Gastric inhibitory polypeptide(GIP), also known as glucose-dependent insulinotropic polypeptide, is an inhibiting hormone of the secretin family of hormones. [5] While it is a weak inhibitor of gastric acid secretion, its main role, being an incretin, is to stimulate insulin secretion. [6]
GIP, along with glucagon-like peptide-1 (GLP-1), belongs to a class of molecules referred to as incretins, [7] which stimulate insulin release on oral food intake.
GIP is derived from a 153-amino acid proprotein encoded by the GIP gene and circulates as a biologically active 42-amino acid peptide. It is synthesized by K cells, which are found in the mucosa of the duodenum and the jejunum of the gastrointestinal tract. [8]
Like all endocrine hormones, it is transported by blood.
Gastric inhibitory polypeptide receptors are seven-transmembrane proteins (GPCRs) found on beta-cells in the pancreas.
It has traditionally been named gastrointestinal inhibitory peptide or gastric inhibitory peptide and was found to decrease the secretion of stomach acid [9] to protect the small intestine from acid damage, reduce the rate at which food is transferred through the stomach, and inhibit the GI motility and secretion of acid. However, this is incorrect, as it was discovered that these effects are achieved only with higher-than-normal physiological level, and that these results naturally occur in the body through a similar hormone, secretin. [10]
It is now believed that the function of GIP is to induce insulin secretion, which is stimulated primarily by hyperosmolarity of glucose in the duodenum. [11] After this discovery, some researchers prefer the new name of glucose-dependent insulinotropic peptide, while retaining the acronym "GIP." The amount of insulin secreted is greater when glucose is administered orally than intravenously. [12]
In addition to its role as an incretin, GIP is known to inhibit apoptosis of the pancreatic beta cells and to promote their proliferation. It also stimulates glucagon secretion and fat accumulation. GIP receptors are expressed in many organs and tissues including the central nervous system enabling GIP to influence hippocampal memory formation and regulation of appetite and satiety. [13]
GIP recently appeared as a major player in bone remodeling. Researchers at Universities of Angers and Ulster evidenced that genetic ablation of the GIP receptor in mice resulted in profound alterations of bone microarchitecture through modification of the adipokine network. [14] Furthermore, the deficiency in GIP receptors has also been associated in mice with a dramatic decrease in bone quality and a subsequent increase in fracture risk. [15] However, the results obtained by these groups are far from conclusive because their animal models give discordant answers and these works should be analysed very carefully.[ citation needed ]
It has been found that type 2 diabetics are not responsive to GIP and have lower levels of GIP secretion after a meal when compared to non-diabetics. [16] In research involving knockout mice, it was found that absence of the GIP receptors correlates with resistance to obesity. [17]
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 vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.
Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duodenum, which are located in the intestinal glands. In humans, the secretin peptide is encoded by the SCT gene.
Peptide hormones are hormones whose molecules are peptides. Peptide hormones have shorter amino acid chain lengths than protein hormones. These hormones have an effect on the endocrine system of animals, including humans. Most hormones can be classified as either amino acid–based hormones or steroid hormones. The former are water-soluble and act on the surface of target cells via second messengers; the latter, being lipid-soluble, move through the plasma membranes of target cells to act within their nuclei.
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 medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.
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.
Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood-glucose–dependent mechanism.
Enteroglucagon is a peptide hormone derived from preproglucagon. It is a gastrointestinal hormone, secreted from mucosal cells primarily of the colon and terminal ileum. It consists of 37 amino acids. Enteroglucagon is released when fats and glucose are present in the small intestine; which decrease the motility to allow sufficient time for these nutrients to be absorbed.
Vildagliptin, sold under the brand name Galvus and others, is an oral anti-hyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas.
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.
Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic effect, diffuse them as local messengers, or transmit them to the enteric nervous system to activate nervous responses. Enteroendocrine cells of the intestine are the most numerous endocrine cells of the body. They constitute an enteric endocrine system as a subset of the endocrine system just as the enteric nervous system is a subset of the nervous system. In a sense they are known to act as chemoreceptors, initiating digestive actions and detecting harmful substances and initiating protective responses. Enteroendocrine cells are located in the stomach, in the intestine and in the pancreas. Microbiota play key roles in the intestinal immune and metabolic responses in these enteroendocrine cells via their fermentation product, acetate.
The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.
The gastric inhibitory polypeptide receptor (GIP-R), also known as the glucose-dependent insulinotropic polypeptide receptor, is a protein that in humans is encoded by the GIPR gene.
Free fatty acid receptor 2 (FFAR2), also termed G-protein coupled receptor 43 (GPR43), is a rhodopsin-like G-protein coupled receptor. It is coded by the FFAR2 gene. In humans, the FFAR2 gene is located on the long arm of chromosome 19 at position 13.12. Like other GPCRs, FFAR2s reside on the surface membrane of cells and when bond to one of their activating ligands regulate the function of their parent cells. FFAR2 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes three other receptors which, like FFAR2, are activated by certain fatty acids: FFAR1, FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids whereas FFAR1 and FFAR4 are activated by long-chain fatty acids.
Rap guanine nucleotide exchange factor (GEF) 4 (RAPGEF4), also known as exchange protein directly activated by cAMP 2 (EPAC2) is a protein that in humans is encoded by the RAPGEF4 gene.
Glucagon/gastric inhibitory polypeptide/secretin/vasoactive intestinal peptide hormones are a family of evolutionarily related peptide hormones that regulate activity of G-protein-coupled receptors from the secretin receptor family.
Daniel Joshua Drucker is a Canadian endocrinologist. A Fellow of the Royal Society, he is a professor of medicine at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto. He is known for his research into intestinal hormones and their use in the treatment of diabetes, obesity, and other metabolic diseases, as well as intestinal failure.
Tirzepatide, sold under the brand name Mounjaro among others, is an antidiabetic medication used for the treatment of type 2 diabetes and for weight loss. Tirzepatide is administered via subcutaneous injections.
Svetlana Mojsov is a Macedonian American, ex- Yugoslavian-born chemist who is a research associate professor at Rockefeller University. Her research considers peptide synthesis. She discovered the glucagon-like peptide-1 and uncovered its role in glucose metabolism and the secretion of insulin. Her breakthroughs were transformed by Novo Nordisk into therapeutic agents against diabetes and obesity.
Glucagon receptor agonists are a class of drugs under development for the treatment of obesity, non-alcoholic fatty liver disease, and congenital hyperinsulinism.
GLP1 poly-agonist peptides are a class of drugs that activate multiple peptide hormone receptors including the glucagon-like peptide-1 (GLP-1) receptor. These drugs are developed for the same indications as GLP-1 receptor agonists—especially obesity, type 2 diabetes, and non-alcoholic fatty liver disease. They are expected to provide superior efficacy with fewer adverse effects compared to GLP-1 mono-agonists, which are dose-limited by gastrointestinal disturbances. The effectiveness of multi-receptor agonists could possibly equal or exceed that of bariatric surgery. The first such drug to receive approval is tirzepatide, a dual agonist of GLP-1 and GIP receptors.
