Incretins are a group of

metabolic Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

s that decrease

blood glucose The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly blood sugar regulation, regulates blood glucose levels as a part of metabolic homeostasis ...

levels. Incretins are released after eating and augment the secretion of

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

released from

pancreatic The pancreas (plural pancreases, or pancreata) is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

beta cells Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vit ...

of the

islets of Langerhans The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% o ...

by a blood-glucose–dependent mechanism. Some incretins (

GLP-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certai ...

) also inhibit

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...

release from the

alpha cell Alpha cells (α-cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream. Discovery Islets of Langerhans we ...

s of the

. In addition, they slow the rate of absorption of nutrients into the

bloodstream In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...

by reducing gastric emptying and may reduce food intake. The two main

peptides Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Dalton (unit), Da or more are called proteins. Chains of fewer t ...

that fulfill criteria for an incretin are the intestinal peptide

glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and cer ...

(GLP-1) and gastric inhibitory peptide (GIP, also known as: glucose-dependent insulinotropic polypeptide). GIP is produced and secreted into the blood by K cells located in the mucosa of the

upper gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...

duodenum The duodenum is the first section of the small intestine in most vertebrates, including mammals, reptiles, and birds. In mammals, it may be the principal site for iron absorption. The duodenum precedes the jejunum and ileum and is the shortest p ...

and upper

jejunum The jejunum is the second part of the small intestine in humans and most higher vertebrates, including mammals, reptiles, and birds. Its lining is specialized for the absorption by enterocytes of small nutrient molecules which have been pr ...

while GLP1 is produced and secreted into the blood by L cells located in the mucosa of the lower gastrointestinal tracts

small Small means of insignificant size Size in general is the Magnitude (mathematics), magnitude or dimensions of a thing. More specifically, ''geometrical size'' (or ''spatial size'') can refer to three geometrical measures: length, area, or ...

and

large intestine The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the Digestion, digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces befor ...

s. Short-chain fatty acids (primarily acetic, propionic, and

butyric acid Butyric acid (; from , meaning "butter"), also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula . It is an oily, colorless liquid with an unpleasant odor. Isobutyric acid (2-met ...

s), which microganisms form in the intestines, bind to the

FFAR2 Free fatty acid receptor 2 (FFAR2), also known as G-protein coupled receptor 43 (GPR43), is a Rhodopsin-like receptor, rhodopsin-like G-protein coupled receptor (GPCR) encoded by the ''FFAR2'' gene. In humans, the ''FFAR2'' gene is located on the ...

and

FFAR3 Free fatty acid receptor 3 (FFAR3, also termed GPR41) protein is a G protein coupled receptor (i.e., GPR or GPCR) that in humans is encoded by the ''FFAR3'' gene (i.e., ''GPR41'' gene). GPRs reside on cell surfaces, bind specific signaling molecu ...

receptors on K cells and L cells to stimulate their respective production and secretion of GIP and GLP-1. Both GLP-1 and GIP are inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4) and are members of the glucagon peptide superfamily.

Medical uses

Medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

s based on incretins are used in the treatment of

type 2 diabetes mellitus Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ur ...

as well as the management of

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. Most of the earliest incretin-targeting agents to be approved fell into the class of

DPP-4 inhibitors Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that Enzyme inhibitors, block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2. The first agent of ...

; these inhibit DPP-4 and prevent the enzymatic degradation of GLP-1 and GIP. The first medication in this class,

sitagliptin Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes. It is in the dipeptidyl peptidase-4 (DPP-4) inhibitor class and works by increasing the production of insulin and decr ...

, received FDA approval in 2006 for the treatment of type 2 diabetes. GLP-1 analogs principally act as agonists of the GLP-1 receptor and are thus insulinotropic. Exenatide was the first drug in this class to be used in the treatment of type 2 diabetes; it received FDA approval in 2005. More recently, longer-acting and more potent GLP-1 analogs have been developed, most notably

semaglutide Semaglutide is an anti-diabetic medication used for the treatment of type2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a ...

, which received FDA approval for type 2 diabetes in 2017. It was subsequently approved for the management of

. In 2021, it was in the Top 100 most-prescribed drugs in the United States. Tirzepatide (Mounjaro) is a potent GIP analog with agonist activity at GIP and GLP-1 receptors. It was approved for the treatment of type 2 diabetes in the United States in May 2022, and for the management of obesity in November 2023.

Effect

The incretin effect describes the phenomenon whereby oral glucose intake elicits a higher insulin response compared to intravenously introduced glucose that produces the same levels of serum glucose levels.

History

In 1932, Belgian

physiologist Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a subdiscipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out chemical and ...

Jean La Barre used the word "incretin" for a gut hormone which stimulates the endocrine pancreas including

release. He also proposed that such incretins could be used as a treatment for diabetes mellitus.

References

{{Authority control Peptide hormones Intestinal hormones Gastric hormones

Medical uses

Effect

History

See also

References