Exendin 4

Exendin-4 is a 39-amino acid peptide incretin mimetic. Exendin-4, also known as Exenatide, was originally isolated from the venom of Gila monster lizard called Heloderma suspectum. Exendin-4 is a long-acting analog of the mammalian intestinal hormone glucagon-like peptide I (GLP-1) and therefore exhibits glucoregulatory activities to control plasma glucose levels. Exendin-4 enhances insulin synthesis and secretion in a glucose-dependent manner, while downregulating inappropriately high glucagon release, slowing gastric emptying and decreasing appetite. The increase in maximum insulin secretion is due to a greater increase in cAMP production in pancreatic β cells. Exendin-4 is a potent agonist of the Glucagon-Like Peptide-1 Receptor (GLP-1R ; Kd = 136pM). It has been reported that exendin-4 is a more potent insulinotropic agent when given intravenously to rats than is glucagon-like peptide-1 (GLP-1) as indicated by the lower ED50 (ED50 0.19 nmol/kg for glucagon-like peptide-1 versus 0.0143 nmol/kg for exendin-4). Subcutaneous administration of exendin-4 at doses of 5µg and 10 µg twice daily attenuates glycemia in patients with type 2 diabetes, who are treated with metformin, an antidiabetic drug and not achieving adequate glycemic control. In these patients, exendin-4 was tolerated and triggered a reduction in glycated hemoglobin (HbA1C ≤ 7%), with no weight gain and no increased incidence of hypoglycemia. Long-term treatment with exendin-4 has a beneficial effect on the pancreatic β-cell function by stimulating both the neogeneration and the proliferation of β-cells when administered to rats. Furthermore, exendin-4 has shown anti-atherosclerogenetic properties as well as the ability to reduce hepatic steatosis in obese ob/ob mice by improving insulin sensitivity.