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.

1. review article
Diabetes, Obesity and Metabolism 13 (Suppl. 1): 158–166, 2011.
© 2011 Blackwell Publishing Ltd
article
review
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: Bo.Ahren@med.lu.se practice: GLP-1 receptor agonists and DPP-4 inhibitors.

2. DIABETES, OBESITY AND METABOLISM review article
Table 1. Potential novel avenues for future development of incretin- HbA1c and body weight. A 26-week head-to-head comparison
based 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. Liraglutide
2 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 than
3 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 unclear
4 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 Inhibitors
Incretin-Based Therapy of Today The alternative strategy for incretin-based therapy is inhi-
bition of the enzyme DPP-4. This prevents the inactivation
GLP-1 Receptor Agonists
of GLP-1, thus enhancing and prolonging the action of
The 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 insulinotropic
ical 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 catalytic
is based on exendin-4, which is the peptide, isolated from the site of DPP-4. They all have high bioavailability upon oral
parotid 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 and
exendin-4 and was introduced clinically in 2005. Exenatide is (in Japan only so far) alogliptin. They are efficient both in
given 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 reduce
baseline levels of 8.2–8.6% (66–70 mmol/mol) with body HbA1c by 0.6–1.1% (6–11 mmol/mol) from baseline levels
weight 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 weeks
in combination with sulphonylurea and/or metformin [7]. with very low risk of hypoglycaemia or other adverse events
Exenatide 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 which
vomiting, seen in 30–50% of patients during the initial weeks exists today shows that incretin-based therapy is efficient in
of therapy. A concern is that acute pancreatitis has occurred reducing glycaemia and has the advantages of being safe with
during treatment [6]. It is not clear, however, whether this is very little adverse events, low risk of hypoglycaemia and no
caused 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 which
the structure of exendin-4 has been prolonged by the addition Future Clinical Development of Existing
of six lysine residues to the C-terminal end. This prolongs the Incretin-Based Therapy
half-life, which enables the compound to be administered once
daily [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 used
the structure of native GLP-1, that is, they are true GLP-1 in several indications in type 2 diabetic patients with
analogues. In liraglutide, a C-16 acyl chain (palmitate) has insufficient glycaemic control, both as monotherapy and
been incorporated at amino acid 20 in the GLP-1 molecule in combination with other existing treatments. A main
via a γ -glutamic acid spacer, and the lysine in position 28 indication today in many guidelines is as add-on to
is exchanged with arginine [8]. The incorporation of the acyl metformin when metformin alone is insufficient for adequate
chain allows for non-covalent binding to albumin, which glycaemic control. The rationale for this algorithm is that
delays both the inactivation by DPP-4 and renal clearance metformin is the first-line pharmacological therapy for type
of the compound and results in a half-life of liraglutide 2 diabetes. The two approaches also complement each other
of 11–15 h. Liraglutide is administered once daily through from a mechanistic perspective. Thus, incretin-based therapy
the subcutaneous route. Liraglutide, like exenatide, reduces improves the islet dysfunction whereas metformin targets
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3. review article DIABETES, OBESITY AND METABOLISM
Table 2. Approved clinical indications for incretin-based therapy in reason behind the current guidelines advocating higher priority
patients with type 2 diabetes with insufficient glycaemic control by the for sulphonylureas than for incretin-based therapy is the
European 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 in
Exenatide X X X combination with insulin. This would improve glycaemia
Liraglutide X X X X without increasing the risk of hypoglycaemia and may also
Sitagliptin X∗ X X X X X X make it possible to reduce the insulin dose, as was shown with
Vildagliptin X X X vildagliptin [21].
Saxagliptin X X X
Met, 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 HbA1c
2 diabetes are targeted by this combination. Furthermore, of <7%. An important issue is whether there exist specific
metformin 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 possibility
effect between incretin-based therapy and metformin on of individualized therapy tailoring incretin-based treatment to
β-cell function. Several studies have documented good specific patient groups. This, however, has not been studied
clinical efficacy along with safety and tolerability with this extensively. What has been repeatedly shown in several clinical
combination [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 higher
Nevertheless, several recent studies have compared incretin- baseline HbA1c. Other characteristics documented in clinical
based therapy versus sulphonylurea as add-on to metformin in trials, such as BMI, gender or diabetes duration, however, do
patients 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 importance
with incretin-based therapy over certain sulphonylureas, for predicting a response, because incretin-based therapy acts
such as glipizide or glimepiride [13–15]. Thus, although the primarily on islet function. Hence, it may be speculated that
reduction 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 patients
hypoglycaemia and no weight gain (DPP-4 inhibitors) or with poor islet function would benefit most from a therapy
weight 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 one
of hypoglycaemia and weight gain. These studies would meta-analysis of clinical trials with sitagliptin did suggest that
therefore support the use of incretin-based therapy as add-on poor insulin secretion predicts a better response [22]. Whether
to metformin, instead of certain sulphonylureas. One reason this is a general phenomenon of incretin-based therapy, and
why incretin-based therapy has not replaced sulphonylureas holds true also when more appropriate measures of insulin
is 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 to
data. 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 metformin
improve during treatment with incretin-based therapy [16], therapy. The study showed first that vildagliptin exhibited better
and long-term studies with hard cardiovascular end points sustainability than glimepiride, as evident from coefficient of
are on-going with results expected in 2014–2015. In regard failure analyses, and second that age was an independent
to overall safety with incretin-based therapy, however, large predictor of sustainability [23]. The reason why age seems
collections 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 postprandial
sulphonylureas may be associated with adverse events, and there hyperglycaemia for glucose control and/or a more marked
are 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 important
glibenclamide [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 signalling
gliclazide [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 patient
between incretin-based therapy and sulphonylureas. Another suitability for treatment. In this context, it is of interest
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4. DIABETES, OBESITY AND METABOLISM review article
that carriers of transcription factor 7-like 2 (TCF7L2) gene pressure, total cholesterol, low-density lipoprotein cholesterol
polymorphism have impaired insulin secretory response to and triglyceride concentrations and increase in high-density
intravenously infused GLP-1 [24]. Similarly, subjects with a lipoprotein cholesterol levels in clinical trials [16]. These
genetic variant of Wolfram syndrome 1 gene (WFS1) have emerging effects may obviously be beneficial for patients
a 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 potential
TCF7L2 or WFS1 gene variants display impaired response to to use incretin-based therapy as adjunct to other treatments
incretin-based therapy is not known, but if so, this would open also in non-diabetic patients with cardiovascular diseases. In
the possibility for pretherapy testing for individualization of fact, a study on treatment with exenatide on infarct size and
treatment. The individualization of incretin-based therapy is, cardiac function when given as an infusion for 72 h in patients
however, 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 stimulate
Widening the Use to New Patient Groups cell growth and reduce apoptosis [31]. Experimental studies
A future development is broadening the use of incretin-based in various models of neurodegenerative disorders, such as
therapy to other patient groups. One potential new indication Alzheimer’s disease, Parkinson’s disease and stroke, have also
is 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-based
diabetes, as well as potentially expanding the β-cell mass, therapy also in these diseases. As recently reviewed, this seems
while 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 of
long-standing (mean 21 years) type 1 diabetes but found no exenatide in the treatment of Parkinson’s disease is ongoing
improvement 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 respond
to incretin-based therapy or that a 6-month period is too Pharmaceutical Development
short. Another study reported reduced meal-induced glucagon of Incretin-Based Strategies
response after treatment with vildagliptin [27], suggesting that
DPP-4 inhibition may be used in type 1 diabetes to lower Longer Duration of Action
glucagon. It has also been discussed whether incretin-based GLP-1 receptor agonists are injected subcutaneously twice
therapy could be initiated in patients with type 1 diabetes (exenatide) or once (liraglutide) daily. There is a development
after islet transplantation to allow preserved function of the to prolong the duration of action, to enable injections once
transplanted islets. One study showed that this might be weekly. The expectation is that this may have better glycaemic
possible; addition of exenatide to immunosuppression after effect with lower risk for adverse events, including nausea
islet transplantation showed improved islet graft function and vomiting, along with being more patient-friendly with a
and facilitated achievement of insulin independence with less lower number of injections. Prolonged durability to allow
islets [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. This
exenatide and liraglutide in a number of studies; body weight long-acting form was recently shown to have a better glycaemic
is usually reduced by 3–5 kg after 1–2 years [6]. This has effect than conventional exenatide given twice daily in a study
motivated studies on the use of GLP-1 in subjects with obesity over 52 weeks, but the reduction in body weight did not
without type 2 diabetes. In a large trial in obese patients (BMI differ [32]. The reduction in HbA1c by exenatide LAR was
30–40 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 by
reduced 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 in
with the comparator orlistat [29]. This was associated with only 7% of the patients. Similar results have been reported
reduced glucose levels and would support the use of GLP-1- in the comprehensive clinical development programme that
based therapy in obesity. Further studies are now on-going to exists for exenatide LAR and in which the compound is
establish whether GLP-1-based therapy also has a place in the examined both as monotherapy and as add-on to metformin
management 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-aminoisobutyric
injury, as well as augmented myocardial contractility [30]. acid. When taspoglutide is prepared in zinc chloride, it
Moreover, incretin-based therapy improves markers for precipitates after subcutaneous injection, resulting in a slow
cardiovascular diseases, as evident by reduction in blood dissociation that prolongs the action, making it suitable for
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5. review article DIABETES, OBESITY AND METABOLISM
once-weekly administration. Taspoglutide has finished phase may be explained by methodological and clinical differences
3 development with good efficacy [33]. However, frequent between studies. Overall, however, there does not seem to be a
reports 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 apical
programme 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 initiates
to albumin. This approach has been undertaken in albiglutide, cellular mechanisms promoting GLP-1 secretion [36]. For
in which a dimer of GLP-1 (with amino acid number 2 carbohydrates, the mechanism involves the sodium-coupled
exchanged 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; the
Albiglutide is administered once weekly, once biweekly or once sodium influx generates an inward current that initiates
monthly. One study has shown that in a 16-week treatment in membrane depolarization, resulting in secretion of GLP-1
patients with type 2 diabetes who are inadequately controlled into the blood stream. Proteins stimulate GLP-1 secretion
with diet and exercise or metformin, albiglutide reduced through amino acid-induced depolarization of the plasma
HbA1c 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 been
hypoglycaemia 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-cells
Orally 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), lysophosphatidylcholine
industry 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 kinase
In an attempt to develop this, two orally active substituted C and inositol-1-4-5-trisphosphate (IP3 )-mediated calcium
cyclobutane GLP-1 receptor agonists were recently shown
release [36]. GPR40 is mainly activated by saturated fatty acids
to improve glucose tolerance in db/db mice as well as
having lengths from 10 to 23 carbons, but also by mono- or
to reduce food intake in mice by mechanisms that are
polyunsaturated fatty acids. It has also been shown that the
inhibited by the GLP-1 receptor antagonist exendin9 – 39 [34].
GPCR GPR120 is expressed in intestinal L-cells [38]. Ligands
Another orally available GLP-1 receptor agonist, developed
for GPR120 are both unsaturated and free fatty acids with
by a specific formulation technique to allow facilitated
carbon chain length between 14 and 22 carbons; the receptor
absorption, 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]. Activation
receptor agonists.
of this receptor stimulates GLP-1 secretion. The endogenous
ligands for TGR5 are bile acids, and it has been proposed that
Stimulation of GLP-1 Secretion this receptor may be a target for incretin-based therapy [39].
An important potential future development of incretin-based
therapy is the generation of compounds that stimulate the Activation of GLP-1 Secretion as Potential Therapy
release of endogenous GLP-1. This could preferentially be The cellular mechanisms responsible for nutrient-regulated
combined with DPP-4 inhibition for stabilizing the released GLP-1 secretion are all potential targets for developing a therapy
GLP-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 increased
and develop GLP-1 secretagogues. This development is based circulating GLP-1 levels but also activate the local gut afferent
on the knowledge of the normal physiological regulation of nerves thereby causing indirect effects. Hence, stimulation of
GLP-1 secretion from the enteroendocrine L-cells. secretion might be efficient even if circulating levels are not
increased. This avenue is currently intensively explored and
Regulation 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 ago
concentration 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 is
levels 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 dose
studies on the regulation of GLP-1 secretion have shown a of 150 mg/mouse in an oral glucose tolerance test, which
reduced secretion in type 2 diabetes and obesity, although increased circulating GLP-1 and insulin levels and improved
other studies have found similar rates [35]. These differences glucose tolerance [40]. Another sugar in this context is
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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 has
Gene Therapy been explored as a potential therapy of overweight, because
An alternative approach for increasing release of GLP-1 is both GLP-1 and glucagon receptor activation reduces body
genetic manufacturing of cells resulting in high expression of weight, and acute administration of glucagon increases energy
Volume 13 No. (Suppl. 1) October 2011 doi:10.1111/j.1463-1326.2011.01457.x 163

7. review article DIABETES, OBESITY AND METABOLISM
expenditure [56,57]. A drawback would be the stimulation of glucagon is therefore of importance in type 2 diabetes, and
hepatic 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 reduction
than to increase, circulating glucose, which may be explained in glucagon by GLP-1 accounts for approximately 50% of the
by its GLP-1 agonistic action overriding its glucagon receptor reduction in glucose, that is, it is of similar importance as the
agonistic 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 contributes
was recently developed (OXM6421) showing reduced food to hyperglycaemia in type 2 diabetes, attempts have been
intake, increased energy expenditure and reduced body undertaken to develop glucagon receptor antagonists. This
weight in rodents [59]. Several oxyntomodulin analogues are has been supported by studies using immunoneutralization
now in preclinical development with the main interest in of glucagon and small molecules with glucagon antagonistic
reducing body weight, with potential additional hope to reduce properties showing reduced glycaemia in experimental
glycaemia. 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 be
the L-cells and released after meal ingestion. After its release, due to the confounding effect of glucagon antagonism on
PYY is cleaved by DPP-4 to PYY3 – 36 , which reduces appetite by liver function, energy expenditure and food intake. Further
activating neuropeptide Y subtype 2 receptors [60]. Infusion of studies are therefore required to establish whether glucagon
PYY3 – 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 PYY
infusion is associated with nausea and increased postprandial
glucose [61]. Why PYY increases prandial glucose is not known, Co-agonists
because 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 type
antiobesity 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 is
through additive effects of PYY3 – 36 and oxyntomodulin and,
prevented. This may be achieved by simultaneous stimulation
at the same time, taking advantage of the glucose-reducing
of GLP-1 receptors. One approach for this has recently been
effect 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]. These
secreted from the I-cells. It consists of several different
molecules were glucagon analogues with additional GLP-1
forms [64] and has appetite-suppressing effects. It has been
receptor agonistic activity. They were PEGylated and could
tested in clinical trials in obesity, although with less success [6].
be administered once weekly. A month’s treatment with these
CCK also stimulates insulin secretion through a direct action
co-agonists in diet-induced obese mice reduced body weight by
on β-cells [65]. The infusion of the C-terminal octapeptide
>20% which was mainly attributed to reduced fat mass. Food
of 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 month
However, 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 results
acetylated through the endoplasmic reticulum enzyme ghrelin
with these hybrid molecules in rodent models have shown
O-acyltransferase (GOAT). It is predominantly produced in
improved lipid metabolism via hormone-sensitive lipase and
the 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 with
such pancreatic islets and the brain [67]. It stimulates food
reduced body weight were observed. The co-agonist concept is
intake, which seems to be a physiological mechanism after
thus an interesting and novel paradigm for the development of
fasting. Ghrelin also inhibits insulin secretion [68] and may
glucagon and GLP-1 based therapy.
also impair insulin sensitivity [67]. These effects suggest that
ghrelin receptor antagonism may be a target for type 2
diabetes treatment. Some studies on this approach have been
undertaken, however with inconclusive results [68]. Therefore, Summary
whether 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 efficient
in the liver which stimulate hepatic glucose production. Its treatment targeting the key islet defects in type 2 diabetes
role in the pathophysiology of type 2 diabetes has been and because the therapy is safe and associated with very low
neglected over past years, but today it is acknowledged anew risk of adverse events as evident after clinical experience of
that the disease is associated with impaired suppression of several years. The development of incretin-based therapy also
glucagon secretion; the inappropriately high glucagon levels illustrates a success for focused research strategies in drug
result in augmented hepatic glucose production and delivery, development. Incretin-based therapy is thus a good example of
thus increasing further blood glucose [2]. Targeting the high successful ‘bench-to-bedside’ clinical research.
´
164 Ahren Volume 13 No. (Suppl. 1) October 2011

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 of
of 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 of
GLP-1-based therapy to further develop the incretin concept 16. Rizzo M, Rizvi AA, Spinas GA, Rini GB, Berneis K. Glucose lowering and
in the management of the disease. Of particular interest for anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and
coming 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. J
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glucagon. We thus undoubtedly look forward to an interesting 18. Zeller M, Danchin N, Simon D et al. Impact of type or preadmission
future in regard to the development of incretin-based therapy sulfonylureas on mortality and cardiovascular outcomes in diabetic
for the management of patients with type 2 diabetes, and patients with acute myocardial infarction. J Clin Endocrinol Metab 2010;
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Conflict 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 with
and/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 and
Servier, 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 type
and 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):
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