Gastric inhibitory polypeptide (GIP) also known as glucose-dependent insulinotropic polypeptide is an important insulin-releasing hormone of the enteroinsular axis that has a functional profile of possible therapeutic value for type 2 diabetes. The 42–amino acid GIP is an important incretin hormone released into the circulation from endocrine K-cells of the duodenum and jejunum after ingestion of food1.
GIP, secretin, glucagons and parathyroid hormone (PTH) belong, together with vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase (AC)-activating polypeptide, to a family of peptides (the VIP-secretin-glucagon family), which also includes growth hormone-releasing hormone and exendins. All the members of this peptide family possess a remarkable amino-acid sequence homology, and bind to G-protein-coupled receptors, whose signaling mechanism primarily involves AC/protein kinase A and phospholipase C/protein kinase C cascades2.
Synthetic fragment peptides of GIP were evaluated for their ability to elevate cellular cAMP production and stimulate insulin secretion. In GIP receptor transfected CHL cells, GIP (4–42) and GIP (17–30) dose-dependently inhibited GIP-stimulated cAMP production, while GIP (1–16) exerted very weak agonist effects on cAMP production. In the clonal pancreatic beta-cell line, BRIN-BD11, GIP (1–16) demonstrated weak insulin releasing activity compared with native GIP. In contrast, GIP (4–42) and GIP (17–30) weakly antagonized the insulin releasing activity of the native peptide. These data demonstrate the critical role of the N-terminus and the involvement of regions of the C-terminal domain in generating full biological potency of GIP3.
GIP was initially discovered and named for its gastric inhibitory properties. In 1886, Ewald and Boas showed that olive oil mixed with a meal inhibited both gastric emptying and acid secretion. In 1930 Kosaka and Lim proposed that this mixture liberated a chemical from the small intestine and went on to show that gastric acid secretion and gastric emptying could be inhibited by intravenously infused extracts of intestinal mucosa.They named the chemical “enterogastrone”. Later, this factor was isolated and found to be localised to the duodenum and jejunum in specific endocrine cells named K-cells.Based on its effects the name “gastric inhibitory polypeptide” was proposed by Brown and Dryburgh in 19714.
The predicted amino acid sequence indicates that GIP is derived by proteolytic processing of a 153-residue precursor, preproGIP. The GIP moiety is flanked by polypeptide segments of 51 and 60 amino acids at its NH2 and COOH termini, respectively. The former includes a signal peptide of about 21 residues and an NH2-terminal propeptide of 30 amino acids. GIP is released from the precursor by processing at single arginine residues. There is a region of nine amino acids in the COOH-terminal propeptide of the GIP precursor that has partial homology with a portion of chromogranin A as well as pancreastatin4.
Mode of action
The receptor for GIP belongs to family B or class 2 of the superfamily of serpentine G-protein-coupled receptors. The GIP receptor harbors a long amino-terminal extension, which together with the first transmembrane region is crucial for agonist binding and receptor activation. The carboxy-terminal cytoplasmic part of the receptor regulates internalization and desensitization. The GIP receptor is activated by its natural ligand GIP 1–42, which is generated by proteolytic cleavage of full length GIP. The GIP receptor is coupled to Gsa subunits of heterotrimeric G proteins, resulting in the activation of membrane-bound adenylyl cyclase and increased intracellular levels of cyclic AMP. It has been shown that GIP increases Ca2+ levels. In a-cells, a GIP-dependent increase in Ca2+ levels is mediated by cAMP-dependent protein kinase (PKA). Another mechanism of GIP-induced insulin secretion involves the suppression of voltage-gated potassium channels by PKA-dependent endocytosis of the GIP receptor. The activated GIP receptor promotes insulin gene transcription and also stimulates pleiotropic signaling cascades regulating proliferation and apoptosis. These include the PKA/CREB, PI3K, and p42/44 ERK1/2 MAPK signaling pathways. In addition, p90RSK is activated by the GIP receptor. Expression of GIP receptors is regulated by transcription factors SP1 and SP35.
In addition to its insulinotropic actions, a number of other potentially important extrapancreatic actions of GIP may contribute to the enhanced antihyperglycemic activity and other beneficial metabolic effects of Ty r1-glucitol GIP. These include the stimulation of glucose uptake in adipocytes, increased synthesis of fatty acids, and activation of lipoprotein lipase in adipose tissue. GIP also promotes plasma triglyceride clearance in response to oral fat loading. In liver, GIP has been shown to enhance insulin-dependent inhibition of glycogenolysis. GIP also reduces glucagon-stimulated lipolysis in adipose tissue as well as hepatic glucose production. Finally, recent findings indicate that GIP has a potent effect on glucose uptake and metabolism in mouse isolated diaphragm muscle. It also stimulates somatostatin secretion and slows down gastric emptying and nutrient absorption1.
1. O’Harte FPM, Mooney MH and Flatt PR (1999). NH2- Terminally Modified Gastric Inhibitory Polypeptide Exhibits Amino-Peptidase Resistance and Enhanced Antihyperglycemic Activity. Diabetes, 48.
2. Nussdorfer GG, Bahçelioglu M, Neri G, Malendowicz LK (2000). Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus- pituitary-adrenal axis. Peptides, 21(2), 309-24.
3. Gault VA, Harriott P, Flatt PR and O'Harte FPM (2002). Cyclic AMP Production and Insulin Releasing Activity of Synthetic Fragment Peptides of Glucose-Dependent Insulinotropic Polypeptide. Bioscience Reports, 22, 523-528.
4. Ballinger A (2003). Gastric inhibitory polypeptide links overnutrition to obesity. Gut, 52(3), 319–320. 5. Hoersch D, Schrader J (2007). Gastric inhibitory polypeptide receptor. UCSD-Nature Molecule Pages.