review article                                                                                                            ...
DIABETES, OBESITY AND METABOLISM                                                                         review articleTab...
review article                                                                             DIABETES, OBESITY AND METABOLIS...
DIABETES, OBESITY AND METABOLISM                                                               review articlethat carriers...
review article                                                                       DIABETES, OBESITY AND METABOLISMonce-...
DIABETES, OBESITY AND METABOLISM                                                                   review article    α-met...
review article                                                                           DIABETES, OBESITY AND METABOLISMe...
DIABETES, OBESITY AND METABOLISM                                                                                          ...
review article                                                                                          DIABETES, OBESITY ...
Upcoming SlideShare
Loading in...5

O futuro na terapia baseada em incretins.


Published on

Neste belo artigo realcei em amarelo as partes que mais me instigaram. Depois traço um paralelismo com a bela conferência do Prof. Buse, realizada em San Diego há um mês.

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

No Downloads
Total Views
On Slideshare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

O futuro na terapia baseada em incretins.

  1. 1. review article Diabetes, Obesity and Metabolism 13 (Suppl. 1): 158–166, 2011. © 2011 Blackwell Publishing Ltdarticlereview The future of incretin-based therapy: novel avenues—novel targets ´ B. Ahren Department of Clinical Sciences Lund, Lund University, Lund, Sweden Incretin-based therapy for type 2 diabetes is based on the antidiabetic effects of glucagon-like peptide-1 (GLP-1) and instituted by GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors targeting the key islet defects of the disease. The treatment is clinically efficient and safe, and associated with a low risk of adverse events. It can be used both in early and late stages of the disease and both as monotherapy and add-on to other therapies. Current research on the future of incretin-based therapy focuses on optimizing its place in diabetes treatment and examines its potential in type 1 diabetes, in subjects with obesity without type 2 diabetes and in cardiovascular and neurodegenerative disorders. Other studies aim at prolonging the duration of action of the GLP-1 receptor agonists to allow weekly administration, and to develop orally GLP-1 receptor agonists. Furthermore, other investigators focus on stimulation of GLP-1 secretion by activating GLP-1-producing L-cells or using gene therapy. Finally, also other gastro-entero-pancreatic bioactive peptides are potential targets for drug development as are synthetic peptides engineered as co-agonists stimulating more than one receptor. We can therefore expect a dynamic development within this field in the coming years. Keywords: CCK, DPP-4 inhibitors, GIP, GLP-1 analogues, GLP-1 receptor agonists, incretin-based therapy Date submitted 31 March 2011; date of final acceptance 14 April 2011 Introduction may be anticipated. This article summarizes its potential developmental avenues. The prevalence of type 2 diabetes has reached exceptionally high levels during recent years. It has also been estimated that less than half of the worldwide patient population reaches Background of Incretin-Based Therapy the treatment targets according to current guidelines. This increases the occurrence of secondary complications of the GLP-1 is a 30 amino acid peptide product of the proglucagon disease. To meet this increasing global health challenge, early gene in the intestinal L-cells. GLP-1 is released into the and intensified treatment of the disease and development circulation after meal ingestion and potentiates glucose- of novel therapies are of key importance. The treatment stimulated insulin secretion [1]. GLP-1 also inhibits glucagon of today includes life style changes (dietary adjustments, secretion [2] and, in rodents, increases β-cell mass through increased physical activity) with addition of metformin as stimulated β-cell neogenesis and proliferation and inhibited a first-line pharmacological therapy. When this is insufficient, apoptosis [3]. In fact, GLP-1-based therapy is the first treatment addition of sulphonylureas, glinides, α-glucosidase inhibitors, that targets both insulin and glucagon secretion. Therefore, thiazolidinediones and/or insulin has until recently been the GLP-1 targets the key islet defects in type 2 diabetes. GLP-1 choice. These treatments offer improvement in glycaemic also delays gastric emptying and induces satiety and has control, but are also associated with significant adverse potential effects in both the cardiovascular and nervous events such as hypoglycaemia, weight gain and gastrointestinal systems [1]. discomfort. In 2005, the treatment choices were expanded The potential use of GLP-1 as a therapeutic agent in type 2 by the introduction of incretin-based therapy. This therapy is diabetes was first suggested in the early 1990s, when GLP-1 was based on the pleiotropic antidiabetic effects of the glucoincretin shown to reduce insulin requirement during meal ingestion in hormone glucagon-like peptide-1 (GLP-1). Several compounds type 2 diabetics [4]. This antidiabetic action was later confirmed within this group have been introduced clinically, and their in several studies [1]. A challenge in the development has use has increased considerably during recent years. Table 1 been the short half-life of GLP-1 (1–2 min), because of the shows how future development of incretin-based therapy rapid inactivation through truncation by removal of the N- terminal dipeptide end by the enzyme dipeptidyl peptidase-4 (DPP-4) [1]. To overcome this shortcoming of native GLP-1, Correspondence to: Dr. Bo Ahren, Department of Clinical Sciences Lund, Lund University, ´ B11 BMC, SE-221 84, Lund, Sweden. two strategies have been explored and developed into clinical E-mail: practice: GLP-1 receptor agonists and DPP-4 inhibitors.
  2. 2. DIABETES, OBESITY AND METABOLISM review articleTable 1. Potential novel avenues for future development of incretin- HbA1c and body weight. A 26-week head-to-head comparisonbased therapy. between the two showed that liraglutide reduced HbA1c more efficiently than exenatide [by 1.1% (12 mmol/mol) Six potential future developments of incretin-based therapy versus 0.8% (9 mmol/mol) from baseline levels of 8.2%1 Define clinical characteristics versus other therapeutics benefits to (66 mmol/mol)] [9]. In contrast, the reduction in body weight establish place in therapy of type 2 diabetes was similar for the two GLP-1 receptor agonists. Liraglutide2 Establish novel indications (type 1 diabetes, obesity, cardiovascular is safe and associated with very low risk for adverse events. and neurodegenrative disorders) Nausea occurs in 5–10% of patients but is less frequent than3 Prolongation of duration of action of GLP-1 receptor agonists with exenatide [9]. Acute pancreatitis has also been observed (weekly active), orally active GLP-1 receptor agonists during treatment with liraglutide. Again, however, it is unclear4 Stimulation of GLP-1 secretion (sugar analogs, amino acids, whether this is caused by liraglutide per se. Furthermore, GPR119 agonists, GPR40 agonists, gene therapy)5 Use of other bioactive gastro-entero-pancreatic hormones rodent studies have shown focal hyperplasia and malignant [glucose-dependent insulinotropic polypeptide (GIP), transformation in thyroid C-cells by liraglutide, although no oxyntomodulin, peptide YY (PYY), cholecystokinin (CCK), such cases or changes in calcitonin levels have been observed ghrelin, glucagon] in patients treated with liraglutide.6 Single co-agonist molecules targeting GLP-1 and glucagon receptors DPP-4 InhibitorsIncretin-Based Therapy of Today The alternative strategy for incretin-based therapy is inhi- bition of the enzyme DPP-4. This prevents the inactivationGLP-1 Receptor Agonists of GLP-1, thus enhancing and prolonging the action ofThe GLP-1 receptors are G-protein-coupled receptors endogenous GLP-1 [10,11]. DPP-4 inhibition increases GLP-1(GPCRs) [5]. The GLP-1 receptor agonists developed for clin- levels, and also the levels of glucose-dependent insulinotropicical use have high affinity to the receptors and are largely polypeptide (GIP), along with increased insulin secretion,resistant to inactivation by DPP-4 [6]. They have therefore the reduced glucagon secretion and improved glycaemia [10].ability to achieve long-standing GLP-1 receptor activation. Several DPP-4 inhibitors have been developed and they are There are two kinds of GLP-1 receptor agonists [6]. One type all orally active small molecules that inhibit the catalyticis based on exendin-4, which is the peptide, isolated from the site of DPP-4. They all have high bioavailability upon oralparotid gland of the Gila monster lizard. Exendin-4 has 53% administration. Sitagliptin was introduced clinically in 2006;identity to native GLP-1 [1]. Exenatide is the synthetic form of it was followed by vildagliptin, saxagliptin linagliptin andexendin-4 and was introduced clinically in 2005. Exenatide is (in Japan only so far) alogliptin. They are efficient both ingiven twice daily through subcutaneous injection and reduces monotherapy and in combination therapy with metformin,HbA1c by approximately 0.8–0.9% (8–9 mmol/mol) from sulphonylureas, thiazolidinediones and insulin. They reducebaseline levels of 8.2–8.6% (66–70 mmol/mol) with body HbA1c by 0.6–1.1% (6–11 mmol/mol) from baseline levelsweight reduction of 1.6–2.8 kg over 30 weeks when used of 7.5–9.8% (58–82 mmol/mol) in studies over 26–52 weeksin combination with sulphonylurea and/or metformin [7]. with very low risk of hypoglycaemia or other adverse eventsExenatide is well tolerated and safe over a 5-year treatment and no weight gain [10].period. The most common adverse events are nausea and In summary, the large body of clinical experience whichvomiting, seen in 30–50% of patients during the initial weeks exists today shows that incretin-based therapy is efficient inof therapy. A concern is that acute pancreatitis has occurred reducing glycaemia and has the advantages of being safe withduring treatment [6]. It is not clear, however, whether this is very little adverse events, low risk of hypoglycaemia and nocaused by exenatide per se, because diabetes by itself is a risk weight gain.factor for acute pancreatitis. Another exendin-4-based compound is lixisenatide, in whichthe structure of exendin-4 has been prolonged by the addition Future Clinical Development of Existingof six lysine residues to the C-terminal end. This prolongs the Incretin-Based Therapyhalf-life, which enables the compound to be administered oncedaily [6]. Lixisenatide is still in clinical development. Place in Therapy The other type of GLP-1 receptor agonists is based on As is seen in Table 2, incretin-based therapy can be usedthe structure of native GLP-1, that is, they are true GLP-1 in several indications in type 2 diabetic patients withanalogues. In liraglutide, a C-16 acyl chain (palmitate) has insufficient glycaemic control, both as monotherapy andbeen incorporated at amino acid 20 in the GLP-1 molecule in combination with other existing treatments. A mainvia a γ -glutamic acid spacer, and the lysine in position 28 indication today in many guidelines is as add-on tois exchanged with arginine [8]. The incorporation of the acyl metformin when metformin alone is insufficient for adequatechain allows for non-covalent binding to albumin, which glycaemic control. The rationale for this algorithm is thatdelays both the inactivation by DPP-4 and renal clearance metformin is the first-line pharmacological therapy for typeof the compound and results in a half-life of liraglutide 2 diabetes. The two approaches also complement each otherof 11–15 h. Liraglutide is administered once daily through from a mechanistic perspective. Thus, incretin-based therapythe subcutaneous route. Liraglutide, like exenatide, reduces improves the islet dysfunction whereas metformin targetsVolume 13 No. (Suppl. 1) October 2011 doi:10.1111/j.1463-1326.2011.01457.x 159
  3. 3. review article DIABETES, OBESITY AND METABOLISMTable 2. Approved clinical indications for incretin-based therapy in reason behind the current guidelines advocating higher prioritypatients with type 2 diabetes with insufficient glycaemic control by the for sulphonylureas than for incretin-based therapy is theEuropean Medicines Agency (EMA) by April 2011. considerably higher cost with incretins. However, proper health-economic studies including the total estimates of the Add-on to Triple therapy cost of diabetes management have not yet been undertaken Met + Met + and would be important. Monotherapy Metformin SU TZD Insulin SU TZD Another potential use of incretin-based therapy is inExenatide X X X combination with insulin. This would improve glycaemiaLiraglutide X X X X without increasing the risk of hypoglycaemia and may alsoSitagliptin X∗ X X X X X X make it possible to reduce the insulin dose, as was shown withVildagliptin X X X vildagliptin [21].Saxagliptin X X XMet, metformin; SU, sulphonylurea; TZD, thiazolidinedione. Individualizing the Therapy∗ Restricted to when metformin is unsuitable. Most, but not all, patients respond to incretin-based therapy in terms of improved glycaemia, and many, but not all,the insulin resistance, that is, the two key factors of type patients in clinical trials have reached the target HbA1c2 diabetes are targeted by this combination. Furthermore, of <7%. An important issue is whether there exist specificmetformin may increase both GLP-1 secretion and GLP-1 characteristics in those who respond versus non-responders.receptor expression [12], suggesting a potential synergistic This would be important because it would allow the possibilityeffect between incretin-based therapy and metformin on of individualized therapy tailoring incretin-based treatment toβ-cell function. Several studies have documented good specific patient groups. This, however, has not been studiedclinical efficacy along with safety and tolerability with this extensively. What has been repeatedly shown in several clinicalcombination [1,6,10]. However, sulphonylureas are still more trials is that the reduction in HbA1c by incretin-based therapy,commonly used as the first add-on therapy to metformin. as other types of treatment, is greater in patients with higherNevertheless, several recent studies have compared incretin- baseline HbA1c. Other characteristics documented in clinicalbased therapy versus sulphonylurea as add-on to metformin in trials, such as BMI, gender or diabetes duration, however, dopatients who are insufficiently controlled with metformin alone not seem to predict the response.and arrived at the conclusion that there may be advantages Baseline islet function may intuitively be of importancewith incretin-based therapy over certain sulphonylureas, for predicting a response, because incretin-based therapy actssuch as glipizide or glimepiride [13–15]. Thus, although the primarily on islet function. Hence, it may be speculated thatreduction in HbA1c is similar between these sulphonylureas baseline poor islet function would predict a lower response.and incretin-based therapy, the latter is associated with less However, the opposite may also be the case, such that patientshypoglycaemia and no weight gain (DPP-4 inhibitors) or with poor islet function would benefit most from a therapyweight loss (GLP-1 receptor agonists), whereas treatment with targeting this key defect. Indirect measures of β-cell function,some sulphonylureas can be associated with high incidences such as HOMA-B index and proinsulin/insulin ratio in oneof hypoglycaemia and weight gain. These studies would meta-analysis of clinical trials with sitagliptin did suggest thattherefore support the use of incretin-based therapy as add-on poor insulin secretion predicts a better response [22]. Whetherto metformin, instead of certain sulphonylureas. One reason this is a general phenomenon of incretin-based therapy, andwhy incretin-based therapy has not replaced sulphonylureas holds true also when more appropriate measures of insulinis that there are still no long-term studies with incretin-based secretion are used, remains to be established.treatment which have included cardiovascular hard end-point Age of the patient has in some studies been shown todata. This is important because long-term durability and safety influence the response, old age predicting a better response.are key factors for a life-long therapy. Several clinical studies This was clearly shown in a 2-year study in which the DPP-have, however, shown that markers for cardiovascular diseases 4 inhibitor vildagliptin was added to on-going metforminimprove during treatment with incretin-based therapy [16], therapy. The study showed first that vildagliptin exhibited betterand long-term studies with hard cardiovascular end points sustainability than glimepiride, as evident from coefficient ofare on-going with results expected in 2014–2015. In regard failure analyses, and second that age was an independentto overall safety with incretin-based therapy, however, large predictor of sustainability [23]. The reason why age seemscollections of data from clinical studies have shown high to be an independent factor of sustainability is not known,safety with very low risk for adverse events [17]. At least some but may be related to a greater dependence on postprandialsulphonylureas may be associated with adverse events, and there hyperglycaemia for glucose control and/or a more markedare also studies indicating increased risk for cardiovascular hyperglucagonaemia in the elderly.disease in patients treated with sulphonylureas such as GLP-1 receptor responsiveness and sensitivity are importantglibenclamide [18], whereas risk was not increased (or even for the response to incretin-based therapy. Consequently,reduced) with sulphonylureas of the second generation, such as patients with impaired GLP-1 receptor expression or signallinggliclazide [19,20]. To ascertain the optimal treatment, however, may exhibit reduced sensitivity to incretin-based therapy. If so,it will be important to perform long-term head-to-head studies pretreatment tests could be developed for identifying patientbetween incretin-based therapy and sulphonylureas. Another suitability for treatment. In this context, it is of interest ´160 Ahren Volume 13 No. (Suppl. 1) October 2011
  4. 4. DIABETES, OBESITY AND METABOLISM review articlethat carriers of transcription factor 7-like 2 (TCF7L2) gene pressure, total cholesterol, low-density lipoprotein cholesterolpolymorphism have impaired insulin secretory response to and triglyceride concentrations and increase in high-densityintravenously infused GLP-1 [24]. Similarly, subjects with a lipoprotein cholesterol levels in clinical trials [16]. Thesegenetic variant of Wolfram syndrome 1 gene (WFS1) have emerging effects may obviously be beneficial for patientsa defective insulin secretory response to GLP-1 but not with type 2 diabetes, and long-term studies are now on-to intravenous glucose, suggesting a specific impairment in going to examine this. However, the potential endothelio-GLP-1 receptor signalling [25]. Whether diabetic subjects with cardioprotective effects of GLP-1 may also suggest a potentialTCF7L2 or WFS1 gene variants display impaired response to to use incretin-based therapy as adjunct to other treatmentsincretin-based therapy is not known, but if so, this would open also in non-diabetic patients with cardiovascular diseases. Inthe possibility for pretherapy testing for individualization of fact, a study on treatment with exenatide on infarct size andtreatment. The individualization of incretin-based therapy is, cardiac function when given as an infusion for 72 h in patientshowever, still far from clinical reality. with acute myocardial infarction is on-going (NCT01254123). Effects of GLP-1 have been studied in nervous tissue and, like in pancreatic β-cells, GLP-1 has been shown to stimulateWidening the Use to New Patient Groups cell growth and reduce apoptosis [31]. Experimental studiesA future development is broadening the use of incretin-based in various models of neurodegenerative disorders, such astherapy to other patient groups. One potential new indication Alzheimer’s disease, Parkinson’s disease and stroke, have alsois type 1 diabetes. The rationale for this is that GLP-1 may shown that GLP-1 receptor activation might be beneficial.preserve and even possibly restore β-cell function in type 1 This may suggest a potential development of GLP-1-baseddiabetes, as well as potentially expanding the β-cell mass, therapy also in these diseases. As recently reviewed, this seemswhile also inhibiting glucagon secretion. One study examined to be closest in the case of Parkinson’s disease [31]. In fact,the influence of exenatide on β-cell function in patients with a 12-month phase 2 clinical study examining the effect oflong-standing (mean 21 years) type 1 diabetes but found no exenatide in the treatment of Parkinson’s disease is ongoingimprovement after 6 months of treatment [26]. This would with estimated completion in December 2011 (NCT01174810).suggest either that islets of type 1 diabetics do not respondto incretin-based therapy or that a 6-month period is too Pharmaceutical Developmentshort. Another study reported reduced meal-induced glucagon of Incretin-Based Strategiesresponse after treatment with vildagliptin [27], suggesting thatDPP-4 inhibition may be used in type 1 diabetes to lower Longer Duration of Actionglucagon. It has also been discussed whether incretin-based GLP-1 receptor agonists are injected subcutaneously twicetherapy could be initiated in patients with type 1 diabetes (exenatide) or once (liraglutide) daily. There is a developmentafter islet transplantation to allow preserved function of the to prolong the duration of action, to enable injections oncetransplanted islets. One study showed that this might be weekly. The expectation is that this may have better glycaemicpossible; addition of exenatide to immunosuppression after effect with lower risk for adverse events, including nauseaislet transplantation showed improved islet graft function and vomiting, along with being more patient-friendly with aand facilitated achievement of insulin independence with less lower number of injections. Prolonged durability to allowislets [28]. Further studies on this indication are on-going. weekly administration has been achieved for exenatide in GLP-1 receptor agonists robustly reduce body weight in exenatide LAR, using a delivery system consisting of poly(lactic-subjects with type 2 diabetes. This has been seen both for go-glycolic) microspheres of biodegradable polymers. Thisexenatide and liraglutide in a number of studies; body weight long-acting form was recently shown to have a better glycaemicis usually reduced by 3–5 kg after 1–2 years [6]. This has effect than conventional exenatide given twice daily in a studymotivated studies on the use of GLP-1 in subjects with obesity over 52 weeks, but the reduction in body weight did notwithout type 2 diabetes. In a large trial in obese patients (BMI differ [32]. The reduction in HbA1c by exenatide LAR was30–40 kg/m2 ) given liraglutide or placebo for 20 weeks, at the 2.0% (21 mmol/mol) from a baseline of 8.3% (67 mmol/mol)highest tested dose of liraglutide (3 mg daily) body weight was and this was associated with a reduction in body weight byreduced by 7 kg compared to 2.8 kg with placebo and 4.1 kg 4.1 kg from 103 kg. Nausea, which was mild, occurred inwith the comparator orlistat [29]. This was associated with only 7% of the patients. Similar results have been reportedreduced glucose levels and would support the use of GLP-1- in the comprehensive clinical development programme thatbased therapy in obesity. Further studies are now on-going to exists for exenatide LAR and in which the compound isestablish whether GLP-1-based therapy also has a place in the examined both as monotherapy and as add-on to metforminmanagement of obese non-diabetic patients. and with comparisons with exenatide, sitagliptin, pioglitazone, GLP-1 receptors are expressed in the cardiovascular liraglutide and insulin glargine [33].system, both in cardiomyocytes and endothelial cells, and, Another long-acting GLP-1 receptor agonist is taspoglutide,as recently reviewed, activation of these receptors results in in which amino acids number 2 (alanine) and 29 (arginine)cardioprotection in animal models of ischaemia–reperfusion in the GLP-1 molecule are replaced by 2-aminoisobutyricinjury, as well as augmented myocardial contractility [30]. acid. When taspoglutide is prepared in zinc chloride, itMoreover, incretin-based therapy improves markers for precipitates after subcutaneous injection, resulting in a slowcardiovascular diseases, as evident by reduction in blood dissociation that prolongs the action, making it suitable forVolume 13 No. (Suppl. 1) October 2011 doi:10.1111/j.1463-1326.2011.01457.x 161
  5. 5. review article DIABETES, OBESITY AND METABOLISMonce-weekly administration. Taspoglutide has finished phase may be explained by methodological and clinical differences3 development with good efficacy [33]. However, frequent between studies. Overall, however, there does not seem to be areports of hypersensitivity and gastrointestinal adverse events generalized defective GLP-1 secretion in type 2 diabetes.have occurred in these trials [30]; therefore, the development The L-cells are of the open-type endocrine cells with apicalprogramme of taspoglutide has been halted. processes extending to the lumen of the gut. This enables Yet another approach to prolong duration is to couple GLP-1 the cells to sense nutrients in the gut lumen, which initiatesto albumin. This approach has been undertaken in albiglutide, cellular mechanisms promoting GLP-1 secretion [36]. Forin which a dimer of GLP-1 (with amino acid number 2 carbohydrates, the mechanism involves the sodium-coupledexchanged for glycine) is genetically fused with human serum glucose transporter 1 (SGLT1) [36]. This transporter co-albumin. This substantially prolongs the duration of action. transports one glucose molecule and two sodium ions; theAlbiglutide is administered once weekly, once biweekly or once sodium influx generates an inward current that initiatesmonthly. One study has shown that in a 16-week treatment in membrane depolarization, resulting in secretion of GLP-1patients with type 2 diabetes who are inadequately controlled into the blood stream. Proteins stimulate GLP-1 secretionwith diet and exercise or metformin, albiglutide reduced through amino acid-induced depolarization of the plasmaHbA1c by ∼0.8% (9 mmol/mol) from a baseline of 8.0% membrane, although the signalling mechanisms differ between(64 mmol/mol) in association with reduction in body weight amino acids. Fat stimulates GLP-1 secretion through activation(by 1.1–1.7 kg depending on the dose) with very low risk of of GPCRs expressed in the L-cells. Several GPCRs have beenhypoglycaemia and a low frequency of nausea [33]. discussed in this context [5]. GPR119 is coupled to Gs, thereby stimulating cAMP production; it is expressed in both L-cellsOrally Active GLP-1 Receptor Agonists and β-cells [37]. The endogenous ligand for GPR119 has not yet been finally identified, both phospholipids and fatty amides,As GPCRs have been widely used by the pharmaceutical such as oleoylethanolamide (OEA), lysophosphatidylcholineindustry for the development of a large number of orally and N-oleoyldopamine (OLDA), have been suggested [35].active agonists [5], there is a potential for producing small Another GPCR expressed both in L-cells and β-cells is GPR40,molecular orally available agonists also to the GLP-1 receptors. which is coupled to Gq thereby activating protein kinaseIn an attempt to develop this, two orally active substituted C and inositol-1-4-5-trisphosphate (IP3 )-mediated calciumcyclobutane GLP-1 receptor agonists were recently shown release [36]. GPR40 is mainly activated by saturated fatty acidsto improve glucose tolerance in db/db mice as well as having lengths from 10 to 23 carbons, but also by mono- orto reduce food intake in mice by mechanisms that are polyunsaturated fatty acids. It has also been shown that theinhibited by the GLP-1 receptor antagonist exendin9 – 39 [34]. GPCR GPR120 is expressed in intestinal L-cells [38]. LigandsAnother orally available GLP-1 receptor agonist, developed for GPR120 are both unsaturated and free fatty acids withby a specific formulation technique to allow facilitated carbon chain length between 14 and 22 carbons; the receptorabsorption, has reached human studies in development is coupled to Gq and cytosolic calcium.(NCT01037582). Much further study is required, however, In addition to these targets, a novel receptor (TGR5)to fully explore the avenue of oral administration of GLP-1 expressed in L-cells was recently discovered [39]. Activationreceptor agonists. of this receptor stimulates GLP-1 secretion. The endogenous ligands for TGR5 are bile acids, and it has been proposed thatStimulation of GLP-1 Secretion this receptor may be a target for incretin-based therapy [39].An important potential future development of incretin-basedtherapy is the generation of compounds that stimulate the Activation of GLP-1 Secretion as Potential Therapyrelease of endogenous GLP-1. This could preferentially be The cellular mechanisms responsible for nutrient-regulatedcombined with DPP-4 inhibition for stabilizing the released GLP-1 secretion are all potential targets for developing a therapyGLP-1 to enable a longer duration of action. Several different aiming at increasing the endogenous GLP-1 concentration.approaches have been undertaken to stimulate GLP-1 secretion Stimulation of GLP-1 secretion would result in increasedand develop GLP-1 secretagogues. This development is based circulating GLP-1 levels but also activate the local gut afferenton the knowledge of the normal physiological regulation of nerves thereby causing indirect effects. Hence, stimulation ofGLP-1 secretion from the enteroendocrine L-cells. secretion might be efficient even if circulating levels are not increased. This avenue is currently intensively explored andRegulation of GLP-1 Secretion From L-Cells some attempts have already been reported:After ingestion of a mixed meal, the plasma GLP-1 • In regard to sugars, it was shown several years agoconcentration starts to increase during the first 10 min; that the fructose analogue 1,5-anhydro-d-fructose (1,5-maximum concentration is reached after 30 min and the AF) stimulates GLP-1 secretion in mice [40]. 1,5-AF islevels return to baseline after 240 min. Furthermore, all formed through breakdown of glycogen by α-1,4-glucan.main macronutrients stimulate GLP-1 secretion [35]. Some Mice were gavaged with this sugar analogue at a dosestudies on the regulation of GLP-1 secretion have shown a of 150 mg/mouse in an oral glucose tolerance test, whichreduced secretion in type 2 diabetes and obesity, although increased circulating GLP-1 and insulin levels and improvedother studies have found similar rates [35]. These differences glucose tolerance [40]. Another sugar in this context is ´162 Ahren Volume 13 No. (Suppl. 1) October 2011
  6. 6. DIABETES, OBESITY AND METABOLISM review article α-methyl-d-glucopyranoside (MDG), which is a non- GLP-1 and responsiveness to stimuli. In one attempt, a DPP- metabolizable sugar substrate for SGLT1. MDG increases 4-resistant GLP-1-like peptide was expressed in hepatocytes GIP, GLP-1 and insulin levels and reduces glucose in normal under control of the liver-type pyruvate kinase promoter [46]. and diabetic db/db mice [41]. Hence, a glucose-like action to Transplantation of these GLP-1-expressing hepatocytes in stimulate SGLT1 in L-cells may be a potential target to raise encapsulated form into CD-1 mice increased plasma GLP-1 endogenous GLP-1 levels. levels and reduced glycaemia. Another study used a helper-• In regard to amino acids, it has been reported that glutamine dependent adenoviral (HDAd) vector for long-term expression stimulates GLP-1 secretion in both non-diabetic and diabetic of exendin-4 in mice [47]. After a single injection of the vector, subjects [42]. Glutamine was given orally at a dose of plasma exendin-4 levels were elevated for the 15-week study 30 g together with a 75 g glucose challenge and resulted period in high-fat fed mice, which improved glucose homeosta- in enhanced GIP, GLP-1 and insulin concentrations. sis and reduced hepatic fat without increasing insulin levels.• In regard to fat, most studies so far explored GPR119 [37]. Yet another study showed that fasting glucose was reduced up This receptor is expressed in both L- and β-cells and to 4 months after injection of a GLP-1 plasmid and double- may thereby upon activation increase insulin secretion stranded, adeno-associated viral (dsAAV) expression vector both through a direct β-cell action and indirectly through in db/db obese mice [48]. Also other approaches with gene GLP-1. Several small molecule GPR119 agonists have been therapy have been undertaken in experimental animals [49]. developed and examined in preclinical and early clinical studies [37]. The best described GPR119 agonist is AR231453, which is selective and potent and increases cAMP in Other Incretins and Bioactive clonal β-cells, GLP-1 secretion from GLUTag cells and Gastro-Entero-Pancreatic Hormones insulin secretion from rodent islets in a glucose-dependent Along the gastrointestinal tract and in the pancreatic islets, manner. It also increases plasma GLP-1 levels, potentiates many bioactive peptides are produced. Many of these stimulate insulin secretion and improves glycaemia during oral glucose insulin secretion and/or induce satiety, that is, have effects that tolerance in mice, particularly when combined with DPP-4 would be beneficial in type 2 diabetes. inhibition [43]. As administration of a GPR119 agonist in GIP is a 42 amino acid peptide produced in the intestinal combination with DPP-4 inhibition would be expected to K-cells. GIP is released after meal ingestion and stimulates augment the effects of each other, a single molecule with both insulin secretion [50]. It is, like GLP-1, inactivated by DPP-4 GPR119 agonistic and DPP-4 inhibitory influence may be and, consequently, circulating levels of intact GIP are increased of particular interest. One such compound (PSN-IV/119-1) by DPP-4 inhibition [11]. Nevertheless, the potential of GIP was reported to result in greater improvement of glycaemia receptor activation as a target to treat diabetes has been ham- than the DPP-4 inhibitor sitagliptin upon oral administration pered by the finding that the effect of GIP to stimulate insulin in ZDF rats [35]. Future and upcoming phase 2 trials with secretion is impaired in type 2 diabetes [51]. It has, however, GPR119 agonists will now be of great interest. recently been shown that 4-week normalization of hyper-• Another potential target is GPR40, because activation of this glycaemia (by insulin) restores the insulinotropic action of GPCR releases both GLP-1 and insulin, and GPR40 knock- GIP [52]. This suggests a potential for using GIP receptor out mice display impaired GLP-1 secretion [44]. Studies agonists as therapeutic agents after initial reduction of hyper- on GPR40 knockout mice have, however, given conflicting glycaemia. As recently reviewed, several GIP receptor agonists results [44]. These and other results, for example, that GPR40 have been developed and tested in preclinical models with might mediate the lipotoxic action on β-cell function (for good antihyperglycaemic action [50]. However, GIP stimulates a review see Ref. [5]), have questioned GPR40 as a fruitful rather than inhibits glucagon secretion [53] and stimulates target for treating the islet dysfunction in type 2 diabetes. lipogenesis, enhances fatty acid uptake and inhibits lipolysis• All three main macronutrients stimulate GLP-1 secre- in adipocytes [50]. These effects are negative for patients with tion [35]. Therefore, augmenting GLP-1 secretion through type 2 diabetes, rather their inhibition would be of advantage. macronutrient ingestion may also be a tentative approach for Therefore, inhibition of GIP receptors, rather than stimu- treatment, although this approach needs to be examined in lation, would be a therapeutic target [50]. In this context, relation to existing guidelines for dietary advice in diabetes. a number of GIP receptor antagonists have been developed One attempt which has been tried is the ‘preload concept’, and tested in various models. An interesting GIP receptor that is, ingestion of a small amount of macronutrients prior to antagonist is Pro3 -GIP, which has been shown to improve the meal to augment incretin hormone secretion to the main hyperglycaemia and insulin resistance in ob/ob mice [54]. How- meal. Accordingly, administration of whey protein (55 g) in ever, whether this approach is feasible in humans has not been 350 ml beef soup 30 min before a meal was found to augment studied yet. GLP-1 and lower glucose levels at the main meal in subjects Oxyntomodulin is a peptide which, like GLP-1, is processed with type 2 diabetes [45]. from the proglucagon gene and cleaved from proglucagon. It is released together with GLP-1 and is an agonist both for GLP-1 and glucagon receptors [55]. Oxyntomodulin hasGene Therapy been explored as a potential therapy of overweight, becauseAn alternative approach for increasing release of GLP-1 is both GLP-1 and glucagon receptor activation reduces bodygenetic manufacturing of cells resulting in high expression of weight, and acute administration of glucagon increases energyVolume 13 No. (Suppl. 1) October 2011 doi:10.1111/j.1463-1326.2011.01457.x 163
  7. 7. review article DIABETES, OBESITY AND METABOLISMexpenditure [56,57]. A drawback would be the stimulation of glucagon is therefore of importance in type 2 diabetes, andhepatic glucose production by glucagon receptor activation. the first therapy successful in this regard is in fact incretin-However, oxyntomodulin has been shown to reduce, rather based therapy [2]. A recent study showed that the reductionthan to increase, circulating glucose, which may be explained in glucagon by GLP-1 accounts for approximately 50% of theby its GLP-1 agonistic action overriding its glucagon receptor reduction in glucose, that is, it is of similar importance as theagonistic effect [58]. Oxyntomodulin is, like GLP-1, inactivated stimulation of insulin secretion [69].by DPP-4, and a DPP-4-resistant oxyntomodulin analogue On the basis of the knowledge that high glucagon contributeswas recently developed (OXM6421) showing reduced food to hyperglycaemia in type 2 diabetes, attempts have beenintake, increased energy expenditure and reduced body undertaken to develop glucagon receptor antagonists. Thisweight in rodents [59]. Several oxyntomodulin analogues are has been supported by studies using immunoneutralizationnow in preclinical development with the main interest in of glucagon and small molecules with glucagon antagonisticreducing body weight, with potential additional hope to reduce properties showing reduced glycaemia in experimentalglycaemia. animals [70,71]. However, this approach to treating diabetes Peptide YY (PYY) is a 36-amino acid peptide produced in has not been successfully developed yet, which might bethe L-cells and released after meal ingestion. After its release, due to the confounding effect of glucagon antagonism onPYY is cleaved by DPP-4 to PYY3 – 36 , which reduces appetite by liver function, energy expenditure and food intake. Furtheractivating neuropeptide Y subtype 2 receptors [60]. Infusion of studies are therefore required to establish whether glucagonPYY3 – 36 induces appetite in both lean and obese subjects, but antagonism alone is a potential target.its potential as an antiobesity agent is not clear, because PYYinfusion is associated with nausea and increased postprandialglucose [61]. Why PYY increases prandial glucose is not known, Co-agonistsbecause PYY does not affect insulin secretion when infused Acute administration of glucagon stimulates energy expendi-in humans [62]. Recently, PYY3 – 36 was suggested for use as ture and inhibits food intake [56,57]. An approach to treat typeantiobesity agent in combination with oxyntomodulin [63]. 2 diabetes would therefore be to stimulate the glucagon recep-This would allow augmented action on appetite suppression tors, provided that the hyperglycaemic effect of glucagon isthrough additive effects of PYY3 – 36 and oxyntomodulin and, prevented. This may be achieved by simultaneous stimulationat the same time, taking advantage of the glucose-reducing of GLP-1 receptors. One approach for this has recently beeneffect of oxyntomodulin. developed in single molecules with the combined property Cholecystokinin (CCK) is the gastrointestinal hormone of activating both glucagon and GLP-1 receptors [72]. Thesesecreted from the I-cells. It consists of several different molecules were glucagon analogues with additional GLP-1forms [64] and has appetite-suppressing effects. It has been receptor agonistic activity. They were PEGylated and couldtested in clinical trials in obesity, although with less success [6]. be administered once weekly. A month’s treatment with theseCCK also stimulates insulin secretion through a direct action co-agonists in diet-induced obese mice reduced body weight byon β-cells [65]. The infusion of the C-terminal octapeptide >20% which was mainly attributed to reduced fat mass. Foodof CCK (CCK-8) has in one study been shown to reduce intake was not altered in these mice, whereas energy expen-glucose and stimulate insulin secretion in type 2 diabetes [66]. diture was increased. A glucose tolerance test after 1 monthHowever, this potential has not been explored in further detail. showed improved glucose tolerance and lowered insulin lev- Ghrelin is a 27- or 28-amino acid peptide which is els, suggestive of improved insulin sensitivity. Other resultsacetylated through the endoplasmic reticulum enzyme ghrelin with these hybrid molecules in rodent models have shownO-acyltransferase (GOAT). It is predominantly produced in improved lipid metabolism via hormone-sensitive lipase andthe X/A-like cells in the oxyntic glands of the gastric fundus, uncoupling protein-1 (UCP-1) in brown adipose tissue [72].although it is expressed also in a number of other tissues, Therefore, both improved glycaemia and lipaemia along withsuch pancreatic islets and the brain [67]. It stimulates food reduced body weight were observed. The co-agonist concept isintake, which seems to be a physiological mechanism after thus an interesting and novel paradigm for the development offasting. Ghrelin also inhibits insulin secretion [68] and may glucagon and GLP-1 based therapy.also impair insulin sensitivity [67]. These effects suggest thatghrelin receptor antagonism may be a target for type 2diabetes treatment. Some studies on this approach have beenundertaken, however with inconclusive results [68]. Therefore, Summarywhether this is a good approach remains to be established. Incretin-based therapy for management of type 2 diabetes Glucagon is produced in islet α-cells and activates receptors represents a true breakthrough because it is an efficientin the liver which stimulate hepatic glucose production. Its treatment targeting the key islet defects in type 2 diabetesrole in the pathophysiology of type 2 diabetes has been and because the therapy is safe and associated with very lowneglected over past years, but today it is acknowledged anew risk of adverse events as evident after clinical experience ofthat the disease is associated with impaired suppression of several years. The development of incretin-based therapy alsoglucagon secretion; the inappropriately high glucagon levels illustrates a success for focused research strategies in drugresult in augmented hepatic glucose production and delivery, development. Incretin-based therapy is thus a good example ofthus increasing further blood glucose [2]. Targeting the high successful ‘bench-to-bedside’ clinical research. ´164 Ahren Volume 13 No. (Suppl. 1) October 2011
  8. 8. DIABETES, OBESITY AND METABOLISM review article Nevertheless, there is potential for further development 15. Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison ofof this therapy, both by developing the concept itself in liraglutide, glimepiride, and placebo, all in combination with metformin,regard to duration of action and by broadening the clinical in type 2-diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32: 84–90.indications. There is also potential for using the success ofGLP-1-based therapy to further develop the incretin concept 16. Rizzo M, Rizvi AA, Spinas GA, Rini GB, Berneis K. Glucose lowering andin the management of the disease. Of particular interest for anti-atherogenic effects of incretin-based therapies: GLP-1 analogues andcoming years is the development of small molecule GLP- DPP-4-inhibitors. Expert Opin Investig Drugs 2009; 18: 1495–1503.1 agonists, GLP-1 secretagogues and co-agonistic hybride 17. White J. Efficacy and safety of incretin based therapies: clinical trial data. Jmolecules combining the actions of GLP-1 with those of Am Pharm Assoc 2009; 49(Suppl. 1): S30–40.glucagon. We thus undoubtedly look forward to an interesting 18. Zeller M, Danchin N, Simon D et al. Impact of type or preadmissionfuture in regard to the development of incretin-based therapy sulfonylureas on mortality and cardiovascular outcomes in diabeticfor the management of patients with type 2 diabetes, and patients with acute myocardial infarction. J Clin Endocrinol Metab 2010;possibly also other diseases. 95: 4993–5002. 19. Khalangot M, Tronke M, Kravchenko V, Kovtun V. Glibenclamide related excess in total and cardiovascular mortality risks; data from large UkranianConflict of Interests observational cohort study. Diabetes Res Clin Pract 2009; 86: 247–253.The author discloses receipts of honoraria for lectures from 20. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control and vascular outcomes in patients withand/or memberships in advisory boards for AstraZeneca, GSK, type 2 diabetes. N Engl J Med 2008; 358: 2560–2572.Merck, Novartis, Novo Nordisk, Roche, Sanofi Aventis andServier, receipt of research grants from AstraZeneca, Merck 21. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in typeand Novartis, and membership of board of the Novo Nordisk 2 diabets. Diabetologia 2007; 50: 1148–1155.Foundation. 22. Williams-Herman D, Swern AS, Davies MJ, Katzeff HL, Stein PP. In patients with type 2 diabetes, sitagliptin effectively lowers A1C regardless of patient age, gender, or body mass index. Diabetes 2008; 57(Suppl. 1):References A148. 1. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. ´ 23. Matthews DR, Dejager S, Ahren B et al. Vildagliptin add-on to metformin Lancet 2006; 368: 1696–1705. produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride with no weight gain: results from a 2-year study. Diabet Obes ´ 2. Dunning BE, Foley J, Ahren B. Alpha-cell function in health and disease: Metab 2010; 12: 780–789. influence of GLP-1. Diabetologia 2005; 48: 1700–1713. ¨ 24. Schafer SA, Tschritter O, Machicao F et al. Impaired glucagon-like peptide- 3. Perfetti R, Hui H. The role of GLP-1 in the life and death of pancreatic 1-induced insulin secretion in carriers of transcription factor 7-like 2 beta-cells. Horm Metab Res 2004; 36: 804–810. (TCF7L2) gene polymorphism. Diabetologia 2007; 50: 2443–2450. ´ 4. Gutniak M, Ørskov C, Holst JJ, Ahren B, Efendic S. Antidiabetic effect of ¨ 25. Schafer SA, Mussig K, Staiger H et al. A common genetic variant in WFS1 ¨ glucagon-like peptide-1 (7–36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 1992; 326: 1316–1322. determines impaired glucagon-like peptide-1-induced insulin secretion. Diabetologia 2009; 52: 1075–1082. ´ 5. Ahren B. Islet G-protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat Rev Drug Discov 2009; 8: 369–385. 26. Rother KI, Spain LM, Wesley RA et al. Effects of exenatide alone and in combination with daclizumab on ß-cell function in long-standing type 1 ´ 6. Ahren B. GLP-1 for type 2 diabetes. Exp Cell Res 2011; 317: 1239–1245. diabetes. Diabetes Care 2009; 32: 2251–2257. 7. Robles GI, Singh-Franco D. A review of exenatide as adjunctive therapy in 27. Foley JE, Liqueros-Saulan M, He YL et al. Effect of vildagliptin on glucagon patients with type 2 diabetes. Drug Des Dev Ther 2009; 3: 219–240. concentration during meals in patients with type 1 diabetes. Horm Metab 8. Knudsen LB. Liraglutide: the therapeutic promise from animal models. Int Res 2008; 40: 727–730. J Clin Pract Suppl 2010; 64: 4–11. 28. Gangemi A, Salehi P, Hatipoglu B et al. Islet transplantation for brittle type 9. Buse JB, Rosenstock J, Sesti G et al. Liraglutide once a day versus exenatide 1 diabetes: the UIC protocol. Am J Transplant 2008; 8: 1250–1261. twice a day for type 2 diabetes: a 26-week randomized, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 39–47. ¨ 29. Astrup A, Rossner S, Van Gaal L et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet ´10. Ahren B. Clinical results of treating type 2 diabetic patients with sitagliptin, 2009; 374: 1606–1616. vildagliptin or saxagliptin—diabetes control and potential adverse events. Best Pract Res Clin Endocrinol Metab 2009; 23: 487–498. 30. Treiman M, Elvewkjaer M, Engstrøm T, Jensen JS. Glucagon-like peptide 1—a cardiologic dimension. Trends Cardiovasc Med 2010; 20: 8–12. ´11. Ahren B, Foley JE. The islet enhancer vildagliptin: mechanisms of improved glucose metabolism. Int J Clin Pract Suppl 2008; 159: 8–14. 31. Harkavyi A, Whitton PS. Glucagon-like peptide 1 receptor stimulation as a12. Cho YM, Kieffer TJ. New aspect of an old drug: metformin as a glucagon- means of neuroprotection. Br J Pharmacol 2010; 159: 495–501. like peptide 1 (GLP-1) enhancer and sensitizer. Diabetologia 2011; 54: 32. Buse JB, Drucker DJ, Taylor KL et al. Duration-1: exenatide once weekly 219–222. produces sustained glycemic control and weight loss over 52 weeks. ´13. Ahren B. Are sulfonylureas less desirable than DPP-4 inhibitors as add-on Diabetes Care 2010; 33: 1255–1261. to metformin in the treatment of type 2 diabetes? Curr Diabet Rev 2011; 33. Madsbad S, Kielgast U, Asmar M, Deacon C, Torekov SS, Holst JJ. An 11: 83–90. overview of once-weekly GLP-1 receptor agonists—available efficacy14. Derosa G, Maffioli P, Salvadeo SAT et al. Exenatide versus glibenclamide and safety data and perspectives for the future. Diabetes Obes Metab in patients with diabetes. Diabetes Technol Ther 2010; 12: 233–240. 2011; 13: 394–407.Volume 13 No. (Suppl. 1) October 2011 doi:10.1111/j.1463-1326.2011.01457.x 165
  9. 9. review article DIABETES, OBESITY AND METABOLISM34. Chen D, Liao J, Li N et al. A nonpeptidic agonist of glucagon-like peptide 1 53. Meier JJ, Gallwitz B, Siepmann N et al. Gastric inhibitory polypeptide receptors with efficacy in diabetic db/db mice. Proc Natl Acad Sci U S A (GIP) dose-dependently stimulates glucagon secretion in healthy human 2007; 104: 943–948. subjects at euglycaemia. Diabetologia 2003; 46: 798–801. ´35. Ahren B, Carr RD, Deacon CF. Incretin hormone secretion over the day. 54. McClean PL, Irwin N, Cassidy RS, Holst JJ, Gault VA, Flatt PR. GIP receptor Vitam Horm 2010; 84: 203–220. antagonism reverses obesity, insulin resistance, and associated metabolic36. Parker HE, Reimann F, Gribble FM. Molecular mechanisms underlying disturbances induced in mice by prolonged consumption of high-fat diet. nutrient-stimulated incretin secretion. Exp Rev Mol Med 2010; 12: e1. Am J Physiol 2007; 293: E1746–1755.37. Shah U, Kowalski TJ. GPR119 agonists for the potential treatment of type 2 55. Pocai Y, Carrington PE, Adams JR et al. Glucagon-like peptide 1/glucagon diabetes and related metabolic disorders. Vitam Horm 2010; 84: 415–448. receptor dual agonism reverses abesity in mice. Diabetes 2009; 58: 2258–2266.38. Hirasawa A, Tsumaya K, Awaji T et al. Fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 2005; 11: 56. Chan EK, Mackey MA, Snover DC et al. Suppression of weight-gain by 90–94. glucagon in obese Zucker rats. Exp Mol Pathol 1984; 40: 320–327.39. Thomas C, Gioiello A, Noriega L et al. TGR5-mediated bile acid sensing 57. Nair KS. Hyperglucagonemia increases resting metabolic rate in man controls glucose homeostasis. Cell Metab 2010; 10: 167–177. during insulin deficiency. J Clin Endocrinol Metab 1987; 64: 896–901. ´40. Ahren B, Holst JJ, Yu S. 1,5-Anhydro-D-fructose increases glucose tolerance ¨ 58. Parlevliet ET, Heijboer AC, Schroder-van der Elst JP et al. Oxyntomodulin by increasing glucagon-like peptide-1 and insulin in mice. Eur J Pharmacol ameliorates glucose intolerance in mice fed a high-fat diet. Am J Physiol 2000; 397: 219–225. 2008; 294: E142–147.41. Moriya R, Shirakura T, Ito J, Mashiko S, Seo T. Activation of sodum-glucose 59. Liu YL, Ford HE, Druce MR et al. Subcutaneous oxyntomodulin analogue cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion administration reduces body weight in lean and obese rodents. Int J Obes in mice. Am J Physiol 2009; 297: E1358–1365. 2010; 34: 1715–1725.42. Greenfield JR, Farooqi IS, Keogh JM et al. Oral glutamine increases 60. le Roux CW, Bloom SR. Peptide YY, appetite and food intake. Proc Nutr circulating glucagon-like peptide 1, glucagon and insulin concentrations Soc 2005; 64: 213–216. in lean, obese, and type 2 diabetic subjects. Am J Clin Nutr 2009; 89: 61. Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A. Effects of PYY1-36 and 106–113. PYY3-36 on appetite, energy intake, energy expenditure, glucose and43. Chu ZL, Carroll C, Alfonso J et al. A role for intestinal endocrine cell- fat metabolism in obese and lean subjects. Am J Physiol 2007; 292: expressed G protein-coupled receptor 119 in glycemic control by E1062–1068. enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic ´ 62. Ahren B, Larsson H. Peptide YY does not inhibit glucose-stimulated insulin peptide release. Endocrinology 2008; 149: 2038–2047. secretion in humans. Eur J Endocrinol 1996; 134: 362–365.44. Kebede MA, Alquier T, Latour MG, Poitout V. Lipid receptors and islet 63. Field BC, Wren AM, Peters V et al. PYY3-36 and oxyntomodulin can be function: therapeutic implications? Diabetes Obes Metab 2009; 11(Suppl. additive in their effect on food intake in overweight and obese humans. 4): 10–20. Diabetes 2010; 59: 1635–1639.45. Ma J, Stevens JE, Cukier K et al. Effects of a protein preload on gastric 64. Neary MT, Batterham RL. Gut hormones: implications for the treatment of emptying, glycemia, and gut hormones after a carbohydrate meal in obesity. Pharmacol Ther 2009; 124: 44–56. diet-controlled type 2 diabetes. Diabetes Care 2009; 32: 1600–1602. ´ 65. Karlsson S, Ahren B. Cholecystokinin and the regulation of insulin secretion.46. Riedel MJ, Lee CW, Kieffer TJ. Engineered glucagon-like peptide-1- Scand J Gastroenterol 1992; 27: 161–165. producing hepatocytes lower plasma glucose levels in mice. Am J Physiol ´ 66. Ahren B, Holst JJ, Efendic S. Antidiabetogenic action of cholecystokinin-8 2009; 296: E936–944. in type 2 diabetes. J Clin Endocrinol Metab 2000; 85: 1043–1048.47. Samson SL, Gonzalez EV, Yechoor V, Bajaj M, Oka K, Chan L. Gene therapy ¨ 67. Castaneda TR, Jong T, Datta R, Culler M, Tschop MH. Ghrelin in the for diabetes: metabolic effects of helper-dependent adenoviral exendin 4 regulation of body weight and metabolism. Front Neuroendocrinol 2010; expression in a diet-induced obesity mouse model. Mol Ther 2008; 16: 31: 44–60. 1805–1812. 68. Tong J, Prigeon RL, Davis HW et al. Ghrelin suppresses glucose-stimulated48. Choi SH, Lee HC. Long-term, antidiabetogenic effects of GLP-1 gene insulin secretion and deteriorates glucose tolerance in healthy humans. therapy using a double-stranded, adeno-associated viral vector. Gene Diabetes 2010; 59: 2145–2151. Ther 2011; 18: 155–163. 69. Hare KJ, Vilsbøll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagono-49. Riedel MJ, Kieffer TJ. Treatment of diabetes with glucagon-like peptide-1 static and insulinotropic effects of glucagon-like peptide 1 contribute gene therapy. Expert Opin Biol Ther 2010; 10: 1681–1692. equally to its glucose-lowering action. Diabetes 2010; 59: 1765–1770.50. Irwin N, Flatt PR. Therapeutic potential for GIP receptor agonist and 70. Madsen P, Kodra JT, Behrens C et al. Human glucagon receptor antagonists antagonists. Best Pract Res Clin Endocrinol Metab 2009; 23: 499–512. with thiazole cores. A novel series with superior pharmacokinetic51. Nauck MA, Heimesaat MM, Ørskov C et al. Preserved incretin activity of properties. J Med Chem. 2009; 52: 2989–2300. glucagon-like peptide-1 [7–36 amide] but not ot synthetic human gastric 71. Winzell MS, Brand CL, Wierup N et al. Glucagon receptor antagonism inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin improves islet function in mice with insulin resistance induced by a Invest 1993; 91: 301–307. high-fat diet. Diabetologia 2007; 50: 1453–1462.52. Højberg PV, Vilsbøll T, Rabøl R et al. Four weeks of near-normalisation of 72. Day JW, Ottaway N, Patterson JT et al. A new glucagon and GLP-1 blood glucose improves the insulin response to glucagon-like peptide-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 2009; 10: and glucose-dependent insulinotropic polypeptide in patients with type 2 749–757. diabetes. Diabetologia 2009; 52: 199–207. ´166 Ahren Volume 13 No. (Suppl. 1) October 2011