Incretin mimetics

Classification and physiology of incretins

Incretins act as natural stimulators of endogenous insulin incretion. They are secreted by the cells of the small intestine immediately after food intake and enhance glucose-stimulated insulin secretion.

The pharmacological group includes two main directions:

1. Glucagon-like peptide-1 (GLP-1) receptor agonists — include agents such as exenatide.
2. Dipeptidyl peptidase-4 (DPP-4) inhibitors — include saxagliptin.

Incretins themselves are represented by GLP-1 (consisting of 30 amino acids) and GIP (glucose-dependent insulinotropic polypeptide). In the body, they are rapidly degraded by the enzyme DPP-4, which is a serine peptidase that cleaves alanine.

Molecular mechanism of action

At the cellular level in pancreatic $\beta$-cells, a complex signaling cascade takes place:

• The molecules bind to GLP-1 receptors on the cell membrane.
• Adenylyl cyclase is activated, which triggers protein kinase A, as well as phospholipase C, which activates protein kinase C.
• The resulting enzymes block ATP-dependent $K^+$ channels.
• An electrophysiological effect ensues — depolarization of the cell membrane.
• Calcium channels open, and $Ca^{2+}$ ions rush into the cell, stimulating the synthesis and secretion of insulin.

Exenatide: features of the first GLP-1 agonist

The drug is derived from the salivary gland of the Gila monster (Heloderma suspectum); structurally, it is 52% homologous to human GLP-1.

• Pharmacodynamics: predominantly activates the glucose-dependent phase of insulin secretion. Since secretion slows down when glucose levels drop, the risk of hypoglycemia remains low.
• Administration: administered subcutaneously at a dosage of 5–10 mcg twice daily, usually combined with metformin or sulfonylureas.
• Pharmacokinetics: maximum concentration is reached in 2 hours, $T_{1/2}$ is 2.4 hours, and elimination occurs via glomerular filtration.

DPP-4 inhibitors and pharmacokinetics of saxagliptin

Drugs of this subgroup block the serine peptidase DPP-4, preventing the degradation of endogenous incretins (GLP-1 and GIP). This increases their plasma concentration by 2–3 times and potentiates the hypoglycemic effect.

Using saxagliptin as an example, the pharmacokinetic profile is as follows:

• Oral bioavailability is 75%.
• Metabolism occurs in the liver with the formation of an active metabolite.
• Elimination is carried out predominantly by the kidneys.
• The half-life of the parent compound is 2.5 hours, and that of the active metabolite is 3.1 hours. The drug is prescribed once daily.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Structural differences between exenatide and human GLP-1 and their impact on enzyme resistance
• The role of the area postrema in the development of dyspeptic disorders
• Features of combination therapy of incretin mimetics with metformin
• Metabolic pathways of saxagliptin and the formation of its active metabolites
• Comparison of elimination pathways of GLP-1 agonists and DPP-4 inhibitors

Other topics in the section "Hormone preparations, their synthetic substitutes, and antagonists"

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