Definition
ChEBI: A bioactive polypeptide of 39 amino acid residues isolated from the saliva of the Gila monster (Heloderma suspectum). High-affinity glucagon-like peptide 1 (GLP-1) receptor agonist (Kd = 136 pM); potently indu
es cAMP formation without stimulating amylase release in pancreatic acini; potentiates glucose-induced insulin secretion in isolated rat islets; protects against glutamate-induced neurotoxicity. A synthetic version is called exenatide.
Description
Exenatide is the first drug in a new class of anti-diabetics known as the incretin
mimetics, and it is indicated as adjunctive therapy to improve glycemic control in
patients with type 2 diabetes who are taking metformin, a sulfonylurea, or both, but
have not achieved adequate glycemic control. Exenatide is a functional analog of the
human incretin Glucagon-Like Peptide-1 (GLP-1). GLP-1 is naturally released from
cells in the GI tract in response to food intake and acts on its receptor on b-cells to
potentiate glucose-stimulated insulin secretion. Exenatide is a long-acting agonist at
the GLP-1 receptor. It is a synthetic version of a 39-amino acid peptide found in the
salivary secretions of the Gila monster lizard.also moderates peak serum glucagon levels during hyperglycemic periods following
meals, but does not interfere with glucagon release in response to hypoglycemia. The
dosing regimen for exenatide is 5 or 10 mg twice daily, administered as a subcutaneous
injection within an hour before morning and evening meals. Following subcutaneous
administration, peak plasma concentrations of exenatide are reached in
2.1 h, and the plasma pharmacokinetic profile is dose proportional. The most common adverse
events reported with exenatide include nausea, vomiting, diarrhea, feeling jittery,
dizziness, headache, and dyspepsia.
General Description
Exendin-4 is an incretin mimetic peptide, which is composed of 39 amino acids. It is an analog of glucagon-like peptide 1 (GLP-1), and an insulinotropic agent, with a long half-life. Exendin-4 was historically isolated from the venom of Gila monster lizard called Heloderma suspectum.
Biochem/physiol Actions
Activates GLP-1 (glucagon-like peptide-1) receptors to increase intracellular cAMP in pancreatic acinar cells; has no effect on VIP receptors.
in vitro
exendin-4 showed a pronounced effect on intracellular camp generation. treatment of glp-1 in combination with exendin-4 showed additive action on the generation of camp. in isolated rat islets and in mouse insulinoma beta tc-1 cells, exendin-4 stimulated the glucose-induced insulin secretion in a dose dependent manner [2]. in basal forebrain cholinergic neurons, exendin-4 greatly reduced ibotenic acid-induced depletion of choline acetyltransferase immunoreactivity [3].
in vivo
in ob/ob mice, administration of exendin-4 (10 μg/kg or 20 μg/kg) improved insulin sensitivity and significantly reduced serum glucose and hepatic steatosis. exendin-4 appeared to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity [1]. in athymic mice, 63% of exendin-4-treated mice achieved graft function compared with 21% of untreated mice (p = 0.033) in the short-term study. 88% of treated mice had functioning grafts compared with 22% of controls (p = 0.015) in the long-term study. exendin-4-treated mice gained significantly more weight than the untreated counterparts [4].
storage
-20°C (desiccate)
References
ding x, saxena n k, lin s, et al. exendin‐4, a glucagon‐like protein‐1 (glp‐1) receptor agonist, reverses hepatic steatosis in ob/ob mice[j]. hepatology, 2006, 43(1): 173-181.gke r, fehmann h c, linn t, et al. exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells[j]. journal of biological chemistry, 1993, 268(26): 19650-19655.perry t a, haughey n j, mattson m p, et al. protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4[j]. journal of pharmacology and experimental therapeutics, 2002, 302(3): 881-888.sharma a, srenby a, wernerson a, et al. exendin-4 treatment improves metabolic control after rat islet transplantation to athymic mice with streptozotocin-induced diabetes[j]. diabetologia, 2006, 49(6): 1247-1253.
