Gastric Inhibitory peptide

Structure

Human GIP is a single 42-aa peptide. The structure of vertebrate GIP is well conserved and both the N-terminal and central regions are important for biological activity because truncated forms of GIP, GIP(1–39), and GIP (1–30) show a high degree of biological activity. The N-terminal two aa residues are cleaved off by dipeptidyl-peptidase 4 (DPP-4) in the circulation to form GIP(3–42), which has no insulinotropic activity.

Gene, mRNA, and precursor

The human GIP gene, GIP, location 17q21.3–q22, spans approximately 10kb. GIP consists of six exons and has potential binding sites for a number of transcriptional factors, including Sp1, AP-1, and AP-2. Human cDNA clones have a 459bp open reading frame that encodes the 153-aa preproGIP. The GIP sequence in proGIP is flanked by single arginine residues, sites for cleavage by prohormone convertases (PCs). GIP and PC1/3 are coexpressed in enteroendocrine K cells, which are located in the mucosa of the duodenum and the jejunum of the gastrointestinal tract, and PC1/3 is sufficient to produce bioactive GIP. GIP is secreted from enteroendocrine K cells. In the rodent gut, GIP distribution extends through to the ileum. The expression of GIP is also reported in the submandibular salivary gland, stomach, and brain.

Synthesis and release

The expression of GIP is regulated by nutrients. The administration of glucose and lipid into the rat gastroin testinal tract increases GIP mRNA levels. Circulating GIP levels are low in the fasted state and increase within minutes of food ingestion. The postprandial levels of circulating GIP are dependent on meal size. The degree to which nutrients regulate GIP secretion is species dependent. Fat is a more potent stimulator than carbohydrates in humans, whereas in the rodent and pig, carbohydrates are more potent than fat. Once released, GIP is rapidly deactivated by DPP-4.

Receptors

The receptor of GIP is a seven-transmembrane GPCR that belongs to a subclass of the family B. Both the relatively long extracellular N-terminal domain and the first transmembrane domain are important for ligand binding and receptor activation. The C-terminal cytoplasmic domain of the receptor is important for receptor desensitization and internalization. Like their peptide ligands, the GIP receptor and the GLP-1 receptor exhibit high degrees of amino acid sequence identity, with similar molecular structures and signaling processes. However, GIP does not bind to the GLP-1 receptor and vice versa. Ligand binding to the GIP receptor primarily activates adenylyl cyclase and increases intracellular cAMP. The activation of the MAP kinase pathway, the phospholipase A2 pathway, and the phosphatidylinositol 3-kinase/protein kinase B pathway have also been reported.

Agonists and Antagonists

[D-Ala2]-GIP is an agonist. Tirzepatide (LY3298176) is a dual agonist of GIP and GLP-1 receptors. GIP(6–30), ANTGIP (GIP-(7–30)-NH2) (a truncated GIP peptide antagonist), GIP(3–30)NH2 (a truncated GIP peptide antagonist), and [Pro3]-GIP; Exendin(9–39) amide are antagonists.

Biological functions

The GIP receptor gene is expressed in both α and β cells in the pancreatic islets, gastrointestinal tract, adipose tissues, adrenal cortex, pituitary, heart, testis, endothelium of major blood vessels, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several regions of the brain. The primary physiological action of GIP is the stimulation of glucose-dependent insulin secretion. GIP is thought to have other functions such as bone remodeling and fat accumulation. GIP and GLP-1 share common properties as incretins, but they also possess different biological characteristics.

Clinical implications

GIP and GLP have implications in the following diseases and conditions:
Type 2 diabetes: In type-2 diabetic patients, GLP-1 retained much of its insulinotropic activity, but the maximum effect of GIP was significantly lower than in normal subjects. It has been suggested that this decreased response is a result of a decreased receptor expression in the pancreas. A reduced insulinotropic effect of GIP was also reported in first-degree relatives of patients with type 2 diabetes.
Food-dependent Cushing’s syndrome: In food- or GIP dependent Cushing’s syndrome, the ectopic adrenal expression of the GIP receptor has been identified. The secretion of cortisol from the adrenal gland was stimulated only briefly, but repeatedly after each food ingestion.
Celiac disease: The serum level of GIP was significantly lower in patients with celiac disease than in healthy people. The increase of glucose in serum from patients was significantly smaller than that occurring in healthy people only during the first hour after the meal, but the absolute number of K cells was not significantly reduced. These results suggest that the release of GIP is influenced by the rate of absorption of nutrients in patients with celiac disease.
Acromegaly: Acromegaly is often associated with fasting and postprandial hyperinsulinemia. In patients with acromegaly, fasting and postprandial GIP levels are abnormally high, suggesting GIP hypersecretion might play a role in the pathogenesis of the hyperinsulinemia that characterizes acromegaly.
Obesity: GIP also links overnutrition to obesity by acting on adipocytes. GIP-reduced mice demonstrate that the partial reduction of GIP alleviates obesity and lessens the degree of insulin resistance under high-fat diet conditions, suggesting a potential therapeutic value.

Description

GIP was originally isolated as a gastric inhibitory polypeptide. After the discovery of its glucose-dependent insulinotropic activity, known as the incretin effect, GIP was renamed glucose-dependent insulinotropic peptide. GIP was originally isolated from the porcine intestinal extract on the basis of its acid inhibitory activity in dogs (gastric inhibitory polypeptide) in the early 1970s, and subsequently renamed glucose-dependent insulinotropic peptide after the finding of its physiologically important role as a potentiator of glucose-stimulated insulin secretion.

Clinical Use

GIP possessing incretin activity enhances glucosestimulated insulin release. GIP agonists are potentially useful for the treatment of diabetes. Moreover, DPP-4 inhibitors are approved for use in diabetes patients because GIP is rapidly deactivated by DPP-4.

Raw materials

Preparation Products