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Physiology, Gastric Inhibitory Peptide
Introduction
The glucose-dependent insulinotropic polypeptide, formerly known as gastric inhibitory peptide (GIP), was first isolated in 1973 from porcine small intestine based on its ability to inhibit gastric hydrochloric acid secretion. Soon after, in 1980, GIP was found to be a weak inhibitor of acid secretion and a potent stimulator of insulin post meals.[1] This phenomenon of higher insulin secretion in response to oral glucose compared to intravenous glucose at the same plasma glucose level is called the incretin effect.[2] GIP is considered the most potent incretin hormone, and along with glucagon-like peptide-1 (GLP-1), it contributes to 25% to 70% of the postprandial insulin response.[3]
Issues of Concern
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Issues of Concern
Patients with type 2 diabetes mellitus have a high burden of renal failure and cardiovascular diseases. They often require a personalized approach based on their genetic predisposition and clinical presentation for glucose control. Further, patients are becoming increasingly resistant to monotherapy with metformin and sulfonylureas. Incretin-based therapy can be administered as an alternative or combination therapy to standard guidelines.[4] Studies have demonstrated lower all-cause mortality and reduced cardiovascular events in patients treated with combination therapy of metformin and dipeptidyl peptidase-4 (DPP-4) inhibitors.[5] Thus, understanding GIP and DPP-4 inhibition is imperative for optimal management of complex patients with type 2 diabetes mellitus.
Cellular Level
GIP is secreted by enteroendocrine K-cells, which are present in high density in the duodenum and upper jejunum but throughout the small intestine.[6][7] Oral ingestion and subsequent absorption of nutrients such as glucose, high amounts of amino acids, and long-chain fatty acids trigger the secretion of GIP.[6] K-cells sense the presence of glucose using a sodium-coupled glucose transporter-1 (SGLT-1) variant that evokes the GIP secretion.
Development
The gene sequence of GIP is well conserved across species.[3] GIP is a peptide hormone consisting of 42 amino acids and derives from the posttranslational processing of pre-pro-GIP, a protein consisting of 153 amino acids. It is structurally similar to members of the secretin/glucagon family, which includes secretin, glucagon, vasoactive intestinal peptide, and growth hormone-releasing factors.[8]
Organ Systems Involved
The action of GIP is primarily on the endocrine pancreas to potentiate glucose-dependent insulin secretion. Secondly, GIP decreases gastrin and gastrin-dependent acid secretion from the stomach's parietal cells.[9] GIP receptors are widely distributed and occur in the adipose tissue, bone, adrenal cortex, heart, pituitary, and brain regions such as the cerebral cortex, hippocampus, and olfactory bulb.[10] Finally, the kidneys are involved in the clearance of GIP.[11][12]
Function
The name given to the augmentation of insulin secretion by the action of gastrointestinal hormones is the entero-insular axis.[13] Therefore, GIP acts in the entero-insular axis as an anabolic hormone that increases insulin levels, glycogen, and fatty acid synthesis and inhibits fat breakdown. GIP also has extrapancreatic functions. In the stomach, GIP reduces acid secretion by the parietal cells. GIP has a dual effect on the bone as it causes the proliferation of osteoblasts and inhibits osteoclastic bone resorption. The widespread expression of GIP-R in the brain suggests that GIP might play an essential function in neurosignaling mechanisms.[14]
Mechanism
GIP acts on class-II G-protein coupled receptors.[15] The signaling mechanism for these receptors primarily involves the activation of adenylate cyclase/protein kinase A and phospholipase C/protein C cascades. High levels of GIP receptors are expressed in the beta cells of the pancreatic islets. The binding of GIP to its receptor increases the intracellular cAMP levels with a downstream increase in calcium ion concentration and exocytosis of insulin.[16] GIP is rapidly inactivated by the ubiquitous enzyme dipeptidyl peptidase 4 (DPP-4), which is the same enzyme that cleaves GLP-1.[16] However, the inactivation of GIP occurs at a slower rate than GLP-1, giving GIP a half-life of 5 to 7 minutes.[3] DPP-4 cleaves alanine and proline residues in position 2 of the N-terminus in peptide chains.[17] Thus, substituting L-alanine for D-alanine residue at position 2 of GIP makes it resistant to the action of DPP-4 and enhances its incretin effect.[18]
Related Testing
GIP is measured in the plasma using commercially available sandwich enzyme-linked immunoassay (ELISA) kits. The ELISA test is specific for GIP and does not cross-react with GLP-1 and GLP-2. GIP-(1-42), the biologically active form of GIP, is metabolized by DPP-4 to form GIP-(3-42). GIP-(3-42) is biologically inactive and is found to have a weak antagonizing effect on GIP receptors in rat models.[19] Specific assays for the N-terminus of GIP-(1-42) are used to quantify the levels of biologically active GIP in plasma.[11] However, an antibody directed against the C-terminal of the GIP peptide can be used to determine the total GIP secretion.[12]
Pathophysiology
Although hyper- or hyposecretion of GIP is not causally related to the pathogenesis of diseases, the secretion of GIP is altered in the following disease states:
Type 2 Diabetes Mellites
An abnormal incretin effect occurs in pathological glucose intolerance.[20] Patients with type 2 diabetes mellitus either have lower levels of GIP or beta-cell resistance to GIP as compared to healthy individuals who demonstrate a dose-dependent incretin response to oral glucose. Since incretins contribute to approximately 70% of the insulin response post meals, reduced incretin effect is responsible for the glucose intolerance seen in diabetics.[21]
Obesity
GIP plays a vital role in lipid metabolism and the development of obesity. Hyperplasia of K-cells and increased GIP levels are observed in obesity, as fat is a potent stimulus of GIP secretion. As mentioned above, GIP is an anabolic hormone that inhibits lipolysis and stimulates lipogenesis.
Food-Induced Cushing Syndrome
GIP, like ACTH, can cause hypersecretion of cortisol after mixed meals, leading to food-induced Cushing syndrome or ACTH-independent macronodular adrenal hyperplasia (AIMAH).[22] GIP-R are present in the zona fasciculate of the adrenal cortex. Following a meal, GIP concentration increases in the blood, causing an increase in cortisol even in the presence of low ACTH. Treatment of AIMAH involves the use of somatostatin analogs such as octreotide.[23]
Clinical Significance
DPP-4 inhibitors (linagliptin, saxagliptin, and sitagliptin) are oral hypoglycemic agents. Inhibition of DPP-4 results in increased plasma concentration of incretins and glucose-dependent insulin release. Therefore, they are beneficial in the treatment of diabetes. Studies have shown that DPP-4 inhibitors are well tolerated, weight neutral, and do not cause hypoglycemia due to their glucose-dependent action.[17] Also, gliptins are cardioprotective as they decrease systolic blood pressure and endothelial inflammation.[24] Although recent studies have shown gliptins to increase the risk of hospitalization with heart failure in patients with type 2 diabetes mellitus, this area requires more research.[25] Patients with type 2 diabetes mellitus are increasingly receiving treatment with modified Roux-en-Y gastric bypass surgery (RYGB). Several studies have demonstrated enhanced GLP-1 response and reduced GIP secretion following RYGB, which contributes to improved glucose tolerance following the surgery in patients with diabetes.[26]
References
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