Exendin 4 – Potent GLP-1R agonist – Hormones

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 suspectum1. This potent GLP-1R agonist 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 levels2. Exendin-4 enhances insulin synthesis and secretion in a glucose-dependent manner,while downregulating inappropriately high glucagon release,slowing gastric emptying and decreasing appetite2. The increase in maximum insulin secretion is due to a greater increase in cAMP production in pancreatic β cells3. 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)3. 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 control4. 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 hypoglycemia4. 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 rats2. Furthermore,exendin-4 has shown anti-atherosclerogenetic properties5 as well as the ability to reduce hepatic steatosis in obese ob/ob mice by improving insulin sensitivity6.

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