Elsevier

Regulatory Peptides

Volume 117, Issue 2, 15 February 2004, Pages 77-88
Regulatory Peptides

Review
Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes

https://doi.org/10.1016/j.regpep.2003.10.028Get rights and content

Abstract

Exenatide (synthetic exendin-4), glucagon-like peptide-1 (GLP-1), and GLP-1 analogues have actions with the potential to significantly improve glycemic control in patients with diabetes. Evidence suggests that these agents use a combination of mechanisms which may include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, enhancement of β-cell mass, slowing of gastric emptying, inhibition of food intake, and modulation of glucose trafficking in peripheral tissues. The short in vivo half-life of GLP-1 has proven a significant barrier to continued clinical development, and the focus of current clinical studies has shifted to agents with longer and more potent in vivo activity. This review examines recent exendin-4 pharmacology in the context of several known mechanisms of action, and contrasts exendin-4 actions with those of GLP-1 and a GLP-1 analogue. One of the most provocative areas of recent research is the finding that exendin-4 enhances β-cell mass, thereby impeding or even reversing disease progression. Therefore, a major focus of this is article an examination of the data supporting the concept that exendin-4 and GLP-1 may increase β-cell mass via stimulation of β-cell neogenesis, stimulation of β-cell proliferation, and suppression of β-cell apoptosis.

Introduction

Exendin-4, the naturally occurring form of exenatide (synthetic exendin-4; AC2993), was originally isolated from the salivary secretions of the lizard Heloderma suspectum (Gila monster; Fig. 1) [1]. In the Gila monster, exendin-4 circulates after the lizard bites down on its prey (ingestion of a meal) and thus represents the first example of an endocrine hormone secreted from salivary glands. [2]. It is unknown whether exendin-4 has a role in fuel homeostasis in the Gila monster [2]. Exendin-4 has a 53% amino acid sequence overlap with mammalian glucagon-like peptide-1 (GLP-1). In mammals, GLP-1 is processed from the proglucagon gene in L-cells in the small intestine [3]. Exendin-4 is transcribed from a distinct gene, not the Gila monster homologue of the mammalian proglucagon gene from which GLP-1 is expressed [4]. In mammals, exendin-4 is resistant to degradation by dipeptidyl peptidase-IV (DPP-IV) and has a much longer plasma half-life than GLP-1, which is degraded by DPP-IV with a half-life of less than 2 min [5], [6].

Exendin-4 is not an analogue of GLP-1. In other words, the structure of the synthetic exendin-4 peptide (exenatide) was not created by sequential modification of the structure of GLP-1. However, exendin-4 and GLP-1 do share many glucoregulatory actions which may be mediated by the known pancreatic GLP-1 receptor [7]. Glucoregulatory actions of exendin-4 include glucose-dependent enhancement of insulin secretion [8], [9], [10], [11], glucose-dependent suppression of inappropriately high glucagon secretion [10], [12], slowing of gastric emptying [10], [13] which may be paradoxically accelerated in people with diabetes [14], and reduction of food intake ([15], [16]; Fig. 2). In addition, exendin-4 has been shown to promote β-cell proliferation and islet neogenesis from precursor cells in both in vitro and in vivo models [17], [18], [19]. These glucoregulatory actions of exendin-4, combined with enhanced pharmacokinetics, result in very high in vivo potency relative to native GLP-1 [11], [20], [21]. The putative mechanisms of action of exendin-4 are compared and contrasted with the actions of GLP-1 and a long-acting GLP-1 analogue in the following sections. One of the most provocative areas of recent research is based on observations that exendin-4 may improve β-cell mass, thereby impeding or even reversing disease progression. Therefore, a major focus of this article will be to examine in detail the published reports supporting the concept that exendin-4 and GLP-1 may increase β-cell mass via stimulation of β-cell neogenesis, stimulation of β-cell proliferation, and suppression of β-cell apoptosis.

The onset of type 2 diabetes is characterized by the emergence of postprandial (post-meal) hyperglycemia and subsequently, fasting hyperglycemia [22]. In most individuals, hyperglycemia results from a failure of pancreatic β-cells to secrete adequate insulin to compensate for insulin-resistance in peripheral tissues [23], [24]. The fraction of glycosylated hemoglobin (A1C) in circulating red blood cells provides an accurate indicator of average glucose concentrations in the blood for the previous 3 months. A1C levels in healthy humans typically comprises 5–6% of total hemoglobin, while A1C values in people with poorly controlled diabetes generally exceed 9% [25]. Results from the United Kingdom Prospective Diabetes Study (UKPDS) showed that a reduction in A1C was associated with a reduced risk of vascular complications, and also reaffirmed that type 2 diabetes is a progressive disease characterized by a continuous loss of β-cell function that current therapies cannot rectify. [26], [27]. Exenatide is the USAN generic drug name for synthetic exendin-4, an investigational therapeutic being studied by Amylin Pharmaceuticals in partnership with Eli Lilly and Company, that may have a beneficial impact on the course of this disease.

Section snippets

GLP-1 receptor

The GLP-1 receptor (GLP-1R) is a seven-transmembrane domain, G-protein coupled receptor, initially described as the exendin receptor [28], [29], [30]. Distribution of the mammalian GLP-1R includes pancreatic periductal- and β-cells, kidney, heart, stomach, and brain [31]. The pancreatic GLP-1 receptor binds exendin-4 and GLP-1 with equal affinity in in vitro assays, and both peptides stimulate the receptor equipotently as demonstrated by the production of cyclic adenosine monophosphate (cAMP)

Glycemic control

Exendin-4, GLP-1, and GLP-1 analogues such as NN2211 have demonstrated abilities to control fasting and postprandial glucose excursions. The effects of GLP-1 on glycemic control in nonhuman models of diabetes have been reviewed elsewhere [44] and will not be extensively covered here, except for comparisons with exendin-4.

Exendin-4 had potent activity in reducing plasma glucose when administered as a single intraperitoneal dose of 0.001 to 10 μg to hyperglycemic db/db mice, a model of type 2

Insulin secretion

Glucose-dependent insulinotropism refers to the ability of agents such as exendin-4 and GLP-1 to stimulate insulin secretion during euglycemia or hyperglycemia, but not during hypoglycemia [2]. Glucose-dependent insulinotropism has also been defined as the amplification of β-cell insulin secretion when circulating glucose concentrations are above, but not below, the normal range [8], [9]. In animal models of diabetes, a predominant acute action of exendin-4 is glucose-dependent insulinotropism,

Glucagon secretion

Circulating glucagon was reduced after exenatide treatment in both the fasting and postprandial states in humans with type 2 diabetes [10]. The observation under fasting conditions supports the hypothesis that suppression of glucagon secretion is not merely a consequence of the slowing of nutrient presentation to the small intestine (gastric emptying). Given the well-documented elevations in fasting and postprandial glucagon levels in patients with type 2 diabetes [55] and the known activity of

Enhanced β-cell mass

One of the most provocative areas of recent research is based on observations that exendin-4 may improve β-cell health, thereby impeding or even reversing disease progression. A number of published reports support the concept that exendin-4 and GLP-1 increase β-cell mass via stimulation of β-cell neogenesis, stimulation of β-cell proliferation, and suppression of β-cell apoptosis (Table 1).

The development of the endocrine pancreas is under multifactorial control, and many of the key proteins or

Gastric emptying

The importance of GLP-1 on gastric emptying and postprandial plasma glucose control was recognized when Dupre et al. [68] described the postprandial benefits of GLP-1 in insulin-deficient patients. The importance of gastric emptying on glycemic excursions has also been affirmed in insulin-replete subjects, and some authors propose that the gastric emptying effect predominates in post-prandial glucose control (reviewed in [2], [69]). Delivery of nutrients from the stomach to the small intestine

Nutrient intake and body weight

Exendin-4 treatment has been associated with reduced food intake and weight loss in experiments in diabetic fatty Zucker (ZDF) rats. Young et al. [11] reported that administration of exendin-4 twice daily (0.1, 1, 10, or 100 μg) for 6 weeks resulted in a dose-dependent reduction in food intake ranging from 13% to 30%, with an exendin-4 ED50 value of 0.14 μg. The corresponding change in body weight exhibited an ED50 value of 0.42 μg exendin-4, with a maximum loss of 27 g (5.6% decrease) at the

Insulin sensitivity

The effects of exendin-4, GLP-1, and GLP-1 analogues on insulin-sensitivity in peripheral tissues are currently under active investigation. However, published reports on the effects of GLP-1 on insulin sensitivity have been inconsistent until recently, perhaps due to the route of GLP-1 administration in these studies (peripheral or central vein) and the confounding effects of GLP-1 on insulin secretion. Based on evidence that GLP-1 may act within the hepatoportal region to regulate glucose

Summary

In conclusion, exenatide (synthetic exendin-4), GLP-1, and GLP-1 analogues have actions that significantly improve glycemic control in animal models of type 2 diabetes. Evidence suggests that these agents achieve improvements in glycemia through a combination of mechanisms which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, enhancement of pancreatic islet health, slowing of gastric emptying, reduction of food intake, and modulation of

Acknowledgments

Thanks to Drs. Thomas Bicsak for the insightful comments on manuscript drafts and Sunil Bhavsar for the graphics assistance.

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