Elsevier

Cellular Signalling

Volume 22, Issue 1, January 2010, Pages 1-8
Cellular Signalling

Review
New insights into the role of cAMP in the production and function of the incretin hormone glucagon-like peptide-1 (GLP-1)

https://doi.org/10.1016/j.cellsig.2009.09.032Get rights and content

Abstract

The proglucagon gene (gcg) encodes both glucagon and glucagon-like pepetide-1 (GLP-1), produced in pancreatic α cells and intestinal endocrine L cells, respectively. The incretin hormone GLP-1 stimulates insulin secretion and pro-insulin gene transcription. GLP-1 also enhances pancreatic β-cell proliferation, inhibits cell apoptosis, and has been utilized in the trans-differentiation of insulin producing cells. A long-term effective GLP-1 receptor agonist, Byetta, has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders. The expression of gcg and the production of GLP-1 can be activated by the elevation of the second messenger cyclic AMP (cAMP). Recent studies suggest that in addition to protein kinase A (PKA), exchange protein activated by cAMP (Epac), another effector of cAMP, and the crosstalk between PKA and the Wnt signaling pathway, are involved in cAMP-stimulated gcg transcription and GLP-1 production as well. Finally, functions of GLP-1 in pancreatic β cells are also mediated by PKA, Epac, as well as the effector of the Wnt signaling pathway. Together, these novel findings bring us a new insight into the role of cAMP in the production and function of the incretin hormone GLP-1.

Introduction

Many peptide and other hormones participated in maintaining blood glucose homeostasis in response to physiological, pathological, and environmental changes. Among them, insulin and two other peptide hormones, glucagon and glucagon-like peptide-1 (GLP-1), are fundamentally impotent. Both glucagon and GLP-1 are encoded by the proglucagon gene (gcg), produced in pancreatic islet α cells and intestinal endocrine L cells, respectively [1], [2]. Glucagon and GLP-1 exert their functions mainly via interacting with their receptors, which belong to the glucagon/VIP seven-transmembrane G-protein coupled receptor (GPCR) super-family. Therefore the second messenger cyclic AMP (cAMP) is among the effectors of gcg encoded peptide hormones. The elevation of cAMP was also shown to play important roles in the activation of gcg transcription and the production of its encoded peptide hormones. The effectors of cAMP signaling, including PKA and Epac, are important in regulating the secretion of GLP-1 as well.

GLP-1 is an important incretin hormone. It stimulates insulin secretion from pancreatic β cells after eating, even before blood glucose levels become elevated. GLP-1R agonist Exenatide (Exendin-4, commercially known as Byetta) has been developed as a drug for treating type II diabetes mellitus (T2D), and potentially, other metabolic disorders. To further explore mechanisms underlying the production and function of GLP-1 may lead to the recognition of novel therapeutic targets for the treatment and the prevention of T2D and its related complications. In this review, we have summarized the current knowledge of the role of cAMP signaling in both the production of GLP-1 in gut endocrine L cells and the function of GLP-1 in pancreatic β cells, focusing on the involvement of Epac and the crosstalk between Wnt and cAMP signaling pathways.

Section snippets

Gcg encodes the incretin hormone GLP-1

In mammals, the expression of gcg is driven by the same gcg promoter in pancreatic islet α cells, gut intestinal endocrine L cells, and certain neuronal cells in the brain [3], [4], [5]. These three types of cells express the identical gcg mRNA, which is translated into the same pro-hormone, pre-proglucagon. Several studies have identified a number of cis-elements within the first 300 bp rat gcg promoter region, including a typical cAMP response element (CRE) and two CRE-like elements [3]. This

Epac as another major effector of cAMP

Studies by Earl Sutherland and colleagues in 1960s on the function of the epinephrine have led to a great discovery that cAMP exerts an intermediary role in many hormonal functions. This was followed by the studies of Edwin Krebs and Edmond Fisher that epinephrine and cAMP stimulate glycogen breakdown by activating glycogen phosphorylase via a protein kinase, namely cAMP-dependent protein kinase (PKA). The PKA holoenzyme consists of two regulatory subunits and two catalytic subunits. When cAMP

The role of PKA

Shortly after the isolation of gcg cDNAs from rodents and humans in 1980s, studies with the methods of DNase I foot-printing, electrophoretic mobility shift assay, as well as chloramphenicol acetyltransferase (CAT) and luciferase (LUC) reporter gene analyses, have revealed the presence of pancreatic cell specific minimum promoter region and three enhancer elements within the first 300 bp rat gcg gene promoter, namely G1, G2 and G3 [37], [38], [39]. Two additional enhancer elements, namely G4 and

Both cAMP-PKA and cAMP-Epac are effectors of GLP-1 in stimulating insulin secretion

Endocrinologists have learned for many years that glucose administration via the gastrointestinal tract provokes a much greater stimulation on insulin secretion than a comparable intravenously glucose administration [67]. This incretin effect is due to the presence of two gastrointestinal hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) [18], [68], [69], [70]. GLP-1 exerts its function via binding to its receptor GLP-1R, a GPCR, and thereby increasing cAMP production via

Function of GLP-1 in maintaining β cell mass, the involvement of the cAMP signaling

GLP-1 is able to enhance β cell proliferation and hence β cell mass. This has been attributed, at least partially, to the activation of epidermal growth factor (EGF) signaling [87]. Pancreatic β cells are very sensitive to both ER stress and oxidative stress, while GLP-1 exerts a protective role against these stresses [88]. Recent studies have revealed two novel mechanisms underlying this protection, both of them involving the cAMP signaling.

Summary and perspective

The fundamental incretin effect of GLP-1 was recognized more than 20 years ago, and this discovery has led to the development of a novel therapeutic drug for T2D treatment. During the past two decades, extensive investigations have shown that both the production of GLP-1 and its stimulation on insulin secretion could be activated by cAMP, involving both PKA and Epac. As summarized in Fig. 4, in the gut endocrine L cells, cAMP elevation may occur in response to the stimulation of a hormone or

Acknowledgements

Tianru Jin would like to thank the Canadian Institutes of Health Research (CIHR, MOP-89987) and Canadian Diabetes Association (CDA, 2341) for providing funding support in conducting his current research on this topic. We regret that due to space limitation, many excellent studies cannot be cited and discussed.

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