Exendin-4, previously known as the investigational agent AC2993, or currently as exenatide, (Byetta) was assessed as a treatment for Type 2 diabetes in multiple clinical trials (originally in the AMIGO studies). For more clinical information, see Exendin-4: Human data and GLP-1 analogues and human diabetes. To review safety issues surrounding use of GLP-1R agonists, including Exenatide to treat diabetes, see GLP-1: Adverse Events
The lizard Heloderma species, including H. horridum and H. suspectum are native to several American states and are poisonous. Lizard venom contains a number of highly bioactive peptides including the peptides exendin-3 and exendin-4. These peptides were named exendins by Eng and Raufman in that they were isolated from an exocrine gland and were subsequently shown to have endocrine actions as described in Purification and structure of exendin-3, a new pancreatic secretagogue isolated from Heloderma horridum venom. J Biol Chem. 1990 Nov 25;265(33):20259-62 and Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992 Apr 15; 267 (11) :7402-5
Although exendin-4 was originally found to stimulate amylase secretion from pancreatic acinar cells, subsequent experiments demonstrated that exendin-4 was a potent agonist for the mammalian GLP-1 receptor, consistent with the ~53% amino acid identity that exendin-4 shares with GLP-1.
Exendin-4 displays similar functional properties to native GLP-1, and regulates gastric emptying, insulin secretion, food intake, and glucagon secretion. Exendin-4 lowers blood glucose in normal rodents and in both mice and rats with experimental diabetes, as reviewed in Bioactive peptides from lizard venoms. Regul Pept. 1996 Jan 16; 61 (1):1-18.
Although the lizard exendin gene is distinct from the lizard proglucagon gene Tissue-specific expression of mRNAs with different open reading frames that encode proglucagon -derived peptides and exendin 4 in the lizard J. Biol. Chem. 1997 272:4108-4115), a separate mammalian exendin gene has not been identified.
The available evidence suggests that exendin-4 exerts the majority of its glucose-lowering effects through the GLP-1 receptor. No convincing evidence to date supports the existence of a separate functional exendin receptor coupled to glucose homeostasis, although non-classical effects of GLP-1 and exendin have been observed in experimental systems that lack the known GLP-1 receptor as discussed in GLP-1 actions and a second GLP-1 receptor
Exendin-4 is much more potent than native GLP-1, largely due to its improved PK profile as a result of resistance to DPP-4-mediated inactivation. In contrast to GLP-1 which contains an alanine at position 2, exendin-4 has a glycine at position 2, hence it is not a substrate for DPP- 4 and has a much longer t1/2 in vivo. The potent glucose-lowering properties of exendin-4, taken together with its comparatively prolonged duration of action, prompted studies employing exendin-4 for the treatment of patients with Type 2 diabetes.
A truncated version of exendin-4, exendin (9-39) binds to but does not activate the GLP-1 receptor, and functions as a GLP-1 receptor antagonist Exendin-3, a novel peptide from Heloderma horridum venom, interacts with vasoactive intestinal peptide receptors and a newly described receptor on dispersed acini from guinea pig pancreas. Description of exendin-3(9-39) amide, a specific exendin receptor antagonist. J Biol Chem. 1991 Feb 15;266(5):2897-902. Exendin (9-39) has been employed as a GLP-1R antagonists in multiple preclinical studies and in human experiments to probe the consequences of disrupting GLP-1R activation.
A long-acting form of exendin-4, designated Exenatide-LAR has been studied in 9 week old ZDF rats. In the absence of Exenatide, HbA1c increased rapidly over the 28 day study period. In contrast, a single injection of Exenatide LAR (a poly-lactide-glycolide microsphere suspension (3% peptide) containing 0, 1, 10, 100, 1,000, 3,000 or 9,000 ug Exenatide ) significantly reduced the rate of deterioration in glycemic control, together with an increased β cell responsivity to glucose, and an increase in insulin sensitivity, as described in Dose-response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats. Diabetologia. 2005 May 25; Review the preliminary human data from the Phase 2 trial of Exenatide LAR described in the August 22 2005 Press Release
Exendin-4 has been administered acutely or for several weeks to mice and rats with experimental diabetes, producing improved glucose control, reduced hemoglobin A1C, increased insulin, weight loss, decreased adiposity, reduced food intake, and stimulation of islet neogenesis and islet proliferation. To review some of the original data, see:
Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).Diabetes. 1999 May;48(5):1026-34.
Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes. 2001 Jul;50(7):1562-70
Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes. 2002 May;51(5):1443-52.
Can GLP-1R agonists like exendin-4 prevent the development of diabetes? Stoffers and colleagues addressed this question using a rat model of intrauterine growth retardation. Uterine artery ligation was performed at gestational day 19, and following birth, Ex-4, 1 nmol/kg, was administered once daily for 6 days. Body weight was significantly reduced in both control and IUGR rat pups treated with Ex-4, even at 3 months of age. Ex-4 treated rats exhibited markedly reduced levels of fasting glucose and improved glucose tolerance even at 3 months of age, in association with highly significant increases in beta-cell mass in 3 month old Ex-4-treated animals. These intriguing findings suggest that activation of GLP-1R signal transduction pathways in the critical neonatal period is sufficient for sustained improvement in β cell mass and function in adult animals. The mechanisms responsible for the effects on weight loss and glucoregulation are not completely clear, but worthy of further study. See Neonatal Exendin-4 Prevents the Development of Diabetes in the Intrauterine Growth Retarded Rat. Diabetes. 2003 Mar;52(3):734-740. The data in this study are consistent with previous reports that 6 days of GLP-1 or Ex-4 administration in the neonatal period in GK rats also led to improved beta cell mass and glucose homeostasis in older animals. See Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes. 2002 May;51 (5):1443-52.
MT-exendin-4 transgenic mice
To assess the consequences of prolonged ongoing continuous exposure to exendin-4, Laurie Baggio and colleagues generated a MT-preproexendin transgene. Correct processing of the transgene to bioactive exendin-4 was observed in transfected cells using a combination of specific antisera and HPLC. Furthermore, transgenic mice expressing the MT-exendin-4 transgene exhibited detectable levels of circulating correctly processed bioactive exendin-4 that are further increased following transgene induction with heavy metals. The transgene was widely expressed in peripheral tissues and brain, with bioactive exendin-4 immunoreactivity detected in both endocrine and non-endocrine tissues. To review the consequences of prolonged exposure to exendin-4 on glucose homeostasis, body weight and islet growth, see Sustained expression of exendin-4 does not perturb glucose homeostasis, b-cell mass or food intake in metallothionein-preproexendin transgenic mice J. Biol. Chem. 2000 275: 34471-34477. To review the cellular determinants for correct processing of preproexendin-4 in mammalian cells, see Cellular specificity of proexendin-4 processing in Mammalian cells in vitro and in vivo. Endocrinology. 2002 Sep;143(9):3464-71