Anorexigenic Effects of GLP-1 and Its Analogues

Abstract

GLP-1 receptors are expressed in the brain, especially in the regions responsible for the regulation of food intake, and intracerebroventricular injection of GLP-1 results in inhibition of food intake. Peripheral administration of GLP-1 dose-dependently enhances satiety and reduces food intake in normal and obese subjects as well as in type 2 diabetic patients. So far, the mechanisms by which GLP-1 exerts its effects are not completely clear. Interactions with neurons in the gastrointestinal tract or possibly direct access to the brain through the blood-brain barrier as observed in rats are possible and discussed in this chapter as well as a novel hypothesis based on the finding that GLP-1 is also expressed in taste cells. Finally, the role of GLP-1 receptor agonists as a possible treatment option in obesity is discussed as well as the role of GLP-1 in the effects of bariatric surgery on adiposity and glucose homeostasis.

Full text

Anorexigenic Effects of GLP-1 and Its Analogues
Baptist Gallwitz
Contents
1 Incretin Hormones................... ....................................................... 186
2 Biosynthesis of GLP-1 and Overview on Its Pleiotropic Actions ........................ 186
3 Central Effects of GLP-1 . . . . . . ............................................................. 189
3.1 Direct Dentral Effects of GLP-1 in the Hypothalamus ............................. 189
3.2 GLP-1 in Taste Cells . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 192
3.3 Central Effects of GLP-1 Influencing Gastrointestinal Functions .................. 192
4 Peripheral Effects of GLP-1 Affecting Satiety . . . ......................................... 193
5 Effects of GLP-1 Receptor Agonists on Body Weight in Humans . . . .................... 196
6 GLP-1 and Bariatric Surgery . . . ............................................................ 199
References ....................................... ................................................ 201
Abstract GLP-1 receptors are expressed in the brain, especially in the regions
responsible for the regulation of food intake, and intracerebroventricular injection
of GLP-1 results in inhibition of food intake. Peripheral administration of GLP-1
dose-dependently enhances satiety and reduces food intake in normal and obese
subjects as well as in type 2 diabetic patients. So far, the mechanisms by which
GLP-1 exerts its effects are not completely clear. Interactions with neurons in the
gastrointestinal tract or possibly direct access to the brain through the blood–brain
barrier as observed in rats are possible and discussed in this chapter as well as
a novel hypothesis based on the finding that GLP-1 is also expressed in taste cells.
Finally, the role of GLP-1 receptor agonists as a possible treatment option in obesity
is discussed as well as the role of GLP-1 in the effects of bariatric surgery on
adiposity and glucose homeostasis.
B. Gallwitz (*)
Medizinische Klinik IV, Otfried-M€
uller-Str. 10, 72076 T€
ubingen, Germany
e-mail: baptist.gallwitz@med.uni-tuebingen.de
H.-G. Joost (ed.), Appetite Control, Handbook of Experimental Pharmacology 209,
DOI 10.1007/978-3-642-24716-3_8, #Springer-Verlag Berlin Heidelberg 2012
185

Keywords Bariatric surgery • GLP-1 • GLP-1 receptor agonists • Gut-brain axis •
Incretins • Obesity
1 Incretin Hormones
Upon stimulation by nutrients after a meal, the intestinal mucosa secretes the
gastrointestinal hormones GLP-1 and GIP (gastric inhibitory polypeptide or glu-
cose-dependent insulinotropic polypeptide) from the endocrine L and K cells,
respectively (Wellendorph et al. 2009). Both hormones are responsible for approxi-
mately 60% of the postprandial insulin secretion and contribute to the so-called
incretin effect. This effect describes the phenomenon that orally ingested glucose
leads to a much larger insulin response than an isoglycemic, intravenous glucose
load (Creutzfeldt 1979; Nauck et al. 1986).
Exogenous GLP-1 application either by subcutaneous or intravenous injection
resulting in supraphysiological GLP-1 plasma concentrations restores the incretin
effect with an adequate insulin response under hyperglycemic conditions (Nauck
et al. 1993).
2 Biosynthesis of GLP-1 and Overview on Its Pleiotropic
Actions
The glucagon gene encodes a large peptide sequence of 158 amino acids that
contains not only the sequence of glucagon but also that of other peptides that are
formed posttranslationally by organ-specific and cell-specific processing (Bell et al.
1983; Holst et al. 2007; Ørskov et al. 1987). In the neuroendocrine L cells of the
intestinal mucosa and in the central nervous system, preproglucagon is cleaved
mainly to generate GLP-1. In the pancreatic alpha cells of the islets, glucagon is the
major biologically active peptide generated from preproglucagon. Figure 1shows
the schematic tissue-specific posttranslational processing of GLP-1.
GLP-1 binds to highly specific GLP-1 receptors that belong to the G protein
coupled seven-transmembrane-spanning (7TM) receptors (Drucker and Nauck
2006). After binding to its receptor, adenylate cyclase is activated, and GLP-1
effects are mediated mainly via the cAMP and protein kinase A pathways
(Gromada et al. 1996; Reimer 2006). GLP-1 shows numerous physiological actions
in various tissues and a broad therapeutic potential (see Fig. 2for details).
The two most important metabolic actions of GLP-1 are that it stimulates insulin
secretion of the pancreatic beta cells and additionally inhibits glucagon secretion
from the alpha cells. These two actions on the islet occur in a strictly glucose-
dependent manner and lead to a normalization of hyperglycemia. Under hypogly-
cemic conditions, the counter-regulation by glucagon is not affected, and insulin
secretion is not stimulated. GLP-1 is therefore not able to elicit hypoglycemia by
186 B. Gallwitz

itself. These physiological properties of GLP-1 later translated into the pharmaco-
therapy of type 2 diabetes with incretin-based therapies (Drucker and Nauck 2006).
Like other gastrointestinal regulatory peptides, GLP-1 has multiple further
actions. In the gastrointestinal tract, GLP-1 slows gastric emptying after a meal.
This effect also contributes to a normalization of postprandial hyperglycemia,
promotes a feeling of fullness and possibly a secondary reduction of appetite
(Meier et al. 2003a; Holst et al. 2008). In addition, GLP-1 binds to its receptor on
hypothalamic neurons and stimulates satiety by direct actions described in detail in
this chapter. These two satiety-promoting effects explain that long-term treatment
with GLP-1 receptor agonists leads to long-term weight loss that persists as long as
GLP-1 is given (Drucker and Nauck 2006).
Animal studies in different rodent species and studies in isolated human islets
showed beneficial long-term actions of GLP-1: insulin synthesis is stimulated, and
beta-cell mass is restored in rodent models of type 2 diabetes (Brubaker and
Drucker 2004; Drucker and Nauck 2006; Fehmann and Habener 1992). Presently,
it is not known whether these findings reflect an additional benefit in type 2 diabetes
therapy in that GLP-1 slows or even stops disease progression. Long-term study
data from clinical studies or clinical use of GLP-1 receptor agonists (GLP-1 RA) in
type 2 diabetes with a sufficient observation time are still not yet available.
delays gastri c em ptyin g
reduces di gestive secretions
delays gastri c em ptyin g
reduces di gestive secretions
stimulates muco sal growth
stimulates hepatic
glucose pruduction
functi ons
see Fig. 2
Fig. 1 Posttranslational processing of proglucagon in different tissues. Differential posttransla-
tional processing of proglucagon in the pancreas and in the gut and brain. The numbers indicate
amino acid positions in the 160-amino acid proglucagon sequence. The vertical lines indicate
positions of basic amino acid residues, typical cleavage sites. GRPP glicentin-related pancreatic
polypeptide, IP-1 intervening peptide-1, IP-2 intervening peptide-2. The major known biological
actions of the peptides resulting from proglucagon processing are also shown (adapted from Holst
2007 and Pellissier et al. 2004)
Anorexigenic Effects of GLP-1 and Its Analogues 187

Furthermore, there are presently no reliable, validated methods to quantify beta cell
mass in humans in a clinical setting.
Additionally, recent studies demonstrated that therapeutic application of GLP-1
or GLP-1 RA improved cardiovascular parameters. Systolic blood pressure is
lowered by GLP-1 RA treatment for type 2 diabetes, and beneficial effects of
GLP-1 on myocardial ischemia were observed in animal models as well as positive
effects on left ventricular function in heart failure. These promising effects may
also have important clinical implications for type 2 diabetes therapy with GLP-1
RA (Courreges et al. 2008; Klonoff et al. 2008; Sokos et al. 2006).
GLP-1 receptors are also expressed in the brain, especially in the regions
responsible for the regulation of food intake (G€
oke et al. 1995), and intracerebro-
ventricular injection of GLP-1 results in inhibition of food intake (Tang-Christensen
Heart
Cardioprotection
Neuroprotection
Appetite
Gastric emptying
Glucose production
Insulin secretion
Glucagon secretion
Insulin biosynthesis
β-cell proliferation
β-cell apoptosis
Glucose uptake
and stora
g
e
Cardiac function
Brain
Intestine
Liver
Adipose
tissue Muscle
Insulin
sensitivity
Stomach
Pancreas
Fig. 2 GLP-1 actions in peripheral tissues. The majority of the effects of GLP-1 are mediated by
direct interaction with GLP-1Rs on specific tissues. However, the actions of GLP-1 in liver, fat,
and muscle most likely occur through indirect mechanisms (adapted from Baggio and Drucker
2007)
188 B. Gallwitz

et al. 1996; Turton et al. 1996). Peripheral administration of GLP-1 dose-depen-
dently enhances satiety and reduces food intake in normal subjects (Flint et al. 1998;
Verdich et al. 2001), obese subjects (N€
aslund et al. 1999), and type 2 diabetic
patients (Gutzwiller et al. 1999; Zander et al. 2002). The mechanisms by which
GLP-1 exerts its effects are not completely clear yet. Interactions with neurons in the
gastrointestinal tract or possibly direct access to the brain through as observed in rats
(Ørskov et al. 1996) are possible and discussed in this chapter as well as other novel
hypothesis based on the finding that GLP-1 is also expressed in taste cells. Finally,
the role of GLP-1 receptor agonists as possible treatment options in obesity is
discussed as well as the role of GLP-1 in the weight losing and metabolic effects
after various methods of bariatric surgery.
3 Central Effects of GLP-1
3.1 Direct Dentral Effects of GLP-1 in the Hypothalamus
As early as in 1988, it was shown that GLP-1 is also synthesized in the CNS in the
caudal part of the nucleus of the solitary tract (Jin et al. 1988) in addition to its
peripheral synthesis in the intestinal L cell. Receptors for GLP-1 are expressed
throughout the brain widely, with highest levels in the paraventricular nucleus
(Larsen et al. 1997b; Van Dijk et al. 1996; Turton et al. 1996). The presence of
both, the peptide GLP-1 and the GLP-1 receptor, in the CNS points toward
important physiological actions of GLP-1 in the CNS in addition to its actions on
the peripheral system.
The first report that GLP-1 exerted effects in the central nervous system (CNS)
came from Turton and colleagues. This group gave intracerebroventricular (icv)
injections of GLP-1 to rats. The injections reduced the food intake of the animals
compared to saline-treated control rats (Turton et al. 1996). The group also
demonstrated the presence of GLP-1-containing neurons in the rat brain in hypo-
thalamic areas that are known to be responsible for regulating satiety and food
intake.
Since then, there has been a great interest in understanding the role of GLP-1 in
the regulation of food intake and satiety. In the rat, other groups confirmed the
findings of Turton by using either GLP-1 or exendin-4, a naturally occurring GLP-1
RA (Meeran et al. 1999; Turton et al. 1996; Tang-Christensen et al. 1996). In
humans, subcutaneous or intravenous application of GLP-1 also reduced hunger
and food intake, prandial injections in obese subjects led to a reduction in food
intake (N€
aslund et al. 2004). Blocking GLP-1 action in the CNS by using the GLP-1
receptor antagonist exendin(9–39) increased food intake in rats that had had icv
injections with exendin(9–39), and additionally facilitated weight gain in these
animals after long-term administration (Turton et al. 1996).
Anorexigenic Effects of GLP-1 and Its Analogues 189

Icv injections of GLP-1 receptor agonists inhibit food intake in rodents (Turton
et al. 1996; Meeran et al. 1999). Repeated icv administration of GLP-1 in rats leads
to weight loss (see Fig. 3). Conversely, icv injection of the GLP-1 receptor antago-
nist exendin(9–39) promoted weight gain in the animals, and exendin(9–39)
administered simultaneously with the central orexigenic agent neuropeptide Y
(NPY) resulted in an increased food intake and weight gain compared with that
observed with neuropeptide Y alone (Meeran et al. 1999; Abu-Hamdah et al. 2009).
In this respect, it is important that the intestinal L cells cosecrete GLP-1 and peptide
YY (PYY). Immunohistological studies demonstrated that these peptides are
Fig. 3 Effect of multiple icv injections of GLP-1 on food intake and body weight. Food intake (a)
and body weight (b) after daily icv injection of GLP-1 or saline as control are shown. The hatched
bars and filled circles represent animals given 3 nmol GLP-1, and the open bars and open circles
represent control animals that received saline. Food intake and body weight were significantly
decreased through the study period in animals receiving GLP-1 (P<0.05 for both groups). Body
weight was similar in noninjected controls (open triangles) and those given icv normal saline
(from Meeran et al. 1999 with permission)
190 B. Gallwitz

colocalized and coreleased from these cells. The truncated PYY(3–36), comprising
the major circulating form of PYY, has been reported to be a potent anorexigenic
agent in rats as well as in man (Batterham et al. 2002,2003). Although these effects
have not been reproduced by others (Tsch€
op et al. 2004; Boggiano et al. 2005),
it was suggested that the corelease of GLP-1 and PYY has an important roles in the
mediation of satiety (Abu-Hamdah et al. 2009).
It has further been demonstrated that GLP-1 may play a role in the regulation of
the hypothalamic pituitary axis via effects on CRH, LH, TSH, oxytocin, and
vasopressin secretion (Beak et al. 1996,1998). The available evidence suggests
that taste and/or food aversion induced by GLP-1 is mediated by different CNS
pathways (Kinzig et al. 2002; Seeley et al. 2000; Tang-Christensen et al. 1996).
The GLP-1 receptor is widely expressed in the rodent brain in the hypothalamic
arcuate nucleus (ARC), the paraventricular nucleus (PVN), and supraoptic nuclei
(Shughrue et al. 1996). Furthermore, GLP-1 neurons of the solitary tract predomi-
nantly project into the PVN (Larsen et al. 1997a). The food-intake decreasing effect
of GLP-1 in rodents is associated with an increase in c-Fos expression in the ARC
(Larsen et al. 1997b). In rats treated with monosodium glutamate, the inhibitory
effect of GLP-1 on hunger-induced feeding was completely abolished (Tang-
Christensen et al. 1998). Additionally, GLP-1 stimulates the electrical activity of
proopiomelanocortin (POMC) neurons via the protein kinase A pathway and
a consecutive increase of L-type calcium currents (Ma et al. 2007). These findings
suggest that the hypothalamic ARC may play a role in GLP-1-induced inhibition of
food intake.
The regulation of energy balance involves the interaction of numerous regu-
latory peptides and neurotransmitters in the hypothalamus. The orexigenic peptides
neuropeptide Y (NPY) and agouti-related peptide (AgRP) as well as the anorexi-
genic peptides POMC and cocaine- and amphetamine-related transcripts (CART)
are produced in the ARC of the hypothalamus and play an important role in the
regulation of energy intake and energy expenditure (Schwartz et al. 2000). The
hypothalamic neurons are sensitive to satiety and hunger signals such as cholecys-
tokinin (CCK) and ghrelin. These hypothalamic neurons are also sensitive to
signals of long-term energy stores such as insulin and leptin (Schwartz et al.
2000). However, the effect of GLP-1 on the expression of these hypothalamic
mediators is not completely known. NPY and AgRP expression as measured by
mRNA concentrations is increased during fasting. These hunger-induced increases
are significantly diminished by icv injections of GLP-1. Conversely, the
expressions of POMC and CART are decreased during fasting, and again, these
changes are attenuated by the icv injection of GLP-1. Additionally, when deter-
mining mRNA concentrations of AMP-activated kinase (AMPK), a stimulation of
hypothalamic AMPKa2 could be observed during fasting that was also inhibited by
GLP-1 application. In summary, these findings suggest that the decreased food
intake mediated by GLP-1 is facilitated by the above mentioned changes of
orexigenic and anorexigenic hypothalamic neurotransmitter expression changes
(Seo et al. 2008).
Anorexigenic Effects of GLP-1 and Its Analogues 191

Another regulatory system most likely to be involved is a GLP-1-mediated
activation of the hypothalamo–pituitary–adrenocortical (HPA) axis (Larsen et al.
1997a; Larsen et al. 1997b). This mechanism primarily involves the stimulation of
corticotropin-releasing factor (CRF) neurons by GLP-1, and this activation may
also be responsible for the inhibition of feeding behavior. There seem to be species
differences regarding this regulatory mechanism: in rats, plasma concentrations of
corticosterone were rapidly increased after central administration of GLP-1,
whereas icv injections of GLP-1 did not alter plasma corticosterone concentrations
in the neonatal chick (Furuse et al. 1997).
In neonatal chicks, a noradrenergic mechanism was shown to contribute to the
anorexigenic effect of GLP-1 (Bungo et al. 2001a). Icv administration of norepi-
nephrine (NE) suppressed food intake and produced narcolepsy comparable to the
effect of GLP-1 in chicks. Although dopamine (DA) did not alter food intake, the
coadministration of inhibitors of dopamine-b-hydroxylase (DBH) or fusaric acid
(FA) attenuated the suppressive effect of GLP-1 on feeding behavior. Thus, it is
suggested that there may be interactive relationships between GLP-1 and noradren-
ergic regulatory systems in chicks (Bungo et al. 2001b), and that additionally, there
may be species differences in GLP-1-mediated appetite control.
3.2 GLP-1 in Taste Cells
GLP-1 and PYY are secreted not only from L cells in the small intestine but also
from mammalian taste cells. Both cell types, human duodenal L cells and taste cells
of the tongue, express the sweet taste receptor G protein gustducin that may
additionally be involved in the regulation of GLP-1 release (Jang et al. 2007).
In many L cells, GLP-1, gustducin, and PYY are colocalized (Jang et al. 2007).
Furthermore, GLP-1 is produced in two subsets of mammalian taste cells (type
2 and type 3).The corresponding GLP-1 receptors are present on adjacent
intragemmal afferent nerve fibers (Shin et al. 2008). It is therefore hypothesized
that GLP-1 (and PYY) activates anorexigenic CNS events prior to stimulating islet
hormones (Egan and Margolskee 2008).
3.3 Central Effects of GLP-1 Influencing Gastrointestinal
Functions
It has also been demonstrated already in 1997 that icv injections of GLP-1 cause
a retardation of liquid gastric emptying (Imery€
uz et al. 1997). Nakade and his group
showed that the peripheral sympathetic nervous system and the central CRF
receptors are involved in the central GLP-1-mediated delay of solid gastric empty-
ing in rats (Nakade et al. 2006).
192 B. Gallwitz

4 Peripheral Effects of GLP-1 Affecting Satiety
GLP-1 exerts potent and important inhibitory effects on gastric emptying and
gastric acid secretion. It is primarily responsible for the “ileal break,” a tightly
regulated process under neural and hormonal control that regulates the passage of
nutrients through the digestive tract. GLP-1 enhances satiety and reduces food
intake (Pitomobo 2008). GLP-1 inhibits these proximal events of the gastrointesti-
nal tract in a negative feedback manner (Ahren 2004). Nauck and colleagues were
able to inhibit gastric emptying after a liquid meal by icv administration of GLP-1
in healthy, normoglycemic volunteers (Nauck et al. 1997). The observed effect of
GLP-1 on gastric emptying was dose dependent and highly significant with physio-
logical GLP-1 plasma concentrations (Nauck et al. 1997; Meier et al. 2002,2003a)
(see Fig. 4). Another study in healthy volunteers investigated the effect of two
different doses of GLP-1 (0.125-nmol/kg or 0.25-nmol/kg body weight)
administered subcutaneously 5 min prior to a mixed test meal (Schirra et al.
1997). The pattern of gastric emptying of the mixed meal as well as pancreatic
secretion, antroduodenal motility, and the glycemic response and the release of
insulin, C-peptide, and glucagon were quantified. The lag period or the time to
reach maximal velocity of gastric emptying was dose-dependently prolonged in
response to the subcutaneous application of GLP-1. However, the maximal empty-
ing velocity, the total emptying rate, and the exponential emptying rate were
unaltered (Schirra et al. 1997). The subcutaneous infusion of GLP-1 resulted in
a dose-dependent inhibition of antral and duodenal motility, and both doses of
GLP-1 led to coordinated antroduodenal contractions. GLP-1 initially reduced
and then transiently stimulated the secretion of pancreatic enzymes. Both doses
of GLP-1 delayed the postprandial insulin peak and enhanced total insulin release.
The postprandial response of pancreatic polypeptide and glucagon was diminished
(Schirra et al. 1997).
In another study, the same group investigated the antropyloroduodenal motility
in humans and the actions of endogenously released GLP-1 on endocrine pancreas
secretion (Schirra et al. 2006). In this study, the GLP-1 receptor antagonist exendin
(9–39) was used to test whether GLP-1 acts as an incretin and/or as an enterogas-
trone in humans. The endogenously secreted GLP-1 significantly enhanced post-
prandial insulin secretion and suppressed the secretion of glucagon (Schirra et al.
2006). During the fasting and postprandial state, antroduodenal motility was
inhibited by GLP-1, which qualifies GLP-1 as an enterogastrone. The stimulation
of pyloric motility that is induced by intestinal glucose was mediated by GLP-1.
The presence of nutrients in the small intestine stimulates the L cells to release
GLP-1 into the circulation. The rise in GLP-1 concentrations not only stimulates the
beta cells to produce insulin but also slows gastric emptying and may lead to
a decrease in appetite and a sensation of fullness (N€
aslund et al. 1999; Flint et al.
2001; Meier et al. 2003b; Silvestre et al. 2003; Ling et al. 2001; Nagai et al. 2004).
The mechanisms by which GLP-1 inhibits gastric emptying appear to be com-
plex and to involve communication with the central and peripheral nervous systems
Anorexigenic Effects of GLP-1 and Its Analogues 193

(D’Alessio 2008; Drucker 2006). Gastric distension increases the expression of
c-Fos in brain stem neurons that produce GLP-1 (Vrang et al. 2003). Furthermore,
icv administration of GLP-1 resulted in reduction of food intake (Kinzig et al.
2002), which is accompanied with increased expression of c-Fos in the brain stem
of the rat (Larsen et al. 1997b; Dakin et al. 2004). The denervation of afferent vagal
060 120 180 240
-5
15
35
55
75
95
1.2 pmol .kg
-1
.min
0.8 pmol.kg
-1
.min
0.4 pmol.kg
-1
.min
Placebo
A: p < 0.0001
B: p < 0.0001
AB: p < 0.0001
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0.0 0.4 0.8 1.2
p < 0.0001
*
*
*
Gatric content
[% of initial value]
coefficient
Gatric emptying
time [min]
GLP-1 dose [pmol•kg-1•min]
Fig. 4 Time and dose dependency of GLP-1 on gastric emptying in humans. Panel A: Time
pattern of gastric emptying of a solid meal (250 kcal) during icv administration of different doses
of GLP-1 (0.4, 0.8, and 1.2 pmol/kg/min; filled symbols) or placebo (open symbols) in patients with
type 2 diabetes (n¼12). Gastric emptying was determined from the measurement of
13
CO
2
in
breath samples collected after the ingestion of the test meal labeled with [
13
C] octanoic acid using
infrared absorptiometry. Data are expressed as the mean + SE. Pvalues were calculated using
repeated measures ANOVA and denote: A, differences between the doses tested; B, differences
over time; and AB, differences due to the interaction of experiment and time. Panel B: Gastric
emptying coefficients. Data are expressed as the mean + SE. Asterisks indicate significant
differences (P<0.05) versus placebo. (from Meier et al. 2003a with permission)
194 B. Gallwitz

fibers abolishes the effects of GLP-1 on gastric emptying in the rat (Imery€
uz et al.
1997). The stimulation to the CNS is most likely responsible for the reduction in
food intake, inhibition of gastric emptying, as well as inhibitory action on gastric
motor function (Kinzig et al. 2002; Imery€
uz et al. 1997). These actions are most
likely mediated by increased action potential and calcium influx in neurons of the
nodose ganglion (Kakei et al. 2002).
Although small peptides such as GLP-1 and exendin-4 are capable of rapidly
crossing the blood–brain barrier and directly accessing the CNS, GLP-1 receptor
agonists with a larger molecule size and a higher molecular weight, such as
albumin-bound GLP-1, that do not cross the blood–brain barrier, are still capable
of inhibiting gastric emptying and food intake (Baggio et al. 2004). These findings
underline the importance of ascending vagal afferents for the GLP-1 receptor-
dependent control of gastrointestinal motility. Interestingly, studies by Meier and
his group (Meier et al. 2005) showed that antagonizing the delaying effects of GLP-
1 on gastric emptying by a prokinetic agent such as erythromycin resulted in an
augmentation of the insulin secretory response after meal ingestion. GLP-1
receptors are also directly expressed in the stomach on gastric parietal cells,
where GLP-1 may directly regulate gastric acid secretion (Schmidtler et al.
1994). However, the effects of GLP-1 on gastric acid secretion were found to be
absent in vagotomized human subjects (Wettergren et al. 1997). Hence, consider-
able evidence supports the importance of vagal innervation for GLP-1 regulation of
gastric secretion and motility.
These observed effects of delayed gastric emptying have been generally
demonstrated with at least physiological or, as in most studies, supraphysiological
doses of exogenously administered GLP-1 (Delgado-Aros et al. 2002; Schirra et al.
1996). Therefore, it remains unclear whether endogenously released GLP-1 has
a significant effect on gastric emptying. Studies in healthy baboons have shown
that with intragastric infusion of glucose and D-xylose (a marker for rate of
emptying of glucose from stomach), plasma levels of D-xylose were similar when
the effects of GLP-1 were blocked with exendin(9–36) amide or with a specific
monoclonal antibody to GLP-1 (D’Alessio et al. 1996; D’Alessio 2008). These
findings suggest that gastric emptying is not increased when the effects of GLP-1
are blocked, at least in the baboon. The use of a DPP-4 inhibitor, which increases
plasma concentrations of endogenous GLP-1, might be expected to delay gastric
emptying, but a study in patients with type 2 diabetes and DPP-4 inhibitor treatment
did not reveal any changes in the gastric emptying of a solid meal (Vella et al.
2007). Most recently, an iv-oral hyperglycemic clamp study in humans was
reported during which 75-g glucose-containing D-xylose was ingested. During the
entire clamp, plasma glucose levels were held at a steady level despite the ingestion
of glucose. Two studies were conducted, with blockade of GLP-1 receptor in one.
The rate of appearance of ingested D-xylose was not different between the two
studies, indicating that endogenously released GLP-1 has at best only a modest
effect on gastric emptying (Salehi et al. 2008).
In a variety of endocrine regulatory systems, a negative feedback mechanism
regulates the secretion of the hormone, e.g., the reproductive hormone regulation by
Anorexigenic Effects of GLP-1 and Its Analogues 195

the hypothalamus. Exogenous infusion of a hormone may also exert negative
feedback regulation of the endogenously released hormone. An example of this is
the documented suppression of C-peptide plasma concentrations when insulin is
infused (Elahi et al. 1982). In this context, it is presently still not known whether
exogenously administered GLP-1 really has a significant impact on the regulation
of endogenously released GLP-1.
5 Effects of GLP-1 Receptor Agonists on Body Weight
in Humans
Native GLP-1 cannot be used in a feasible way for treatment of type 2 diabetes or
obesity due to its very short biological half-life of 1–2 min. For this reason, long-
acting GLP-1 receptor agonists were developed. In 1992 exendin-4, a reptilian
peptide isolated from the lizard Heloderma suspectum was identified as a long-
acting GLP-1 receptor agonist (Raufman et al. 1992;G
€
oke et al. 1993). Exendin-4
has a 53% sequence homology with GLP-1 and has a biological half-life of
approximately 3.5 h. The synthetic form of exendin-4, exenatide, was the first
GLP-1 receptor agonist that was approved for type 2 diabetes therapy in patients
not sufficiently controlled on a therapy with metformin or sulfonylureas or
a combination of both (Klonoff et al. 2008). Exenatide (Byetta
®
, Eli Lilly
Pharmaceuticals, Indianapolis, USA and Amylin Pharmaceuticals, San Diego,
USA) is given subcutaneously twice daily.
Liraglutide (Victoza
®
, Novo Nordisk Pharmaceuticals, Copenhagen, Denmark)
was the first human GLP-1 analogue that was developed for once daily subcutane-
ous application. Liraglutide has a half-life of 13.5 h. It has a fatty acid side chain
that allows heptamer formation of the molecule that prevents direct DPP-4 action as
well as fast dissociation from the subcutaneous tissue into the circulation. Further-
more, the fatty acid side chain allows albumin binding that further protracts
degradation and prolongs biological availability (Garber et al. 2009; Madsbad
et al. 2011).
Presently, even longer-acting GLP-1 receptor analogues are being developed in
order to reduce the frequency of injections, to reduce fasting glucose more effi-
ciently, and to reduce the gastrointestinal side effects (mainly fullness and nausea)
that are associated with the fluctuation of GLP-1 receptor agonist plasma
concentrations. Compounds with an exendin-4/exenatide backbone are exenatide
once weekly (Bydureon
®
, Eli Lilly Pharmaceuticals, Indianapolis, USA and
Amylin Pharmaceuticals, San Diego, USA) that has just received a positive opinion
by the regulatory agencies in the United States and Europe and is expected to be
marketed later in 2011 (Madsbad et al. 2011).
Lixisenatide (Sanofi-Aventis Pharmaceuticals, Paris, France) is an exendin-4
analogue for once daily application, presently in phase III of the clinical study
program (Christensen et al. 2011; Madsbad et al. 2011).
196 B. Gallwitz

Albiglutide, an albumin-bound-human GLP-1 fusion protein (GlaxoSmithKline
Pharmaceuticals, London, UK) is feasible for once weekly dosing and is also
presently in phase III of the clinical study program (Madsbad et al. 2011;St
Onge and Miller 2011).
Another human GLP-1 receptor agonist in earlier development for once weekly
dosing is LY2189265 (Dulaglutide, Eli Lilly Pharmaceuticals, Indianapolis, USA)
(Glaesner et al. 2010; Madsbad et al. 2011). Table 1gives an overview on the GLP-1
receptor agonists available and in development and their respective characteristics.
Chronic peripheral administration of GLP-1 RA agonists (exendin-4/exenatide
and liraglutide) has consistently been associated with reductions in food intake and
weight loss in animal studies and in humans (Szayna et al. 2000; Young et al. 1999;
Schnabel et al. 2006; Garber et al. 2009). Also, weight loss was documented in
a pivotal study in which a continuous 6-week infusion of GLP-1 was given to obese
type 2 diabetic patients (Zander et al. 2002). Conversely, a continuous subcutaneous
administration study of a lower dose of GLP-1 (1.5 pmolkg
1
min
1
) for 12 weeks
Table 1 GLP-1 receptor agonists and their characteristics. The available GLP-1 receptor
agonists as well as substances advanced in clinical development are shown
Substance Chemical backbone Dosing interval Approval/
developmental status
Exenatide (Byetta
®
, Eli
Lilly and Amylin)
Exendin-4 Twice daily Approved 2005
Liraglutide (Victoza
®
,
NovoNordisk)
Human GLP-1 with two
amino acid exchanges
and a c-16 fatty acid side
chain
Once daily Approved 2009
Exenatide QW
(Bydureon
®
, Eli
Lilly and Amylin)
Exendin-4, incorporated into
a matrix of poly(D,L-
lactide-co-glycolide)
(PLG) to prolong action
Once weekly Approved 2011
Lixisenatide
(Sanofi-Aventis)
Exendin-4, 44 amino acids
with C-terminal
extension (C-terminal
with six Lys residues and
one Pro deleted)
Once daily Phase III clinical
investigation
Albiglutide (Syncrea
®
,
GlaxoSmithKline)
Human GLP-1 receptor
agonist consisting of two
copies of a 30-amino acid
sequence of a dipeptyl
peptidase-4-resistant
human GLP-1 (as a
tandem repeat) coupled
to serum human albumin
Once weekly
(planned)
Phase III clinical
investigation
LY2189265
(Dulaglutide
®
,
Eli Lilly)
DPP-4-protected GLP-1
analogue is fused to a
modified
immunoglobulin G4
(IgG4) Fc fragment
Once weekly
(planned)
Phase III clinical
investigation
Anorexigenic Effects of GLP-1 and Its Analogues 197

produced no significant weight loss (Meneilly et al. 2003). This study most likely
demonstrates that weight loss with exogenous GLP-1 administration is only possi-
ble, when much larger doses are given.
In most phase 3 studies with exenatide and liraglutide, the weight loss was in the
range of 2–3 kg after 26 weeks of treatment compared with placebo, and greatest
when added to metformin (Madsbad 2009). In studies with a longer duration, a
plateau of the weight loss is seen in the same range (Garber et al. 2009,2011).
Presently, long-acting GLP-1 receptor agonists that require a single weekly dose
only, or other long-range dosing regimens, are in clinical development (Madsbad
et al. 2011). Summarizing the known effects on body weight, there does not seem to
be a difference between the short-acting, established GLP-1 RA and the novel long-
acting ones. The weight loss in a study comparing the novel, once weekly GLP-1
RA albiglutide with exenatide did not reveal a significant difference in the body
weight development. The weight loss amounted from 1.1 to 1.7 kg in the
albiglutide groups compared with 0.7 kg in the placebo group and 2.4 kg in
the exenatide group (Rosenstock et al. 2009).
Exenatide once weekly (exenatide QW) is a new dosage form of the active drug
exenatide. Exenatide QW’s microsphere technology enables very slow release due
to the use of a slowly biodegradable polymer as the exenatide carrier. This changes
both the effect and adverse effect profiles versus the short-acting receptor stimula-
tion produced by the established, unretarded exenatide for twice daily application.
Long-term stimulation of GLP-1 receptors results in superior lowering of fasting
blood glucose levels and HbA1c (Kim et al. 2007). In subjects on first-line treatment
with metformin, exenatide QW produced a superior HbA1c reduction. Because of
the weaker inhibition of gastric emptying, gastrointestinal side effects are reduced
by about one-third (20% with exenatide QW versus 35% with exenatide)
(Linnebjerg et al. 2008; Wang et al. 2008). In addition, a relevant loss in mean
weight (ranging from 2.3 kg to 3.7 kg) was seen in all studies (Drucker et al. 2008;
Buse et al. 2010; Bergenstal et al. 2010; Diamant et al. 2010; Kim et al. 2007).
Another GLP-1 RA in development is CJC-1134-PC (ConjuChem, Montreal,
Quebec, Canada), which consists of an exendin-4 molecule covalently linked to
human recombinant albumin. Its half-life of approximately 8 days corresponds to
that of circulating albumin (Thibaudeau et al. 2006; Baggio et al. 2008). At present,
it is unclear whether the modest effect on body weight is explained by a reduced
efficacy in engaging the central nervous system regions regulating appetite and
body weight, because large proteins like albumin are not expected to cross the
blood–brain barrier (Chuang et al. 2002). Alternatively, the compound can still
regulate feeding and body weight via the vagus nerve (Abbott et al. 2005; Imery€
uz
et al. 1997).
With respect to weight control, no clinically significant differences seem to exist
within the entire group of GLP-1 receptor agonists, although it remains possible
that the CJC-1134-PC is less effective (Chuang et al. 2002; Wang et al. 2009).
With the short-acting GLP-1 RA liraglutide, a clinical study was performed
in obese, nondiabetic subjects to investigate the efficacy and safety as a weight-
loss-promoting drug. In a placebo-controlled 20-week trial, with an open-label
198 B. Gallwitz

orlistat (120 mg t.i.d.) comparator arm, study participants were assigned to arms of
four liraglutide doses (1.2 mg/d, 1.8 mg/d, 2.4 mg/d, or 3.0 mg/d) or to placebo.
Participants on liraglutide lost significantly more weight than did those on placebo
and orlistat. The mean weight loss caused by liraglutide was dose dependent and
amounted to 4.8 kg, 5.5 kg, 6.3 kg, and 7.2 kg for the respective liraglutide doses
(1.2 mg/d, 1.8 mg/d, 2.4 mg/d, or 3.0 mg/d) and was 2.1 kg greater than that in the
placebo group. The weight loss with placebo amounted to 2.8 kg and with orlistat
4.1 kg (Astrup et al. 2009) (see Fig. 5).
6 GLP-1 and Bariatric Surgery
The mechanisms involved in weight loss and metabolic improvements after bariat-
ric surgery are dependent on the type of surgery performed and are not yet
completely understood. They are presently under thorough investigation. Changes
in the size of the gastric pouch and the length and parts of the intestinal surfaces
after bariatric surgery determine the contact of food with enteroendocrine cells and
consequently also the gut hormonal response. Each type of bariatric surgery has
Fig. 5 Dose dependent effects of the GLP-1 RA liraglutide on body weight in obese subjects. Five
hundred sixty-four individuals (age range 18–65 years, BMI 30–40 kg/m) were randomized to one
of four liraglutide doses (1·2 mg, 1·8 mg, 2·4 mg, or 3·0 mg, n¼90–95) or to placebo (n¼98)
administered once a day subcutaneously, or orlistat (120 mg, n¼95) three times a day orally.
Weight change was analyzed by intention to treat. Data are mean (95% CI) (ANCOVA estimate)
for the intention-to-treat population with the last observation carried forward (from Astrup et al.
2009 with permission)
Anorexigenic Effects of GLP-1 and Its Analogues 199

a different effect on hormonal secretion and thus may play a significant role in the
mechanism of weight loss (Vetter et al. 2009).
Rubino and colleagues evaluated the early effects of Roux-Y gastric bypass
(RYGB) on glucose, insulin, glucagon, insulin-like growth factor-1, GIP, GLP-1,
CCK, adrenocorticotropic hormone (ACTH), corticosterone, and neuropeptide Y
(Rubino et al. 2004; Thomas and Schauer 2010). RYGB led to a decrease in BMI
paralleled by a significant decrease in glucose, insulin, leptin, and an increase in
ACTH levels 3 weeks after surgery. The other hormones, especially GLP-1, did not
change significantly. However, of the six diabetic patients in the study, all had
normal glucose and insulin levels after surgery and did not require any diabetic
medications.
It has been observed that the initial weight loss observed with either laparoscopic
sleeve gastrectomy (LSG) as a restrictive surgical method or RYGB as a diversion
method of surgery leads to similar results (Thomas and Schauer 2010). There are
metabolic differences however, demonstrating that patients with RYGB show
a rapid normalization of fasting glucose and an improvement of insulin clearance
and sensitivity, but these changes do not occur in patients with LSG. Testing the
different cohorts of patients after RYGB or LSG with a mixed meal tolerance test,
the dramatic increase in insulin secretion and an increase in GLP-1 are only
observed in the RYGB group (Thomas and Schauer 2010).
In obese patients with coexisting type 2 diabetes, both types of bariatric
procedures were associated with an improvement of hyperglycemia. RYGB was
associated with an insulinotropic response with an oral mixed meal but not with
intravenous glucose, consistent with an incretin effect. These data suggest a differ-
ent effect of the two procedures on pancreatic beta-cell function. The improvement
may be due to insulin sensitivity and therefore a reduced insulin response following
gastric restriction only (Thomas and Schauer 2010). It is still not known, however,
whether the portion that is bypassed causes this effect or whether this effect is due
to nutrients that rapidly reach the distal ileum and release insulinotropic and beta-
cell-enhancing hormones (Kashyap et al. 2010). The limitations of the study are the
small sample size and the sample being a nonrandomized convenience sample.
To evaluate the potential role of the exclusion of the proximal small intestine in
the improvement of diabetes mellitus after gastric bypass surgery, Peterli and his
group conducted a prospective, randomized, controlled trial comparing RYGB and
LSG. Patients were evaluated 1 week and 3 months after surgery before and after
a standard test meal. At 3 months, body weight and BMI decreased significantly and
comparably in both groups with markedly increased postprandial plasma insulin
and GLP-1 levels (Dirksen et al. 2010). RYGB patients had increased insulin
responses as early as 1 week after the surgery; however, no significant differences
were seen at 3 months in insulin or GLP-1 levels. Thus, both procedures improved
glucose homeostasis, insulin, and GLP-1 and PYY levels (Peterli et al. 2009).
Two different hypotheses have been proposed to explain these conflicting data.
One offered is the “hindgut explanation,” suggesting that the rapid transit of
nutrients to the distal intestine improves glucose metabolism by stimulating secre-
tion of GLP-1 and other appetite-suppressing gut peptides such as PYY. Insulin
200 B. Gallwitz

secretion is increased and glucose tolerance improves, affecting body weight and
food intake (Cummings et al. 2007; Patrita et al. 2007). On the other hand, Rubino
and his group proposed the “foregut hypothesis.” They propose that there is a yet-
unknown factor that promotes insulin resistance and type 2 diabetes. When food
bypasses the duodenum and proximal jejunum after bariatric surgery, this so-called
anti-incretin or decretin factor is inhibited, and thus insulin resistance is decreased
and glucose tolerance improves. Other factors may help to explain the differences
seen among the various types of procedures (Vetter et al. 2009; Cummings et al.
2008). Likewise, because GLP-1, PYY, and GIP are secreted by the small intestine,
differences in the length of the roux limb may contribute to the secretion of these
gut hormones and thus the results seen. Finally, as this is a relatively new, evolving
field of research, there are most likely unknown factors to be considered (Thomas
and Schauer 2010).
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