Physiological Roles of Gastrointestinal Peptide Hormones
The ingestion of nutrients elicits the secretion of gastrointestinal hormones intimately involved in the regulation of gut and gallbladder motility, digestive juice secretion, and postprandial carbohydrate metabolism. In particular, incretin hormones stimulate insulin secretion from the endocrine pancreas. Through the action of incretin hormones, enteral nutrition provides a more potent insulinotropic stimulus relative to an isoglycemic intravenous challenge. This phenomenon is named the "incretin effect" [3,21-23].
The first incretin to be identified, GIP, was purified from porcine intestine extracts by virtue of its ability to inhibit gastric acid secretion (therefore, the original name was gastric inhibitory polypeptide) [7,24]. Soon, it was discovered that GIP displayed potent insulinotropic actions in animals [8,25] and in human subjects . GIP was shown to be a 42 amino acid peptide hormone [7,24] synthesized in duodenal and jejunal enteroendocrine K cells  in the proximal small bowel (duodenum and jejunum) (Fig. 1).
Much later, the second incretin hormone, glucagon-like peptide-1 (GLP-1), was identified as a partial sequence of the cDNAs and genes encoding proglucagon [14,27]. After posttranslational processing of proglucagon in gut endocrine L-cells [16,28-30], GLP-1 exists in two circulating equipo-tent molecular forms, GLP-1 ("glycine-extended GLP-1") and GLP-1 [7-36] amide ("amidated GLP-1") [31,32] (Fig. 1). The amidated form is more abundant in the circulation following meal ingestion in humans . Although the majority of GLP-1 is synthesized in the distal ileum and colon, plasma levels of GLP-1, like GIP, increase shortly after starting meals. This leaves two possibilities: Either there is an upper gut signal mediating GLP-1 release from more distal stores  (i.e. the locations where GLP-1 is most abundant ). Alternatively, GLP-1 is predominantly released from the sparse L-cells that are present in the upper gut [28,34]. Quantitative considerations make it appear feasible that GLP-1 from gut segments coming into direct contact with chyme is the source of postprandial increments in GLP-1 concentrations .
Proteolytic Degradation of Incretin Hormones by Dipeptidyl Peptidase-4
Plasma levels of total GLP-1 (including proteolytic degradation products) are low ("basal") in the fasted state (approximately 5 pmol/L) and increase rapidly following meal ingestion, reaching levels in plasma
Hls^^^^^^^^^^Thr^^AsnVal^^SerTyrLeuGlu Gly Gin Ala Ala LysG lu'^^Ile Ala^^l^^ Val Lys GlyArg -NH,
Fig. 1. Peptide structures of the two main incretin hormones, glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide, GIP), and glucagon-like peptide 1 (GLP-1). Amino acids shared between both peptides are shown in dark blue, and amino acids unique to GIP and GLP-1 are shown in light and dark green, respectively. The red arrow indicates the position of cleavage by dipeptidyl peptidase-4 (DPP-4), the alanine residue in position 2, which is recognized by DPP-4, is highlighted by a red margin.
of 15-50 pmol/L . Only a minor proportion of circulating GLP-1 (approximately 10-20%) is intact, biologically active GLP-1. This is true after endogenous secretion  as well as during exogenous administration, for example, during continuous intravenous infusion or after subcutaneous injection . The major reason is the rapid proteolytic degradation and inactivation by dipeptidyl peptidase-4 (DPP-4) , an aminopeptidase recognizing peptides with a proline or alanine in the second aminoterminal position . It removes the first two aminoterminal amino acids, rendering the breakdown products (GLP-1 [9-36] amide or GLP-1 [9-37]) biologically inactive or even weakly antagonistic [40-44]. The circulating levels of intact GLP-1 and GIP are further kept low by rapid renal clearance [45,46]. Whether additional proteases such as human neutral endopep-tidase 24.11 are also essential determinants of GLP-1 inactivation remains under active investigation [47,48]. Mice with targeted inactivation of the DPP-4 gene exhibit increased levels of plasma GIP and GLP-1, increased insulin secretion, and reduced glucose excursion following a glucose challenge .
GIP and GLP-1 exert their actions via engagement of structurally distinct G protein-coupled receptors. GIP receptors are predominantly expressed on islet P-cells, and to a lesser extent, in adipose tissue and in the central nervous system [50-53]. In contrast, GLP-1 receptors are expressed in pancreatic endocrine P-cells [54,55] and in several peripheral tissues including the central and peripheral nervous system, heart, kidney, lung, and the gastrointestinal tract [56,57]. Activation of both incretin receptors on P-cells leads to rapid increases in levels of cyclic AMP and intracellular calcium, followed by insulin exocytosis, in a glucose-dependent manner . Incretin receptor signaling is associated with protein kinase A activation, induction of gene transcription, enhanced levels of (pro-)insulin biosynthesis , and the stimulation of P-cell proliferation [60,61]. GLP-1 and GIP receptor activation protect P-cells against toxin-induced apoptosis (elicited by glucotoxicity -hyperglycemia, lipotoxicity - high concentrations of free fatty acids, streptozotocin, or hydrogen peroxide) and enhanced P-cell survival, findings observed in studies of both rodent [62-64] and human islets .
The main functions of GIP are the glucose-dependent augmentation of insulin secretion during periods characterized by physiological hyperglycemia, the incretin function sensu strictu [8,9,18,66,67]. Animal experiments suggest that GIP receptors on adipose tissue are essential for adipocyte triglyceride storage after meal ingestion: GIP receptor knock-out mice do not become obese when fed a high-fat diet .
GLP-1 does not only display glucose-dependent insulinotropic ("incretin") activity [15,17,18,68], but also inhibits glucagon secretion [11,69], decelerates gastric emptying [70-73] and reduces food ingestion [74-78], and promotes enhanced glucose disposal via neural mechanisms involving receptors in the "hepatoportal" region . All these actions, which are summarized in Fig. 2 and Table 1, potentially contribute to glucoregulation. It is of interest that GLP-1 effects on glucagon secretion, like those on insulin secretory responses, are glucose-dependent, whereas counter-regulatory release of glucagon in response to hypoglycemia remains undisturbed even in the presence of pharmacological concentrations of GLP-1 .
The physiological importance of endogenous GIP and GLP-1 for glucose homeostasis can be examined using specific receptor antagonists or knock-out mice. Acute antagonism of either GIP or GLP-1 action lowers insulin secretion and increases plasma glucose following oral glucose ingestion in rodents [80,81]. Similarly, mice with inactivating mutations in the GIP or GLP-1 receptors exhibit reduced glucose-stimulated insulin secretion and impaired glucose tolerance [66,82]. GLP-1, but probably not GIP, is essential also for the control of fasting glucose concentrations, as acute antagonism or genetic disruption of GLP-1 action leads to increased levels of fasting glucose in rodents .
Effects of GLP-1 Receptor Antagonists in Human Subjects
The GLP-1 receptor antagonist exendin [9-39] has been used to elucidate the role of endoge-nously secreted GLP-1 in human volunteers. Administration of exendin [9-39] leads to a
reduction in glucose-stimulated insulin secretion, diminished glucose clearance, and increased glucagon secretion [83,84]. Indirect evidence suggests more rapid gastric emptying following disruption of GLP-1 action in humans as expected from the activity profile of GLP-1 (Fig. 2) .
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