INCRETINS: TYPES AND THEIR STRUCTURE, FUNCTIONS, MECHANISM OF ACTION - BIOLOGY - 2025

The incretins are gastrointestinal hormones that stimulate secretion of physiological concentrations of insulin. The term is currently used to refer to two different intestinal hormones, which have different technical names: GIP or "glucose-dependent insulinotropic polypeptide" and GLP-1 or "glucagon-like peptide 1".

"Incretin" is a word and a concept coined in 1932 by the Belgian physiologist Jean La Barre, who introduced it to define the intestinal hormonal factors that complemented the effects of secretin on endocrine pancreatic secretion.

Scheme of the mechanism of action of some incretins and their inhibitors (Source: Clinical Cases, Ilmari Karonen via Wikimedia Commons)

In other words, La Barre used the term incretin to denote any intestinal hormone that, under physiological conditions, was capable of stimulating or contributing to the secretion of pancreatic hormones such as insulin, glucagon, pancreatic polypeptide (PP) and somatostatin. pancreatic.

However, at present the term "incretin" is used only to denote those hormones capable of stimulating glucose-dependent pancreatic insulin synthesis, specifically two peptides known as GIP and GLP-1. However, the advent of new technology and deeper endocrinological studies could reveal many other peptides with similar activities.

Types of incretins and their structure

Traditionally, only two incretins have been defined in humans: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1); the two hormones work additively in stimulating insulin secretion.

The first of these to be isolated was the glucose-dependent insulinotropic polypeptide (GIP, Glucose-dependent Insulinotropic Polypeptide). It is a peptide hormone of about 42 amino acids and belongs to the glucagon-secretin peptide family.

Structure of the incretin GIP (Source: User: Ayacop via Wikimedia Commons)

The second incretin discovered was glucagon-like peptide 1 (GLP-1, from English Glucagon-Like Peptide-1), which is a by-product of the gene that codes for the hormone “proglucagon”; part of the C-terminal end of the protein, to be more exact.

Features

Initially, incretins were defined as factors derived from the intestinal tract that have the ability to lower plasma glucose levels through stimulation of the secretion of pancreatic hormones such as insulin and glucagon.

This concept was maintained with the advent of radioimmunoassays, where permanent communication between the intestine and the endocrine pancreas was confirmed.

Oral administration of glucose was shown to be associated with significant increases in plasma insulin levels, especially compared to results obtained with glucose administered intravenously.

Stimuli for the secretion and action of the pancreatic hormone Insulin (Source: Daniel Walsh and Alan Sved via Wikimedia Commons)

Incretins are thought to be responsible for the secretion of almost 70% of plasma insulin after oral administration of glucose, as these are hormones secreted in response to nutrient intake, which enhances the secretion of glucose-insulin. dependent.

Many efforts are currently being made regarding the oral or intravenous administration of incretins to patients with diseases such as type 2 diabetes mellitus or oral glucose intolerance. This is because studies have shown, albeit preliminarily, that these substances facilitate the rapid decline in glycemic levels after food intake.

Mechanism of action

GIP: Glucose-dependent insulinotropic polypeptide

This incretin is produced by the K cells of the small intestine (in the duodenum and jejunum, specifically) in response to the ingestion of fat or glucose, and is responsible for increasing the secretion of insulin stimulated by glucose.

The expression of the gene coding for this hormonal factor has been demonstrated in humans and rodents both in the stomach and in the intestine. Studies with this hormone indicate that it is derived from a 153 amino acid "proGIP" precursor, which has two signal peptides at its N- and C-termini, which are cleaved to yield an active peptide of 42 residues.

The half-life of GIP is less than 7 minutes once it is synthesized and enzymatically processed. This peptide is recognized by a specific receptor, the GIPR, which is located in the plasma membrane of the cells of the pancreas, in the stomach, in the small intestine, in adipose tissue, in the adrenal cortex, in the pituitary gland, in the heart, lungs and other important organs.

When GIP binds to its receptors in the beta cells of the pancreas, it triggers an increase in the production of cAMP, also the inhibition of ATP-dependent potassium channels, the increase in intracellular calcium and, finally, the exocytosis of the insulin storage granules.

In addition, this peptide can stimulate gene transcription and insulin biosynthesis, as well as the other components of pancreatic beta cells to "census" glucose. Although GIP works mainly as an incretin hormone, it also exerts other functions in other tissues such as the central nervous system, bones, among others.

GLP-1: Glucagon-like peptide 1

This peptide is produced from the gene that encodes "proglucagon", so it is a peptide that shares close to 50% identity with the glucagon sequence and is therefore called "glucagon-like" peptide.

GLP-1, a post-translational proteolytic product, is tissue specific and is produced by the L cells of the intestine in response to food intake. Like GIP, this incretin has the ability to increase glucose-stimulated insulin secretion.

Gene expression and processing

This peptide is encoded in one of the exons of the proglucagon gene, which is expressed in the alpha cells of the pancreas, in the L cells of the intestine (in the distal ileum), and in neurons of the brain stem and hypothalamus.

In the pancreas, the expression of this gene is stimulated by fasting and hypoglycemia (low concentrations of glucose in the blood), and is inhibited by insulin. In intestinal cells, the expression of the gene for proglucagon is activated by an increase in cAMP levels and by food intake.

The product resulting from the expression of this gene is post-translationally processed in enteroendocrine L cells (in the small intestine), resulting not only in the release of glucagon-like peptide 1, but also in other somewhat unknown factors such as glicentin, oxynomodulin, glucagon-like peptide 2, etc.

Production and action

The ingestion of foods, especially those rich in fats and carbohydrates, stimulates the secretion of the GLP-1 peptide from intestinal enteroendocrine L cells (nerve stimulation or mediated by many other factors can also occur).

Some functions of the GLP-1 peptide in addition to its action as an incretin hormone (Source: BQUB13-Cbadia via Wikimedia Commons)

In humans and rodents, this peptide is released into the bloodstream in two phases: 10 to 15 minutes after ingestion and 30 to 60 minutes later. The active life of this hormone in the blood is less than 2 minutes, as it is rapidly proteolytically inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).

GLP-1 binds to a specific membrane receptor (GLP-1R) on various cells in the body, including some of the endocrine cells of the pancreas, where it stimulates glucose-dependent insulin secretion.

How?

The binding of GLP-1 to its receptor on beta cells of the pancreas activates the production of cAMP mediated by adenylate cyclase in these cells. There is a direct inhibition of ATP-dependent potassium channels, which depolarizes the cell membrane.

Subsequently, intracellular calcium levels increase, which is the result of the GLP-1-dependent influx of extracellular calcium through voltage-dependent calcium channels, the activation of non-selective cation channels and the mobilization of calcium reserves. intracellular.

It also increases mitochondrial synthesis of ATP, which favors depolarization. Later the voltage-gated potassium channels are closed, preventing the repolarization of beta cells and, finally, exocytosis of the insulin storage granules occurs.

In the gastrointestinal system, the binding of GLP-1 to its receptors has an inhibitory effect on gastric acid secretion and gastric emptying, which attenuates the increase in blood glucose levels associated with food intake.

References

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6. Rehfeld, JF (2018). The origin and understanding of the incretin concept. Frontiers in endocrinology, 9.
7. Vilsbøll, T., & Holst, JJ (2004). Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia, 47 (3), 357-366