1. General Information

The incretin concept arose with the realization that oral glucose induced a greater increase in insulin secretion than did intravenous administration in normal humans (71). Intestinal extracts were then shown to potentiate insulin secretion in dogs and this led to the discovery of two primary gut hormones with incretin activity, gastric inhibitory peptide (GIP) and glucagon like peptide-1 (GLP-1) (10, 15, 18, 28, 75). The incretin effect accounts for up to 60% of insulin secretion after oral glucose (83). Clinical interest has focused on GLP-1 as GIP is no longer active in Type 2 diabetes. GLP mimetics are currently widely used in the treatment of Type 2 diabetes while both physiological and pathophysiological effects on the exocrine pancreas are less clear.

GLP-1 Synthesis

GLP-1 and GLP-2 were identified in the distal small intestinal mucosa as the product of post-translational processing by prohormone convertase 1/3 (PC1/3) of the proglucagon gene product (9) which in the Islets is processed by PC2 to yield glucagon (75, 87, 97). The human proglucagon amino acid sequence contains 160 amino acids with pancreatic glucagon made up of residues 33-61 and GLP-1 derived from residues 72-108 after further processing (Figure 1). Recent work has shown GLP-1 to also be produced in islet α cells and that this intra-islet GLP-1 is necessary for β-cell function (22). In gut endocrine cells, proglucagon is processed to glicentin, oxyntomodulin, GLP-1 and GLP-2, all of which have biological activity (28).  For GLP-1, the C-terminal amino acid glycine is converted to an amide which increases stability in plasma and the product is known as GLP-1 (1-36 amide). However, prior to secretion the amino terminal is cleaved resulting in GLP-1 (7-36 amide) which is the major form in human plasma and is commonly referred to as GLP-1 (89). This 29 amino acid peptide has about 50 % homology to glucagon and is the primary circulating form in humans which has incretin activity. In some species (rodents, pigs) there are also appreciable amounts of GLP-1 (7-37) which has similar activity to the 7-36 amide. For further details on proglucagon processing see the reviews by Holst (51) and Muller et al (78). GLP-1 is also produced in the central nervous system where proglucagon is processed similar to the gut (15). In a micellar environment GLP-1 assumes a structure with an N–terminal random coil segment and two helical segments separated by a linker region (112).

Figure 1. Diagram of the differential processing of the proglucagon gene product in α-cells of the pancreas and L-cells in the gut. Only the biologically active products are shown. For further details of cleavage sites and processing see reference (52).

Cells producing and secreting “enteroglucagon” were originally identified by immunohistochemistry with glucagon antibodies and it was noted that the cells in the gut mucosa differed from islet α-cells that produce glucagon (42). These cells were further characterized as containing large (canine) to medium (human) solid round granules by electron microscopy and termed L-cells (11). L-cells are of the open type with apical processes extending towards the gut lumen with secretory granules in the basolateral pole where they can be released and their secretory material enter capillaries. About half of L-cells show costaining for PYY, another GI hormone, which is present in the same secretory granules (85). In the upper gut, GLP-1 can colocalize with CCK (45) or GIP (77). Both immunoreactive gut glucagon and L-cells are present most abundantly in the distal small intestine and colon (31, 62). This distal location presents problems explaining the rapid release after a meal.

GLP-1 Secretion

While GLP-1 secretion was originally described in response to glucose, it also occurs with ingestion of a mixed meal and the GLP-1 response is greater than to glucose alone indicating synergy in the stimulation by fat and protein along with glucose (1, 78, 132). This is also the case for plasma insulin levels in humans where a mixed liquid meal is a stronger stimulus than oral glucose alone.  Recent studies of isolated L-cells (95) and a L-cell derived cell line, GLUTag cells, have shown stimulation of GLP-1 secretion by glucose acting to inhibit K+ channels as in islet beta cells, by activation of the SGLT-1 transporter leading to depolarization (91), or activation of sweet taste receptors (T1R2 / T1R3) which activate Gq and PLC. Free fatty acids act on receptors including GPR 43, GPR119 and GPR 120, and FFAR (29, 51, 113), and proteins may act through the Ca²⁺ sensing receptor (CaSR) which responds to amino acids (24) or the peptide transporter PepT1 (69). Nutrient stimulation causes an intracellular increase in both cAMP and Ca²⁺ which then mediates GLP-1 secretion (114). The increase in Ca²⁺ is mediated by IP3 induced release of intracellular Ca²⁺ and by depolarization leading to activation of voltage dependent Ca²⁺ channels.  A summary diagram is shown in Figure 2.

Figure 2. Regulation of GLP-1 secretion by nutrients acting via G protein coupled receptors and transporters. Nutrient receptors are located on the apical surface where exposed to luminal contents and secretion occurs at the basolateral pole where secreted GLP-1 can activate receptors on vagal afferent nerve endings or enter capillaries and travel through the systemic circulation to reach the islets. GLP-1 secretion may also be regulated by neurotransmitters such as ACh and PACAP.

GLP-1 in plasma can be measured by RIA although some antibodies react with multiple proglucagon products containing the antigenic epitope.  The most specific antibodies are directed at the amidated C-terminus of GLP-1. The rise in plasma GLP-1 is clearly meal related with fasting levels of about 5-15 pM and stimulated levels of 40-80 pM in normal men (59, 90). The response begins within 10 min but is generally slower than cephalic phase events and peaks after an hour. Ileal instillation of carbohydrate or lipid induced a more rapid stimulation of GLP-1 (63). How GLP-1 secretion occurs so rapidly is still unclear but may be due to the presence of some L-cells in the upper jejunum (31). The vagal nerve may also be involved (96) and somatostatin exerts a strong inhibitory influence (47).

GLP-1 has a plasma half-life of only 1.5-3 min with a high clearance indicating degradation in blood (52, 72). The main enzyme involved, dipeptidyl peptidase-4 (DPP-4) also known as CD26, cleaves off the two N-terminal residues resulting in GLP-1 (9-36 amide) which is inactive or acts as an inhibitor at the GLP-1 receptor (23). This form has a half-life of about 4 min as it is further degraded by the kidneys. DPP-4 is present on the apical endothelial surface of capillaries including those in the intestine. As a result, much of the GLP-1 in intestinal veins is already degraded (46). Mice in which CD26 has been deleted showed increased levels of plasma GLP-1 (67). In humans, the half-life is similar in healthy subjects and obese patients with type 2 diabetes (120). Because of the rapid degradation of GLP-1, therapeutic use of GLP-1 to enhance insulin secretion makes use of long acting, degradation resistant analogs of GLP-1 or DPP-4 inhibitors. The exendins are bioactive peptides isolated from the venom of Gila Monster. Exendin-4 is a 39 amino acid peptide with 53% identity to GLP-1 (34) and is fully active at GLP-1 receptors and not degraded by DPP-4. Exendin-4 (Exenatide) mimicks GLP-1 but is much more potent in vivo following parenteral administration (28). Its half-life is about 6 hours and it is given twice daily. A long acting DPP-4 resistant, fatty acylated human GLP-1 analog (Liraglutide) has also been developed and needs to be administered only once daily. DPP-4 inhibitors (DPP-4i) enhance plasma levels of GLP-1 and several other GI hormones including GIP by inhibiting their degradation. A major advantage is that they can be given orally while a potential disadvantage is that other hormones could also be affected.  Interestingly, DPP-4 inhibition does not have to take place systemically but only in the intestine as shown with oral administration of low doses of inhibitor (122).

GLP-1 Action

The major target tissues for GLP-1 are the pancreatic islet cells but it also has actions on gastrointestinal secretion and motility of the stomach and exocrine pancreas. GLP-1 also affects food intake, body weight, and has direct effects on the heart (52, 103).

GLP-1 exerts its actions on target cells by binding to specific high affinity receptors.  These were initially identified by high affinity binding of ¹²⁵I-GLP or ¹²⁵I-[Y³⁹]exendin-4 to beta cell lines, gastric chief and parietal cells and pancreatic acinar cells (39, 88, 94, 104). GLP-1 and exendin-4 show a similar nM affinity while glucagon, secretin, VIP and GLP-2 have at least a hundred times lower affinity for the GLP-1 receptor. The rat receptor was cloned by expression cloning of an islet cDNA library followed by identification of human clones (25, 26, 41, 111). The receptor belongs to the G-protein coupled 7 transmembrane domain family and has 40% homology to the secretin receptor. It is considered to belong to the Class B family of GPCRs whose members possess an extracellular N-terminal domain of 100-150 amino acids connected to the 7TM domain core typical of all G protein receptors (26). This N-terminal domain has a characteristic structure and participates in binding of the ligand (2, 73). It also has three glycosylation sites necessary for insertion into the plasma membrane (17, 40).

GLP-1R mRNA is most abundant in islets and lung with lesser amounts in the stomach. In islets, receptors are present on beta cells; whether they are present on alpha or delta cells is controversial (49, 88). The specificity of initial antibodies to GLP-1R protein was also controversial.  The binding properties of the expressed receptor are similar to native receptors. Both native and cloned receptors signal through the activation of both adenylyl cyclase and phospholipase C (76, 129). Activation of specific heterotrimeric G proteins involves different regions of the receptors intracellular loops, primarily the third intracellular loop (8, 50, 68). Cyclic AMP, however, is the main intracellular mediator of GLP-1 action in beta cells and other target cell types (27, 65). Recent insights into GLP-1R signaling in beta cells is summarized in (115).

The effects of GLP-1 receptor agonists on inhibition of food intake and body weight loss are currently of considerable interest (118). Studies of endogenous GLP-1 release and administration of long acting GLP-1 agonists show two mechanisms of action (78). Long acting agonists appear to penetrate permeable areas of the blood-brain barrier and act directly on neurons with GLP-1R in the paraventricular nucleus (PVN) and Area Postrema (56, 102, 105). By contrast, physiological levels of GLP-1 in the portal vein signal through vagal afferents and neurons in the nucleus tractus solitarius (NTS) (3). Other evidence also suggests that GLP-1R in the cerebral cortex affects hedonic feeding by targeting areas involved in reward and addiction (110).

GLP-1 is also believed to participate in weight loss after bariatric surgery which brings food more rapidly into the distal small intestine.  Plasma GLP-1 is increased and this is responsible in part for weight loss and metabolic improvement which occurs before weight loss (55)

2. Action of GLP-1 on the pancreas

Physiology of GLP-1 as an incretin

The primary action of GLP-1 for lowering blood glucose is the stimulation of insulin secretion by potentiating the action of glucose (20, 74, 80, 125). Intestinal release of GLP-1 augments initial insulin secretion in vivo in part through a vagal-vagal reflex leading to cholinergic stimulation of islet beta cells. The direct action of GLP-1 which can also be demonstrated in the perfused pancreas, with isolated islets and with beta cell derived cell lines involves activation of the beta cell GLP-1R which couples through the heterotrimeric G-protein Gs to activate adenylyl cyclase and increase intracellular cAMP (27, 65). Cyclic AMP acts in beta cells through both PKA and Epac2. This action leads to closure of glucose-dependent ATP-sensitive K⁺ channels which depolarizes the cell and thereby opens voltage dependent Ca²⁺ channels allowing Ca²⁺ influx which stimulates insulin secretion. The Epac2 arm activates PLC epsilon through Rap1 and this also leads to increased intracellular Ca²⁺ (Figure 3). These mechanisms are central to restoring function in type 2 diabetes as in that condition glucose does not stimulate adequate Ca²⁺ influx. The action is self-limiting as when the increased insulin release reduces plasma glucose, the ability of GLP-1 to act is turned off (44).  Thus there is little risk of hypoglycemia. In addition to this mechanism, PKA has recently been shown to phosphorylate Snapin and regulate the SNARE complex thereby augmenting Ca²⁺ mediated exocytosis (106). GLP-1 has also been reported to increase secretory granules docked at the plasma membrane and also increases the frequency of compound exocytosis (60).

In rodent models, GLP-1 also enhances modest beta cell mitogenesis and inhibits apoptosis thereby leading to enhanced beta cell mass (13, 107, 135). There are also reports of enhanced islet neogenesis from duct precursors (21). These actions lead to a prolonged or durable action after ceasing GLP-1 treatment (131). Whether these actions occur in humans is unclear especially since cessation of GLP-1 therapy rapidly leads to the reappearance of diabetes. However, one report indicated that stimulation of freshly isolated human islets inhibited apoptosis (36).

Other actions of GLP-1 that also contribute to restoring glucose regulation in Type 2 diabetes include inhibition of glucagon secretion, slowing of gastric emptying, suppression of appetite and modest reduction in body weight (37, 48, 84, 118). These appear to be less important, however, as restoring GLP-1R in the pancreas in a receptor KO mouse restored glucose tolerance (61).

Glucagon Like Peptide 1 (GLP-1) mimetic drugs which mimick the action of native GLP-1 as an incretin hormone have become a common second line of therapy for Type 2 diabetes (61, 80). Two classes exist. The first, degradation resistant analogs of GLP-1 (Exenatide and Liraglutide) must be given by subcutaneous injection once or twice daily. The second class is inhibitors of the GLP-1 degrading enzyme, dipeptidyl pepitidase IV (Sitagliptin and related drugs) which can be given orally and increase the plasma level of GLP-1 and other peptides degraded by DPP-4. These drugs by increasing insulin secretion and possibly, beta cell mass, decrease plasma glucose and lipids and have a secondary action to reduce food intake and bring about weight loss. Slowing of gastric emptying also plays a role in the action of Exenatide (16). They are often used in combination with a Metformin drug. However, a number of case reports and analysis of adverse effect databases raised the possibility that the drugs increase the incidence of acute pancreatitis. The FDA has issued warnings which have also been contested. For further coverage of this issue see the following references (6, 30, 35, 99, 100). More recently, the possibility that GLP-1 mimetics predispose to pancreatic cancer has been raised and disputed (38, 82).

Figure 3. Actions of GLP-1 to potentiate glucose stimulated insulin secretion from islet β cells. GLP-1 binds to specific receptors on beta cells that activate adenylyl cyclase and through cAMP activates PKA and EPAC2 which act to potentiate insulin secretion.

Actions of GLP-1 on exocrine pancreas

Infusion of GLP-1 to mimic postprandial levels inhibits pancreatic exocrine secretion in response to intragastric infusion of a liquid meal in man (127). Although GLP-1 can inhibit gastric emptying thereby reducing pancreatic stimulation, in follow-up studies, GLP-1 was shown to inhibit pancreatic digestive enzyme secretion stimulated by carbachol infusion (43). This effect appears to explain the carbohydrate stimulated “ileal brake” where plasma GLP-1 increases without a change in PYY (64). This effect may be mediated through central neural pathways as has been established for the action of GLP-1 to inhibit gastric acid secretion (52). Studies in the pig showed GLP-1 inhibited pancreatic secretion induced by hypoglycemia (central neural stimulation) but not that due to vagal nerve stimulation (126). These inhibitory effects of GLP-1 could be mediated by activation of vagal afferents in the distal small intestine or by hormonal effects on the NTS-DMV circuitry (123). It must involve either an action of an inhibitory neurotransmitter or reduction of a stimulatory one.

Direct effects on isolated pancreatic cells

Study of possible direct effects of GLP-1 on acini began with the discovery of biologically active peptides in Gila monstor venom (33, 34) and the identification of a specific receptor for Exendin-4 on guinea pig isolated pancreatic acini that increased the production of cAMP (93, 94). This effect was then shown to be mimicked by GLP-1 that acted on the same receptor (94). Interestingly, neither exendin-4 or GLP-1 stimulated amylase release from isolated acini of guinea pig or rat pancreas but both potentiated secretion induced by CCK (66, 94, 124). This potentiation was also seen with other Ca²⁺ mediated secretagogues. The failure of GLP-1 to stimulate amylase release in guinea pig acini is surprising as all other ways of increasing cAMP in these cells does stimulate amylase release. More recent studies of isolated acini from mouse and rat pancreas showed a small but dose dependent stimulation of amylase release comparable to that induced by VIP or secretin (54, 98). This effect was mediated by cAMP and PKA and was absent in mice with genetic deletion of the GLP-1R (54). Satoh et al have presented evidence that stimulation of amylase release requires phosphorylation of the MARCKS protein (98). Longer term effects on gene expression and growth have also been reported to be activated by c-Src or mTOR signaling (57, 128) .

AR42J cells, a rat pancreatic acinar-derived cell line but which shows some islet characteristics has also been studied. GLP-1 increased cAMP but did not affect amylase secretion; however, in this cell line GLP-1 increased intracellular Ca2+ levels (136). The stimulation of amylase secretion by GLP-1 may not have physiological importance as the concentrations of peptide required are higher than seen in peripheral blood.

Although early studies were unclear (92), more recent studies with Western blotting, immunolocalization, and PCR have shown the presence of GLP-1R in acinar and in some cases duct cells (54, 128). In situ hybridization initially revealed pancreatic GLP-1R mRNA only in the β cells (12, 53, 116) but this may have been due to the lower level in the exocrine pancreas. Reports of localization of GLP-1R to pancreatic ducts have appeared and exendin 4 treatment of isolated human ducts increased the number of insulin positive cells (133). A recent study reported GLP-1 receptors on activated pancreatic stellate cells both in pancreatitis and isolated stellate cells in culture (81). Overall, the possibility of direct effects of GLP-1 from the gut or islets on exocrine pancreas is unclear and worthy of further study.

Possible relation to pancreatitis or pancreatic adenocarcinoma

Another type of study of the exocrine pancreas has been to give GLP-1 mimetics or DPP-4 inhibitors to animals over a prolonged period of time and evaluate the pancreas for evidence of pancreatitis or precancerous lesions. Six studies have evaluated the effects of the mimetics, exenatide (86, 108, 109, 134) or liraglutide (79, 109). None of the studies resulted in frank pancreatitis but two reported some increase in pancreatic inflammation at high levels of exenatide. Nachnani et al (79) in a study in rats reported animals receiving exenatide for 75 days showed more acinar inflammation and pyknotic nuclei and these animals weighed less. In a later study of small numbers of rats studied for 10 weeks, exenatide increased inflammatory cell infiltrate with interstitial edema and fibrosis in 5 of 15 rats (122). Two studies evaluated the effect of exendin on pancreatic gene expression in mice. Koehler et al showed that exendin administration induced antiinflamatory genes such as PAP (58). De Leon et al compared genes induced by exendin to those expressed following partial pancreatectomy and found a set that included multiple Reg genes as well as fragilis and serpin b1a (21). Four published studies showed no pancreatitis effects including one in which the pancreas of rats, mice and monkeys showed no change with liraglutide at concentrations 60 fold higher than used in humans for up to two years (86). Other studies showed no effect of exenatide for 13 weeks (108, 109) or liraglutide for 13 weeks (121). Fewer studies have been carried out with DPP-4 inhibitors. One study reported one rat out of 8 expressing human islet amyloid polypeptide (HIP) as a model for diabetes developed pancreatitis when treated with sitaglyptin for 12 weeks (70). In a larger study of mice expressing HIP, no evidence of pancreatitis was seen in mice given sitaglyptin for 1 year (4). Similar unpublished preclinical data on file at Merck has been summarized (35). Two studies have also evaluated whether exenatide would modify experimental pancreatitis induced by caerulein. No effect was seen by Koehler et al (58) and in the work of Tatarkiewciz et al (108) high doses of exenatide inhibited the pancreatitis. A recent double blind placebo controlled large trial of sitaglyptin for effects on heart disease in humans also showed no effect on the rate of acute or chronic pancreatitis (100). Overall, studies in animals and cells have not shown a plausible mechanism for induction of panreatitis (130).

Other studies have reported effects on overall growth of the pancreas (as opposed to islet growth) or evidence of increased exocrine mitogenesis. Ellenbroek et al (32) reported pancreatic weight was increased after 6 weeks on liraglutide with a 65% increase in proliferating acinar cells and no change in duct cell proliferation. Tschen et al reported increased proliferation of duct cells in response to exendin similar to that found in beta cells (117); and Koehler et al (58) reported exendin increased pancreatic mass in mice after one week. However, most studies of pancreatic mass or exocrine cellular proliferation have reported no change with exenatide, liraglutide, or dulaglutide (86, 108, 109, 119, 121). Thus there does not appear to be a consistent change. Other studies have evaluated acinar-ductal metaplasia (ADM) and PanIN formation, a precancerous lesion. In eight rats with transgenic expression of HIP to induce diabetes, three given sitaglyptin showed clear ADM (70). Increased Ki67 staining indicating DNA replication occurred in both ADM and in normal ductal epithelial cells. Gier et al (38) reported PanIN lesions located primarily in pancreatic duct glands of normal rats treated with exendin-4. This is of concern since a recent study of human pancreas from organ donors who had been treated with incretin mimetic drugs for a year also showed the increased presence of PanIN lesions (13, 14). In a study of transgenic mice with a Kras G12D mutation which induces PanINs and eventually pancreatic cancer, treatment with exendin-4 increased higher grade PanIN lesions (35, 38). Further longer term studies of normal and genetically modified rodents are clearly warranted.

3. Tools for the study of GLP-1

a. Antibodies. A large number of antibodies to GLP-1 are listed in Biocompare but I have no personal experience with them. Monoclonal antibodies to the GLP-1 receptor in primates (3F52) and another to rodent GLP-1R (7F38A2) are available from the Developmental Studies Hybidoma Bank at the University of Iowa.

b. Measurement of GLP-1. A number of ELISA or other sandwich antibody based techniques are available in kit form, including from EMD Millipore and ALPCO which measure active GLP-1 without significant contribution from GLP-1 (9-36 amide). These are designed for human plasma and require 100 µl. Eagle Bioscience sells a kit optimized for rat/mouse that requires 20 µl of plasma. As the amino acid sequence is identical between human and laboratory animal species any kit can be used for any species.

c. Mouse Models. Because GLP-1 cannot be deleted specifically without affecting the other products of the proglucagon gene including glucagon, attention has focused on the GLP-1 receptor gene which can be deleted independent of the glucagon receptor. Earlier studies using these mice include (5-7, 101). Receptors can be deleted in specific tissues with Cre-Lox or knocked down by local administration of antisense RNA such as in specific brain nuclei (19).

4. Acknowledgement

We thank Ernesto Bernal-Mizrachi for reading the manuscript and commenting on the use of the GLP-1 mimetics in treating Type 2 diabetes.

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