Introduction
History
Investigation of pancreatic hormones began at the turn of the 20th century. In 1902, Bayliss and Starling discover a pancreatic secretin involved in regulation of water homeostasis, giving rise to interest in pancreatic hormones. Shortly after, in 1906, Moore et al. hypothesize involvement of gastrointestinal hormone extracts in maintenance of the endocrine pancreas. Jean La Barre purifies glucose-lowering gut extracts in 1929 and characterizes them as incretins, which is short for intestine secretion insulin. Finally, in 1984, gastric inhibitory peptide (GIP) is isolated from porcupine intestine. Although GIP was initially characterized for its gastric inhibitory effects (hence the name), it was also shown that the polypeptide played an integral role in insulin signaling and secretion. Interestingly, it was found that the effect of GIP on insulin levels was still seen in its absence, hinting toward the presence of an additional incretin, which has now been classified as glucagon-like peptide-1 (GLP-1).[1]
Biological Role
Figure 1. The biological roles of GIP and and GLP-1, incretin hormones.
The GIP receptor (GIPR) helps facilitate the transport of glucose into/out of the cell through the stimulation of insulin secretion.
[2]. GIPR is a type of
G-Protein Coupled Receptor (GPCR), and its natural ligand, GIP, serves as an initiator of a cellular signaling cascade, thereby activating adenylyl cyclase and increasing cAMP levels. Subsequently, insulin secretion is stimulated.
Insulin, a peptide hormone, is secreted by the pancreas in response to glucose ingestion, allowing intake of glucose into the cell via the
Glut2 transporter. Notably, GIP, as well as GLP-1, serve a multitude of biological roles (Figure 1) other than insulin signaling.
[1]
General Structure
The Receptor and G Protein (GIPR)
appears as a typical G-Protein Coupled Receptor, containing a with seven helical passes and an , where the ligand binds. These two domains comprise the . Intracellularly, the receptor is bound to a G-Protein which is comprised by the , , and subunits, where the Beta and Gamma subunits typically dimerize. Upon binding of GIP to the receptor, the intracellular signaling cascade is initiated through Gs⍺iN18 stimulation of adenylyl cyclase and increased [cAMP].
Glucose-dependent Insulinotropic Polypeptide
The binds to its receptor extracellularly, inserting itself N-terminus down into the transmembrane and extracellular domains of the GIP receptor. The polypeptide is 42 residues in length and takes on a helical structure.
Active Site
A crucial binding interaction within the active site occurs between and receptor residues W296 and Q224. The hydroxyl of the tyrosine residue forms a hydrogen bond to the amide of the glutamine, and the aromaticity of both the tyrosine and tryptophan residues results in pi stacking between them. In GIP agonist diabetes medications, conservation of the Tyr1 residue can determine the drug’s efficacy in initiating a GIP-like response.[2]
Associated Diseases
In individuals with diabetes, insulin is improperly under-secreted or unresponsive to elevated blood glucose levels. Considering its role as the initial metabolite in glycolysis, when glucose is not effectively transported into the cell, it renders the body unable to successfully execute energy production through cellular respiration (Glycolysis --> the Krebs Cycle --> the Electron Transport Chain --> ATP synthesis).
Medical Relevance
Many anti-diabetes drugs exist for patients with both Type I and Type II diabetes, including a new dual GIP and GLP-1 agonist known as Tirzepatide (Brand Name: Mounjaro, Manufacturer: Lilly). Tirzepatide is capable of inducing the effects of both GIP and GLP-1 cellular signalling by mimicking each ligand and binding to their respective receptor. Increased presence (or, the apparent increased presence) of GIP and GLP-1 leads to enhanced stimulation of insulin secretion, thereby reducing blood glucose levels.[3]
Tirzepatide Structure
Structurally, as a dual agonist, closely resembles GIP and GLP-1. The sequence alignment of all three polypeptides showcases the highly integrated nature of both GIP and GLP-1 into the amino acid sequence of Tirzepatide with very few alterations (Figure 2).
Figure 2. Sequence alignment of GLP-1, GIP, and Tirzepatide. Residues shown in black are found in all three amino acid sequences. Pink or red coloration denotes residues that are unique to GIP or GLP-1, respectively. The sequence of tirzepatide is colored accordingly, and residues differing from both GIP and GLP-1 are highlighted in blue. Residues that differ across all three structures are boxed.
The allows for simulation of a highly similar interaction between Tirzepatide and the GIP receptor. Had this been altered, Tirzepatide would not nearly bind with as high of an affinity for GIPR. The Tyr1 residue facilitates strong contacts with the TMD core. Several do not align with either the sequence of GIP or GLP-1 and are located toward the C-terminus end of the structure. They include Ala21, Gln24, Ile27, and Gly30. The are Asp21, Asn24, Leu27, and Lys30. Interestingly, these residues do not interact with the receptor, thus their mutation doesn't alter the overall binding affinity of Tirzepatide to GIPR.
[2] Other significant structural modifications were made to maximize GIPR-Tirz interactions.The AIB (alpha-aminoisobutyric) residues (Figure 2) prevent degradation of the polypeptide by peptidases such as DPP-4.
[4]
Because Tirzepatide was modeled after two distinct polypeptides, its binding to each of the receptors has hallmark differences. The Tirz-GIPR complex is rotated ~8.3º compared to Tirz-GLP-1R, with the C-terminus translated closer to the TMD core. ECL1 interactions with Tirzepatide are diminished in GIPR due to the presence of several . Fortunately, the ɑ-helical extension provides another recognition point for Tirzepatide; a hydrogen bond between and stacking between K16 (Tirz) and F127 (GIPR). Primary interactions between the receptor and Tirzepatide occur within the first 27 residues (Figure 3).[4]
Figure 3. Amino acid sequence of Tirzepatide and the type of interaction it forms with the GIP receptor. Salt bridges (blue), hydrogen bonds (red), pi stacking (orange), and Van der Waals (gray) interactions are highlighted.
Future Directions
In addition to treating diabetes, GIP and GLP-1 agonists have grown in recently popularity due to their weight loss inducing effects. The dual agonism of Tirzepatide is thought to be more effective than agonists of GLP-1/GIP alone, though no published studies have formally confirmed this hypothesis. Further research into other pancreatic hormones is required to determine additional routes of insulin stimulation.
