Glucagon-Like Peptide 1 Secretion by the L-Cell the View from Within Gareth E

Glucagon-Like Peptide 1 Secretion by the L-Cell The View From Within Gareth E. Lim1 and Patricia L. Brubaker1,2 Glucagon-like peptide 1 (GLP-1) is a gut-derived peptide GLP-1 receptor antagonists as well as GLP-1 receptor null secreted from intestinal L-cells after a meal. GLP-1 has mice have demonstrated that GLP-1 makes an essential numerous physiological actions, including potentiation of contribution to the “incretin” effect after a meal (3,4). glucose-stimulated insulin secretion, enhancement of However, GLP-1 secretion is reduced in patients with type ␤-cell growth and survival, and inhibition of glucagon 2 diabetes (5–7), and this may contribute in part to the release, gastric emptying, and food intake. These antidia- reduced incretin effect and the hyperglycemia that is betic effects of GLP-1 have led to intense interest in the use observed in these individuals (8). Thus, interest has now of this peptide for the treatment of patients with type 2 focused on the factors that regulate the release of this diabetes. Oral nutrients such as glucose and fat are potent physiological regulators of GLP-1 secretion, but non-nutri- peptide after nutrient ingestion. Many different GLP-1 ent stimulators of GLP-1 release have also been identified, secretagogues have been described in the literature over including the neuromodulators acetylcholine and gastrin- the past few decades, including nutrients, neurotransmit- releasing peptide. Peripheral hormones that participate in ters, neuropeptides, and peripheral hormones (rev. in energy homeostasis, such as leptin, have also been impli- 9,10). However, the specific receptors, ion channels, and cated in the regulation of GLP-1 release. Recent studies intracellular signaling proteins expressed by the GLP-1– have begun to elucidate the intracellular signaling path- producing intestinal L-cell have only recently begun to be ways that mediate the effects of GLP-1 secretagogues on characterized. The purpose of this review is to integrate the intestinal L-cell. The purpose of this review is to the literature regarding the signal transduction pathways summarize the known signaling mechanisms of GLP-1 secretagogues based on the available literature. A better used by the major GLP-1 secretagogues. An improved understanding of the pathways underlying GLP-1 secretion understanding of the mechanisms regulating GLP-1 secre- may lead to novel approaches by which the levels of this tion may lead to novel approaches to enhance GLP-1 levels important insulinotropic hormone can be enhanced in pa- in vivo, thereby providing an alternative approach to the tients with type 2 diabetes. Diabetes 55 (Suppl. 2):S70–S77, use of this peptide in the treatment of patients with type 2 2006 diabetes. SYNTHESIS AND DEGRADATION OF GLP-1 Although the proglucagon gene is expressed in enteroen- lucagon-like peptide 1 (GLP-1) is an intestinal docrine L-cells and pancreatic ␣-cells (11), GLP-1 is hormone that exerts profound effects in the synthesized by posttranslational processing of proglu- regulation of glycemia, stimulating glucose-de- cagon only in the intestine. The L-cells are predomi- pendent insulin secretion, proinsulin gene ex- G ␤ nantly located in the ileum and colon and have been pression, and -cell proliferative and anti-apoptotic identified as open-type epithelial cells that are in direct pathways, as well as inhibiting glucagon release, gastric contact with nutrients in the intestinal lumen (12). emptying, and food intake (1). The demonstrated success Furthermore, L-cells are located in close proximity to of GLP-1 to lower glycemia has led to approval of the both neurons and the microvasculature of the intestine GLP-1 receptor agonist exendin-4 (Byetta) for the treat- (13,14), which allows the L-cell to be affected by both ment of patients with type 2 diabetes (2). Studies using neural and hormonal signals. In fetal rat intestinal L-cell cultures and immortalized murine L-cells, proglucagon From the 1Department of Physiology, University of Toronto, Toronto, Ontario, gene expression is enhanced by activation of the protein Canada; and the 2Department of Medicine, University of Toronto, Toronto, kinase A (PKA) pathway (15,16). Although originally Ontario, Canada. thought to be mediated through CREB binding to the Address correspondence and reprint requests to Dr. P.L. Brubaker, Room 3366, Medical Sciences Building, University of Toronto, 1 King’s College cAMP response element in the proglucagon gene, recent Circle, Toronto, ON M5S 1A8 Canada. E-mail: [email protected]. studies have demonstrated that cAMP-dependent pro- Received for publication 23 March 2006 and accepted in revised form 2 May glucagon gene expression in the L-cell occurs via ␤-cate- 2006. P.L.B. has received honoraria from and is a consultant for Amgen. nin–mediated activation of the bipartite transcription This article is based on a presentation at a symposium. The symposium and factor, TCF4 (17). Interestingly, a very recent report has the publication of this article were made possible by an unrestricted educa- linked variants of TCF4 to the risk for development of tional grant from Servier. GABA, ␥-aminobutyric acid; GIP, glucose-dependent insulinotropic peptide; type 2 diabetes (18), implicating GLP-1 in the etiology of GLP-1, glucagon-like peptide 1; GRP, gastrin-releasing peptide; KATP channel, this disease. ATP-sensitive Kϩ channel; MAPK, mitogen-activated protein kinase; MUFA, Tissue-specific expression of prohormone convertase monounsaturated fatty acid; PKA, protein kinase A; PKC, protein kinase C; isoforms directs the synthesis of specific proglucagon- STAT, signal transducer and activator of transcription. DOI: 10.2337/db06-S020 derived peptides in the L-cell and ␣-cell (Fig. 1). Hence, © 2006 by the American Diabetes Association. cleavage of proglucagon by prohormone convertase 1/3, The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance which is expressed in the L-cell, liberates GLP-1 and with 18 U.S.C. Section 1734 solely to indicate this fact. GLP-2, as well as the glucagon-containing peptides, glicen- S70 DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006 G.E. LIM AND P.L. BRUBAKER FIG. 1. Tissue-specific posttranslational processing of proglucagon liberates different proglucagon-derived peptides. Prohormone convertase 2 in the ␣-cell releases glicentin-related pancreatic peptide (GRPP), glucagon, intervening peptide-1 (IP1), and the major proglu- FIG. 2. Regulation of GLP-1 secretion by ingested nutrients. After a cagon fragment. In the L-cell, cleavage of proglucagon by prohormone meal, nutrients in the duodenum activate a proximal-distal neuroen- convertase 1/3 yields glicentin, oxyntomodulin, GLP-1, IP2, and GLP-2. docrine loop, which stimulates GLP-1 secretion from L-cells in the ileum and colon. In rodents, GIP, released from K-cells, activates vagal afferents, which subsequently causes GLP-1 secretion through vagal tin and oxyntomodulin (19,20). In contrast, ␣-cell expres- efferents and enteric neurons that release acetylcholine (Ach) and sion of prohormone convertase 2 leads to synthesis of GRP. Movement of nutrients toward more distal sections of the intestine leads to the direct interaction of nutrients with L-cells, which glucagon, glicentin-related pancreatic peptide, and the also stimulates GLP-1 secretion. major proglucagon fragment, which contains within its sequence both GLP-1 and GLP-2. Early studies on L-cell secretagogues used antibodies that targeted a mid-se- in GLP-1 secretion must be mediated indirectly, through a quence epitope of glucagon, resulting in detection of neuro/endocrine pathway, rather than through direct in- glicentin/oxyntomodulin (i.e., enteroglucagon or gut glu- teractions of the luminal contents with L-cells (27). Al- cagon-like immunoreactivity) as well as of glucagon. Be- though a very recent study has detected GLP-1– cause these peptides, as well as GLP-2, are synthesized immunoreactive cells in the duodenum of humans (30), and secreted from the L-cell in a 1:1 stoichiometric ratio this remains controversial. Therefore, to elucidate the with GLP-1 (21,22), such studies therefore indirectly also mechanism(s) underlying proximal nutrient-stimulated examined GLP-1 synthesis and secretion. Hence, the re- GLP-1 secretion, we developed a rodent model of GLP-1 sults of studies using antisera against any of the intestinal secretion in which nutrient flow to the distal intestine was proglucagon-derived peptides are discussed in this review prevented, thereby excluding the possibility of direct synonymously. Finally, bioactive GLP-1 exists in two equi- 7-36NH2 7-37 interactions of the luminal nutrients with the L-cell (Fig. potent forms, GLP-1 and GLP-1 , in the circula- 2). In this model, placement of glucose or fat into the tion, of which the former is predominant (23). Secreted duodenum induced an immediate and prolonged stimula- GLP-1 is rapidly degraded by the ubiquitous enzyme tion of the L-cell that was comparable in magnitude to dipeptidyl peptidase IV (24), resulting in an extremely increments in proglucagon-derived peptides observed short half-life for GLP-1 of ϳ2 min (23). when nutrients were placed directly into the ileum (27). Furthermore, when nutrients were placed in the duode- SYSTEMIC REGULATION OF GLP-1 SECRETION num of the rat, a prompt rise in glucose-dependent insuli- Nutrient ingestion is the primary physiological stimulus to notropic peptide (GIP) levels was also observed, and the L-cell and results in a biphasic pattern of GLP-1 infusion of GIP or treatment of primary rat L-cells in secretion. An initial rapid rise in circulating GLP-1 levels culture with GIP also stimulated proglucagon-derived pep- occurs 15–30 min after a meal, followed by a second minor tide secretion (22,27,31), thus implicating GIP in the peak at 90–120 min (25).

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