Exendin-4

New diabetes drugs

Diabetes is a metabolic disorder characterized by chronic hyperglycemia caused by a variety of causes , high blood sugar is caused by insulin secretion or its effect defect. Diabetes can be divided into type 1 diabetes, type 2 diabetes, other specific types of diabetes, and gestational diabetes, among which type 2 diabetes account for more than 90%.
Exendin-4 is a new diabetes drug successfully developed by American Eli Lilly Company it belongs to incretin analogues, it is the first member of the incretin analogues family , it is the synthetic peptide compound, which can simulate physiological behavior of the natural state secretion of GLP-1 in vivo ,it is similar to human pancreatic glucagon-like peptide effect-1 (GLP-1),it can promote glucose-dependent insulin secretion, it has inhibition effect of inappropriate glucose-dependent glucagon secretion, slowing gastric emptying, it improves the sensitivity of peripheral tissues to insulin, and it makes blood sugar adequately controlled. Clinically it is used for the treatment of type Ⅱ diabetes patients whose blood sugar is unbale to be controlled by metformin, sulfonylurea, or combination of metformin and sulfonylurea.
From April 28, 2005 to October 29, 2008, the US Food and Drug Administration (abbreviation: FDA) Adverse Event Reporting System had received reports of 78 cases of patients with renal exenatide change. In the meantime, the United States had made a total of more than 6.6 million Exendin-4 prescription, therefore, FDA thought the received 78 cases was in a small proportion of the proportion of all patients reporting use of the drug. Currently FDA has completed an assessment of these reported cases, including 62 cases of acute renal failure cases and 16 cases of renal insufficiency cases. Acute renal failure or renal dysfunction occurs three days to two years after treatment. The age span is 23 years to 83 years, mean age is 60 years.
The above information is edited by the chemicalbook of Tian Ye.

Uses

Exendin-4 can activate the GLP-1 receptor, the receptor can increase cAMP levels of pancreatic acinar cells in intracellular , but it has no effect on VIP receptor.

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.

Description

Exendin-4 is a 39 amino acid polypeptide and incretin mimetic involved in the glucose-dependent enhancement of insulin secretion. It was first isolated from Gila monster saliva. It also promotes the reduction of hyperglycemia, glucose-dependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, and reduction of food intake, often with body weight reduction or blunting of weight gain. The synthetic form, Exenatide, is a glucagon-like peptide-1 (GLP-1) agonist approved for the treatment of diabetes mellitus type II， has a long half-life.

Originator

Amylin (US)

Uses

Antidiabetic.

Uses

Exendin-4 has been used as incretin mimetics for the treatment in HepG2 cells to exclude the influence of auxiliary material. It has also been used as an r (GLP-1R) agonist to exclude interference from auxiliary material.

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.

brand name

Byetta

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

[1]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.
[2]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.
[3]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.