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. Author manuscript; available in PMC: 2022 Jun 13.
Published in final edited form as: Compr Physiol. 2020 Mar 12;10(2):577–595. doi: 10.1002/cphy.c190025

Glucagon-like Peptide-1: Actions and Influence on Pancreatic Hormone Function

Ellen M Davis 1, Darleen A Sandoval 1,*
PMCID: PMC9190119  NIHMSID: NIHMS1812124  PMID: 32163198

Abstract

GLP-1 was described as an incretin over 30 years ago. GLP-1 is encoded by the preproglucagon gene (Gcg), which is expressed in the intestine, the pancreas, and the central nervous system. GLP-1 activates GLP-1 receptors (GLP-1r) on the β-cell to induce insulin secretion in a glucose-dependent manner. GLP-1 also inhibits α-cell secretion of glucagon. As few, if any, GLP-1r are expressed on α-cells, indirect regulation, via β- or δ-cell products has been thought to be the primary mechanism by which GLP-1 inhibits glucagon secretion. However, recent work suggests that there is sufficient expression of GLP-1r on α-cells for direct regulation as well. Although the predominant source of circulating GLP-1 is the intestine, the α-cell becomes a source of GLP-1 when the islet is metabolically stressed. Recent work suggests the possibility that this source of GLP-1 is also be important in regulating nutrient-induced insulin secretion in a paracrine fashion. More work is also accumulating regarding the role of glucagon, another Gcg-derived protein produced by the α-cell, in stimulating insulin secretion by acting on GLP-1r. Altogether, these data clearly demonstrate the important role of Gcg-derived peptides in regulating insulin secretion. Because of GLP-1’s important role in glucose homeostasis, it has been implicated in the success of bariatric surgery and has been successfully targeted for the treatment of type 2 diabetes mellitus.

Introduction: History of GLP-1 as an Incretin

After the discovery of insulin and the development of the radioimmunoassay to assess plasma insulin levels, a debate ensued over whether glucose was the only stimulus for insulin secretion. Spurred on by work demonstrating that glucose removal from the blood was more rapid with oral versus intravenously (IV) glucose in dogs (211), McIntyre et al. (153) found that glucose was lower but insulin was higher after isocaloric loads of glucose administered into the jejunum versus IV in man. Months later, a second study had similar findings with oral versus IV glucose (61). These data in conjunction with multiple reports in the 1920s and 1930s that intestinal mucosa had hypoglycemic properties led the authors of both papers to hypothesize that a gut-derived humoral substance contributed to the regulation of insulin secretion (Figure 1). Yet, it was not until the 1970s when the first “incretin” was discovered. When gastric inhibitory polypeptide (GIP; aka glucose-dependent insulinotropic peptide) was infused into humans IV, insulin immunoreactivity increased and glucose tolerance was improved (54). However, while gut extracts containing GIP increased insulin secretion, removal of GIP from the extracts only blunted the insulin response by 30% suggesting the presence of additional incretins (56).

Figure 1.

Figure 1

The incretin effect: Glucose levels are lower while insulin levels are higher when the same dose of glucose is administered directly into the gut versus when administered intravenously (IV). This difference in insulin between the gut and venous infusion is the “incretin effect” which occurs in response to GLP-1 and GIP secreted from the distal gut. Adapted, with permission, from McIntyre N, et al. (153).

With the discovery of glucagon and in the pursuit of understanding its form and function, two other peptides were found on the same mRNA (10, 142). These peptides were glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2). At this time, the biological function of these peptides was unknown but later work demonstrated that GLP-1, but not GLP-2, stimulated insulin release in rat islets (210) and when infused in humans (127). This latter study found that GIP was less effective at increasing insulin levels and concluded that GLP-1 was a physiological incretin in man. We now know that GLP-1 has a wide array of physiological functions, yet its role in the pancreas is still the most widely studied. The purpose of this article is to discuss the role and mechanisms associated with GLP-1 and glucagon-like peptide-1 receptor (GLP-1r) signaling in the regulation of pancreatic hormone secretion and consequently glucose homeostasis. Consideration is also given to its role in bariatric surgery and the current state of GLP-1 pharmaceuticals.

Regulation of Preproglucagon (Gcg) Expression

We now know that preproglucagon (Gcg) is the gene that codes for GLP-1 and it is expressed in a specific population of intestinal enteroendocrine cells called L-cells. Gcg is also expressed within pancreatic islet α-cells, and in a distinct set of neurons within the nucleus of the solitary tract (NTS) (81, 108). Gcg undergoes tissue-specific posttranslational modification by prohormone convertases (PC). In intestinal L-cells and neurons of the NTS, a specific isoform of PC, PC1/3, is predominantly expressed and yields GLP-1, oxyntomodulin, and GLP-2 as the physiologically relevant products (134, 228, 238). In contrast, the α-cell predominantly expresses another PC isoform, PC2, which yields glucagon (92). Gcg codes for other bioactive proteins including the proglucagon fragments glicentin, glicentin-related pancreatic polypeptide (GRPP), and major proglucagon fragment (MPGF), but the functional significance of these peptides is unclear.

Nutrient status is clearly an important factor in regulating Gcg expression across all three organs for which it is expressed. Re-feeding after fasting (49, 109), dietary fibers (15, 49, 170), long-chain fatty triglycerides (109), and peptones (171, 198), all increase intestinal Gcg expression, and amino acids stimulate α-cell hyperplasia and glucagon secretion (215). Interestingly, in vitro work in cell lines suggest that physiological stimuli such as peptones act via cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) signaling to regulate transcriptional responses of Gcg (73, 250). In fact, increases in cAMP lead to increases in Gcg expression in both the pancreas and intestine (4, 21, 49, 141). Downstream of cAMP but a pathway that is distinct from protein kinase A (PKA), activation of exchange protein activated by cAMP 2 (EPAC) also increases Gcg transcription in both α- and L-cells (101, 140). In contrast, specific to the L-cell, Gcg expression has been shown to be downstream of the canonical Wnt signaling pathway (a specific signaling transduction pathway), β-catenin and transcription factor 7 like 2 (TCF7L2) (28). Although the mechanisms are unclear, it is also well established that bowel resection or injury causes a large increase in intestinal Gcg expression (125). The function is likely related to the increase in GLP-2, which functions as an intestinal growth factor (see Ref. 13 for review). Distinct regulatory mechanisms for Gcg transcriptional control between tissues is in parallel with the distinct patterns of prohormone processing in the major cell types producing Gcg peptides.

Regulation of Intestinal GLP-1 Secretion

Within the intestine, the density of Gcg-expressing cells increases from the proximal to distal gut with the expression being highest in the colon (7). L-cells within the intestinal epithelium and have apical processes that extend into the gut lumen allowing direct access to ingested nutrients (58), and all three macronutrients (carbohydrate, fat, protein) individually stimulate GLP-1 secretion (120, 249).

Greater numbers of enteroendocrine cells that express Gcg within the lower intestine suggests that postprandial GLP-1 secretion is derived from the ileum and colon. Indeed, nutrient infusions directly into the ileum cause significantly greater increases in portal vein (the major blood vessel that collects intestinal secretions) concentrations of GLP-1 (90). Interestingly, in ex vivo studies from human tissue, the duodenum and ileum but not the colon were found to be glucose responsive (218) which is different than what is reported in mouse colon (178, 191) but are consistent with data where patients that have had colon resection have normal GLP-1 responses to glucose (185). An argument has been made that duodenal secretion of GLP-1 is responsible for early phase GLP-1 secretion (222) but no direct link has been found. However, the anatomic distribution of the L-cells (highest number in distal gut) and the rapid increase in postprandial circulating GLP-1 (35) that occurs before nutrients reach the distal gut (8, 63) is evidence supportive of neural, endocrine and/or paracrine mechanisms being more critical to nutrient-induced increases in circulating GLP-1 (164).

One possibility is that there are feed-forward neural or paracrine signals from the upper gut to the ileum that stimulates the release of GLP-1 (14, 83). Transection of the gut below the duodenum resulted in a delayed GLP-1 response to nutrients compared to when the gut is simply ligated, the latter being a procedure that preserves neural innervation (196). Further support for neural regulation of GLP-1, bilateral subdiaphragmatic vagotomy in conjunction with intestinal transection completely abolishes nutrient-induced GLP-1 secretion (196). In rodents, human enteroendocrine cells, and in perfused porcine ileum, cholinergic agonists, which bind to receptors in both the enteric and parasympathetic nervous system (PNS), stimulate GLP-1 secretion (4, 14, 84, 192). Conversely, norepinephrine and α-adrenergic agonists inhibit (84) and β-adrenergic agonists stimulate (52, 182) GLP-1 secretion suggesting that sympathetic neural innervation of the gut is also important in the regulation of GLP-1 secretion. In humans, atropine, which is a PNS agonist, blunts glucose-induced increases plasma GLP-1 (8). Together these data lend support to the idea that neuronal influences are at play in the regulation of postprandial GLP-1 secretion.

Despite the anatomic limitations, there are several potentially overlapping nutrient-sensing mechanisms that have been found to regulate intestinal GLP-1 secretion. Both passive glucose transport through the sodium-glucose cotransporter 1 (SGLT1) (158, 191) and active glucose transport through glucose transporter 2 (GLUT2) have been found to regulate intestinal GLP-1 secretion as inhibitors for each transporter blocks GLP-1 release (218). Similar to pancreatic β-cells that secrete insulin, potassium adenosine tri-phosphate (KATP) channels and its associated sulfonylurea receptor are also expressed in L-cells (173, 190). Data suggest that increased glucose metabolism within L-cells leads to an increase in ATP and consequently depolarization of KATP channels triggering GLP-1 secretion (179, 190, 191). Interestingly, GLUT2 is linked to KATP channels (145) while SGLT1 is linked to voltage-gated sodium and calcium channels in GLP-1 secretion (218). However, in animal models pharmacological (128) or genetic (197) blockade of SGLT1 had a bigger impact on blunting GLP-1 secretion compared to the same manipulations towards GLUT2. In contrast, ex vivo studies in human tissue suggest GLUT2 may be more important (218). It is unknown whether these differences are simply due to the species or the experimental conditions; in particular for the ex vivo experiments.

Early work demonstrating that PKA activators could stimulate GLP-1 secretion from cell lines suggested that G-coupled protein receptors (GPCR) were involved in the regulation of GLP-1 secretion (12, 16, 192). Gαs and Gαq-coupled receptors responding to luminal bile acids and long-chain fatty acids have demonstrated potent effects on GLP-1 secretion (87). Bile acids signaling through the Gαs protein-coupled bile acid receptor 1, or TGR5, stimulate GLP-1 secretion (87, 180). Bile acids also signal through farnesoid X receptor (FXR), a nuclear transcription factor, but TGR5 is the primary bile acid receptor that can drive GLP-1 secretion (115). Offering clinical promise, in vitro data using primary enteroendocrine cells and an intestinal cell line indicated that pharmacologic TGR5 agonists are more potent GLP-1 secretagogues and are better at enhancing L-cell responses to calcium and glucose-induced GLP-1 secretion compared to naturally occurring bile acids (180).

Long-chain fatty acids and their derivatives specifically activate multiple types of GPCRs including, GPR119, GPR120, and GPR40 (96), and this activation also stimulates GLP-1 secretion. GPR119 is a Gαs-coupled protein receptor and it is highly co-localized to L-cells within the GI tract. GPR119 agonists increase GLP-1 secretion (29) and GPR119 knockout mice have a reduced GLP-1 response to an oral glucose load (132). However, a randomized double-blind placebo controlled trial revealed that GPR119 agonism was not as effective at increasing total and active GLP-1 responses to glucose or a mixed liquid meal nor was it as effective at improving glucose control over a 2-week study period (116). In contrast to GPR119, a Gαs-coupled receptor, GPR120, and GPR40 are Gαq-coupled receptors that signal through protein kinase C. Activation of both GPR40 and GPR120 result in increased GLP-1 secretion (57, 91, 99, 143); however, their role may be more pharmacological than physiological. While members of these GPCR families were under active investigation as drug targets for the treatment of type 2 diabetes mellitus (T2DM), due to lack of efficacy, the number of drugs in the pipeline has been drastically reduced.

Another type of GPCR that is expressed in the GI tract and has been found to be linked to GLP-1 secretion is “sweet taste receptors” (102). These same receptors are expressed in the tongue and are integral in sweet taste perceptions. Their function in the GI tract is less clearly understood. Nonnutritive agonists of sweet taste receptors do increase GLP-1 levels and mice null for one such sweet taste receptor, α-gustducin, have reduced GLP-1 responses to an oral glucose load (102). Some data suggest that pharmacological inhibition of sweet taste receptors blunt GLP-1 responses to nutrients (217), but other studies found no impact of sweet taste receptor agonists on GLP-1 secretion in humans (146, 178) or in in vivo or ex vivo studies in rats (208).

Altogether it seems that many molecular signaling pathways have been linked to GLP-1 secretion (Figure 2), and it is possible that all of these pathways are involved in order to provide an integrated response that also allows for fine tuning of GLP-1 secretion. One example of this is recent work that found a synergistic action of pharmacological TGR5 and GPR40 activation on the electrophysiological properties of L-cells (76). However, while data in mouse models are promising, there are currently no therapies currently in clinical trials focused on GPCR signaling to increase plasma GLP-1. Whether this is because these GPCRs are not important or whether increasing intestinal GLP-1 secretion, alone, is sufficient for obesity and/or T2DM treatment remains to be determined.

Figure 2.

Figure 2

Intestinal GLP-1 secretion: Several factors have been linked to GLP-1 secretion. The parasympathetic nervous system (PNS) stimulates GLP-1 secretion via cholinergic muscarinic receptors (MR). Activation of α-adrenergic (AR) receptors stimulates while activation of β-adrenergic receptors inhibits GLP-1 release. Various GPCRS including ones activated by bile acids and various fatty acids stimulate GLP-1 through PKA signaling and increases in calcium-induced exocytosis. Lastly, direct glucose sensing, predominantly via SGLT1 in humans, activates sodium (Na+), and calcium (Ca2+) voltage-gated channels to lead to the release of GLP-1.

GLP-1 Receptor Distribution and Signaling

Direct regulation of insulin secretion

The GLP-1r is a GPCR that is expressed within the pancreas, lung, adipose tissue, kidney, heart, vascular smooth muscle, and in a number of specific nuclei within the CNS (21, 74). Most of what we know about GLP-1r signaling is derived from studying the β-cell population of GLP-1r. When glucose is transported into the β-cell, its metabolism generates ATP, which provides energy for the closure of KATP channels and consequently an increase in intracellular calcium; the latter being necessary for exocytosis of insulin. Binding of the GLP-1r produces cAMP and consequently activation of PKA and EPAC2 (94), which potentiates glucose-stimulated insulin release (94, 144, 200). With fasting and when intracellular ADP is increased, PKA activation hyperpolarizes the β-cell membrane by increasing KATP channel conductance. When ADP levels are reduced with glucose metabolism, PKA phosphorylates a subunit of the KATP channel leading to channel closure and depolarization (136). This extends to pharmaceutical activation of the GLP-1r in that GLP-1r agonists are weak insulin secretagogues at basal glucose levels. Further, the ability of GLP-1 to suppress feeding, an action dependent upon CNS receptors, is blunted in fasted conditions (159, 243) and dependent upon nutrient-dependent intracellular pathways (88) indicating that CNS GLP-1r signaling is also dependent upon nutrient availability.

Although pharmacological data make it very clear that GLP-1 regulates insulin secretion, genetic data suggest that the system is more complex than a simple endocrine model of insulin regulation. Genetic models demonstrate that although GLP-1 regulates insulin secretion through the β-cell GLP-1r (131), the necessity of these receptors depends on the route of delivery of nutrients. Mice with an inducible knockout of the β-cell GLP-1r have normal oral, but impaired IP glucose tolerance (214). This is interesting as even whole body GLP-1r KO mice have greater impairments in IP versus oral glucose tolerance. Importantly, these responses could also be explained by the redundancy of insulinotropic signals from the gut or nervous system during oral versus IP glucose loads, but in the end still demonstrate that β-cell GLP-1r, in and of themselves, are not necessary for oral glucose tolerance.

GLP-1r regulation of insulin secretion independent of the β-cell GLP-1r

If GLP-1 has a role for regulating insulin secretion independent of its β-cell receptor, what would the population of receptors be? Given the rapid postprandial increase in insulin, one possibility is the nervous system GLP-1r. Indeed, direct administration of GLP-1 into the 3rd cerebral ventricle (ICV) increases insulin secretion (122, 209); an effect that is maintained in mice fed a high-fat diet (17). In both mice and rats, administration of ICV exendin-4(939) (Ex9), a potent GLP-1r antagonist, during oral glucose impairs glucose tolerance and reduces insulin levels (104, 209, 229).

There are no detectable GLP-1r on the liver or on skeletal muscle and yet GLP-1 has repeatedly been shown to not just increase insulin secretion but also to improve insulin sensitivity. Despite the lack of hepatic GLP-1r expression, intravenous GLP-1 inhibits hepatic glucose production independent of islet hormones in humans (184). CNS GLP-1r activation may also explain this finding. When administered directly into the arcuate nucleus of rats, GLP-1 decreases hepatic glucose production under clamped conditions where glucose and insulin were held constant (209). The specific population of neurons responsible for this effect is not clear as deletion of GLP-1r within the hypothalamus or even more specifically on pro-opiomelanocortin neurons with the arcuate nucleus of the hypothalamus also do not impact normal glucose regulation (18). GLP-1 activates vagal afferent neuronal activity and administration of GLP-1r antagonists into the portal vein impairs glucose tolerance (234) suggesting that the peripheral nervous system is also important in mediating GLP-1 effects on glucose homeostasis. However, neither genetic deletion of CNS nor vagal neuronal GLP-1r is not necessary for normal glucose regulation (213), but CNS (213) and specifically glutamatergic excitatory (vs. GABAergic inhibitory) neurons (1) that express GLP-1r are necessary for the weight-reducing effects of liraglutide, a long-acting GLP-1 agonist. Lastly, in obese mice and in humans, administration of GLP-1 agonists reduces hepatic steatosis (42, 78, 176, 220). Whether these effects are also due to CNS activation is unclear but they do seem to be independent of the effect of chronic GLP-1 administration to reduce body weight. It remains to be seen whether the discrepancy between the genetic versus pharmacological manipulation of CNS GLP-1r signaling and the impact on glucose regulation is due to a species difference or a development compensation in the mice. The CNS distribution of the GLP-1r is dispersed, and different populations of receptors have sometimes very different functions (see Ref. 119 for review). As neuroscience technology becomes more sophisticated, the capability to tease this system apart becomes more promising.

GLP-1r Regulation of β-cell Mass

In addition to stimulating insulin secretion, GLP-1r activation benefits β-cell survival and importantly does so in the presence of multiple apoptotic conditions including hyperglycemia, hyperlipidemia, inflammatory cytokines, and oxidative stress (47). The exact signaling mechanisms that drive β-cell growth and differentiation are still being resolved. However, phosphatidylinositol 3-kinase (PI3K) rather than PKA activation seems to be the principle signaling mechanism by which the GLP-1r controls β-cell growth and apoptosis. GLP-1 also induces a rapid cAMP-dependent activation of extracellular signaling kinase, ERK1/2, and a delayed β-arrestin [an adaptor protein necessary for GLP-1r signaling (216)]-dependent increase of ERK1/2 signaling (186). Providing a direct link, β-arrestin has been found to be necessary for the antiapoptotic effects of GLP-1 (186) and GLP-1 administration to a β-cell line reduces H2O2-induced apoptosis through both cAMP and PI3K (but not ERK1/2) signaling with independent but additive effects (97). Liraglutide also protects against apoptosis via PI3K signaling and the consequent phosphorylation of AKT (114). Recent work has demonstrated that GLP-1-induced activation of PI3K is through activation of epidermal growth factor receptor 1 (EGFR), a tyrosine kinase receptor. EGFR has been found to be necessary for the ability of exendin-4 (Ex4), another long-acting GLP-1r agonist, to regulate β-cell mass and proliferation (68). Because EGFR directly activates PI3K, these data provide a link between GLP-1r signaling, PI3K, and β-cell proliferation. Downstream of AKT phosphorylation in the activation of β-cell proliferation is Wnt signaling, a pathway established in cancer biology to be critical for cell proliferation and survival. Activation AKT leads to accumulation of cytosolic β-catenin and subsequent translocation to the nucleus where it forms a complex with TCF7L2 (139), a transcription factor that activates expression of Wnt target genes (242). siRNA silencing of β-catenin and a dominant negative insertion of TCF7L2 in INS-1 cells (a β-cell line) blunted the ability of Ex4 to stimulate β-cell proliferation (139), indicating that Wnt signaling is necessary for GLP-1-induced β-cell proliferation.

These data illustrate the wide-ranging signaling pathways induced by GLP-1r activation to regulate β-cell mass and function. There is still much debate about the relevance of this impact of GLP-1 signaling in cell lines and in mice versus in humans. While it was found that short-term incretin therapies do not expand β-cell mass in young male mice (31), In a model that enables assessment of human β-cell replication in vivo, it was found that Ex-4 induced proliferation occurred only in juvenile, but not adult islets (36). This work provides an important advance in our understanding of the decline in β-cell proliferation that occurs with aging and indicates that even pharmacological GLP-1 signaling may not be critical in driving proliferation in humans.

Impact of GLP-1 on Glucagon Secretion

GLP-1-induced inhibition of glucagon secretion has been demonstrated in a variety of species including humans (175, 195). Activation of the GLP-1r also inhibits glucagon release from isolated islets or in perfused pancreas studies (53). While the data are clear that GLP-1 inhibits glucagon, the mechanisms are debated as some report low (148, 193), if any (176, 226), expression of the GLP-1r on α-cells. One possibility is that the impact of GLP-1 on glucagon release is indirect through the release of glucagon-regulating hormones from nearby β- and/or δ-cells (53, 77). While somatostatin secreted from δ-cells inhibited glucagon secretion, a somatostatin antagonist only partially blunted the GLP-1-induced decrease in glucagon (89) suggesting additional mechanisms at play.

GLP-1 also acts on β-cells to secrete insulin, which is known to suppress glucagon (233). However, co-secreted with insulin are amylin, zinc (Zn2+) and GABA; all of which have also been shown to individually suppress the release of glucagon. For example, GABA released from β-cells enhances glucose inhibition of glucagon secretion by acting via an Akt kinase-dependent pathway (246). Co-secreted with insulin in hyperglycemic conditions, Zn2+ has been found to have inhibitory action on glucagon release from α-cells (79, 147, 252) and α-TC6 cells (an α-cell line) (79). The potential role of Zn2+ has found increasing interest due to the fact that genome-wide association studies (GWAS) have revealed that rare variants of a Zn2+ transporter gene are associated with improved glucose homeostasis and protection from T2DM (65). To determine whether the impact of Zn2+ was independent of insulin, streptozotocin-treated (to kill β-cells) rats were studied during pancreatic perfusion studies (252). In these rats, disruption of the intrapancreatic infusion of insulin bound to Zn2+, but not of insulin unbound to Zn2+, accelerated glucagon secretion, indicating that Zn2+ but not insulin inhibits glucagon secretion. The thinking is that Zn2+ inhibits pyruvate-induced glucagon secretion via the opening of KATP channels and subsequent inhibition of α-cell electrical activity (100). It is important to note that contrasting data exist suggesting that Zn2+ does not regulate glucagon (188). However, given the connection to the GWAS data, at a minimum Zn2+ is important for glucose control and a logical link for that is through inhibiting the release of glucagon.

In addition to Zn2+, insulin is co-secreted with amylin, and amylin has also been found to dose-dependently suppress arginine-mediated glucagon secretion in rats (71) while pharmacological inhibition of amylin signaling enhances glucagon secretion (70). Pramlintide, an amylin receptor agonist, improves glycemic control in T2DM patients and at least part of that effect is via inhibition of postprandial glucagon secretion (64). A caveat to all of these studies demonstrating that β-cell products could play an indirect role in GLP-1-mediated regulation of glucagon is that GLP-1 maintains the ability to inhibit glucagon secretion in type 1 diabetic patients who have little to no endogenous insulin (34, 117) demonstrating that GLP-1 inhibition of glucagon secretion does not fully depend on β-cell products.

Besides the low expression levels of the GLP-1r on the α-cell, another caveat to the potential direct role of GLP-1 on glucagon regulation is that generally, GLP-1r activation generates cAMP and increases in cAMP are associated with increased, rather than decreased, glucagon release. Recently, an α-cell GLP-1r KO mouse was generated by crossing a loxP flanked humanized GLP-1r mouse with a Gcg-Cre mouse (251). Theoretically, this will eliminate the GLP-1r only from α-cells as neither L-cells nor Gcg-expressing neurons express the GLP-1r. In these mice, the glucagon response to increasing glucose loads was increased rather than decreased in the α-cell GLP-1r KO mice. While ad lib fed glucagon levels were higher in the α-cell GLP-1r KO mice, a curious finding was that these mice had impaired intraperitoneal IP glucose tolerance and increased glucagon response to an IP glucose load, a condition that does not stimulate gut-derived GLP-1 secretion. Interestingly, the α-cell GLP-1r KO mice also showed decreased glucagon levels during hypoglycemia but had significantly higher glucagon levels postprandially. These data suggest that GLP-1 has a bi-directional regulatory role in glucagon secretion that is dependent upon nutrient status. Regardless, a couple of studies have provided a basis for an evolving story on how GLP-1 might mechanistically inhibit glucagon levels. The idea is that there are low numbers of GLP-1r on α-cells but these receptors have enough capacity to generate proportionately small amounts of cAMP (148). This small amount of cAMP mediates suppressive effects glucagon secretion through discrete inhibition of high voltage N-type calcium channels in mice (148) and via P/Q-type voltage-gated calcium channels in humans (187). In their hands, GLP-1 retained this inhibitory effect with either insulin or somatostatin antagonists onboard (148, 187). However, it would be interesting to know if somatostatin and insulin signaling are synergistic in the paracrine effect; that is if both antagonists were given, would GLP-1 still inhibit glucagon release. Regardless, this model explains how low and high intracellular cAMP concentrations with the α-cell could have opposing actions on glucagon secretion. Thus, while there is much to be learned about the signaling that drives GLP-1-induced inhibition of glucagon secretion, there are multiple indirect and direct mechanisms at play. The inhibitor action of GLP-1 on glucagon levels is often over-looked in favor of its role as an insulin secretagogue, but it is clear that pharmacologically this is one mechanism by which GLP-1r agonists improve glycemia in T2DM patients (86).

Role of α-cell Produced Gcg in Insulin Secretion

α-Cell GLP-1 during metabolic stress

PC1/3, which processes GLP-1 (and GLP-2 and oxyntomodulin) from Gcg, is more predominantly expressed in the gut and CNS, but α-cell PC1/3 activity and/or expression is found in embryonic and neonatal mice, with pregnancy, and in models of prediabetes and diabetes (118, 172, 224, 245). Although previous work has demonstrated that 1% to 5% of preproglucagon is processed to GLP-1 in the islets (126, 156), α-cell GLP-1 clearly increases when the pancreas is under metabolic stress (27, 60, 227). Although the incretin model that intestinally secreted GLP-1 is the functional source of GLP-1, these data do suggest that the α-cell pool of GLP-1 also has a functional role in the pancreas.

Streptozotocin (STZ), a β-cell toxin, is used to model diabetes in animals. In rats administered STZ, there is an acute increase in islet Gcg and PC1/3 expression that leads to an increased processing of α-cell Gcg to GLP-1 (172). While the function of α-cell GLP-1 under metabolic stress conditions is unknown, glucagon receptor (GcgR) KO animals have a developmentally driven increase in pancreatic GLP-1 production and are also, interestingly, resistant to STZ-induced diabetes (30). Further, blockade of the GLP-1r in GcgR deficient mice prevented the improved glucose tolerance seen in the mice (174). Additionally, mice with a cre-inducible α-cell KO of PC1/3 (although the extent to which intestinal and CNS PC1/3 expression was intact is unknown) had reduced levels of GLP-1 in the islet and greater impairments of glucose and insulin in response to STZ (227). Altogether these data suggest that α-cell GLP-1 production provides a protective effect on β-cell function during times of stress. Further examples of this are that in cultured α-cell lines or isolated islets, high media glucose concentrations increase PC1/3 expression and cellular GLP-1 content (152, 240). α-Cell hyperplasia also occurs with high-fat diet and this precedes β-cell mass expansion (59), and in both human and mouse islets there is positive correlation between islet levels of GLP-1 and adiposity (138). Together these data suggest a role for α-cell GLP-1 production in the adaptation to metabolic disease. Whether this increase is as a protective factor that eventually fails or a part of the pathophysiology is unknown.

Although our focus here is on pancreatic GLP-1, GLP-1 in the circulation, presumably due to intestinally secreted GLP-1, also increases with inflammation and the mechanism by which this occurs has been linked to one particular cytokine, interleukin 6 (IL-6). IL-6 is increased in inflammatory conditions including exercise and obesity (59, 60). Under severe inflammatory conditions such as sepsis, or when induced by exogenous lipopolysaccharide (LPS) administration, there is a systemic increase in GLP-1 that is dependent on IL-6 (111, 181). In response to LPS, the increase in GLP-1 is dose dependent, and GLP-1 levels remain elevated for 8-h (111). Whereas in IL-6 knockout mice, there is no increase in GLP-1 after LPS administration (111). With 90 min of exercise in mice, there is an acute increase in IL-6 and GLP-1 and again this increase in GLP-1 was not seen in IL-6 knockout mice (60). To look at α-cell production specifically, IL-6 injections were given twice daily for over a week and the protein content of pancreatic GLP-1 and insulin were both increased (60). Despite the evidence showing that IL-6 increases GLP-1 secretion from the α-cell, the function, and whether it relates to glucose regulation or not, during this kind of inflammatory state is unknown. After several hours, LPS treatment causes elevated IL-6 levels and hypoglycemia to develop and Ex4 administration blunts this hypoglycemic effect in rats suggesting that the effect of GLP-1 is related to glucose control (247) although the direction goes opposite of what we normally think of as GLP-1-mediated glucose control. Another leading hypothesis is that IL-6 induced GLP-1 is a part of a negative-feedback loop to inhibit or restrain inflammatory responses. Rat islets treated with liraglutide showed both decreased pro-inflammatory cytokine levels (IL-6 and TNF-α) and the islets had improved function (133). Both the glucose and anti-inflammatory effect of GLP-1 point to α-cell GLP-1 acting locally rather than centrally. However, whether these pharmacological agonists have the same function as endogenously secreted GLP-1 from the α-cell remains an important unresolved question.

Thus, both metabolic (hyperglycemia, STZ-induced, diabetes) and physiological (exercise, inflammation) stress conditions influence IL-6 circulating levels which may be the factor that triggers GLP-1 secretion from the α-cell (Figure 3). However, the role of increased GLP-1 secreted from the α-cell under inflammatory conditions, how it impacts overall glucose homeostasis, and how this may be targeted pharmacologically is unknown.

Figure 3.

Figure 3

Factors that impact α-cell GLP-1 production. Metabolic stress, systemic inflammation, exercise, hyperglycemia, obesity, and diabetes stimulate α-cell GLP-1 production. IL-6 seems to be a primary factor that leads to this increase. The function of this increase is unknown but regulation of β-cell mass and function is a likely endpoint.

α-Cell GLP-1 in normal glucose regulation

The accepted dogma of GLP-1 secreted from the intestine and acting on the pancreas in an endocrine manner is difficult to reconcile given the observations that GLP-1 is rapidly degraded by dipeptidylpeptidase 4 (DPP4) and very little, in fact, only approximately 10% of intestinally secreted GLP-1 reaches the circulation (39, 82, 93). While the role of α-cell-secreted GLP-1 became established during states of metabolic stress, the question remains whether or not it has a role in normal glucose control. Although controversial, pancreatic GLP-1 has been found in normal islets and its expression increases with increasing glucose concentrations (152, 227, 240). In isolated human islets, the amount of GLP-1 was low under basal conditions and was only present in the cell lysates, not the culture medium in one study (240). However, others have found pancreatic GLP-1 to be higher in human versus mouse islets (227). In addition, PC1/3 activity can also be up-regulated by activating a bile acid receptor (TGR5) known to regulate GLP-1 secretion (145). These data suggest that the conditions by which α-cell GLP-1 is assessed may be important in the ability to detect GLP-1 levels.

Recently, the role of pancreatic Gcg, the gene that encodes GLP-1, was explored using a Cre lox-P mouse model that selectively reactivated the endogenous Gcg gene in the pancreas versus the intestine while the remaining tissues remained devoid of Gcg (27). To understand the role of GLP-1r activation specifically, glucose responses to Ex9, a GLP-1r antagonist, was examined. Ex9 had no impact on Gcg deficient animals indicating that Ex9 was a true GLP-1r antagonist, in vivo. This indicates that the presence of GLP-1 is necessary for the ability of Ex9 to impair glucose. Interestingly, animals that only expressed pancreatic, but not animals that expressed only intestinal Gcg had impaired glucose tolerance (whether oral or IP) in response to Ex9. Thus, the source of the GLP-1 ligand necessary for the ability of Ex9 to impair glucose tolerance was pancreatic and not intestinal GLP-1.

However, there is an important caveat to this work. It has been known for quite some time that glucagon increases insulin secretion (233) but whether this was physiological or pharmacological was debated. Further, whether this was through glucagon action on glucagon or GLP-1r was also studied. At the time studies had indicated that glucagon acted on the GLP-1r only at pharmacological concentrations (223) although other data suggested a more complex relationship and that glucagon could act on both glucagon and GLP-1r to regulate insulin secretion (155). Recently, three independent islet perfusion studies demonstrated that glucagon increases insulin not by acting on GcgRs but by acting on GLP-1r (22, 221, 253). At a first pass, these data suggest the possibility that it was pancreatic glucagon rather than pancreatic GLP-1 that was responsible for the ability of Ex9 to impair glucose tolerance in the previous study (27). However, the ability of glucagon to bind to the GLP-1r is extraordinarily less potent than GLP-1 (221). In addition, it would mean that the entirety of Ex9’s action is by impairing glucagon action on β-cell GLP-1r since Ex9 had no impact on glucose tolerance in animals that had fully restored intestinal Gcg expression and postprandial circulating GLP-1 levels (27). Lastly, the experimental conditions that lead to the increase in glucagon and glucagon action on the GLP-1r were specific to having both elevations in glucose and amino acids. The in vivo experiments described above (27) were only done with oral glucose.

Other mouse models have been derived in an attempt to separate the role of α-cell glucagon and GLP-1. One used a diphtheria toxin-inducible α-cell KO of Gcg and this mouse had a small impairment of age-induced IP glucose tolerance (227). Administration of DPP4 inhibitor, but not glucagon, restored glucose tolerance in these mice. The authors suggest this provides evidence that intestinally derived GLP-1 can compensate for the lack of α-cell GLP-1. However, DPP4 inhibitors increase bioactive GLP-1 AND GIP and previous work demonstrates that these drugs can fully improve glucose tolerance even if only one of the incretins have intact signaling (66). Isolated islets from another mouse model with α-cell KO of PC1/3 had reduced levels of GLP-1 in the islet and reduced glucose-stimulated insulin secretion (227). These mice also had impaired intraperitoneal, but not oral glucose tolerance (227). Similarly, β-cell GLP-1r KO mice have normal oral but not intraperitoneal, glucose tolerance (131, 209). Thus, a model where paracrine, rather than endocrine action of preproglucagon peptides in regulating insulin emerges. Because of the nature of preproglucagon processing, it will be difficult to distinguish between the impact of α-cell derived glucagon versus GLP-1 on local GLP-1r. However, this work clearly demonstrates that the conventionally accepted role of GLP-1 biology is inadequate. The combined impact factors driving an increase in α-cell GLP-1 and glucagon are summarized in Figure 4.

Figure 4.

Figure 4

Recent work highlights a more complexity to the role of Gcg-derived peptides in the incretin effect. While historical work suggests intestinal GLP-1 is important in regulating glucose homeostasis, there may be a role for α-cell derived GLP-1 as well. In addition, in response to amino acids, glucagon is secreted and acts on local GLP-1r to regulate insulin secretion.

If we ignore the intestinal versus pancreatic source of GLP-1 topic and just focus on the fact that GLP-1 regulates insulin secretion by acting directly on β-cell GLP-1rs and either directly or indirectly suppresses glucagon then under what circumstance is glucagon important for β-cell GLP-1r signaling? Of the components of a mixed meal (lipids, carbohydrates, and proteins), free fatty acids, if anything decreases glucagon levels in man (72), carbohydrates potently suppress glucagon, and proteins (amino acids) potently stimulate glucagon secretion (232). Interestingly, free fatty acids suppress the ability of arginine to stimulate glucagon secretion in man (72) suggesting that even in a mixed meal situation, increases in glucagon levels are restrained. In addition to GLP-1 suppressing glucagon, insulin and somatostatin, which also increase during a meal, also suppress glucagon levels. Many questions arise from these observations. Is the system set-up to suppress redundant signals? Is the increase in glucagon during a high protein meal necessary to increase insulin? Is GLP-1 versus glucagon necessary for different phases of insulin secretion? Are both GLP-1 and glucagon synergistic or additive in insulin control? All of these are possibilities. However, in animals devoid of both GLP-1 and glucagon, insulin response to an intravenous and oral glucose load appear to be normal suggesting that GLP-1 and glucagon, together, are not necessary for insulin secretion and/or that redundant in vivo mechanism are able to compensate (27). As has been suggested before, it could be that glucagon offers an additional redundant signal that allows for fine-tuning of glucose control in the face of metabolic stress whether it is exercise, hypoglycemia, or postprandial glucose control.

Targeting α-cell production of GLP-1, specifically, in T2DM therapeutics is an idea that is being explored. One study used adenovirus-mediated expression of PC1/3 in α-cells to increase islet production of GLP-1 and was able to improve glucose-stimulated insulin secretion in a mouse model of type 1 diabetes (241). In addition, pharmaceutical activation of GPR142, a GCPR that is expressed in pancreatic islets and that has previously been shown to enhance glucose-dependent insulin secretion (225, 239), also increases GLP-1 secretion from the α-cell (137). Moreover, using isolated mouse islets treated with Ex9, the researchers showed that insulin secretion induced by GPR142 activation is dependent on GLP-1 (137). Thus, regardless of our understanding of the physiology or pathophysiology of islet produced GLP-1, these data suggest that this pool of GLP-1 could be targeted to treat T2DM and avoid some of the CNS side-effects (i.e., nausea) associated with long-acting GLP-1 agonists.

Targeting GLP-1 in Pharmacology

GLP-1 agonists and DPP4 inhibitors

The development of GLP-1-based drugs has been one of the major advances in diabetes medicine in recent years. The currently approved pharmaceutical strategies targeted to the GLP-1 system are aimed at either increasing endogenous GLP-1 levels with inhibitors for the protease that inactivates GLP-1 or long-acting GLP-1r agonists resistant to DPP4 cleavage (2, 51). DPP4 inhibitors are effective at stimulating insulin and reducing glucagon actions; attributes that are credited to GLP-1r signaling (46). However, DPP4 acts on GIP as well as 40 additional substrates (160). GIP is the only additional substrate of note for glucose regulation and works in both humans (5, 167) and mice (66, 85) suggest that both GIP and GLP-1 signaling are targets for the improved glucose control with these drugs.

There are now multiple GLP-1r agonists currently available for the management T2DM (20, 48, 51). Various strategies are used to extend the half-lives of these agonists compared to native GLP-1 including using a synthetic analog of Ex4 (Byetta) and the addition of a fatty acid side chain to native GLP-1 to facilitate albumin binding (Liraglutide/Victoza). In an effort to improve convenience and compliance (149), modifications of these drugs are also being made to extend the half-life to allow for once-weekly injections (Bydureon and semaglutide/Ozembic). Besides being more convenient for the patient, there seem to be added benefits of creating a more stable pharmacodynamics profile (i.e., reducing the peaks and troughs of drug action) as these drugs induce less nausea, a common side-effect of rapid-acting compounds (19, 50, 98, 194). An added benefit of these drugs compared to DPP4 inhibitors is the added weight loss (236) and for some specific GLP-1r agonists (liraglutide and semaglutide) there is a reduction in cardiovascular events (168). Because of the impact of these drugs on weight loss, there are now multiple formulations approved to specifically treat obesity independent of T2DM. Interestingly, although T2DM patients do see improvements in body mass, there is a larger benefit for the obese nondiabetic patient for weight loss.

The neural pathways leading to the weight loss effects of these drugs are being actively pursued in preclinical work. Part of the reason for this effort is to determine whether the neural circuitry that drives the weight loss effect is distinct from the circuitry that drives the nausea effect of these drugs. In animal work, we know that some neuronal regions regulating the impact of GLP-1 on food intake are distinct from those regions that regulate nausea (121, 129). As discussed above, previous preclinical work in mice and rats established that the CNS (113, 213), but not the peripheral nervous system (213) is critical in mediating the impact of long-acting GLP-1r agonists on body mass. With newer advances in neuroscience techniques, we now know that glutamatergic rather than GABAergic neurons (1) are the specific type of neurons necessary for the ability of liraglutide to induce weight loss. However, given that neither hypothalamic (Nkx2.1 neurons), PVN (Sim1 neurons), nor POMC neurons were not necessary for the ability of long-acting agonists to reduced body mass (18), the hunt is still on for the specific population of neurons responsible for the pharmaceutical reduction in body mass. Better understanding of the neural mechanisms of these processes would benefit the therapeutic utility of these agents.

Poly-agonists

An exciting recent pharmaceutical strategy to the treatment of obesity and T2DM has been the development of hybrid peptides that activate more than one receptor to generate an effect (202). Given that obesity and T2DM are diseases with integrated pathology, a multifaceted approach is likely necessary for more effective treatment. These agents are touted as mimicking the broad range of peptide increases seen after bariatric surgery. Some of the first compounds developed using this strategy were glucagon/GLP-1 co-agonists, peptides engineered to activate the cognate receptors of both peptides in different relative potencies (37, 38). The rationale behind this line of drug development is that both glucagon and GLP-1 bind specific and distinct receptor populations in the brain to cause satiety (9, 103), and activating both receptors could lead to synergistic effects. Peptides with equal agonism for each of the target drugs (e.g., GLP-1/glucagon) seem to have the most therapeutic promise (37, 38). In the case of glucagon, greater glucagon potency would lead to greater energy expenditure and suppression of food intake, but there seems to be a threshold beyond which glucose control worsens despite weight loss. The results for combined agonism in mice and rats are promising with improved glucose tolerance but also greater reductions in body weight and fat with the dual agonists compared to GLP-1r agonism alone (38, 183). Although there may be subtleties in the formulation that lead to species differences, the results in humans have not been as exciting as in mice. Specifically, a recent phase 2a clinical trial found reductions in body weight and improvements in glucose control but the degree of the improvements seemed to be within the range of what is seen with long-acting GLP-1r agonists alone (3, 189). Interestingly, a GIP receptor/GLP-1r dual agonist in phase 2 trials caused greater improvements in both HbA1c% and weight loss compared to the GLP-1 agonist alone (67). Given that GIP is thought to be important for lipogenesis, the mechanism for this effect of the dual agonist is unclear. Regardless, this drug shows great promise in improving glucose control and weight loss in T2DM patients.

Bariatric Surgery and GLP-1

Why does GLP-1 increase with surgery?

Bariatric surgery is currently the most effective strategy at the treatment of obesity and its comorbidities. There are many types of bariatric surgeries. Roux-en-Y gastric bypass (RYGB; a small gastric pouch is formed and the jejunum is connected directly to the small pouch) used to be the most widely performed bariatric surgeries but its utilization has been reduced to about 20% of the procedures in the last couple of years (40). Currently, the most common surgery in the US is vertical sleeve gastrectomy (VSG; 80% of the stomach along the greater curvature is removed), which comprises about 60% of performed bariatric procedures. The switch is likely due to the fact that VSG is surgically more simplistic, leads to fewer long-term malabsorptive issues, and although dogma persists that it is less effective, randomized clinical trials demonstrate similar efficacy between VSG and RYGB (see Ref. 112 for meta-analysis).

Among the many similar physiological effects between these two surgeries is about a 10-fold increase in postprandial levels of GLP-1; something observed in both patients and rodent models of surgery (26, 105, 107, 231). A long-standing hypothesis for why GLP-1 (and other gut peptides for that matter) are increased after RYGB is that the shorter length of small bowel leads to more rapid nutrient delivery further down into the GI tract where the majority of L-cells are located (62). VSG also increases nutrient delivery to the distal gut thanks to a restricted stomach size that increases gastric pressure (26) and consequently gastric emptying rate (26, 154). Indeed, speed of nutrient delivery may be important after RYGB as the increase in nutrient-induced GLP-1 was eliminated if nutrients were delivered to the bypassed limb (169). However, in rats after VSG, glucose infused slowly and directly into the duodenum caused similar increases in GLP-1 as when the same glucose load was delivered orally (26). These data suggest that intestinal L-cells are either increased in number or in nutrient-sensitivity after VSG. While one study demonstrated that VSG in rats increased L-cell number (24) another did not (161). Differences in diet, as well as the control groups utilized (pair-fed vs. ad lib fed sham groups), could lead to differential structural and functional changes in the gut nutrient-sensing pathways (11). On the other hand, RYGB is more consistently associated with intestinal hypertrophy regardless of dietary exposure (24, 162). The intestine is considered a major site of glucose disposal after RYGB and this may provide energy for intestinal metabolic pathways to support tissue growth (203). In humans, this increase in glucose absorption after RYGB was associated with the exaggerated release of insulin and GLP-1 (43). Thus, the anatomical differences between the surgeries may lead to different adaptations in either the morphological or mechanical function of the GI tract and either of these adaptations can regulate prandial GLP-1 responses.

Another common physiological response to both RYGB and VSG is the significant increase in total and various sub-species of plasma bile acids (55, 124, 212). Bile acids have demonstrated effects on stimulating GLP-1 secretion from L-cells by acting through a specific G protein-coupled receptor (TGR5) versus their other common receptor a nuclear transcription factor, FXR (115). However, surgery-induced increases in bile acids have been demonstrated to be important for the increase in postprandial GLP-1 in one (41), but not another study (151). Further, these two studies had divergent results on the necessity of TGR5 for surgery-induced weight loss and improvements in glucose homeostasis (41, 151). Conversely, FXR seems to be necessary for the full effects of VSG, independent of GLP-1 (201). Thus, although this will require future validation, it seems that the surgery-induced increase in GLP-1 is due to intestinal responses to nutrient delivery. With RYGB, this is more acute, but with VSG, chronic adaptations are more critical.

GLP-1 as mechanism for the metabolic success of surgery

Although T2DM is thought to be chronic and progressive, bariatric surgery leads to large improvements in insulin secretion and sensitivity which results in a remission of T2DM for many patients. The consistency of the finding that GLP-1 increases with surgery in addition to this increase being associated with greater prandial insulin release (231) and greater weight loss (199) after surgery has led to the suggestion that GLP-1 is an integral mechanism for the success of surgery (Figure 5). While the postprandial GLP-1 response may be required for the insulin and glucose responses to a meal after bariatric surgery, whether GLP-1 is responsible for the resolution of T2DM is less clear. One study found that postprandial GLP-1 responses were a significant predictor of T2DM remission after RYGB (163), yet another found similar postprandial GLP-1 responses 2 years after VSG whether the patients had postoperative remission, relapse, or lack or remission of T2DM (107).

Figure 5.

Figure 5

Postprandial GLP-1 increases several-fold after bariatric surgery and has been implicated as a mechanism in both positive and negative impacts of bariatric surgery. On the positive side, GLP-1 has been implicated in increasing postprandial insulin levels to restrain post-prandial glucose homeostasis, improvements in insulin sensitivity lead to reductions in fasting insulin, improved hepatic insulin sensitivity, and overall improved β-cell function. However, on the negative side, the increase in postprandial insulin is thought to contribute to post-bariatric hypoglycemia which occurs in as much as 30% of surgery patients.

In support of a role for GLP-1, multiple studies have demonstrated that administration of the GLP-1r antagonist, Ex9, reduces the insulin response to a glucose load in both humans and rodents (25, 106, 110, 206). However, these data come with an interpretative problem (235). There is no dispute that GLP-1 regulates postprandial insulin. The same dose of Ex9 impairs glucose and reduces insulin in control subjects (107) and rats (25). The degree of this impairment is similar between surgery and control conditions. If GLP-1 was more important in glucose control after surgery, the degree of impairment should be greater. Thus, the question is whether what we are seeing after surgery is reflective of the normal response or is reflective of greater importance of GLP-1 during surgery.

The incretin effect is credited to both GLP-1 and GIP (166, 237) with each thought to contribute equally to insulin secretion in nonobese, non-T2DM subjects (166). Both T2DM and to a lesser extent, obesity, reduce (123, 165), while bariatric surgery enhances, the incretin effect (130). However, there is little agreement as to whether bariatric surgery leads to an increase in GIP suggesting that the extent to which GIP contributes to the enhanced incretin effect is debatable. In an effort to determine the importance of GIP after RYGB, RYGB patients were given a DPP4 inhibitor to increase the bioavailability of both GIP and GLP-1 and then combined this with Ex9 to block GLP-1r signaling; an experimental condition that would isolate the impact of GIP signaling on glucose tolerance (219). The DPP4 inhibitor failed to improve glucose tolerance or β-cell function while GLP-1r signaling was blocked in RYGB patients. In contrast, T2DM patients that had not undergone bariatric procedures fully responded to the DPP4 inhibitor with improved glucose tolerance and insulin secretion even when combined with Ex9 (167). Together these data suggest that RYGB shifts the balance of the incretin effect toward GLP-1 and away from GIP.

Qualitatively, rodents and humans respond similarly to bariatric surgery. Both have substantial weight loss, elevated gastric emptying rate, and increased postprandial insulin and GLP-1 levels. While human work is limited to acute pharmacological intervention, preclinical work offers the additional ability to genetically manipulate the GLP-1 system and test its role in the metabolic success of surgery. One would hope that this would lead to less interpretive issues. Whole-body GLP-1r KO mice have similar weight loss and improvements in glucose tolerance compared to littermate controls after both VSG (157, 244) and RYGB (248) suggesting a limited role of GLP-1r in surgical success. Central nervous system GLP-1r has been shown to be important for regulating body weight and glucose homeostasis in rodents (18, 122, 209) and may be a target population for the impact of surgically induced GLP-1 to act in regulating body mass and glucose. However, Ex9 infused directly into the CNS of rats during RYGB or sham surgeries (248) had no significant impact on the surgery-induced reductions in body mass. Thus far, the data would seem to be in agreement that GLP-1r signaling is not necessary for the metabolic success of surgery. However, in the last few years, conflicting reports have been published. To examine the specific role of β-cell GLP-1r, two slightly different versions of an inducible Cre-loxP strategy were used to knock out these receptors and VSG was performed. One study found that β-cell GLP-1r were necessary for surgery-induced improvements in glucose tolerance and glucose-stimulated insulin secretion, but not weight loss (69); while the other found not only that these receptors were not necessary for VSG-induced improvements in glucose tolerance but those glucose responses were essentially normalized to the WT levels (44). Differences in diet, mouse models, and/or some other factor may contribute either independently or in combination to the differences in these experimental findings. Regardless, we are still left with no solid conclusion as to whether GLP-1 is necessary for the success of surgery.

The increase in GLP-1 after surgery may also have a trophic effect on β-cell mass. GLP-1 increases β-cell mass in rodents and has also been suggested to increase β-cell function in humans following bariatric surgery (80). In isolated islets, VSG mice had changes in their genetic and functional signature favoring calcium signaling and insulin secretion (45). In a pooled group of VSG and RYGB patients, pancreatic fat deposition as assessed by PET imaging was found to be reduced alongside improvements in β-cell function (95). These data suggest the possibility that the impact of surgery on the pancreas could be due to the weight loss itself and is independent of GLP-1’s trophic effect.

With both human and rodent work, the clear finding is that the increase in postprandial GLP-1 drives acute glucose responses to a meal after bariatric surgery but whether or not they are required for long-term improvements in glucose control, T2DM remission, and/or for weight loss are debatable. However, this may be difficult to determine as the degree of β-cell destruction prior to surgery may be more critical in determining whether those β-cells can recover sufficiently to resolve T2DM (6).

GLP-1 in post-bariatric hypoglycemia

One increasingly recognized surgery complication is post-bariatric hypoglycemia (PBH) (207). This is reflected in a subset of bariatric patients and is associated with symptoms of postprandial “dumping syndrome” characterized not only by hypoglycemia, but also hyperinsulinemia, sweating, nausea or vomiting, and heart palpitations. Given that adrenergic and cholinergic symptoms in the postprandial state can be nonspecific, PBH has recently been redefined as the presence of neuroglycopenic symptoms (difficulty thinking, weakness, fatigue) with concomitant hypoglycemia (<54 mg/dL) (207) that is relieved within minutes of carbohydrate ingestion. Initial reports indicated a prevalence of less than 1% for hypoglycemia requiring hospitalization, but 10% for clinically recognized hypoglycemia (135, 150). However, the use of continuous glucose monitoring (CGM) has highlighted that hypoglycemia occurs much more frequently (closer to 30%) and is observed with similar frequency in both RYGB and VSG (23, 177, 230). This condition threatens the safety of affected patients as hypoglycemia impairs cognition and increases the risk for syncope, cardiac arrhythmias, seizures, coma, and even death.

Hypoglycemia is a complication for T1DM and T2DM, but for those patients, medications can be adjusted to minimize the occurrence. The mechanism for PBH is unknown and creates a difficult therapeutic challenge. The dominance of postprandial timing indicates that hypoglycemia is partly due to the exaggerated systemic appearance of ingested glucose secondary to altered anatomy and subsequent disproportionate insulin response to a meal. One hypothesis is that this phenomenon is caused by the exaggerated postprandial GLP-1 and consequently insulin levels. Postprandial glucose, GLP1, and insulin have been found to be even higher in patients susceptible to PBH (75). Multiple studies have now demonstrated that administration of Ex9 can lower postprandial insulin and prevent hypoglycemia in RYGB patients (32, 33, 204, 205). However, patients with PBH still have higher peak glucose levels after GLP-1r antagonist treatment compared to asymptomatic patients. In addition, the rapid time course of the postsurgical increase in postprandial GLP-1 and insulin secretion (days) does not mirror the delayed development of PBH (years). Importantly, although GLP-1 is likely not a mechanism for PBH, Ex9 therapies may still be a way to treat PBH.

In conclusion, GLP-1 increases with bariatric surgery are likely due to acute and/or chronic responses to rapid nutrient entry seen with RYGB and VSG, respectively. This increase in GLP-1 likely plays an important role in the acute glucose and insulin responses to a given meal. However, whether these increases are responsible for the overall improvements in glucose homeostasis, body mass, or in the onset of PBH is something that is still debated.

Conclusions

GLP-1 was suggested to be an incretin over 32 years ago. Indeed, GLP-1 actions in the islet are implicated in the success of surgery and have been exploited for effective glucose control in T2DM patients. However, the incretin model is much too simple for the complexity of the system. GLP-1 has a wide array of physiological effects that go beyond the β-cell. Further, GLP-1 and glucagon released from the α-cell may be important for β-cell proliferation and function suggesting that paracrine regulation of the β-cell needs to be incorporated into our thinking surrounding GLP-1 function. These interesting interactions and/or overlapping functions of GLP-1 and glucagon and GPCR signaling requires further exploration. What is true, is that GLP-1r agonists are safe and effective therapies for obesity and T2DM and will remain an active area of exploration.

Didactic Synopsis.

Major teaching points

  • Glucagon-like peptide-1 (GLP-1) is an important post-prandial stimulus of pancreatic insulin secretion and regulator of glucose homeostasis.

  • GLP-1 is coded by the preproglucagon gene which is expressed in the gut, brain, and α-cells of the pancreas.

  • Due to tissue-specific posttranslational processing, GLP-1 is predominantly made in the gut and brain but can also be made in the pancreatic α-cells in response to nutrients and under times of stress.

  • Recent work suggests that α-cell GLP-1 and glucagon, another preproglucagon-derived peptide, can stimulate insulin secretion through the GLP-1r.

  • GLP-1 has been implicated as a cause of the metabolic success of surgeries performed to correct obesity but research in genetic mouse models challenges this assumption.

  • GLP-1 has been targeted very successfully for the treatment of both type 2 diabetes and obesity.

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