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doi:10.1152/physrev.00034.2006.
Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
Holst JJ. The Physiology of Glucagon-like Peptide 1. Physiol Rev 87: 1409 –1439, 2007; doi:10.1152/physrev.00034.2006.—
Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine
L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge
regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the
posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and
molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the
enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of
GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of
this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions)
or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the
possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin
hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also
inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake”
mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions,
GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased
secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for
postprandial reactive hypoglycemia.
www.prv.org 0031-9333/07 $18.00 Copyright © 2007 the American Physiological Society 1409
1410 JENS JUUL HOLST
cagon, one of the first radioimmunoassays to be devel- of the NH2-terminal extension peptide, which was named
oped (296), it was confirmed that the gastrointestinal tract glicentin-related pancreatic polypeptide (GRPP) (282).
contains substances with glucagon immunoreactivity, i.e., From studies of the biosynthesis of glucagon in the
reacting with the antibodies employed in the radioimmu- pancreatic islets, however, it was evident that a large
noassay (297). In addition, in immunohistochemical stud- molecule (mol wt ⬃10,000), subsequently designated “the
ies, some intestinal endocrine cells could be stained using major proglucagon fragment” (MPGF) that did not con-
glucagon antibodies (83), but it was also shown that these tain the glucagon sequence, was also formed in parallel
cells differed from the pancreatic A-cells with respect to with glucagon (236). As the structures of glucagon-encod-
granule morphology (83), and they were hence designated ing mRNA and of the glucagon gene were determined (14,
as “L-cells” (26). Furthermore, in 1968, it was established 15), it became evident that, in mammals, this major frag-
(298) that the glucagon-like immunoreactive material that ment of proglucagon contains two glucagon-like se-
was secreted in response to an oral glucose load differed quences, now designated glucagon-like peptides 1 and 2
from true glucagon both physicochemically and biologi-
secreted peptide is GLP-1-(7–37) (97, 190). This poses with the base resting on the basal lamina and a long
special problems with respect to the measurement of cytoplasmic process reaching the gut lumen. This process
GLP-1 secretion in these species (see below). The se- is equipped with microvilli that protrude into the lumen. It
quence of naturally occurring GLP-2 was found to corre- may be via these microvilli that the L-cell can sense the
spond to PG 126 –158 (27, 103). A comparison of GLP presence of nutrients in the lumen and transform this
sequences among species shows that the GLP-1 sequence information into a stimulation of secretion. The peptide
is preserved 100% in all mammals, where this has been products of the A- and L-cells have been identified at the
studied, and the sequence homology is pronounced cellular level by immunocytochemistry. As expected, an-
across other classes of animals (149). GLP-2 shows more tisera directed against the midregion of glucagon (“side
variation with, e.g., four substitutions between human viewing”) stain the pancreatic A-cells as well as the intes-
and porcine GLP-2. The Ala in position 7 of human inter- tinal L-cells, whereas antibodies against the free COOH
vening peptide 2 is also variable with Thr or Asn in, e.g., terminus of glucagon (which is not exposed in the L-cells)
the porcine and bovine peptides.
secretion of these hormones would occur by postprandial last of which may be released in small amounts from both
luminal stimulation. pancreas and gut. With such antisera, it may be possible
As mentioned, the proglucagon gene is also ex- to measure what might be designated “total glucagon”
pressed in the central nervous system. Thus cells immu- concentrations. But results obtained in these assays are
noreactive for GLP-1, glucagon, and glicentin have been not easy to interpret, because the peptides measured may
demonstrated in the nucleus of the solitary tract of the be derived from both the pancreas and the gut. Upon oral
brain stem of rats , monkeys, and humans (52, 144, 145). administration of carbohydrates, pancreatic A-cell secre-
These neurons project to many regions in the brain, in tion is suppressed and L-cell secretion stimulated, and in
particular the nuclei of the hypothalamus, including the this case, such assays may provide a reasonable estimate
arcuate and the paraventricular nuclei (161). The process- of L-cell secretion. The designation “enteroglucagon se-
ing of proglucagon has been examined both at the level of cretion” is sometimes coined for the results of such mea-
the cell bodies and at the levels of the fibers projecting to surements. More specific information may be obtained
the hypothalamus (161). The pattern was intestinal with a with antisera that react exclusively with the unmodified
hibit the polarity of the L-cell, and it is therefore difficult the importance of the neural regulation (100). It was
to extrapolate results obtained with these cells to natural confirmed that the sympathetic innervation to the gut is
L-cells. GLP-1 secretion from the GLUTag cells may also inhibitory to GLP-1 secretion (with norepinephrine as the
be stimulated by metabolizable sugars by a mechanism responsible transmitter), whereas the extrinsic vagal in-
that involves closure of ATP-sensitive K⫹ channels (8). nervation had no effect. Intrinsic, cholinergic activity may
This seems to be consistent with the recent demonstra- play a minor role, however.
tion of stimulation of GLP-1 secretion from isolated seg- One of the most powerful mechanisms for regulation
ments of porcine ileum by glucose administered both of GLP-1 secretion appears to be a local paracrine control
luminally and via the perfusate (98). Fructose stimulates exerted by neighboring somatostatin producing D-cells
secretion both in vivo and in the GLUTag cells (107), (97). Elimination of somatostatin’s restraint (by immuno-
suggesting that GLUT5 transporters may also be involved. neutralization) may increase GLP-1 secretion up to eight-
Involvement of neurohormonal mechanisms to ex- fold, much more than observed with any other stimulus. It
plain the rapid postprandial onset of secretion has been deserves mentioning that the neuropeptide gastrin releas-
323) including the stomach, where the receptor is ex- the incretin effect ensures that postprandial glucose ex-
pressed on the parietal cells (262). Its function is not cursions are limited and similar regardless of the carbo-
known for all these locations (see below). For instance, in hydrate load. The increase in insulin secretion is mainly
the parietal cells, activation of the receptor increases due to the actions of insulinotropic gut hormones (177,
aminopyrine accumulation, which is an indirect indicator 178). The same gut hormones are also released by mixed
of acid secretion (258), whereas in vivo, GLP-1 strongly meals, and given that their postprandial concentrations in
inhibits acid secretion (see below). Numerous attempts plasma are similar and that the elevations in glucose
have been made to identify alternative GLP-1 receptors or concentrations are also similar, it is generally assumed
subtypes (see below), but at present only a single GLP-1 that the incretin hormones are playing a similarly impor-
receptor has been identified, whether expressed in the tant role for the meal-induced insulin secretion. Part of
brain, the stomach, or the pancreas (322). However, the increase in the peripheral insulin concentrations may
since the pulmonary receptor was found to differ from be due to a decreased hepatic uptake of insulin during
the islet receptor with respect to electrophoretic mobility, oral glucose ingestion, resulting in more insulin being
interaction with the GLP-1 receptor located on the cell the intracellular ATP levels and, thereby, to glucose me-
membrane of the beta cells (124). Binding of GLP-1 to the tabolism of the beta cells, but may also be affected
receptor causes activation, via a stimulatory G protein, of (closed, resulting in subsequent depolarization of the
adenylate cyclase resulting in the formation of cAMP. plasma membrane and opening of voltage-sensitive cal-
Most of the actions of GLP-1 are secondary to the forma- cium channels) by protein kinase A (PKA) activated by
tion of cAMP (see Fig. 6). Subsequent activation of pro- GLP-1 (85, 132, 170). Apparently, PKA-mediated phos-
tein kinase A and the cAMP-regulated guanine nucleotide phorylation of S1448 in the SUR1 subunit leads to KATP
exchange factor II (cAMP-GEFII, also known as Epac2) channel closure via an ADP-dependent mechanism. In
leads to a plethora of events including altered ion channel animals with a targeted deletion of the SUR1 subunit of
activity, elevation of intracellular calcium concentrations, the channels, the incretins can still elevate cAMP levels,
and enhanced exocytosis of insulin-containing granules but no longer stimulate glucose-induced insulin secretion
(130). GLP-1 also stimulates coordinated oscillations in (199). However, this impairment was thought to be due to
both intracellular calcium and cAMP, and these are po- a restriction in the beta cells to sense cAMP correctly,
FIG. 6. Summary of the cellular actions of GLP-1 that lead to stimulation of insulin secretion. Binding of GLP-1 to its receptors couple to
activation of adenylate cyclase; intracellular cAMP levels are elevated leading to activation of protein kinase A (PKA) and cAMP-regulated guanine
nucleotide exchange factor II (cAMP-GEFII, also known as Epac2). These two proteins are likely to mediate the plethora of molecular mechanisms
(summarized below in points 1– 6). 1) GLP-1 acts synergistically with glucose to close ATP-sensitive K⫹ (KATP) channels and thus facilitates
membrane depolarization and the induction of electrical activity. 2) Once electrical activity is initiated, the slower time course of inactivation of the
Ca2⫹ channels results in prolonged bursts of action potentials. In addition, each action potential will be associated with a slightly greater Ca2⫹ influx
because the amplitude of the Ca2⫹ current is moderately increased (86). 3) Antagonism by GLP-1 of the delayed rectifying K⫹ (Kv) channels will
increase excitability and results in prolongation of the duration of action potentials. 4) In the presence of stimulatory levels of glucose and GLP-1,
Ca2⫹ influx through the Ca2⫹ channels feeds forward into mobilization of Ca2⫹ from intracellular stores by Ca2⫹-induced Ca2⫹ release through PKA-
and cAMP-GEFII-dependent mechanisms. 5) Ca2⫹ mobilization from intracellular stores will stimulate mitochondrial ATP synthesis, which will
promote further membrane depolarization via closure of KATP channels. ATP is also required for stimulation of exocytosis of the insulin-containing
granules. 6) The elevation in the cytoplasmic free Ca2⫹ concentration ([Ca2⫹]i) triggers the exocytotic response that is further potentiated by
increased cAMP levels. This effect is principally attributable to the ability of cAMP to accelerate granule mobilization resulting in an increased size
of the pools of granules that are immediately available for release. These effects depend both on cAMP binding to PKA and cAMP-GEFII.
Quantitatively the last mechanism is by far the most important one and may account for 70% or more of the total insulinotropic activity of GLP-1
and GIP (86). [Modified from Holst and Gromada (124).]
tion and calcium influx, may uncouple the glucose depen- bility that GLP-1 could be useful as a therapeutic agent in
dency of GLP-1 (40). Thus GLP-1 administration to iso- conditions with increased beta-cell apoptosis, which
lated perfused rat pancreases at low perfusate glucose would include type 1 as well type 2 diabetes in humans
concentrations normally does not affect insulin secretion, (32). Thus treatment of mice with the GLP-1 agonist ex-
but resulted in dramatic stimulation of insulin secretion endin 4 reduced beta-cell apoptosis induced by strepto-
after pretreatment with sulfonylurea drugs (40, 89). In- zotocin (while GLP-1 receptor knockout mice were ab-
deed, 30 – 40% of patients treated with both sulfonyl urea normally susceptible to streptozotocin-induced beta-cell
compounds and a GLP-1 agonist (exendin 4, see below) apoptosis) (169). Also, cytokine-induced apoptosis may
experience, usually mild, hypoglycemia. be inhibited, and GLP-1 agonism increased cell survival
cAMP generated by activation of the GLP-1 receptor and reduced caspase activation in BHK fibroblasts ex-
may also influence the exocytotic process directly, and pressing a transfected GLP-1 receptor (169). In this con-
this process has been estimated to account for up to 70% nection, it is of considerable interest that exendin treat-
of the entire secretory response (124). Also, ATP may ment (in combination with lisophylline) prior to the de-
hyperglucagonemia as well as exaggerated glucagon re- inhibit pancreatic secretion in response to intraduodenal
sponses to meal ingestion (288), and since it is likely that stimulation (84). The inhibitory effect of GLP-1 on acid
the hyperglucagonemia contributes to the hyperglycemia secretion could be elicited by physiological elevations of
of the patients (265), this effect may be as important the GLP-1 concentrations in plasma and was, remarkably,
clinically as the insulinotropic effects (see below). In- additive to the inhibitory effects of PYY, which is released
deed, in patients with type 1 diabetes and complete lack from the L-cell in parallel with GLP-1 (324). Together the
of beta-cell activity (C-peptide negative), GLP-1 is still two peptides almost abolished gastrin-stimulated secre-
capable of lowering fasting plasma glucose concentra- tion, indicating that these two peptides are the likely
tions, presumably as a consequence of a powerful lower- mediators of the “ileal brake effect,” i.e., the endocrine
ing of the plasma glucagon concentrations (35). The inhibition of upper gastrointestinal functions elicited by
mechanism of GLP-1-induced inhibition of glucagon se- the presence of unabsorbed nutrients in the ileum (113,
cretion is not completely elucidated. Insulin is generally 163, 249). These effects of GLP-1, also designated enter-
thought to inhibit glucagon secretion, and local elevations gastrone effects, are likely to be physiological, since stim-
F. Central Targets for Peripherally pretation was that physiological amounts of GLP-1 de-
Released GLP-1 pended on reflex pathways for stimulation of insulin se-
cretion, whereas higher doses leading to higher plasma
As alluded to above, very little GLP-1 reaches the concentrations might activate islet receptors directly and
systemic circulation in the intact form. One may ask why therefore equally in control and denervated mice. Thus,
particularly GLP-1 is degraded so extensively that a rise in regarding the mechanism of GLP-1-stimulated insulin se-
the concentration of the intact peptide frequently may not cretion under physiological circumstances, the neural
be noticeable after intake of smaller meals. The observa- pathway may be more important than the endocrine
tion has led to the hypothesis that GLP-1 must act locally route. However, the concentration of intact GLP-1 does
in the lamina propria before being degraded (96, 123; see rise after meal intake and rises more the larger the meal
Fig. 9). Once released from the L-cells, GLP-1 diffuses is (317). Thus it seems probable that the endocrine route
across the basal lamina and enters the lamina propria. becomes more prominent after extensive L-cell stimula-
Here it is taken up by capillaries, the endothelial mem- tion.
branes of which will then degrade the hormone, because The pathways whereby GLP-1 exerts its “ileal brake”
they express DPP-IV (96). However, on its way to the effects (119) also seem to depend on signaling via afferent
capillary, GLP-1 may interact with afferent sensory nerve sensory neurons relaying in the brain stem or the hypo-
fibers arising from the nodose ganglion, sending impulses thalamus and regulating efferent parasympathetic outflow
to the nucleus of the solitary tract and onwards to the (139, 328). Thus GLP-1 has no effect on vagally stimulated
hypothalamus (See Fig. 9) (123). Recent observations that antral motility in isolated perfused preparations of the pig
the GLP-1 receptor is expressed in nodose ganglion cells stomach (328) and no effect on vagally stimulated exo-
support this view (198). In addition, it has been demon- crine secretion from isolated perfused porcine pancreas
strated that intraportal administration of GLP-1 causes (127). Furthermore, as mentioned, the acid inhibitory ac-
increased impulse activity in the vagal trunks (220). These tivity in humans exclusively depends on vagal mecha-
impulses may be reflexly transmitted to the pancreas nisms (325, 329). Finally, the inhibitory effect on gastric
(197). Studies in rats employing ganglionic blockers have emptying in rats is lost after vagal deafferentation (139).
shown that the insulin response to intraportal administra- Studies in rats have suggested that a hepatoportal
tion of GLP-1 and glucose may be reduced to that glucose sensor may reflexly influence peripheral glucose
elicited by glucose alone after ganglionic blockade (11) metabolism and that this sensor is somehow linked to a
(see Fig. 10). Similarly, in mice rendered sensory dener- GLP-1 receptor expression, since its effects on peripheral
vated by neonatal administration of the neurotoxin cap- glucose disposal are abrogated by exendin 9 –39 and can-
saicin, low doses of GLP-1 that augmented glucose-in- not be demonstrated in GLP-1 receptor knockout mice
duced insulin secretion in control animals had little effect (29). In dogs, pharmacological amounts of intraportal
in the denervated mice, whereas high doses had the same GLP-1 were required to elicit changes in peripheral glu-
effects in control and denervated animals (1). The inter- cose metabolism (218), and in further dog studies, insulin-
independent effects of GLP-1 on glucose disposal in the actions of the peptide. Early studies indicated an effect on
liver required long-term (up to 5 h) infusions and were appetite and food intake (259), and subsequent more
independent of route of administration (portal vs. periph- detailed studies confirmed these effects after intracere-
eral) (39). Similar to the findings in mice, intraportal broventricular administration of low doses of the peptide
GLP-1 and glucose infusions in other dog studies were (278, 294). The proglucagon-producing neurons of the brain
found to decrease peripheral glucose levels indepen- stem may represent a link in a system whereby entero-
dently of hyperinsulinemia (140). However, it should be ceptive stress, but possibly also food ingestion, transmits
noted that peripheral administration of GLP-1 to dogs at a satiety signals to the brain (160, 253). Thus the cells are
similar rate is claimed not to enhance glucose-induced activated (show c-fos expression) upon distension of the
insulin secretion in this species (141). This is again in stomach (319). GLP-1 receptors are expressed in many
sharp contrast to very consistent findings in humans (135, regions of the brain and in particular in the arcuate nu-
157) and therefore suggests that dogs (and possibly mice) cleus and other hypothalamic regions involved in the
differ radically from humans in this respect. regulation of food intake (79). Destruction of the arcuate
nucleus with perinatal monosodium glutamate abolishes
G. Effects on Appetite and Food Intake the inhibitory effect of intracerebroventricularly adminis-
tered GLP-1 on food intake and appetite (280), indicating
There have been reports on the presence of glucagon that this nucleus is essential for the response. As men-
in the brain for many years (277), and it has been specu- tioned earlier, processing of proglucagon in the brain
lated that the peptide might play a role in regulation of stem neurons leads to the formation of GLP-1 as well as
food intake. When GLP-1 was also discovered in the brain GLP-2 and oxyntomodulin, all of which have been re-
(144), it was relevant to investigate the possible central ported to inhibit food intake after intracerebroventricular
lar (LV) end-diastolic pressure, compared with wild-type myocardial oxygen uptake, 6-min walking distance, and
controls. At the age of 5 mo, echocardiography and his- quality of life, and the treatment was well tolerated (269).
tology demonstrated increased LV thickness. In addition, In other studies (216), again involving pacing-induced
there was impaired LV contractility and diastolic function dilated cardiomyopathy in conscious dogs as a model, the
after insulin administration. LV contractility was also re- effects of 48-h infusions of either GLP-1 or its primary
duced after exogenous epinephrine. These data suggest metabolite after DPP-IV degradation [which occurs with a
that GLP-1 exerts physiologically important effects on half-life of 1–2 min in the circulation of pigs and humans
cardiac function. (46, 309)], GLP-1 9 –36 amide, were investigated. The dogs
In a more recent study, Bose et al. (22) demonstrated were studied under basal as well as insulin-stimulated
that GLP-1 significantly reduced infarction size in both conditions (hyperinsulinemic euglycemic clamps). The dogs
in vitro (isolated perfused rat heart) and in vivo models of with dilated cardiomyopathy demonstrated insulin resis-
ischemia-reperfusion damage. The protective effect
tance. Surprisingly, both GLP-1 and GLP-1 9 –36 amide
in vitro was abolished by the GLP-1 receptor antagonist
2. Neurotropic and other neural effects the chosen approach has been questioned because insulin
secretion was markedly stimulated in the GLP-1 experi-
GLP-1 may also possess neurotropic effects. Thus
ment, but not in the control experiment. A valid control
intracerebroventricular GLP-1 administration was associ-
experiment might involve infusion of insulin to achieve
ated with improved learning in rats and also displayed
similar levels as those achieved during GLP-1 infusion
neuroprotective effects (55, 238), and GLP-1 has been
(ideally identical intraportal concentrations). In further
proposed as a new therapeutic agent for neurodegenera-
studies, Toft-Nielsen et al. (287) administered GLP-1 to
tive diseases, including Alzheimer’s disease (239). It has
healthy subjects with or without concomitant infusion of
been reported that cerebral GLP-1 receptor stimulation
500 g/h somatostatin. Glucose assimilation was then
increases blood pressure and heart rate and activates
studied by an intravenous glucose tolerance test. It turned
autonomic regulatory neurons in rats, leading to down-
out that even with this (high) dose of somatostatin, insu-
stream activation of cardiovascular responses (335). Fur-
lin (and C-peptide) secretion was still slightly stimulated
thermore, it has been suggested that catecholaminergic
by GLP-1. In agreement with this, the glucose elimination
creas are prevented. Zander et al. (340) infused GLP-1 or evidence that the effects were transmitted via receptors
saline continuously for 6 wk to patients with type 2 dia- distinct from the classical GLP-1 receptor (336). Most
betes and determined insulin sensitivity by hyperinsuline- recently, GLP-1 was again reported to enhance glucose
mic euglycemic clamps before and after the treatment. uptake in human myocytes, and evidence for the involved
Insulin sensitivity was unchanged in the saline-treated signaling pathways was provided (80). It should be men-
group, but was almost doubled in the GLP-1-treated tioned that other studies failed to identify actions of
group. The study was not designed to elucidate the un- GLP-1 on glucose metabolism in muscle tissue (72). Some
derlying mechanisms, but it should be noted that GLP-1 of the cited studies suggested that GLP-1 may activate
was administered during the clamp (and actually resulted more than one receptor. As discussed above, a study of
in a slightly higher insulin level) and that the GLP-1- the enterogastrone effects of GLP-1 and PYY in dogs,
treated subjects experienced markedly improved glyce- where the GLP-1 receptor antagonist exendin 9 –39 was
mic control as well as lower free fatty acid levels and also incapable of blocking the inhibitory actions of GLP-1 (71),
lost ⬃2 kg of body weight. The weight loss as well as suggested that another receptor was involved. In other
strated that the diurnal L-cell secretion (measured as L-cells is highest, as the likely explanation for exagger-
enteroglucagon secretion) was dramatically decreased in ated GLP-1 responses after bariatric surgery, GLP-1 secre-
morbid obesity (128), and in a subsequent study, again tion is also strongly dependent on gastric emptying rates
in morbidly obese subjects, there was no measurable and hence the rate of exposure of the small intestinal
increase in postprandial GLP-1 secretion (201). However, mucosa to nutrients (187). Therefore, conditions with
after a jejuno-ileal bypass operation, meal responses were accelerated gastric emptying are also associated with ex-
restored to normal values. This should not be interpreted aggerated GLP-1 responses (187). It was, therefore, pro-
to suggest that the weight loss restored L-cell sensitivity posed that exaggerated GLP-1 secretion might be respon-
to meal stimulation, since it is known that abnormal sible for the postprandial reactive hypoglycemia that may
exposure of the distal gut to unabsorbed nutrients as be observed after gastric surgery (gastrectomy) (187) as
occurs after jejuno-ileal bypass as well as gastric bypass well as after gastric bypass operations (264). Indeed, if the
operations results in exaggerated L-cell secretion (129, postprandial glucose and GLP-1 responses observed in
235). However, obese subjects showing decreased post- such patients were reproduced in healthy subjects by
or near normal (288). Regarding GLP-1, a significant and believed that several of the many actions of GLP-1 are
sometimes substantial reduction in meal-induced GLP-1 involved in its antidiabetic effects (115). One important
secretion is found whether this is measured as the con- mechanism is of course the restoration of glucose-induced
centrations of the intact hormone or the metabolite GLP-1 insulin secretion. Generally, peripheral insulin levels do not
9 –36 amide (see above) (288, 312). In contrast to GIP, the increase during chronic GLP-1 treatment, but these levels
insulinotropic effect of GLP-1 is retained in patients with are maintained in spite of the concomitant reductions of
type 2 diabetes (206), and it is possible with infusions of plasma glucose by up to 5– 6 mM (340). Upon intravenous
GLP-1 to completely normalize glucose-induced insulin infusion of GLP-1 to fasting type 2 diabetic subjects, insulin
secretion in the patients as analyzed in hyperglycemic secretion first rises, but then, as plasma glucose concentra-
clamp experiments (150, 314). However, from dose-re- tions are lowered, decreases again to baseline levels (210).
sponse studies it appears that the potency of GLP-1 with The numerous molecular actions of GLP-1 on the beta cell
respect to enhancing glucose-induced insulin secretion is have been discussed above. Another important factor is the
greatly reduced (to ⬃20%) in the patients compared with inhibition of glucagon secretion. Again, during intravenous
effects of the peptide at all. GLP-1 analogs still under Univ. of Copenhagen, DK-2200 Copenhagen, Denmark (e-mail:
clinical development include Liraglutide, which consists holst@mfi.ku.dk).
of the GLP-1 molecule to which is attached a C-16 acyl
chain (via a glutamic acid linker) to Lys-26 (while Lys-33
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