Physiol Rev 87: 1409 –1439, 2007;
doi:10.1152/physrev.00034.2006.
The Physiology of Glucagon-like Peptide 1
JENS JUUL HOLST
Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
I.
II.
III.
IV.
V.
VI.
Introduction and Historical Overview
Proglucagon Gene Expression, Posttranslational Processing, and Chemical Structures
Proglucagon Distribution
Measurement, Release, and Metabolism
Regulation of Secretion
Effects of Glucagon-like Peptide 1
A. The GLP-1 receptor
B. The incretin effect
C. Effects on the beta-cells
D. Effects on glucagon secretion
E. Effects on the gastrointestinal tract
F. Central targets for peripherally released GLP-1
G. Effects on appetite and food intake
H. Other effects
I. Whole body effects, peripheral effects, and effects on insulin action
VII. Glucagon-like Peptide 1 Pathophysiology
A. Obesity
B. Reactive hypoglycemia
C. Diabetes
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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.
I. INTRODUCTION AND
HISTORICAL OVERVIEW
The glucoregulatory hormone glucagon was discovered in 1923 as a hyperglycemic substance present in
pancreatic extracts (196). Subsequent research indicated
that hyperglycemic substances were also present in exwww.prv.org
tracts of the gastrointestinal mucosa, and Sutherland and
DeDuve suggested in 1948 (276), based on bioassays, that
gastric extracts might contain glucagon, a finding that was
confirmed in several subsequent studies. Furthermore,
endocrine cells that resemble the pancreatic A-cells were
reported to be present in the gastrointestinal mucosa
(225). Upon the advent of the radioimmunoassay for glu-
0031-9333/07 $18.00 Copyright © 2007 the American Physiological Society
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cagon, one of the first radioimmunoassays to be developed (296), it was confirmed that the gastrointestinal tract
contains substances with glucagon immunoreactivity, i.e.,
reacting with the antibodies employed in the radioimmunoassay (297). In addition, in immunohistochemical studies, some intestinal endocrine cells could be stained using
glucagon antibodies (83), but it was also shown that these
cells differed from the pancreatic A-cells with respect to
granule morphology (83), and they were hence designated
as “L-cells” (26). Furthermore, in 1968, it was established
(298) that the glucagon-like immunoreactive material that
was secreted in response to an oral glucose load differed
from true glucagon both physicochemically and biologically. Furthermore, it was demonstrated that this “gut
glucagon-like immunoreactivity” was heterogeneous, consisting of at least two distinct moieties differing in molecular size (301). Through contributions from independent
groups, it was eventually demonstrated that the two predominant molecular forms of gut glucagon-like immunoreactivity both contain the entire 29-amino acid glucagon
sequence (13, 114, 116, 281) (see Fig. 1). One has a COOHterminal octapeptide extension, and the other has the
same COOH-terminal extension plus an NH2-terminal extension of 30 amino acids. The former molecule was
named oxyntomodulin because of its effects on the oxyntic mucosa in some species (13), and the latter was designated glicentin partly because of its glucagon-like immunoreactivity and partly because it was first thought to
consist of 100 amino acids (274). Full sequence analysis,
however, revealed it to consist of 69 amino acids (281).
The NH2-terminal extension of glucagon in glicentin was
identified also in extracts from the pancreas, from which
it was shown to be secreted in parallel with glucagon
(193, 282). Conceivably, therefore, glicentin was a proglucagon, a biosynthetic precursor for glucagon, which in the
pancreas was cleaved to glucagon and equimolar amounts
of the NH2-terminal extension peptide, which was named
glicentin-related pancreatic polypeptide (GRPP) (282).
From studies of the biosynthesis of glucagon in the
pancreatic islets, however, it was evident that a large
molecule (mol wt ⬃10,000), subsequently designated “the
major proglucagon fragment” (MPGF) that did not contain the glucagon sequence, was also formed in parallel
with glucagon (236). As the structures of glucagon-encoding mRNA and of the glucagon gene were determined (14,
15), it became evident that, in mammals, this major fragment of proglucagon contains two glucagon-like sequences, now designated glucagon-like peptides 1 and 2
(GLP-1 and GLP-2, respectively). For a while it was
thought that the GLP-2 moiety was an evolutionary late
addition to the gene, since fish and bird proglucagon
appeared to contain only a single glucagon-like peptide
corresponding to GLP-1 (172). Subsequent research, however, established that the proglucagon genes in these
species (there are two glucagon encoding genes in fish)
also contain the GLP-2 encoding sequence, which, however, is sequestered by differential splicing upon pancreatic expression of the gene (142) but remains in sequence
upon intestinal expression.
In further studies of the processing and secretion of
proglucagon products in humans and other mammals, it
was confirmed that, in the pancreas, the two glucagon-like
peptides are contained in a single large molecule, the
major proglucagon fragment, secreted in parallel with
glucagon (121, 189, 227, 229). In the intestinal mucosa,
however, the two glucagon-like peptides are formed and
secreted separately, whereas the NH2-terminal part of the
precursor, i.e., the part that corresponds to glicentin,
remains uncleaved (189, 227) or partly cleaved into GRPP
and oxyntomodulin (see Fig. 1). This review deals with
the physiology and pathophysiology of GLP-1.
FIG. 1. Differential posttranslational 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.
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THE PHYSIOLOGY OF GLUCAGON-LIKE PEPTIDE 1
II. PROGLUCAGON GENE EXPRESSION,
POSTTRANSLATIONAL PROCESSING,
AND CHEMICAL STRUCTURES
The structure of proglucagon was deduced from the
sequence of the cDNA encoding hamster proglucagon
(15) and the human proglucagon gene (14). Also the murine and bovine genes were cloned (105, 171). Apparently,
only a single gene encodes proglucagon in mammalian
species, and identical mRNAs are produced in the pancreas and the intestines (189, 221). The differences in the
proglucagon products in these tissues are, therefore, due
to tissue-specific, differential, posttranslational processing of proglucagon (189, 227). The proglucagon gene is
also expressed in certain neurons in the nucleus of the
solitary tract in the brain stem (161). Recent studies
have shed some light on the mechanisms that result in the
tissue specificity and the mechanisms that regulate the
expression of the proglucagon gene in the gut in vivo.
Thus it has been established that the transcription factor
pax6 is expressed in intestinal endocrine cells and activates proglucagon transcription (292). Mice with a dominant negative pax6 mutation exhibit a total absence of gut
endocrine cells expressing GLP-1 or GLP-2. Disruption of
the pax6 gene disrupts both islet development and selectively eliminates the endocrine cell population of the
small and large bowel, including the proglucagon-producing cells (111, 292). Yi et al. (338) recently demonstrated
that ␤-catenin, the major effector of the Wnt signaling
pathway, activates proglucagon expression in intestinal,
but not in islet cells. Furthermore, this effect was mediated by the transcription factor TCF-4, which is highly
expressed in intestinal endocrine cells, but not in islets.
Both TCF-4 and ␤-catenin bind to the proglucagon gene
promoter, and a dominant negative TCF-4 repressed proglucagon expression in an intestinal cell line that expresses proglucagon and produces GLP-1 (338). It is of
interest that ⬃1,250 nucleotides of the rat proglucagon
gene promoter direct the expression to pancreatic islets
and neurons of the brain, whereas additional upstream
sequences extending to ⫺2,250 are required for expression of the gene in intestinal endocrine cells (166). However, the mechanisms regulating tissue specific proglucagon gene expression in humans appear to differ from
those described for the rat gene (213, 214), and unfortunately, little is known about the regulation of the human
gene.
The TCF-4-mediated regulation of proglucagon expression in the gut is of considerable interest in view of
the recent demonstration in several unrelated populations
of a genetic association of a specific single nucleotide
polymorphism (SNP), the microsatellite DG10S478 in intron 3 of the TCF4 gene (now designated TCF7L2), and
the development of type 2 diabetes. These findings raise
the possibility that this SNP influences disease suscepPhysiol Rev • VOL
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tibility through modulation of intestinal proglucagon
gene expression and hence possibly plasma levels of
GLP-1 (81).
The differential posttranslational processing of proglucagon in the pancreas and gut results in the pancreas
in the formation of glucagon, the GRPP, a small fragment
corresponding to the proglucagon sequence (PG) 64 – 69
and the major proglucagon fragment corresponding to PG
72– 60 (121) (see Fig. 1), and all of these peptide products
are secreted in parallel upon stimulation (121). The processing in the alpha cells is due to the coexpression of the
prohormone convertase PC2, which has been demonstrated to be both necessary and sufficient for cleaving
proglucagon as outlined (256). In agreement with this,
animals in which the PC2 gene is disrupted cannot cleave
proglucagon in the alpha cells (73) and, as a result, have
lower glucose levels than wild-type animals and improved
tolerance to glucose, and they develop alpha cell hyperplasia, features that also characterize mice with a deletion
of the glucagon receptor gene (77).
The intestinal processing results in the formation of
glicentin, corresponding to proglucagon residues 1– 69,
part of which may be cleaved further to oxyntomodulin,
corresponding to PG 33– 69 (9, 227). The proglucagon
sequence that corresponds to the major proglucagon fragment contains pairs of basic amino residues, canonical
cleavage sites for the prohormone convertases, flanking
both of the glucagon-like peptide sequences in the human
cDNA, and it was therefore predicted that the prohormone might be cleaved at these sites (227) and that the
sequences of GLP-1 and GLP-2 would therefore correspond to PG 72–108 and 126 –158, 126 –159, or 126 –160
(the nucleotide codon encoding residue 160 is found in a
separate exon and was therefore overlooked in the first
cloning experiments). However, sequencing of the naturally occurring peptides extracted from human gut revealed that the structure of native GLP-1 corresponds to
PG 78 –107 (126). This turned out to be of utmost importance, since the truncated peptide was found to be a
potent stimulator of glucose-induced insulin secretion,
whereas full-length GLP-1 was inactive (126, 191). The
truncation also had consequences for the nomenclature,
since the naturally occurring peptide was henceforth designated either truncated GLP-1 or GLP-1 7–36amide (or
GLP-1 7–37). In current literature, the unqualified designation GLP-1 covers only the truncated peptide. It was
also found that the Gly corresponding to PG 108 serves as
substrate for amidation of the COOH-terminal Arg (226),
but the biological consequences of the amidation are
unclear. The amidated and the Gly-extended forms have
similar bioactivities and overall metabolism (232), although the amidated form may exhibit slightly improved
stability towards plasma enzymes (326). In humans, almost all of GLP-1 secreted from the gut is amidated (231),
whereas in many animals (rodents, pigs), part of the
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secreted peptide is GLP-1-(7–37) (97, 190). This poses
special problems with respect to the measurement of
GLP-1 secretion in these species (see below). The sequence of naturally occurring GLP-2 was found to correspond to PG 126 –158 (27, 103). A comparison of GLP
sequences among species shows that the GLP-1 sequence
is preserved 100% in all mammals, where this has been
studied, and the sequence homology is pronounced
across other classes of animals (149). GLP-2 shows more
variation with, e.g., four substitutions between human
and porcine GLP-2. The Ala in position 7 of human intervening peptide 2 is also variable with Thr or Asn in, e.g.,
the porcine and bovine peptides.
The processing of proglucagon in the intestinal
L-cells results from the actions of coexpressed prohormone convertase (PC) 1/3, which is both necessary and
sufficient for the complete processing (295, 344). Interestingly, the NH2-terminal cleavage site of GLP-1 is not a
classical pair of basic amino acids, but represents a single
Arg residue; however, in vitro coexpression of PC 1/3 and
proglucagon has demonstrated efficient cleavage at this
site (255). In agreement with this, mutations in PC 1/3 lead
to abnormalities in GLP-1 processing and secretion, associated with multiple endocrinopathies (143) (undoubtedly
because PC 1/3 is important for processing of many regulatory peptides/hormones), and mice with a targeted
deletion of the PC-1/3 gene are unable to process proglucagon to GLP-2 and GLP-1 (295, 344). Interestingly, it was
recently demonstrated that adenovirus-mediated expression of PC 1/3 in the pancreatic alpha cells increases islet
GLP-1 secretion, resulting in improved glucose-stimulated
insulin secretion and enhanced survival in response to
cytokine treatment as well as enhanced performance after transplantation to mouse models of type 1 diabetes, a
finding of considerable clinical interest (see below) (331).
III. PROGLUCAGON DISTRIBUTION
It has been known since 1968 that endocrine cells
resembling pancreatic A-cells occur in the intestinal mucosa (225). Later research demonstrated cells that are
indistinguishable at the electron microscopic level from
the pancreatic A-cells in the oxyntic mucosa of some
species (275). Particularly in dogs such cells are abundant
and appear to secrete apparently true glucagon in appreciable amounts (167). Similar cells have not been found in
humans, however (120). The majority of the intestinal
proglucagon-derived peptides are secreted from the
L-cells, which differ clearly from the A-cells by their granule morphology (224). A-cell granules show a distinct halo
of less electron-dense material surrounding a core of
dense material, whereas the granules of the L-cells are
homogeneous without halo formation. The L-cell is an
open-type endocrine cell with a slender triangular form
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with the base resting on the basal lamina and a long
cytoplasmic process reaching the gut lumen. This process
is equipped with microvilli that protrude into the lumen. It
may be via these microvilli that the L-cell can sense the
presence of nutrients in the lumen and transform this
information into a stimulation of secretion. The peptide
products of the A- and L-cells have been identified at the
cellular level by immunocytochemistry. As expected, antisera directed against the midregion of glucagon (“side
viewing”) stain the pancreatic A-cells as well as the intestinal L-cells, whereas antibodies against the free COOH
terminus of glucagon (which is not exposed in the L-cells)
only stain the A-cells. Antisera against the NH2-terminal,
non-glucagon part of glicentin stain both the A-cells and
the L-cells because they react with GRPP in the pancreas
and with glicentin in the gut (224). As expected from their
common origin, both GLP-1 and GLP-2 show complete
coexistence with glucagon (side-viewing antisera) upon
immunohistochemical examination (189, 227, 229). GLP-1
and GLP-2 immunoreactivity have been colocalized with
glucagon in the electron-dense core of the A-cells, presumably due to their presence in the major proglucagon
fragment (302).
The density of L-cells shows a maximum in the ileum
in most species (25, 62); no or very few cells are present
proximal to the ligament of Treitz in humans and other
primates. A considerable number is present in the colon
(151), particularly the distal part. Surprisingly, the entirely
unrelated peptide YY (PYY) has also been localized to the
L-cells in all mammals studies so far (23) and was even
found to be localized to the same granules as glicentin by
immunocytochemistry at the electron microscopic level
(23). The distribution was reexamined in a recent study
involving combined in situ hybridization, peptide chemistry, and immunohistochemistry. In this study of endocrine
cells of the porcine, rat, and human small intestines (195),
GLP-1 nearly always (92%) colocalized with either the
incretin hormone GIP (glucose-dependent insulinotropic
polypeptide, formerly known as gastric inhibitory
polypeptide) or the enterogastrone hormone PYY. GIP
and PYY were rarely colocalized. In the mid small intestine, 55–75% of the cells staining for either GLP-1 or GIP
also expressed the other incretin hormone. Concentrations of extractable GIP and PYY were highest in the
midjejunum [154 (95–167) and 141 (67–158) pmol/g, median and range, respectively], whereas GLP-1 concentrations were highest in the ileum [92 (80 –207) pM], but,
importantly, GLP-1, GIP, and PYY immunoreactive cells
were found throughout the (porcine) small intestine. This
finding is of particular interest in view of the finding that
GIP can stimulate GLP-1 secretion. GIP is only active in
pharmacological concentrations (99), but might act locally in a paracrine or autocrine manner. This study (195)
thus suggested that simultaneous, rather than sequential,
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THE PHYSIOLOGY OF GLUCAGON-LIKE PEPTIDE 1
secretion of these hormones would occur by postprandial
luminal stimulation.
As mentioned, the proglucagon gene is also expressed in the central nervous system. Thus cells immunoreactive for GLP-1, glucagon, and glicentin have been
demonstrated in the nucleus of the solitary tract of the
brain stem of rats , monkeys, and humans (52, 144, 145).
These neurons project to many regions in the brain, in
particular the nuclei of the hypothalamus, including the
arcuate and the paraventricular nuclei (161). The processing of proglucagon has been examined both at the level of
the cell bodies and at the levels of the fibers projecting to
the hypothalamus (161). The pattern was intestinal with a
pronounced contribution of processed oxyntomodulin,
and this is important, since such neurons would be expected upon stimulation to release simultaneously three
hormonal products (oxyntomodulin, GLP-1, and GLP-2),
which all have been demonstrated to inhibit food intake
when administered intracerebroventricularly (see below).
IV. MEASUREMENT, RELEASE,
AND METABOLISM
As will be apparent from the above, measurement in
plasma of the products of proglucagon gene expression
will require assays for at least eight different peptides,
three from the pancreas (glucagon, GRPP, major proglucagon fragment) and five from the intestine (glicentin,
oxyntomodulin, GLP-1, GLP-2, and intervening peptide 2).
For estimation of the secretory state of the alpha or
L-cells, it might be proposed to measure just a single
proglucagon product, because studies involving isolated
perfused preparations of the pancreas or the ileum have
shown that the pancreatic and intestinal products, respectively, are secreted synchronously and in equimolar
amounts. [This does not apply to glicentin and oxyntomodulin, since oxyntomodulin is a breakdown product of
glicentin. Therefore, it is the sum of the two moieties
which equals the secreted amount of other proglucagonlike GLP-1 and -2 (193, 227)]. However, each of the proglucagon products is being eliminated from the circulation at its own particular rate (see below). A reliable
estimate of the secretion and the plasma concentration of
any of the products will therefore require specific measurement.
Methods for determination of the glucagon-containing products date back to the first descriptions of bioassays and radioimmunoassays for glucagon (104, 117). The
cross-reaction of certain antisera with material from the
gut caused considerable confusion in these early days.
Antisera directed against the midregion of glucagon, also
called “side-viewing antisera,” will react with any product
that contains this sequence, i.e., glucagon, glicetin, oxyntomodulin, and proglucagon (or glicentin) 1– 61 (10), the
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last of which may be released in small amounts from both
pancreas and gut. With such antisera, it may be possible
to measure what might be designated “total glucagon”
concentrations. But results obtained in these assays are
not easy to interpret, because the peptides measured may
be derived from both the pancreas and the gut. Upon oral
administration of carbohydrates, pancreatic A-cell secretion is suppressed and L-cell secretion stimulated, and in
this case, such assays may provide a reasonable estimate
of L-cell secretion. The designation “enteroglucagon secretion” is sometimes coined for the results of such measurements. More specific information may be obtained
with antisera that react exclusively with the unmodified
and unextended COOH terminus of glucagon. Such antisera do not react with glicentin and oxyntomodulin and
therefore mainly measure pancreatic glucagon (117). By
subtracting the results obtained with COOH-terminal antisera from those obtained with side-viewing antisera, one
gets, at least in principle, the concentration of the gut
peptides glicentin and oxyntomodulin (104), and the combined assays, therefore, represent another method for
quantification of enteroglucagon or gut glucagon-like immunoreactivity (117).
The specificity and accuracy problems that trouble
the glucagon assays apply to the assays of GLP-1 and
GLP-2 as well. Again, side-viewing antibodies will react
with both intestinal and pancreatic products. As mentioned, in humans, almost all of intestinal GLP-1 is COOHterminally amidated, and assays directed against the amidated COOH terminus will therefore reliably measure
intestinal GLP-1 secretion [although a small contribution
of GLP-1 1–36amide from the pancreas cannot be excluded (121)]. Assays in species where both GLP-1 7–36
amide and GLP-1 7–37 are produced in the gut (rodents,
pigs) pose a special problem. In principle, assays directed
against the intact NH2 terminus might be useful here (90),
as would sandwich assays where one antibody is NH2
terminal and the other COOH terminal but capable of
reacting with both the amidated and the Gly-extended
forms. A few assays are based on this principle (317), and
one is commercially available (Linco, St. Charles, MO;
www.lincoresearch.com). The greatest problem with this
approach, however, is related to the rapid degradation of
GLP-1. GLP-1 is extremely susceptible to the catalytic
activity of the enzyme dipeptidyl peptidase IV (DDP-IV),
which cleaves off the two NH2-terminal amino acids (44).
The metabolite thus generated, GLP-1 9 –36 amide or
GLP-1 (9 –37), is inactive and may even act as a competitive antagonist at the GLP-1 receptor (44, 153), although
its formation does not seem to result in antagonism
in vivo (339). In studies of GLP-1 secretion from isolated
perfused porcine ileum, it has been shown that a very
large part of the GLP-1 that leaves the gut is already
degraded to the inactive metabolite (96) (see Fig. 2). At
first, the degradation was calculated to amount to about
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FIG. 2. The endocrine pathway for the actions of GLP-1. GLP-1
secretion is stimulated by nutrients in the gut lumen (a magnified
intestinal villus with an open-type L-cell is shown at the lower left).
GLP-1 diffuses across the basal lamina into the lamina propria and is
taken up by a capillary, only to be broken down by dipeptidyl peptidase
IV (DPP-IV), located on the luminal surface of the endothelial cells
(white cells lining the capillary) so that only 25% of the secreted amount
reaches the portal circulation. In the liver, a further 40 –50% is destroyed
so that only 10 –15% enters the systemic circulation and may reach the
pancreas and the brain via the endocrine pathway (perhaps even less
because of the continued proteolytic activity of soluble DPP-IV present
in plasma).
two-thirds of the total amount secreted, but subsequent
studies revealed that also the porcine gut releases significant amounts of nonamidated GLP-1 9 –37 (97), which
was not taken into account in the original study. Therefore, ⬍25% of newly secreted GLP-1 leaves the gut in an
intact, active form. A similar degradation amounting to
⬃40 –50% takes place in the liver (46), and it can therefore
be calculated that only ⬃10 –15% of newly secreted GLP-1
reaches the systemic circulation in the intact form (see
Fig. 2). This is in contrast to the fact that virtually all of
GLP-1 stored in the granules of the L-cells is intact (96). It
has been shown that the degradation is due to the actions
of the enzyme DDP-IV, which is expressed not only in the
enterocyte brush border but also in the endothelial cells
lining the capillaries of the lamina propria (96). In agreement with this, inhibitors of DPP-IV can completely prevent this degradation (96). DPP-IV activity is also responsible for the extremely rapid initial whole body metabolism of GLP-1, which results in an apparent half-life for
intact GLP-1 in plasma of 1–2 min and a metabolic clearance rate exceeding cardiac output by a factor of 2–3 (46,
309). The metabolite is also cleared rapidly, mainly in the
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kidneys, with a half-life of 4 –5 min (182, 309). It has been
established that GLP-1 is also a substrate for the enzyme,
neutral endopeptidase 24.11 (134), and recent studies
have shown that inhibition of this enzyme will enhance
survival of both endogenous and exogenous GLP-1 in vivo
(242). However, the enhanced survival will only be apparent if the NH2-terminal degradation by DDP-IV has been
prevented. Because of the extensive degradation, the
plasma concentrations of the intact hormone are very low
and may not even rise significantly in response to small
meals (312). However, determination of the concentrations of the metabolite, which will be much higher, may
reveal that a stimulation of the L-cells has nevertheless
taken place. It follows that for estimation of L-cell secretion it is best to measure the sum of the intact hormone
and the primary metabolite. In humans, this can be accomplished with assays for the amidated COOH terminus
of the molecule, which is common to the intact hormone
and the metabolite, because in humans, all of the GLP-1
released from the gut is amidated (231). Such assays are
frequently designated “total” GLP-1 assays. Clearly, for
estimation of the impact of circulating intact GLP-1 for
insulin secretion via the endocrine route, it is necessary to
measure the concentration of the intact hormone, which
may be accomplished with sandwich assays as mentioned
(often designated “active GLP-1 assays”). However, as will
be evident below, this is unlikely to reflect to total influence of L-cell secretion on insulin secretion.
V. REGULATION OF SECRETION
GLP-1 secretion is clearly meal related (233). In the
fasting state, the plasma concentrations are very low.
They are not immeasurable though, and it has been demonstrated that the fasting concentrations can be lowered
with somatostatin in humans (287), suggesting that there
is a certain basal rate of secretion. This also seems evident from studies involving DPP-IV inhibitors, which increase the levels of intact endogenous GLP-1 (174) also in
the intervals between meals and in the fasting state (174).
This would not have been possible without a significant
interdigestive and fasting secretion of GLP-1. Meal intake
causes a rapid increase in L-cell secretion, most evident
when measured with COOH-terminal assays (233) (see
Fig. 3), but often measurable also with assays for the
intact hormone (317). The response is noticeable after
⬃10 min, but occurs later than the “cephalic phase” stimulation of insulin secretion (3), suggesting that the neuronal, possibly vagal, signals that cause insulin secretion
do not influence GLP-1 (or GIP) secretion. There are
many reasons to believe that it is the actual presence of
nutrients in the gut lumen and possibly their interaction
with the microvilli of the L-cells (62) that are responsible
for the GLP-1 response. Thus a very rapid GLP-1 response
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THE PHYSIOLOGY OF GLUCAGON-LIKE PEPTIDE 1
FIG. 3. Plasma concentrations of insulin, GLP-1 (total), and gastric
inhibitory peptide (GIP; total) during the day time in healthy subjects.
Note the rather low concentrations of GLP-1 compared with the high
concentrations of GIP. Arrows indicate large meals. Values are means ⫾
SE (n ⫽ 8 subjects). [From Orskov et al. (233).]
is seen in humans after ileal instillations of lipids or
carbohydrate in amounts corresponding to “the physiological malabsorption” of these nutrients (164). The osmolarity of the solutions appears not to be of importance,
since hyperosmolar salt solutions have no effect (240).
The meal response depends on the size of the meal (317)
and is strongly correlated to the gastric emptying rate
(187). The response is uninfluenced by minor intestinal
resections (which interrupt intramural reflex pathways)
(212). It has been suggested that the purpose of having
two incretin hormones is related to their location with
one, GIP, being predominantly secreted from the upper
small intestine, and the other mainly secreted from the
lower small intestine where the density of the L-cells is
higher. Conceivably, therefore, smaller loads of rapidly
absorbable nutrients would preferentially activate the upper incretin hormone, i.e., GIP, whereas ingestion of
larger meals containing more complex nutrients requiring
more extensive digestive processing would also activate
the distal incretin, i.e., GLP-1. Experiments with ␣-glycosidase inhibitors such as acarbose, which delay upper
Physiol Rev • VOL
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intestinal digestion and absorption of carbohydrates and
cause a transfer of nutrients to distal segments of the gut,
are consistent with this. Acarbose reduces GIP secretion,
but augments GLP-1 secretion (244) and may, partly because of this, improve glucose tolerance in patients with
diabetes. Other experiments, however, suggest that the
secretion of GIP is closely linked to that of GLP-1 and vice
versa. Thus, in the laboratory of the author, volunteers
were intubated with long (ileal) or short (duodenal) catheters, and small amounts of glucose were instilled to
produce a selective response of either of the incretin
hormones. Surprisingly, the glucose instillation resulted
in almost equal GIP and GLP-1 responses whether introduced proximally or distally (118; unpublished studies).
This may be explained by the fact that both GLP-1- and
GIP-producing cells are found throughout the small intestine and by the above-mentioned finding that a significant
number of gut endocrine cells in several mammals, including humans, produce both GIP and GLP-1 (195). In
agreement with this, a mixed meal will normally cause a
release of both peptides, but whereas the GIP concentrations may increase to several hundred picomolar, GLP-1
concentrations (intact ⫹ metabolite) rarely exceed 50 pM
(233) (see Fig. 3). In subjects with accelerated gastric
emptying, for instance after gastrectomy or gastric bypass
operations for obesity, the secretion of GLP-1 may be
greatly exaggerated (6, 187, 235) and may in such patients
be the cause of reactive hypoglycemia, because of a
resulting inappropriate hyperinsulinemia (76, 286) (see
below).
It has often been said that indirect mechanisms for
release were required to explain the rapid onset of the
meal response, taking the distal location of the L-cells into
consideration. However, although the density of L-cells is
higher in the ileum, there are numerous L-cells in the
proximal jejunum as already pointed out, and these may
very well be responsible for the early response. The dependency of the response on the magnitude of the meal
may reflect that a larger area of the gut and thereby an
increasing number of L-cells is being exposed with larger
meals.
Little is known about the mechanisms whereby nutrients stimulate GLP-1 secretion. In canine ileum, blockade of the luminal sodium/glucose cotransporter, SGLT-1,
with phlorizin inhibited GLP-1 secretion (273), suggesting
that absorption of glucose is essential, but unfortunately
the experiment could not distinguish between effects of
the blocker on the L-cells or on neighboring cells. Gribble
et al. (82) recently found that SGLT-1 was important for
glucose-induced GLP-1 secretion in a proglucagon-expressing cell line called GLUTag (82). The GLUTag cell
line is derived from a colonic neuroendocrine tumor generated in a transgenic mouse expressing the simian virus
40 (SV40) T-antigen under the control of the proglucagon
promoter (53). Unfortunately, this cell line does not ex-
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JENS JUUL HOLST
hibit the polarity of the L-cell, and it is therefore difficult
to extrapolate results obtained with these cells to natural
L-cells. GLP-1 secretion from the GLUTag cells may also
be stimulated by metabolizable sugars by a mechanism
that involves closure of ATP-sensitive K⫹ channels (8).
This seems to be consistent with the recent demonstration of stimulation of GLP-1 secretion from isolated segments of porcine ileum by glucose administered both
luminally and via the perfusate (98). Fructose stimulates
secretion both in vivo and in the GLUTag cells (107),
suggesting that GLUT5 transporters may also be involved.
Involvement of neurohormonal mechanisms to explain the rapid postprandial onset of secretion has been
considered by several authors. In rats, glucose-dependent
insulinotropic peptide (GIP) has been shown to stimulate
GLP-1 secretion via activation of a neural pathway involving the vagus nerve (254). Administration of muscarinic
cholinergic agonists to isolated perfused rat ileum and
colon resulted in stimulation of GLP-1 secretion (54, 109),
and studies in anesthetized rats and in fetal rat intestinal
cells suggested that both M1 and M2 muscarinic receptors
could be involved in control of GLP-1 release (7). Catecholamines could also be part of a neural stimulatory
pathway in rats, as infusion of a ␤-adrenergic agonist
stimulated GLP-1 secretion in isolated perfused rat ileum
and colon (54, 241).
In humans and pigs, none of the known duodenal
peptides (including GIP), in normal physiological postprandial concentrations, is capable of stimulating GLP-1
secretion (68, 99, 206). Indeed, in the author’s laboratory,
a systematic search of fractionated (gel and high-performance liquid chromatography) extracts of the duodenal
mucosa was carried out using GLP-1 secretion from isolated perfused ileum as bioassay, but no unknown GLP-1
stimulating agents could be identified (95, 99). Infusion of
atropine in humans delays the increase of both plasma
glucose and GLP-1 after an oral glucose load and reduces
the GLP-1 response (12), but these effects likely reflect
the effects of atropine on gastrointestinal motility. Studies
using the human NCI-H716 cell line have shown that
cholinergic agonists stimulated GLP-1 release and suggested, as mentioned above, that M1 and M2 muscarinic
receptors are involved (7, 251). In isolated perfused porcine ileum, GLP-1 secretion could be increased by infusion of acetylcholine during coinfusion of phentolamine
(an ␣-adrenergic blocker, which will eliminate the sympathetic inhibition of GLP-1 secretion) (97). All this suggests that acetylcholine could be a transmitter in a neural
stimulatory pathway for GLP-1 secretion. However, another study in conscious pigs indicated that the vagus
nerve is not involved in control of GLP-1 release (18).
Finally, in recent extensive studies employing both isolated perfused porcine ileum and intact pigs, a variety of
neurally active agents as well as electrical stimulation of
the abdominal vagal trunks were employed to investigate
Physiol Rev • VOL
the importance of the neural regulation (100). It was
confirmed that the sympathetic innervation to the gut is
inhibitory to GLP-1 secretion (with norepinephrine as the
responsible transmitter), whereas the extrinsic vagal innervation had no effect. Intrinsic, cholinergic activity may
play a minor role, however.
One of the most powerful mechanisms for regulation
of GLP-1 secretion appears to be a local paracrine control
exerted by neighboring somatostatin producing D-cells
(97). Elimination of somatostatin’s restraint (by immunoneutralization) may increase GLP-1 secretion up to eightfold, much more than observed with any other stimulus. It
deserves mentioning that the neuropeptide gastrin releasing polypeptide (GRP), as well as its COOH-terminal decapeptide neuromedin C, and the related 14-amino acid
frog-skin peptide bombesin (which exhibits strong
COOH-terminal homology to GRP) are powerful stimulants of GLP-1 secretion (96, 227). A release of GRP can be
measured from vagally innervated organs during vagal
stimulation, but as mentioned, vagal stimulation does not
result in a release of GLP-1 (154). Lipids provide a rather
strong stimulus for GLP-1 secretion (63), and in this connection it is of interest that L-cells were recently reported
to express a deorphanized G protein-coupled receptor for
long-chain saturated fatty acids, GPR120 (112). Furthermore, activation of this receptor with fatty acids stimulated secretion of GLP-1 both in vitro and in vivo. In
recent studies involving the GLUTag cell line, which as
mentioned is a model for the L-cells and expresses the
GPR120 receptor, the atypical protein kinase C (PKC-␨),
known to be involved in fatty acid signaling in many cells,
was found to be required for oleic acid-induced GLP-1
secretion (136). In other recent studies involving GLUTag
cells, the neurotransmitters glycine and GABA were reported to provide a strong stimulus for secretion (74).
VI. EFFECTS OF GLUCAGON-LIKE PEPTIDE 1
A. The GLP-1 Receptor
The GLP-1 receptor is a class 2, G protein-coupled
receptor (176) and was first cloned by expression cloning
from a rat pancreatic islet library by Bernard Thorens in
1992. Thorens subsequently also cloned the highly homologous human receptor (283, 284) and also confirmed that
the 53% homologous lizard peptide exendin 4 is a full
agonist and the truncated peptide exendin 9 –39 is a potent antagonist of the receptor (78) (see also sect. VII). The
GLP-1 receptor belongs to the same family as the GIP and
the glucagon receptors (176). The receptor typically couples via a stimulatory G protein to adenylate cyclase (285,
330). The signaling in beta cells is discussed below. The
receptor is widely distributed in pancreatic islets, brain,
heart, kidney, and the gastrointestinal tract (5, 28, 33, 322,
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323) including the stomach, where the receptor is expressed on the parietal cells (262). Its function is not
known for all these locations (see below). For instance, in
the parietal cells, activation of the receptor increases
aminopyrine accumulation, which is an indirect indicator
of acid secretion (258), whereas in vivo, GLP-1 strongly
inhibits acid secretion (see below). Numerous attempts
have been made to identify alternative GLP-1 receptors or
subtypes (see below), but at present only a single GLP-1
receptor has been identified, whether expressed in the
brain, the stomach, or the pancreas (322). However,
since the pulmonary receptor was found to differ from
the islet receptor with respect to electrophoretic mobility,
whereas the primary sequence was identical, it was concluded that glycosylation patterns might differ (158). Biological consequences of such differences are unknown.
As mentioned, exendin 9 –39 acts as a potent and specific
antagonist at the GLP-1 receptor (284), and all effects of
GLP-1 transmitted via this receptor would be expected to
be blocked by the antagonist. However, in certain experiments involving effects of afferent vagus signaling or
enterogastrone effects of GLP-1 (see below), this has not
been the case (71, 219), raising speculations about the
existence of another receptor. Currently, its nature remains elusive. There is considerable controversy with
respect to possible effects of GLP-1 on adipose tissue,
muscle tissue, and the liver, and coupled to this is of
course the question whether the GLP-1 receptor is expressed in these tissues. Some studies have been negative
(28), and others less clear (33). In addition, there may be
differences between species, with dogs possibly expressing the receptor in muscle and adipose tissue (257) and
mice expressing it in liver (33). See below for a further
discussion of extrapancreatic effects of GLP-1.
B. The Incretin Effect
One of the most important functions of GLP-1 is to
act as an incretin hormone (124, 310).
“The incretin effect” designates the amplification of
insulin secretion elicited by hormones secreted from the
gastrointestinal tract. In the most strict sense, it is quantified by comparing insulin responses to oral and intravenous glucose administration, where the intravenous infusion is adjusted so as to result in the same (isoglycemic)
peripheral (preferably arterialized) plasma glucose concentrations (177, 237). In healthy subjects, oral administration causes a two- to threefold larger insulin response
compared with the intravenous route. It is, however, important to realize that the effect varies with the size of the
glucose challenge, being small with, e.g., 25 g and very
large with 100 g of glucose (208). In these dose-response
experiments, the plasma glucose excursions were identical despite the increasing glucose loads. In other words,
Physiol Rev • VOL
1417
the incretin effect ensures that postprandial glucose excursions are limited and similar regardless of the carbohydrate load. The increase in insulin secretion is mainly
due to the actions of insulinotropic gut hormones (177,
178). The same gut hormones are also released by mixed
meals, and given that their postprandial concentrations in
plasma are similar and that the elevations in glucose
concentrations are also similar, it is generally assumed
that the incretin hormones are playing a similarly important role for the meal-induced insulin secretion. Part of
the increase in the peripheral insulin concentrations may
be due to a decreased hepatic uptake of insulin during
oral glucose ingestion, resulting in more insulin being
passed on to the peripheral circulation rather than representing an increased secretion. This could be mistaken for
an incretin effect. However, if the analysis is based on
measurements of insulin’s C-peptide instead of insulin, it
is possible to eliminate the influence of the varying hepatic extraction of insulin since C-peptide is not taken up
by the liver. Several studies have shown that during isoglycemic glucose challenges in healthy subjects, plasma
C-peptide concentrations show very similar changes as do
insulin concentrations with much higher response to the
oral versus the intravenous challenge. This proves that
the larger response to oral versus intravenous glucose is
due to increased secretion of insulin. Calculation of the
incretin effect can also be based on measurements of
actual prehepatic insulin secretion rates. These can be
calculated from measurements of C-peptide levels by application of C-peptide elimination kinetics and deconvolution. The actual prehepatic insulin secretion rates also
exhibit much larger increases after oral compared with
isoglycemic intravenous glucose stimulation (175).
Many hormones have been suspected to be responsible for the incretin effect (125), but today there is ample
evidence to suggest that the two most important incretins
are GIP and GLP-1 (310). Both have been established as
important incretin hormones in mimicry experiments in
humans, where the hormones were infused together with
intravenous glucose to concentrations approximately corresponding to those observed during oral glucose tolerance tests. Both hormones powerfully enhanced insulin
secretion, each of them actually to an extent that can fully
explain the insulin response (157, 202). Likewise, administration of GLP-1 and GIP receptor antagonists to rodents
or immunoneutralization have clearly indicated that both
hormones play an important role for the incretin effect
(75, 155). However, there has been some uncertainty
about the relative roles of the two hormones. GIP is
circulating in 10-fold higher concentrations than GLP-1
[and this is true also with respect to the concentrations of
the intact hormones (312)], whereas GLP-1 appears more
potent than GIP (206). Furthermore, it is often emphasized that both hormones require elevated plasma glucose
concentrations for stimulation of insulin secretion, for
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GIP may be as much as 8 mM. The insulinotropic potential
of GLP-1 and GIP was, therefore, reinvestigated in recent
human experiments involving clamping of blood glucose
at fasting and postprandial levels and exact copying of the
meal-induced concentrations of both GLP-1 and GIP by
intravenous infusions (See Figs. 4 and 5). The results
showed that both hormones are active with respect to
enhancing insulin secretion from the beginning of a meal
(even at fasting glucose levels) and that they contribute
almost equally, but with the effect of GLP-1 predominat-
FIG. 5. Insulin and glucagon responses in healthy volunteers to
intravenous infusions of GLP-1 and GIP at normal postprandial physiological concentrations (see Fig. 3) carried out during clamping of plasma
glucose at fasting levels and at 1 and 2 mM above that (see Fig. 4). The
responses to the glucose alone are also shown. Note that both GIP and
GLP-1 stimulate insulin secretion even at fasting glucose levels. Also
note that whereas GIP has litte effect on glucagon secretion, GLP-1
causes an additional inhibition. [Modified from Vilsboll et al. (315).]
ing at higher glucose levels (315). The effects of the two
hormones with respect to insulin secretion have been
shown to be additive in humans (204). It should be noted
that only GLP-1, not GIP, causes an inhibition of glucagon
secretion exceeding that elicited by glucose clamping.
From studies in mice with targeted lesions of the both
GLP-1 and GIP receptors, it was concluded that both
hormones are essential for a normal glucose tolerance
and that the effect of deletion of one receptor was “additive” to the effect of deleting the other (102, 243). Thus
there is little doubt that the incretin effect plays an important role in postprandial insulin secretion and, therefore, glucose tolerance in humans and animals.
FIG. 4. Incretin effect of GLP-1 and GIP in humans. Postprandial
concentrations of GIP and GLP-1 (see Fig. 3) were copied by intravenous
infusion in healthy volunteers, while plasma glucose levels were
clamped at fasting levels, and at 1 and 2 mM above that. The insulin and
glucagon responses to these infusions are shown in Fig. 5. [Modified
from Vilsboll et al. (315).]
Physiol Rev • VOL
C. Effects on the Beta-Cells
GLP-1’s insulinotropic activity, which is strictly glucose dependent, is, at least partly (see below), exerted via
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interaction with the GLP-1 receptor located on the cell
membrane of the beta cells (124). Binding of GLP-1 to the
receptor causes activation, via a stimulatory G protein, of
adenylate cyclase resulting in the formation of cAMP.
Most of the actions of GLP-1 are secondary to the formation of cAMP (see Fig. 6). Subsequent activation of protein kinase A and the cAMP-regulated guanine nucleotide
exchange factor II (cAMP-GEFII, also known as Epac2)
leads to a plethora of events including altered ion channel
activity, elevation of intracellular calcium concentrations,
and enhanced exocytosis of insulin-containing granules
(130). GLP-1 also stimulates coordinated oscillations in
both intracellular calcium and cAMP, and these are potentiated by glucose (56). Furthermore, sustained elevations of cAMP concentrations induce nuclear translocation of the catalytic subunit of the cAMP-dependent
protein kinase, presumably leading to CREB activation
and likely cell proliferation and survival. The effects of
glucose and GLP-1 may converge at the level of the KATP
channels of the beta cells. These channels are sensitive to
1419
the intracellular ATP levels and, thereby, to glucose metabolism of the beta cells, but may also be affected
(closed, resulting in subsequent depolarization of the
plasma membrane and opening of voltage-sensitive calcium channels) by protein kinase A (PKA) activated by
GLP-1 (85, 132, 170). Apparently, PKA-mediated phosphorylation of S1448 in the SUR1 subunit leads to KATP
channel closure via an ADP-dependent mechanism. In
animals with a targeted deletion of the SUR1 subunit of
the channels, the incretins can still elevate cAMP levels,
but no longer stimulate glucose-induced insulin secretion
(199). However, this impairment was thought to be due to
a restriction in the beta cells to sense cAMP correctly,
since inhibitors of PKA did not inhibit the insulin response to GLP-1 (199). There is also evidence that GLP-1
acts as a glucose sensitizer. Thus GLP-1 has been found to
facilitate glucose-dependent mitochondrial ATP production (293). At any rate, it is of potential clinical importance that sulfonylurea drugs, which bind to and close the
KATP channels and thereby cause membrane depolariza-
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 PKAand 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).]
Physiol Rev • VOL
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JENS JUUL HOLST
tion and calcium influx, may uncouple the glucose dependency of GLP-1 (40). Thus GLP-1 administration to isolated perfused rat pancreases at low perfusate glucose
concentrations normally does not affect insulin secretion,
but resulted in dramatic stimulation of insulin secretion
after pretreatment with sulfonylurea drugs (40, 89). Indeed, 30 – 40% of patients treated with both sulfonyl urea
compounds and a GLP-1 agonist (exendin 4, see below)
experience, usually mild, hypoglycemia.
cAMP generated by activation of the GLP-1 receptor
may also influence the exocytotic process directly, and
this process has been estimated to account for up to 70%
of the entire secretory response (124). Also, ATP may
directly influence the exocytotic process and may, therefore, represent another site of convergence for the glucose- and GLP-1-mediated signals (86). Other changes
that occur in the beta cells appear to be PKA independent.
Thus the actions of GLP-1 on the insulin gene promoter
appear to be mediated by both PKA-dependent and -independent mechanisms, the latter possibly involving the
mitogen-activated protein kinase pathway (146). The effect of GLP-1 on the insulin promoter appears to be
mediated by two distinct cis-acting sequences, both in a
PKA-dependent and PKA-independent manner (268).
There is also evidence that glucose and GLP-1, by increasing intracellular calcium, may potentiate insulin gene
transcription in a calcineurin- and nuclear factor of activated T-cells (NFAT)-dependent manner (162). The transcription factor PDX-1, a key regulator of islet growth and
insulin gene transcription, appears to be essential for
most of the glucoregulatory, proliferative, and cytoprotective actions of GLP-1 (168). In addition, GLP-1 upregulates
the genes for the cellular machinery involved in insulin
secretion, such as the glucokinase and GLUT2 genes (31).
Much attention was aroused by the finding that GLP-1
appeared to be essential for conveying “glucose competence” to the beta cells, i.e., without GLP-1 signaling, beta
cells would not be responsive to glucose (86, 133). However, the beta cells of mice with disruption of the GLP-1
receptor gene show preserved glucose competence (69).
It is possible, however, that glucagon from neighboring
alpha cells may substitute, since glucagon may also provide glucose competence to beta cells (69).
As already alluded to, GLP-1 also has trophic effects
on beta cells (59). Not only does it stimulate beta-cell
proliferation (57, 66, 271, 333), it also enhances the differentiation of new beta cells from progenitor cells in the
pancreatic duct epithelium (343). Thus GLP-1 has been
demonstrated to be capable of differentiating the pancreatic duct cell line AR42J into endocrine insulin-secreting
cells (168, 343). Most recently, GLP-1 has been shown to
be capable of inhibiting apoptosis of beta cells including
human beta cells (30, 65). Since the normal number of
beta cells is maintained in a balance between apoptosis
and proliferation (21), this observation raises the possiPhysiol Rev • VOL
bility that GLP-1 could be useful as a therapeutic agent in
conditions with increased beta-cell apoptosis, which
would include type 1 as well type 2 diabetes in humans
(32). Thus treatment of mice with the GLP-1 agonist exendin 4 reduced beta-cell apoptosis induced by streptozotocin (while GLP-1 receptor knockout mice were abnormally susceptible to streptozotocin-induced beta-cell
apoptosis) (169). Also, cytokine-induced apoptosis may
be inhibited, and GLP-1 agonism increased cell survival
and reduced caspase activation in BHK fibroblasts expressing a transfected GLP-1 receptor (169). In this connection, it is of considerable interest that exendin treatment (in combination with lisophylline) prior to the development of diabetes markedly improved glucose
control in NOD mice, a model of type 1 diabetes, and
preserved the number of intact islets and reduced the
extent of inflammation in the remaining islets (337), again
suggesting that GLP-1 treatment might be able to reduce
the beta-cell destruction in human autoimmune diabetes.
GLP-1 treatment was demonstrated to delay the onset of
diabetes when given to 8-wk-old db/db mice, which develop diabetes secondary to an inactivating mutation of
the hypothalamic leptin receptor causing massive obesity
(320). Impressively, GLP-1 or exendin 4 administration for
5 days in the neonatal Goto-Kakisaki (GK) rat, a polygenetic and hypoinsulinemic model of type 2 diabetes, resulted in persistent improvement in glucose homeostasis
and maintenance of beta-cell mass adult age (290). It is
important to note that the trophic effects of GLP-1 agonists in rodents, like their insulinotropic properties, are
coupled to the presence of hyperglycemia, and also to
note that as GLP-1 alleviates hyperglycemia, which is in
itself a very strong stimulus to beta-cell growth in rodents;
this growth stimulus is reduced (272). Thus, in nondiabetic rats, the increase in beta-cell mass was transient and
disappeared upon prolonged administration (6 wk) of a
stable long-acting GLP-1 analog (20).
A most striking demonstration of the beta-cell protective/proliferative effects of GLP-1 receptor activation
was provided by Stoffers et al. (270), who studied the
diabetes developing in rats subjected to intrauterine
growth retardation. Treatment with exendin 4 in the neonatal period completely prevented development of diabetes and restored beta-cell mass, which otherwise is
strongly reduced in these animals.
The complicated and incompletely elucidated mechanisms that could be involved in the GLP-1-induced trophic effects on the beta cells were reviewed recently (24,
51, 267).
D. Effects on Glucagon Secretion
GLP-1 strongly inhibits glucagon secretion (228).
Since in patients with type 2 diabetes there is fasting
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hyperglucagonemia as well as exaggerated glucagon responses to meal ingestion (288), and since it is likely that
the hyperglucagonemia contributes to the hyperglycemia
of the patients (265), this effect may be as important
clinically as the insulinotropic effects (see below). Indeed, in patients with type 1 diabetes and complete lack
of beta-cell activity (C-peptide negative), GLP-1 is still
capable of lowering fasting plasma glucose concentrations, presumably as a consequence of a powerful lowering of the plasma glucagon concentrations (35). The
mechanism of GLP-1-induced inhibition of glucagon secretion is not completely elucidated. Insulin is generally
thought to inhibit glucagon secretion, and local elevations
of insulin levels around the alpha cells might inhibit their
secretion in a paracrine manner, but the preserved and
pronounced inhibitory effect of GLP-1 in type 1 diabetic
patients without residual beta-cell function (35) would
suggest that other mechanisms must also be involved.
Similarly, GLP-1 strongly inhibits glucagon secretion in
isolated rat pancreas perfused with low perfusate glucose
concentration and immeasurable insulin secretion (41).
GLP-1 stimulates pancreatic somatostatin secretion (228),
which in turn might inhibit glucagon secretion by paracrine interaction (67), as evidenced by the ability of somatostatin antibodies as well as a somatostatin receptor 2
antagonist to abolish the inhibitory effect of GLP-1 (41).
Interestingly, in isolated alpha cells, ⬃20% of which may
express the GLP-1 receptor (106) (although this is controversial, Ref. 188), GLP-1 appears to stimulate GLP-1
secretion (50).
The inhibitory effect of GLP-1 on glucagon secretion in vivo is only observed at glucose levels at or
above fasting levels (see Fig. 5). In studies involving
graded hypoglycemic clamping in humans, the inhibitory effect of GLP-1 was lost at glucose levels just
below normal fasting levels, and the normal stimulation
of glucagon secretion at hypoglycemic levels was unimpeded by GLP-1 (205). This is important because it
implies that treatment with GLP-1 (see below) does not
weaken the counterregulatory responses to hypoglycemia and, therefore, does not lead to an increased risk of
hypoglycemia.
1421
inhibit pancreatic secretion in response to intraduodenal
stimulation (84). The inhibitory effect of GLP-1 on acid
secretion could be elicited by physiological elevations of
the GLP-1 concentrations in plasma and was, remarkably,
additive to the inhibitory effects of PYY, which is released
from the L-cell in parallel with GLP-1 (324). Together the
two peptides almost abolished gastrin-stimulated secretion, indicating that these two peptides are the likely
mediators of the “ileal brake effect,” i.e., the endocrine
inhibition of upper gastrointestinal functions elicited by
the presence of unabsorbed nutrients in the ileum (113,
163, 249). These effects of GLP-1, also designated entergastrone effects, are likely to be physiological, since stimulation of endogenous GLP-1 secretion by intraileal instillation of nutrients corresponding to the “physiological
malabsorption,” resulted in concomitant inhibition of gastric and pancreatic secretions (164) (See Fig. 7). Further
studies documented that GLP-1 could completely abolish
acid secretion resulting from pure vagal stimulation in
humans (as elicited by modified sham feeding: the “chewand-spit technique”) (325) and that the inhibitory effect
was lost in people that had had a truncal vagotomy for
duodenal ulcer disease (329). This would indicate that all
of the actions of GLP-1 on gastric functions are mediated
via vagal pathways (see below). In recent studies Schirra
et al. (260) were able to demonstrate the importance of
endogenous GLP-1 for regulation of antroduodenal motility (and pancreatic endocrine secretion) by administration of the GLP-1 receptor antagonist exendin 9 –39 (see
Fig. 8). The physiological relevance of the ileal-brake
effects of GLP-1 in humans thus seems established.
E. Effects on the Gastrointestinal Tract
Further important effects of GLP-1 include inhibition
of gastrointestinal secretion and motility (211, 327). It was
first noted that GLP-1 inhibits gastrin-induced acid secretion in humans (261), and subsequently demonstrated that
GLP-1 also inhibits meal-induced secretion as well as
gastric emptying and pancreatic secretion (327). The effect on pancreatic exocrine secretion was first suspected
to be secondary to the inhibition of gastric emptying, but
in subsequent studies, GLP-1 was demonstrated to also
Physiol Rev • VOL
FIG. 7. Relationship between (total) plasma GLP-1 responses and
inhibition of gastric acid secretion in healthy volunteers undergoing ileal
instillations of solutions of NaCl, protein, lipid, and carbohydrates
(CHO) corresponding to the amounts normally present in this section of
the gut after mixed meal ingestion. [From Layer et al. (164), with kind
permission of Springer Science and Business Media.]
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FIG. 8. Antroduodenal motility (pressure waves) in response to intraduodenal glucose infusions in healthy volunteers with or without infusion
of a GLP-1 receptor antagonist (exendin 9 –39). The antagonist clearly enhanced to motor responses, indicating removal of a GLP-1-mediated
inhibition. [From Schirra et al. (260), with permission from BMJ Publishing Group Ltd.]
F. Central Targets for Peripherally
Released GLP-1
As alluded to above, very little GLP-1 reaches the
systemic circulation in the intact form. One may ask why
particularly GLP-1 is degraded so extensively that a rise in
the concentration of the intact peptide frequently may not
be noticeable after intake of smaller meals. The observation has led to the hypothesis that GLP-1 must act locally
in the lamina propria before being degraded (96, 123; see
Fig. 9). Once released from the L-cells, GLP-1 diffuses
across the basal lamina and enters the lamina propria.
Here it is taken up by capillaries, the endothelial membranes of which will then degrade the hormone, because
they express DPP-IV (96). However, on its way to the
capillary, GLP-1 may interact with afferent sensory nerve
fibers arising from the nodose ganglion, sending impulses
to the nucleus of the solitary tract and onwards to the
hypothalamus (See Fig. 9) (123). Recent observations that
the GLP-1 receptor is expressed in nodose ganglion cells
support this view (198). In addition, it has been demonstrated that intraportal administration of GLP-1 causes
increased impulse activity in the vagal trunks (220). These
impulses may be reflexly transmitted to the pancreas
(197). Studies in rats employing ganglionic blockers have
shown that the insulin response to intraportal administration of GLP-1 and glucose may be reduced to that
elicited by glucose alone after ganglionic blockade (11)
(see Fig. 10). Similarly, in mice rendered sensory denervated by neonatal administration of the neurotoxin capsaicin, low doses of GLP-1 that augmented glucose-induced insulin secretion in control animals had little effect
in the denervated mice, whereas high doses had the same
effects in control and denervated animals (1). The interPhysiol Rev • VOL
pretation was that physiological amounts of GLP-1 depended on reflex pathways for stimulation of insulin secretion, whereas higher doses leading to higher plasma
concentrations might activate islet receptors directly and
therefore equally in control and denervated mice. Thus,
regarding the mechanism of GLP-1-stimulated insulin secretion under physiological circumstances, the neural
pathway may be more important than the endocrine
route. However, the concentration of intact GLP-1 does
rise after meal intake and rises more the larger the meal
is (317). Thus it seems probable that the endocrine route
becomes more prominent after extensive L-cell stimulation.
The pathways whereby GLP-1 exerts its “ileal brake”
effects (119) also seem to depend on signaling via afferent
sensory neurons relaying in the brain stem or the hypothalamus and regulating efferent parasympathetic outflow
(139, 328). Thus GLP-1 has no effect on vagally stimulated
antral motility in isolated perfused preparations of the pig
stomach (328) and no effect on vagally stimulated exocrine secretion from isolated perfused porcine pancreas
(127). Furthermore, as mentioned, the acid inhibitory activity in humans exclusively depends on vagal mechanisms (325, 329). Finally, the inhibitory effect on gastric
emptying in rats is lost after vagal deafferentation (139).
Studies in rats have suggested that a hepatoportal
glucose sensor may reflexly influence peripheral glucose
metabolism and that this sensor is somehow linked to a
GLP-1 receptor expression, since its effects on peripheral
glucose disposal are abrogated by exendin 9 –39 and cannot be demonstrated in GLP-1 receptor knockout mice
(29). In dogs, pharmacological amounts of intraportal
GLP-1 were required to elicit changes in peripheral glucose metabolism (218), and in further dog studies, insulin-
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THE PHYSIOLOGY OF GLUCAGON-LIKE PEPTIDE 1
1423
FIG. 9. The neural pathway for the actions of
GLP-1. GLP-1 secretion is stimulated by nutrients in the
gut lumen (a magnified intestinal villus with an opentype L-cell is shown at the lower left), and newly released GLP-1 diffuses across the basal lamina into the
lamina propria. On its way to the capillary, however, it
may bind to and activate sensory afferent neurons (f)
originating in the nodose ganglion (c), which may in turn
activate neurons of the solitary tract nucleus (a). The
same neuronal pathway may be activated by sensory
neurons in the hepatoportal region (29) (e) or in the liver
tissue (39) (d). Ascending fibers from the solitary tract
neurons may generate reflexes in the hypothalamus, and
descending impulses (from neurons in the paraventricular nucleus?) may activate vagal motor neurons (b), that
send stimulatory (h) or inhibitory (g) impulses to the
pancreas and the gastrointestinal tract. Interactions between ascending sensory nerve fibers and vagal motorneurons may also take place at the level of the brain
stem.
independent effects of GLP-1 on glucose disposal in the
liver required long-term (up to 5 h) infusions and were
independent of route of administration (portal vs. peripheral) (39). Similar to the findings in mice, intraportal
GLP-1 and glucose infusions in other dog studies were
found to decrease peripheral glucose levels independently of hyperinsulinemia (140). However, it should be
noted that peripheral administration of GLP-1 to dogs at a
similar rate is claimed not to enhance glucose-induced
insulin secretion in this species (141). This is again in
sharp contrast to very consistent findings in humans (135,
157) and therefore suggests that dogs (and possibly mice)
differ radically from humans in this respect.
G. Effects on Appetite and Food Intake
There have been reports on the presence of glucagon
in the brain for many years (277), and it has been speculated that the peptide might play a role in regulation of
food intake. When GLP-1 was also discovered in the brain
(144), it was relevant to investigate the possible central
Physiol Rev • VOL
actions of the peptide. Early studies indicated an effect on
appetite and food intake (259), and subsequent more
detailed studies confirmed these effects after intracerebroventricular administration of low doses of the peptide
(278, 294). The proglucagon-producing neurons of the brain
stem may represent a link in a system whereby enteroceptive stress, but possibly also food ingestion, transmits
satiety signals to the brain (160, 253). Thus the cells are
activated (show c-fos expression) upon distension of the
stomach (319). GLP-1 receptors are expressed in many
regions of the brain and in particular in the arcuate nucleus and other hypothalamic regions involved in the
regulation of food intake (79). Destruction of the arcuate
nucleus with perinatal monosodium glutamate abolishes
the inhibitory effect of intracerebroventricularly administered GLP-1 on food intake and appetite (280), indicating
that this nucleus is essential for the response. As mentioned earlier, processing of proglucagon in the brain
stem neurons leads to the formation of GLP-1 as well as
GLP-2 and oxyntomodulin, all of which have been reported to inhibit food intake after intracerebroventricular
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FIG. 10. Insulin responses to intraportal infusions of glucose and
GLP-1 in rats with or without intravenous infusion of a ganglionic
blocker (chlorisondamine). Note that the ganglionic blocker completely
eliminated the GLP-1-induced enhancement of glucose-stimulated insulin secretion. [From Balkan and Li (11).]
administration (37, 279). Thus it is possible that the impact on food intake of activation of these neurons is
underestimated when only a single transmitter is studied.
Nutrients in the ileum are thought to have a satiating effect, curtailing food intake (249), and GLP-1 is
released simultaneously (164). Does peripheral GLP-1
play a physiological role as a satiating agent? Several
studies have shown that infusions of GLP-1 significantly
and dose dependently enhance satiety and reduce food
intake in normal subjects (70, 305). The effect on food
intake and satiety is preserved in obese subjects (200)
as well as in obese subjects with type 2 diabetes (91,
340). This raises the possibility that GLP-1 is not only a
physiological regulator of food intake but also has a
therapeutic potential. Recent clinical studies have
shown that subcutaneous injections of a stable GLP-1
receptor agonist (exendin 4) given twice daily for several years to people with type 2 diabetes are associated
with a gradual and linear weight loss with no signs of
impaired efficacy with time (19, 108).
The mechanism whereby peripherally administered GLP-1 inhibits food intake is not clear. It is unlikely to be related to the effect on gastric motility and
emptying, since appetite reduction can be elicited also
in fasting subjects (93). It is more likely that interaction
with sensory neurons in the gastrointestinal tract or the
hepatoportal bed is involved as discussed above. Another possibility is that peripherally administered
GLP-1 can access the brain via leaks in the blood-brain
barrier such as the subfornical organ and the area
postrema, as demonstrated to occur in rats (230). It has
also been claimed that regulatory peptides from the
periphery can somehow access the arcuate nucleus
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perhaps via diffusion from the median eminence (160).
Recent studies have demonstrated that infusions of the
orexigenic peptide ghrelin may dampen the effects of
GLP-1 on gastric emptying and food intake, and the
authors suggested that the stimulating effect of ghrelin
on food intake might derive at least in part from its
ability to attenuate the effects of GLP-1 (and PYY 3–36)
on gastric emptying and food intake (34).
It should be noted that GLP-1 receptor knockout
mice do not become obese (263), but this may reflect the
redundancy of the appetite regulating mechanisms rather
than ineffectiveness of the signal. In fact, the efficacy of
the appetite-reducing effect was convincingly demonstrated not only in the clinical studies referred to above
but also in recent studies involving life-long administration of exendin 4 to rats. The treated animals survived
longer than controls, an effect that was thought to result
from decreased food intake and hence a significantly
lower body weight (110).
Central administration of GLP-1 may also affect
drinking behavior. Thus intracerebroventricular GLP-1
profoundly inhibited angiotensin II-induced drinking behavior in rats, and water intake was suppressed by exogenous GLP-1 in rats habituated to a water restriction
schedule. In contrast to the effects of GLP-1 on food
intake, these effects were reproduced by intraperitoneal
administration of GLP-1. Furthermore, intracerebroventricular GLP-1 stimulated urinary excretion of water and
sodium (278). Subsequent studies confirmed that intravenous infusion of pharmacological doses of GLP-1 may
modulate drinking behavior and increase renal sodium
excretion in healthy volunteers as well as in patients with
type 2 diabetes (92, 94). However, long-term treatment of
patients with type 2 diabetes with GLP-1 analogs does not
seem to be associated with disturbances of fluid or electrolyte balance.
H. Other Effects
1. Cardiovascular
It is well established that there are glucagon receptors in the heart and that glucagon has inotropic and
chronotropic actions on the heart. Now it turns out that
there are also GLP-1 receptors in the heart (28, 33, 283).
GLP-1 was also demonstrated to increase cAMP levels in
adult rat cardiac myocytes (307), but in that study GLP-1
decreased contraction amplitude as opposed to isoproterenol, which augmented amplitude and, again unlike isoproterenol, GLP-1 did not bring about any intracellular
calcium transients, but did cause a modest intracellular
acidification. Further evidence for a role for GLP-1 in
cardiac function was derived from studies in mice lacking
the GLP-1 receptor (87). At the age of 2 mo, these animals
had reduced resting heart rate and elevated left ventricu-
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THE PHYSIOLOGY OF GLUCAGON-LIKE PEPTIDE 1
lar (LV) end-diastolic pressure, compared with wild-type
controls. At the age of 5 mo, echocardiography and histology demonstrated increased LV thickness. In addition,
there was impaired LV contractility and diastolic function
after insulin administration. LV contractility was also reduced after exogenous epinephrine. These data suggest
that GLP-1 exerts physiologically important effects on
cardiac function.
In a more recent study, Bose et al. (22) demonstrated
that GLP-1 significantly reduced infarction size in both
in vitro (isolated perfused rat heart) and in vivo models of
ischemia-reperfusion damage. The protective effect
in vitro was abolished by the GLP-1 receptor antagonist
exendin 9 –39, cAMP inhibitors, as well as phosphatidylinositol 3-kinase and mitogen-activated protein kinase inhibitors, suggesting involvement of these pathways in the
protective response. Zhao et al. (342) were also able to
demonstrate direct effects of GLP-1 on myocardial contractility and glucose uptake in normal and postischemic
isolated rat hearts. They measured LV function, myocardial glucose uptake, and lactate production under basal
conditions and after low-flow ischemia with or without
GLP-1 or buffer or insulin. GLP-1 increased myocardial
glucose uptake almost threefold via increased nitric oxide
production and GLUT1 translocation, but decreased LV
pressure. Furthermore, GLP-1 treatment significantly improved postischemia LV end-diastolic pressure and LV
developed pressure. Thus, in the normal resting heart,
GLP-1 reduces contractility. However, it increases glucose uptake by mechanisms distinct from insulin, but
improves recovery after ischemia in a fashion similar to
that of insulin.
The cardiac effects of GLP-1 were studied in conscious dogs with pacing-induced dilated cardiomyopathy,
which was induced by 28 days of rapid pacing (215).
The dogs received a 48-h infusion of GLP-1 (1.5
pmol䡠kg⫺1 䡠min⫺1, a dose that efficaciously lowers plasma
glucose in diabetic patients but does not cause significant
side effects). The GLP-1 infusion was associated with
large improvements in LV performance, stroke volume,
and cardiac output as well as significant decreases in LV
end-diastolic pressure, heart rate, and, interestingly, systemic vascular resistance. GLP-1 also increased myocardial insulin sensitivity and glucose uptake. The same
group also reported (217) effects of a 72-h infusion of
GLP-1 (same dose) added to background therapy in 10
patients with acute myocardial infarction (AMI) and LV
ejection fraction ⬍40% after successful primary angioplasty compared with placebo. Both groups had severe LV
dysfunction [LV ejection fraction (LVEF) ⫽ 29 ⫾ 2%].
GLP-1 significantly improved LVEF (to 39 ⫾ 2%) and also
improved global and local wall motion indices. Most recently, the same group studied the effects of a 5-wk
infusion of GLP-1 added to standard therapy in 12 patients
with heart failure. GLP-1 significantly improved LVEF,
Physiol Rev • VOL
1425
myocardial oxygen uptake, 6-min walking distance, and
quality of life, and the treatment was well tolerated (269).
In other studies (216), again involving pacing-induced
dilated cardiomyopathy in conscious dogs as a model, the
effects of 48-h infusions of either GLP-1 or its primary
metabolite after DPP-IV degradation [which occurs with a
half-life of 1–2 min in the circulation of pigs and humans
(46, 309)], GLP-1 9 –36 amide, were investigated. The dogs
were studied under basal as well as insulin-stimulated
conditions (hyperinsulinemic euglycemic clamps). The dogs
with dilated cardiomyopathy demonstrated insulin resistance. Surprisingly, both GLP-1 and GLP-1 9 –36 amide
significantly and equally reduced LV end diastolic pressure and increased LV performance and cardiac output.
Both peptides increased myocardial glucose uptake independently of insulin. Since during the infusion of GLP-1
7–36 amide ⬃80% of the peptide is metabolized to GLP-1
9 –36 amide, these results would suggest that GLP-1 9 –36
is the active peptide. In recent animal and human studies
(45, 181), the metabolite GLP-1 9 –36 amide was demonstrated to lower blood glucose slightly and independently
of insulin and glucagon secretion, which remained unaffected by the metabolite. The mechanism of action could
not be revealed, but may be related to the cardiac effects.
The cardiac effect of the metabolite/GLP-1 has potential
clinical implication because it would suggest that it would
not be observed after administration of analogs of GLP-1
that are stabilized against the actions of DPP-IV and therefore do not lead to the formation of the metabolite (see
below).
In summary, GLP-1 is likely to have physiological
effects on the heart. In the basal state, GLP-1 may inhibit
contractility, but after cardiac injury GLP-1 has constantly
increased myocardial performance both in experimental
animals and in patients. GLP-1 enhances insulin secretion
and may enhance myocardial performance via the combined effects of enhanced insulin secretion and action
[insulin therapy has been demonstrated to have beneficial
effects of its own on the course of myocardial infarction
in patients with type 2 diabetes (341) ], but also appears to
have direct effects that are independent of insulin action.
The potentially important observation that it may be the
metabolite of GLP-1 that is the active agent in cardiac
protection requires independent confirmation and raises
the question of the nature of the receptor involved, but
may be consistent with the finding that GLP-1 9 –36 amide
appears to lower blood glucose in humans and pigs independent of insulin and glucagon secretion.
As discussed above, the GLP-1 receptor is expressed
in the lungs (158), but the functions of GLP-1 in the lungs
are unclear, although it has been reported to increase the
secretion of macromolecules from the neuroendocrine
cells (252).
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2. Neurotropic and other neural effects
GLP-1 may also possess neurotropic effects. Thus
intracerebroventricular GLP-1 administration was associated with improved learning in rats and also displayed
neuroprotective effects (55, 238), and GLP-1 has been
proposed as a new therapeutic agent for neurodegenerative diseases, including Alzheimer’s disease (239). It has
been reported that cerebral GLP-1 receptor stimulation
increases blood pressure and heart rate and activates
autonomic regulatory neurons in rats, leading to downstream activation of cardiovascular responses (335). Furthermore, it has been suggested that catecholaminergic
neurons in the area postrema expressing the GLP-1 receptor may link peripheral GLP-1 and central autonomic
control sites that mediate the diverse neuroendocrine and
autonomic actions of peripheral GLP-1 (334). However,
peripheral administration of GLP-1 in humans is not associated with changes in blood pressure or heart rate
(340).
I. Whole Body Effects, Peripheral Effects,
and Effects on Insulin Action
After the incretin functions of GLP-1 were established in humans (157) and the hormone was demonstrated to be capable of normalizing the elevated plasma
glucose levels in patients with type 2 diabetes (210),
several studies were carried out to elucidate in more
detail its mechanisms of action. Hvidberg et al. (135)
studied glucose turnover in fasting healthy subjects in
response to physiological and supraphysiological infusions of GLP-1 and found that insulin secretion was enhanced and glucagon secretion inhibited by both. Concomitantly, hepatic glucose production was inhibited, and
therefore, the plasma glucose concentration fell by ⬃1
mM. Glucose clearance was also increased, but this was
interpreted to be a consequence of the increased insulin
concentrations. The role of the suppression of glucagon
was studied further in subjects with type 1 diabetes and
no residual beta-cell function (35). In these subjects an
infusion of GLP-1 significantly lowered fasting glucose
levels, concurrently with a marked lowering of plasma
glucagon concentrations. It was concluded that the glucose-lowering action in this case was due to a decreased
hepatic glucose production resulting from decreased glucagon secretion. D’Alessio et al. (36) found in a study
involving the minimal model approach (a computerized
calculation of insulin sensitivity and insulin-independent,
glucose-mediated glucose uptake, based on frequent determinations of insulin and glucose concentrations after
an intravenous glucose infusion) that GLP-1 was capable
of increasing glucose-mediated glucose uptake (glucose
effectiveness) in healthy subjects by a mechanism independent of insulin secretion. However, the relevance of
Physiol Rev • VOL
the chosen approach has been questioned because insulin
secretion was markedly stimulated in the GLP-1 experiment, but not in the control experiment. A valid control
experiment might involve infusion of insulin to achieve
similar levels as those achieved during GLP-1 infusion
(ideally identical intraportal concentrations). In further
studies, Toft-Nielsen et al. (287) administered GLP-1 to
healthy subjects with or without concomitant infusion of
500 ␮g/h somatostatin. Glucose assimilation was then
studied by an intravenous glucose tolerance test. It turned
out that even with this (high) dose of somatostatin, insulin (and C-peptide) secretion was still slightly stimulated
by GLP-1. In agreement with this, the glucose elimination
rate (Kg) was increased by GLP-1. Fortuitously, these
results documented the exquisite sensitivity of the approach. The somatostatin infusion rate was then increased to 1,000 ␮g/h, and now insulin secretion remained
constant. In this case, there was no change of Kg during
GLP-1 administration, and it was concluded that GLP-1
had no direct effect on glucose uptake by the peripheral
tissues (or at least that any effect must be very small).
Subsequently, the effects of physiological elevations of
GLP-1 or saline infusions on insulin-stimulated glucose
uptake were studied in human volunteers by the euglycemic hyperinsulinemic clamp technique (234). In addition,
somatostatin was administered to clamp insulin secretion
at a low level, whereas basal glucagon and growth hormone levels were maintained by intravenous infusion.
Furthermore, glucose turnover rates were evaluated by a
tracer technique. However, there were no differences between GLP-1 and saline infusions with respect to any
parameter studied, including glucose infusion rates required to maintain euglycemia, glucose appearance and
disappearance rates, as well as forearm arteriovenous
glucose differences. Vella et al. (304) studied the effects of
pharmacological doses of both the GLP-1 receptor agonist
exendin 4 and the native peptide in healthy subjects in
three-step hyperinsulinemic clamp experiments. Both
peptides increased cortisol secretion, but neither influenced insulin action (304). In further studies, GLP-1 was
infused in supraphysiological amounts to patients with
type 2 diabetes, and insulin sensitivity was estimated
using clamp techniques (4). However, in these experiments, there was no effect of GLP-1 on insulin sensitivity
either. In further studies, Vella et al. (303) infused pharmacological (treatment relevant) doses of GLP-1 or saline
to subjects with type 2 diabetes while at the same time
infusing glucose to mimic postprandial glucose concentrations and clamping insulin and glucagon levels at basal
or postprandial levels. Under these conditions, GLP-1 had
no influence on glucose disappearance or suppression of
endogenous glucose production. On the basis of all these
studies, it seems justified to conclude that GLP-1 has very
little acute effect on insulin-dependent and -independent
glucose turnover when its effects on the endocrine pan-
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THE PHYSIOLOGY OF GLUCAGON-LIKE PEPTIDE 1
creas are prevented. Zander et al. (340) infused GLP-1 or
saline continuously for 6 wk to patients with type 2 diabetes and determined insulin sensitivity by hyperinsulinemic euglycemic clamps before and after the treatment.
Insulin sensitivity was unchanged in the saline-treated
group, but was almost doubled in the GLP-1-treated
group. The study was not designed to elucidate the underlying mechanisms, but it should be noted that GLP-1
was administered during the clamp (and actually resulted
in a slightly higher insulin level) and that the GLP-1treated subjects experienced markedly improved glycemic control as well as lower free fatty acid levels and also
lost ⬃2 kg of body weight. The weight loss as well as
reduced gluco- and lipotoxicity induced by GLP-1 were
considered likely explanations for the improved insulin
sensitivity. Similar findings were made in a study involving 3 mo of continuous subcutaneous infusion of GLP-1 to
diabetic subjects (183). However, the same group reported acute augmentation by GLP-1 of insulin-mediated
glucose uptake in elderly patients with diabetes (185) and
also reported insulin-mimetic effects of GLP-1 in obese
subjects compared with nonobese matched controls (60).
Nevertheless, the group was unable to identify effects of
GLP-1 on insulin-mediated glucose uptake in patients
with type 1 diabetes (184). D’Alessio et al. (36), who were
the first to suggest extrapancreatic metabolic effects of
GLP-1 in humans, later studied eight healthy subjects
using somatostatin clamp and tracer techniques similar to
those employed by Orskov et al. (234) and reported a 17%
decrease in rate of glucose appearance resulting in a
lower blood glucose and concluded that GLP-1 had extrapancreatic metabolic effects, possibly mediated via intraportal GLP-1 receptors (see below). As already discussed, it may be difficult to control GLP-1-stimulated
insulin secretion with somatostatin, and the significance
of these findings cannot be settled presently.
However, in contrast to the human studies, several,
mainly in vitro, studies support that GLP-1 may have
effects on peripheral tissues and/or the liver that are
independent of its effects on the islet hormones. Thus it
has been reported that membranes from human adipose
tissue express GLP-1 receptors (186), and similar findings
have been reported for rats (300). GLP-1 was also reported to enhance fatty acid synthesis in explants of rat
adipose tissue (223) and was reported to enhance insulinstimulated glucose uptake in 3T3-L1 adipocytes (61, 321).
Evidence was provided, however, that the responsible
receptor differed from the GLP-1 receptor (192). Nevertheless, in studies involving direct determination of lipolysis rates in human subcutaneous tissue, Bertin et al. (16)
were unable to find any effects of GLP-1. GLP-1 receptors
have also been claimed to be present in rat skeletal muscle (49), and GLP-1 was reported to stimulate glucose
metabolism in human myocytes (173). Similar observations were made in studies of L6 myotubes, and there was
Physiol Rev • VOL
1427
evidence that the effects were transmitted via receptors
distinct from the classical GLP-1 receptor (336). Most
recently, GLP-1 was again reported to enhance glucose
uptake in human myocytes, and evidence for the involved
signaling pathways was provided (80). It should be mentioned that other studies failed to identify actions of
GLP-1 on glucose metabolism in muscle tissue (72). Some
of the cited studies suggested that GLP-1 may activate
more than one receptor. As discussed above, a study of
the enterogastrone effects of GLP-1 and PYY in dogs,
where the GLP-1 receptor antagonist exendin 9 –39 was
incapable of blocking the inhibitory actions of GLP-1 (71),
suggested that another receptor was involved. In other
studies, the local paracrine actions of GLP-1 in the canine
ileum could not be blocked by exendin 9 –39 (38). The
effects of intraportal GLP-1 on impulse traffic in vagal
afferent sensory nerve fibers were also resistant to exendin 9 –39 (219). The liver has repeatedly been reported
to be a target for GLP-1, although initial careful studies
indicated that hepatocytes did not express GLP-1 receptor (17). Thus GLP-1 has been reported to bind to rat
hepatic membranes but without influencing adenylate cyclase activity, as expected from the classical GLP-1 receptor (308). Rather, inositol phosphoglycans were thought
to act as mediators (291). The same group also described
activation of phosphatidylinositol 3-kinase/protein kinase
B, protein kinase C, and protein phosphatase-1 pathways
to transmit the actions on glycogen synthase in rat hepatocytes (250). Ikezawa et al. (138) reported inhibition of
glucagon-induced glycogenolysis in isolated perivenous
rat hepatocytes. Along the same lines, some studies have
reported effects of exendin 4 that are not shared by
GLP-1. Thus exendin 4, but not GLP-1, was reported to
enhance insulin sensitivity in 3T3 adipocytes (137). The
two peptides were also reported to activate different signaling pathways in human myotubes (80). Again, it should
be noted that these in vitro studies are in sharp contrast
to the in vivo studies, particularly in humans, as discussed
above.
VII. GLUCAGON-LIKE PEPTIDE 1
PATHOPHYSIOLOGY
Abnormal function of GLP-1 has been implicated in
three pathological conditions: obesity, postprandial reactive hypoglycemia, and type 2 diabetes.
A. Obesity
A role for GLP-1 in the development of obesity was
suggested partly because of the apparently physiological
effects of the hormones on appetite and food intake (305),
and partly because of the reports that GLP-1 secretion
may be reduced in obesity. Thus, in 1983, it was demon-
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strated that the diurnal L-cell secretion (measured as
enteroglucagon secretion) was dramatically decreased in
morbid obesity (128), and in a subsequent study, again
in morbidly obese subjects, there was no measurable
increase in postprandial GLP-1 secretion (201). However,
after a jejuno-ileal bypass operation, meal responses were
restored to normal values. This should not be interpreted
to suggest that the weight loss restored L-cell sensitivity
to meal stimulation, since it is known that abnormal
exposure of the distal gut to unabsorbed nutrients as
occurs after jejuno-ileal bypass as well as gastric bypass
operations results in exaggerated L-cell secretion (129,
235). However, obese subjects showing decreased postprandial GLP-1 responses compared with lean controls
did exhibit improved secretion after weight loss (306).
The mechanism whereby obesity lowers GLP-1 secretion
is not known, but may be related to the insulin resistance
that accompanies weight gain (248). It has been suggested
that particularly the L-cell responsiveness to carbohydrates is affected (247) and that circulating fatty acids
could be responsible (246). However, in a large study in
both diabetic and nondiabetic subjects, in which body
mass index again emerged as a significant negative factor
for meal-induced GLP-1 secretion, free fatty acid levels
did not appear to influence the responses upon multiple
regression analysis (288).
Together, the data would suggest that the decreased
GLP-1 secretion in obesity, which is not a consistent
finding (317), develops secondarily to weight gain. However, in view of the likely role of GLP-1 as a regulator of
appetite and food intake, it remains possible that the
decreased secretion results in inadequate postprandial
satiation and therefore contributes to the positive energy
balance of developing obesity. Further support for an
important role of GLP-1 (and PYY) in the regulation of
appetite and food intake comes from studies of GLP-1
secretion after bariatric surgery. As a rule, the weight loss
after surgery does not involve malabsorption, and although the reduced gastric capacity undoubtedly contributes, the secretion of GLP-1 (and PYY) is greatly elevated,
particularly after bypass operations, and is believed to
result in reduced appetite and food intake and hence
weight loss (165, 194, 235). It is of interest that the operations also cause a dramatic improvement in glucose
tolerance that occurs very early postoperatively, before a
major weight loss has been achieved (88). Again, it is
thought that the exaggerated GLP-1 secretion may be
responsible, via its effects on insulin and glucagon secretion.
B. Reactive Hypoglycemia
In agreement with increased exposure to nutrients of
the distal small intestinal mucosa, where the density of
Physiol Rev • VOL
L-cells is highest, as the likely explanation for exaggerated GLP-1 responses after bariatric surgery, GLP-1 secretion is also strongly dependent on gastric emptying rates
and hence the rate of exposure of the small intestinal
mucosa to nutrients (187). Therefore, conditions with
accelerated gastric emptying are also associated with exaggerated GLP-1 responses (187). It was, therefore, proposed that exaggerated GLP-1 secretion might be responsible for the postprandial reactive hypoglycemia that may
be observed after gastric surgery (gastrectomy) (187) as
well as after gastric bypass operations (264). Indeed, if the
postprandial glucose and GLP-1 responses observed in
such patients were reproduced in healthy subjects by
intravenous infusion, it was possible to create a dramatic
hypoglycemic response, partly due to enhanced insulin
secretion and partly due to suppressed glucagon secretion (286). In gastrectomized subjects with reactive hypoglycemia, postprandial glucagon concentrations may be
elevated compared with nonoperated controls (6), but
this is probably a consequence of the generalized sympathetic discharge that accompanies the “dumping syndrome” of which the reactive hypoglycemia is part (76). It
has been proposed that the gastric bypass operations in
some cases might result in the development of hyperinsulinemic pancreatic nesidioblastosis as a result of the
trophic effects of GLP-1 on the beta cells (235, 264).
However, in a subsequent reanalysis of the pancreatic
sections on which this hypothesis was based, the existence of nesidioblastosis could not be confirmed (179),
and the most likely explanation for the hypoglycemic
attacks is probably exaggerated GLP-1-stimulated insulin
secretion in combination with alleviation of insulin resistance after weight loss and lack of downregulation of
functional beta cell mass [which may have been increased
because of obesity (32)] after weight loss.
The effects of GLP-1 on appetite and food intake
show up very strongly in clinical studies involving native
GLP-1, GLP-1 analogs, or GLP-1 receptor activators like
exendin. Although nearly all studies so far have been
aimed at treating type 2 diabetes, an important and constant finding has been a continued and sustained weight
loss both in short-term and chronic studies (19, 108, 148,
340). This obviously has important clinical implications.
C. Diabetes
The main clinical interest in GLP-1 focuses on its role
in the development and treatment of type 2 diabetes. Type
2 diabetes is characterized by a severely reduced or absent incretin effect (203), and this undoubtedly contributes to the inappropriate insulin secretion that characterizes the disease. It is now clear that the incretin defect is
due to an almost complete loss of the insulinotropic effect
of GIP (206, 314), whereas the secretion of GIP is normal
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THE PHYSIOLOGY OF GLUCAGON-LIKE PEPTIDE 1
or near normal (288). Regarding GLP-1, a significant and
sometimes substantial reduction in meal-induced GLP-1
secretion is found whether this is measured as the concentrations of the intact hormone or the metabolite GLP-1
9 –36 amide (see above) (288, 312). In contrast to GIP, the
insulinotropic effect of GLP-1 is retained in patients with
type 2 diabetes (206), and it is possible with infusions of
GLP-1 to completely normalize glucose-induced insulin
secretion in the patients as analyzed in hyperglycemic
clamp experiments (150, 314). However, from dose-response studies it appears that the potency of GLP-1 with
respect to enhancing glucose-induced insulin secretion is
greatly reduced (to ⬃20%) in the patients compared with
healthy controls (150). Thus both defects in the secretion
and actions of the incretin hormones are responsible for
the reduced incretin effect and hence the inadequate insulin secretion seen in the patients. The question then
arises whether these defects are primary or secondary in
relation to diabetes, but the evidence to date suggests that
the abnormalities are secondary to the development of
diabetes and/or insulin resistance. Thus the secretion of
both GIP and GLP-1 is normal in glucose-tolerant first-degree relatives of individuals with type 2 diabetes (222). Similarly, incretin secretion was normal in women with previous
gestational diabetes who are at particularly high risk for
developing type 2 diabetes (180). In a study in identical
twins, discordant for type 2 diabetes (at the time of investigation), only the diabetic twin had decreased GLP-1 secretion (299). And finally, in patients with diabetes secondary to
chronic pancreatitis, a similar incretin deficiency develops
early in the development of diabetes, and reduced effects of
the incretin hormones are also similar to those observed in
the classical obese type 2 diabetic patients (311). In a detailed study of 55 patients with type 2 diabetes as well as in
individuals with impaired or normal glucose tolerance, mealinduced GLP-1 secretion was negatively associated with
body mass index as discussed above, but also with the
presence or absence of diabetes (lower responses in diabetic subjects), whereas factors such as the presence or
absence of neuropathy and concentrations of free fatty acids
in plasma did not seem to play a role (288). As already
mentioned, it is possible that insulin sensitivity is of importance (248). The molecular mechanisms underlying the reduced beta-cell sensitivity to GLP-1 and the nearly lost sensitivity to GIP are currently unknown. However, the fact that
insulin secretion can be restored to normal levels by administration of GLP-1 (in other words, that the beta-cell responsiveness to glucose is normalized) is clearly of considerable
clinical interest and provides part of the background for the
clinical use of GLP-1 receptor agonists in diabetes treatment.
Intravenous administration of slightly supraphysiological
amounts of GLP-1 can completely normalize fasting glucose
concentrations in type 2 diabetic patients regardless of the
severity and duration of disease (207, 289) and may nearly
normalize also postprandial glucose responses (245). It is
Physiol Rev • VOL
1429
believed that several of the many actions of GLP-1 are
involved in its antidiabetic effects (115). One important
mechanism is of course the restoration of glucose-induced
insulin secretion. Generally, peripheral insulin levels do not
increase during chronic GLP-1 treatment, but these levels
are maintained in spite of the concomitant reductions of
plasma glucose by up to 5– 6 mM (340). Upon intravenous
infusion of GLP-1 to fasting type 2 diabetic subjects, insulin
secretion first rises, but then, as plasma glucose concentrations are lowered, decreases again to baseline levels (210).
The numerous molecular actions of GLP-1 on the beta cell
have been discussed above. Another important factor is the
inhibition of glucagon secretion. Again, during intravenous
infusion of GLP-1 to fasting type 2 diabetic subjects, glucagon secretion is suppressed as long as plasma glucose is still
elevated, but as glucose concentrations approach normal
values, glucagon secretion again rises to baseline levels
(210). In chronic studies, mean glucagon levels may be
significantly lowered or remain at baseline levels, but this
again occurs in the face of much lower plasma glucose
concentrations which, all others being equal, would have
resulted in higher levels of glucagon (340). As already alluded to, the importance of the inhibition of glucagon secretion for the antidiabetic actions of GLP-1 showed up clearly
in a study in patients with type 1 diabetes and no residual
beta-cell function. In these patients GLP-1 infusion still lowered plasma glucose in parallel with a rather strong reduction in glucagon levels (35).
The inhibition of gastric emptying also plays an important role as this greatly reduces postprandial glucose
excursions (332). This effect, which in healthy subjects
shows rapid tachyphylaxis (181a), is retained also in
chronic studies involving short-acting GLP-1 receptor
agonists (exendin 4) (147).
The clinical results with GLP-1 receptor activators,
now often designated incretin mimetics, are promising
and suggest that one can expect lasting improvement of
glycemic control as evidenced by much improved levels
of glycated hemoglobin (HbA1c) (19). Synthetic exendin 4
(exenatide) was approved for diabetes treatment in 2005
and is commercially available under the trade name
Byetta (www.byetta.com). Exendin 4 was isolated from
the venom of the lizard, Heloderma suspectum, in a systematic search for biologically active peptides (64) and is,
as discussed above, a full agonist for the GLP-1 receptor
which is equipotent with GLP-1 (284). Unlike GLP-1, it is
not degraded by DPP-IV and is cleared in the kidneys only
by glomerular filtration (266), whereby the molecule obtains a half-life of ⬃30 min (58). After subcutaneous injection of the maximally tolerated dose, a significant elevation of its plasma concentration may be observed for
5 h (156). Because of its stability relative to GLP-1, exendin 4 has been very useful as a tool for elucidating the
actions of GLP-1 particularly in rodents, where the survival of GLP-1 is so brief that it is difficult to detect any
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1430
JENS JUUL HOLST
effects of the peptide at all. GLP-1 analogs still under
clinical development include Liraglutide, which consists
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
is substituted by Arg to prevent acylation here) (152).
Thereby, the molecule binds to albumin and acquires
some of the pharmacokinetics of this molecule. The renal
elimination is prevented for the bound molecule, and its
half-life after subcutaneous injections is ⬃12 h. Clinically,
the molecule has similar actions as continuously infused
GLP-1 (48) and appears to have a similar clinical potential
as exendin 4 (318).
The antidiabetic effects of GLP-1 can also be exploited by protecting endogenous GLP-1 from degradation by the enzyme DPP-IV (122). Administration of inhibitors of this enzyme increases the circulating levels of
both active GLP-1 and GIP, and this is associated with the
expected antidiabetic effects (43). The inhibitors are
small molecules that are active upon oral administration,
and they appear to have chronic antidiabetic effects that
are very similar to those obtained with the incretin mimetics, which all require parenteral administration (2).
However, the inhibitors have little effects on body weight,
presumably because the plasma concentrations of active
GLP-1 are not elevated sufficiently to exert this effect
(42). One explanation for this appears to be a negativefeedback inhibition of L-cell secretion by the elevated
levels of active GLP-1 brought about by DPP-IV inhibition
(47), an effect which may be mediated by a paracrine
action of somatostatin secreted from neighboring D-cells
in the gut (97, 98). Because of the negative-feedback
inhibition, the concentrations of active GLP-1 only rise by
a factor of two to three, where one would have expected
an up to fivefold increase if L-cell secretion had been
unaltered (122). Elegant experiments in mice with deletions of the genes for the two incretin hormone receptors
have shown that whereas DPP-IV inhibitors effectively
lowered blood glucose and stimulated insulin secretion in
animals with a single deletion, they had no effect in mice
in which both receptor genes were deleted (102). Thus
their effect in nondiabetic mice can be ascribed to enhancement of the actions of both incretin hormones,
while mechanisms beyond protection of these hormones
do not appear to play a role. Several specific inhibitors are
currently undergoing clinical development, and for two
inhibitors [Januvia (www.Merck.com) and Galvus
(www.novartis.com)], applications for registration as new
drugs were filed with the American Food and Drug Administration in 2006, and Januvia was approved in Mexico
and the United States in the fall of 2006.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence:
J. J. Holst, Dept. of Medical Physiology, The Panum Institute,
Physiol Rev • VOL
Univ. of Copenhagen, DK-2200 Copenhagen, Denmark (e-mail:
holst@mfi.ku.dk).
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