. Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia. 1999;42:856-64.
38 - Xiong X, Shao W, Jin T. New insight into the mechanisms unedrlying the function of the incretin hormone glucagon-like peptide-1 in pancreatic β-cells. Involvement of the Wnt signaling pathway effector β-catenin. Islets. 2012;4(6):359-65.
39 - Egan JM, Bulotta A, Hui H, Perfetti R. GLP-1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells. Diabetes Metab Res Rev. 2003;19:115-23.
40 - Edvell A, Lindstrom P. Initiation of increased pancreatic islet growth in young normoglycemic mice (Umea _/?). Endocrinology. 1999;140:778-83.
41 - Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di MU, et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology. 2002;143:4397-408.
42 - Stoffers DA, Kieffer TJ, Hussain MA, Drucker DJ, Bonner-Weir S, Habener JF, et al. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes. 2000;49: 741-8.
43 - Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting inincreased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999;48:2270-6.
44 - Zhou J, Wang X, Pineyro MA, Egan JM. Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon-and insulin-producing cells. Diabetes. 1999;48:2358-66.
45 - Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102-10.
46 - Spindel ON, World C, Berk BC. Thioredoxin interacting protein: redox dependent and independent regulatory mechanisms. Antioxid Redox Signal. 2012;16:587-96.
47 - Chen J, Couto FM, Minn AH, Shalev A. Exenatide inhibits beta-cell apoptosis by decreasing thioredoxin-interacting protein. Biochem Biophys Res Commun. 2006; 346:1067-74.
48 - Chen J, Hui ST, Couto FM, Mungrue IN, Davis DB, Attie AD, et al. Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes. FASEB J. 2008;22:3581-94.
49 - Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000;85:4053-59.
50 - Fehmann HC, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev. 1995;16:390-410.
51 - De Heer J, Hoy M, Holst JJ. GLP-1, but not GIP, inhibits glucagon secretion via somatostatin in the perfused rat pancreas. Diabetologia. 2005;48 Suppl 1:A64.
52 - Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol Endocrinol Metab. 1997;273:E981-E988.
53 - Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78–107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993;38:665-73.
54 - Wettergren A, Petersen H, Orskov C, Christiansen J, Sheikh SP, Holst JJ. Glucagon-like peptide-1 7–36 amide and peptide YY from the L-cell of the ileal mucosa are potent inhibitors of vagally induced gastric acid secretion in man. Scand J Gastroenterol. 1994;29:501-5.
55 - Wettergren A, Wojdemann M, Meisner S, Stadil F, Holst JJ. The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7–36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut. 1997;40:597-601.
56 - Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and-independent pathways. Circulation. 2008;117:2340-50.
57 - Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962-5.
58 - Read PA, Khan FZ, Dutka DP. Cardioprotection against ischaemia induced by dobutamine stress using glucagonlike peptide-1 in patients with coronary artery disease. Heart. 2012;98:408-13.
59 - Liu H, Hu Y, Simpson RW, Dear AE. Glucagon-like peptide-1 attenuates tumour necrosis factor-alpha-mediated induction of plasminogen [corrected] activator inhibitor-1 expression. J Endocrinol. 2008;196:57-65.
60 - Gutzwiller JP, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89:3055-61.
61 - Hsieh J, Longuet C, Baker CL, Qin B, Federico LM, Drucker DJ, et al. The glucagon-like peptide 1 receptor is essentialfor postprandial lipoprotein synthesis and secretion in hamsters and mice. Diabetologia. 2010;53:552-61.
62 - Perry TA, Greig NH. A new Alzheimer’s disease interventive strategy: GLP-1. Curr Drug Targets. 2004;5: 565-71.
63 - Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46-52.
64 - Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes. 2003;52 (2):380-6.
65 - Nauck MA, Holst JJ, Willms B. Glucagon-like peptide 1 and its potential in the treatment of non-insulin-dependent diabetes mellitus. Horm Metab Res. 1997;29:411-6.
66 - Toft-Nielsen MB, Madsbad S, Holst JJ. Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J Clin Endocrinol Metab. 2001;86: 3853-60.
67 - Hucking K, Kostic Z, Pox C et al. Alpha-Glucosidase inhibition (acarbose) fails to enhance secretion of glucagon-like peptide 1 (7–36 amide) and to delay gastric emptying in type 2 diabetic patients. Diabetic Medicine. 2005; 22:470-6.
68 - Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulindependent) diabetic patients. Diabetologia. 1993; 36:741-4.
69 - Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7–36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab. 1996;81:327-32.
70 - Kendall DM, Kim D, Maggs D. Incretin mimetics and dipeptidyl peptidase-IV inhibitors: a review of emerging therapies for type 2 diabetes. Diabetes Technol Ther. 2006;8: 385-96.
71 - Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154(2):103-12.
72 - Arnolds S, Dellweg S, Clair J, Dain MP, Nauck MA, Rave K, et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care. 2010;33(7):1509-15.
73 - Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007;50(6):1148-55.
74 - Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007;30(7):1862-4.
75 - Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R, CV181-040 Investigators. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract. 2009;63(9):1395-406.
76 - DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S, et al. Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32(9):1649-55.
77 - Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13(3):258-67.
78 - Forst T, Uhlig-Laske B, Ring A, Graefe-Mody U, Friedrich C, Herbach K, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet Med. 2010;27(12):1409-19.
79 - Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13(1):65-74.
80 - Seino Y, Miyata Y, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab. 2012 Oct;14(10):927-36.
81 - Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2010;26(7):540-9.
82 - Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006739. doi:10.1002/14651858.CD006739.pub2.
83 - Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298(2):194-206.
84 - Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagon like peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173(7):534-9.
85 - Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al;. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-26.
86 - White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-35.
87 - Eurich DT, Simpson S, Senthilselvan A, Asche CV, Sandhu-Minhas JK, McAlister FA. Comparative safety and effectiveness of sitagliptin in patients with type 2 diabetes: retrospective population based cohort study. BMJ. 2013;346:f2267.
88 - Riddle MC, Drucker DJ. Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1. Diabetes Care. 2006;29(2):435-49.
89 - Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD006423
90 - Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ. 2012;344:d7771
91 - Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab. 2002;87(3):1282-90.
92 - Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bicsak TA, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88(7):3082-9.
93 - Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999;48(12):2270-6.
94 - Stoffers DA, Desai BM, DeLeon DD, Simmons RA. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes. 2003;52(3):734-40.
95 - Riddle MC, Henry RR, Poon TH, Zhang B, Mac SM, Holcombe JH, et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev. 2006;22(6):483-91.
96 - Ratner RE, Maggs D, Nielsen LL, Stonehouse AH, Poon T, Zhang B, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8(4):419-28.
97 - Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG, GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143(8):559-69.
98 - Gallwitz B, Guzman J, Dotta F, Guerci B, Simor R, Basson BR, et al. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet. 2012 Jun;379(9833):2270-8.
99 - Arnolds S, Dellweg S, Clair J, Dain MP, Nauck MA, Rave K, et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care. 2010;33(7):1509-15.
100 - 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;28(5):1092-100.
101 - 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;27(11):2628-35.
102 - Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. 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;28(5):1083-91.
103 - Zinman B, Hoogwerf BJ, Duran Garcia S, Milton DR, Giaconia JM, Kim DD, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007;146(7):477-85.
104 - Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care. 2010;33(11):2349-54.
105 - Girman CJ, Kou TD, Cai B, Alexander CM, O'Neill EA, Williams-Herman DE, et al. Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes. Diabetes Obes Metab. 2010;12(9):766-71.
106 - Gonzalez-Perez A, Schlienger RG, Rodriguez LA. Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study. Diabetes Care. 2010;33(12):2580-5.
107 - Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141(1):150-6.
108 - Halfdanarson TR, Pannala R. Incretins and risk of neoplasia. BMJ. 2013;346:f3750.
109 - Cohen D. Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed? BMJ. 2013;346:f3680.
110 - Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62(7):2595-604.
111 - Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, et al. Pancreatic safety of incretin-based drugs--FDA and EMA assessment. N Engl J Med. 2014 Feb;370(9):794-7.
112 - Weise WJ, Sivanandy MS, Block CA, Comi RJ. Exenatide-associated ischemic renal failure. Diabetes Care. 2009;32(2):e22-3.
113 - Gedulin BR, Smith P, Prickett KS, Tryon M, Barnhill S, Reynolds J, et al. Dose-response for glycaemic and metabolic changes 28 days after single injection of longacting release exenatide in diabetic fatty Zucker rats. Diabetologia. 2005;48:1380-5.
114 - Faludi P, Brodows R, Burger J, Ivanyi T, Braun DK. The effect of exenatide re-exposure on safety and efficacy. Peptides. 2009;30:1771-4
115 - Diamant M, Van Gaal L, Stranks S, Northrup J, Cao D, Taylor K, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375(9733):2234-43.
116 - Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al, DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372(9645):1240-50.
117 - Blevins T, Pullman J, Malloy J, Yan P, Taylor K, Schulteis C, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011 May; 96(5):1301-10.
118 - lbrond B, Jakobsen G, Larsen S, Agerso H, Jensen LB, Rolan P, et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects Diabetes Care. 2002;25(8):1398-404.
119 - Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473-81.
120 - Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, et al. LEAD-1 SU study group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-78.
121 - Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. 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. Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study Group. Diabetologia. 2009;52(10):2046-55.
122 - Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473-86.
123 - Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47.
124 - Buse JB, Nauck M, Forst T, Sheu WH, Shenouda SK, Heilmann CR, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013; 381(9861):117-24.