Introduction

The glucose-dependent insulinotropic polypeptide (GIP), formerly termed "gastric inhibitory peptide," was first isolated in 1973 from porcine small intestine for its capacity to suppress gastric hydrochloric acid secretion. Comparative studies by John Brown and Raymond Pederson in 1970 provided the first evidence for its existence.[1] Subsequent investigations in 1980 demonstrated that GIP is only a weak inhibitor of acid secretion but a potent stimulator of postprandial insulin release.[2]

The incretin effect is defined as the enhanced insulin secretion observed in response to oral glucose compared to intravenous glucose, despite equivalent plasma glucose levels.[3] GIP is one of the principal incretin hormones and, together with glucagon-like peptide 1 (GLP-1), accounts for 25% to 70% of the postprandial insulin response.[4] For decades, GIP was regarded as an ineffective insulinotropic agent with limited therapeutic potential. The recent success of tirzepatide and emerging triple agonists targeting GLP-1, GIP, and glucagon receptors has renewed interest in GIP physiology and pharmacology.

Issues of Concern

Type 2 diabetes mellitus (T2DM) is associated with a high burden of renal failure and cardiovascular disease. Glucose control frequently requires a personalized approach guided by genetic predisposition and clinical presentation. Resistance to monotherapy with metformin or sulfonylureas has become increasingly common. Incretin-based therapy may be employed as an alternative or combined with standard regimens.[5] Combination therapy with metformin and dipeptidyl peptidase 4 (DPP-4) inhibitors has been associated with lower all-cause mortality and fewer cardiovascular events.[6]

Recent therapeutic strategies that target GIP in addition to other incretin hormones have demonstrated reductions in glycemic levels, greater weight loss, and fewer adverse cardiovascular outcomes. A comprehensive understanding of GIP physiology and DPP-4 inhibition is essential for optimizing the management of T2DM.

Cellular Level

GIP is secreted by enteroendocrine K cells, which are most abundant in the duodenum and proximal jejunum but are distributed throughout the small intestine.[7] The hormone is synthesized as pro-GIP and subsequently cleaved by prohormone convertase 1/3 (PC1/3) into its active form.[8]

Nutrient ingestion is the primary stimulus for GIP release. Glucose, large neutral amino acids, and long-chain fatty acids are potent GIP secretagogues.[9] K cells detect luminal glucose through a mechanism mediated by sodium-coupled glucose transporter 1 (SGLT1). Fructose, which enters cells via glucose transporter 5 (GLUT5), does not effectively stimulate GIP secretion in healthy adults.[10] Insulin contributes to negative feedback regulation by suppressing K-cell activity and thereby limiting GIP release.[11]

GIP exerts its effects through a 7-transmembrane G protein-coupled receptor, activating adenylate cyclase and increasing cyclic adenosine monophosphate (cAMP). This rise in cAMP activates protein kinase A, ultimately leading to insulin secretion from pancreatic β-cells.[12] Transcriptional regulation of GIP involves the GIP promoter region, which contains 2 binding sites for cAMP response element binding protein 1 (CRE-BP1).[13] Additional transcription factors that govern K-cell differentiation and function further modulate GIP gene expression.

Several peptides influence GIP secretion and activity. Gastrin-releasing peptide (GRP) and somatostatin regulate K-cell output, while xenin-25, a 25-amino acid neurotensin-related peptide produced by K cells, enhances GIP-mediated insulin release. The potentiating effect of xenin-25 on glucose-stimulated insulin secretion is attenuated in T2DM.[14] This synergistic action appears to be mediated by cholinergic neural pathways rather than a direct effect on pancreatic β-cells.[15]

Development

GIP was first purified from porcine intestinal extracts in the early 1970s, with John Brown among the key researchers involved in its identification.[16] The gene sequence is highly conserved across mammalian species. GIP is a 42-amino acid peptide hormone generated through posttranslational processing of pre-pro-GIP, a 153–amino acid precursor protein. The molecule shares structural homology with members of the secretin/glucagon peptide family, which includes secretin, glucagon, vasoactive intestinal peptide, GLPs, and growth hormone–releasing factors.[17]

Organ Systems Involved

The principal action of GIP is on the endocrine pancreas, where it potentiates glucose-dependent insulin secretion. A secondary effect is the suppression of gastrin release and gastrin-dependent gastric acid secretion from parietal cells.[18]

GIP receptors are widely distributed and have been identified in adipose tissue, bone, adrenal cortex, heart, pituitary, and brain regions, including the cerebral cortex, hippocampus, and olfactory bulb.[19] In the heart, receptor expression is present at low levels in cardiomyocytes, adipocytes, and pericytes of both atria and ventricles.[20] Low-level expression has also been demonstrated in the immune system, primarily in subsets of T cells and macrophages.[21]

Renal clearance contributes significantly to GIP metabolism.[22][23] Tissues with high metabolic activity, such as hepatocytes and skeletal myocytes, do not express GIP receptors. However, GIP exerts indirect effects on these systems through neural mechanisms and vascular actions of circulating mediators.[24]

Function

The term "enteroinsular axis" refers to the augmentation of insulin secretion by gastrointestinal hormones in response to nutrient intake.[25] Within this axis, GIP functions as an anabolic hormone by enhancing insulin secretion, stimulating glycogen and fatty acid synthesis, and inhibiting lipolysis. GIP receptors are expressed on pancreatic α, β, δ, and PP cells. Oral glucose absorption provides the stimulus for β-cells in the islets of Langerhans to intensify insulin secretion.[26] In healthy adults, GIP increases glucagon release from pancreatic α-cells during hypoglycemia and fasting but has little effect during hyperglycemia.[27]

GIP also exerts extrapancreatic effects. In the stomach, the hormone reduces gastric acid secretion from parietal cells. In bone, GIP promotes osteoblast proliferation and inhibits osteoclast-mediated resorption. The widespread expression of GIP receptors in the brain indicates a role in neurosignaling.[28] Central receptor activity is implicated in the regulation of appetite, satiety, food and energy intake, and energy expenditure. Effects on body weight regulation have contributed to the therapeutic relevance of GIP and related incretin hormones. In experimental models, GIP has demonstrated neuroprotective activity and has been linked to hippocampal neurogenesis in rats and mice (see Image. Tissue-Specific Actions of Glucose-Dependent Insulinotropic Polypeptide).[29]

Mechanism

GIP acts through class II G protein-coupled receptors.[30] The primary signaling pathways involve the activation of adenylate cyclase with subsequent protein kinase A signaling, as well as phospholipase C-mediated activation of protein kinase C. GIP receptors are expressed at high levels in pancreatic β-cells. Ligand binding increases intracellular cAMP, leading to elevated intracellular calcium concentrations and exocytosis of insulin granules.

GIP is rapidly inactivated by DPP-4, the same enzyme responsible for GLP-1 degradation.[31] Inactivation occurs more slowly than with GLP-1, conferring a plasma half-life of 5 to 7 minutes. DPP-4 cleaves alanine or proline residues at the 2nd position of the peptide N-terminus.[32] Substitution of L-alanine with D-alanine at position 2 renders GIP resistant to DPP-4 activity and enhances its incretin effect.[33]

Related Testing

Plasma GIP levels are measured using commercially available sandwich enzyme-linked immunoassay (ELISA) kits. These assays are specific for GIP and do not cross-react with GLP-1 or GLP-2. The biologically active form, GIP (1-42), is metabolized by DPP-4 to generate GIP (3-42), which is inactive and exhibits weak antagonistic activity at GIP receptors in rat models.[34] Quantification of active GIP in plasma is achieved with assays targeting the N-terminus of GIP (1-42). Antibodies directed against the C-terminal region of the peptide are used to measure total GIP secretion.

Pathophysiology

Alterations in GIP secretion and action have been documented in several pathological conditions. Although hypersecretion or hyposecretion is not causally related to disease pathogenesis, changes in GIP regulation are observed in the disorders described below.

Type 2 Diabetes  Mellitus

An abnormal incretin effect is a feature of pathological glucose intolerance.[35] Patients with T2DM either have reduced circulating GIP concentrations or β-cell resistance to GIP, in contrast to healthy individuals who exhibit a dose-dependent incretin response to oral glucose. Since incretins contribute to approximately 70% of the postprandial insulin response, a diminished incretin effect accounts for the impaired glucose tolerance observed in diabetes.[36]

The insulinotropic response to GIP is impaired primarily during the late phase of insulin secretion.[37] In contrast, GIP-mediated regulation of glucagon secretion does not differ between patients with T2DM and healthy controls. Following bariatric surgery, an augmented GIP response has been observed in patients with diabetes.[38] Partial restoration of GIP function has also been reported after optimization of glycemic control with insulin, sulfonylureas, or DPP-4 inhibitors.

Obesity

GIP is a key regulator of lipid metabolism and contributes to the pathophysiology of obesity. K-cell hyperplasia and elevated GIP levels are frequently observed in individuals with obesity, as dietary fat is a potent stimulus of GIP secretion. GIP exerts anabolic effects by suppressing lipolysis and promoting lipogenesis. The incretin effect of GIP is attenuated in obesity and shows an inverse correlation with body mass index.[39]

Food-Induced Cushing Syndrome

GIP, similar to ACTH, can cause postprandial hypersecretion of cortisol, resulting in food-induced Cushing syndrome or ACTH-independent macronodular adrenal hyperplasia (AIMAH).[40] GIP receptors are expressed in the zona fasciculata of the adrenal cortex. Circulating GIP concentrations rise after a meal, which can drive cortisol secretion even when ACTH levels are low. ACTH-independent macronodular adrenal hyperplasia arises from a germline mutation or somatic loss of KDM1A expression, leading to cortisol secretion in response to gut-derived GIP.[40] Treatment strategies include the use of somatostatin analogs such as octreotide.[41] 

Cystic Fibrosis 

In cystic fibrosis, pancreatic exocrine insufficiency leads to digestive abnormalities that can blunt enteroinsular axis activity, in which GIP is a key component. The insulinotropic effect of GIP has been shown to be attenuated in patients with cystic fibrosis and pancreatic insufficiency.[42] This impaired incretin response may contribute to an increased risk of diabetes development in this population.

Insulinoma and Other Neuroendocrine Tumors

Overproduction of GIP and upregulation of GIP receptor expression have been reported in insulinomas and somatotropinomas. Despite the marked hypersecretion of GIP in insulinomas, the insulinotropic effect of GIP appears to be abolished in many cases.[43] 

Kidney Disease

Circulating GIP concentrations are elevated because of reduced renal clearance in patients with chronic kidney disease or renal failure. Although GIP receptors have not been detected in renal tissue, no additional biological effects of elevated circulating GIP have been identified to date.

Clinical Significance

DPP-4 inhibitors, including linagliptin, saxagliptin, and sitagliptin, are oral hypoglycemic agents. By inhibiting DPP-4, these agents increase circulating incretin concentrations and enhance glucose-dependent insulin secretion. DPP-4 inhibitors are generally well tolerated, weight-neutral, and do not cause hypoglycemia because of their glucose-dependent mechanism of action. Cardioprotective effects have also been reported, including reductions in systolic blood pressure and endothelial inflammation.[44] However, clinical trials have shown that saxagliptin, but not other DPP-4 inhibitors, is associated with an increased risk of hospitalization for heart failure in patients with T2DM.[45]

Modified Roux-en-Y gastric bypass surgery is increasingly used in managing T2DM. Several studies have demonstrated that this procedure enhances GLP-1 secretion and alters GIP secretion, which collectively contribute to improved glucose tolerance after surgery.[46]

GIP receptors have also become therapeutic targets in the development of new antidiabetic medications. Tirzepatide, a dual GLP-1 and GIP receptor agonist, has demonstrated superior efficacy in weight reduction and glycemic control compared with GLP-1 receptor agonists such as semaglutide, particularly at higher doses of 10 and 15 mg.[47][48] Tirzepatide has also received U.S. Food and Drug Administration approval for the treatment of obstructive sleep apnea, and ongoing clinical studies are investigating its potential benefits in several other conditions, including polycystic ovarian syndrome, psoriasis, cardiovascular disease, and alcohol use disorder. Furthermore, triple-receptor agonists such as reatrutide are in phase III clinical trials and may provide additional therapeutic benefit in weight management and T2DM.

Tirzepatide is associated with adverse effects that are typical of incretin-based therapies, most notably gastrointestinal symptoms such as nausea, vomiting, diarrhea, and constipation. These events are dose-dependent, generally mild to moderate, and arise from delayed gastric emptying and central appetite regulation mediated primarily through GLP-1 receptor activation. Less common but clinically relevant risks include gallbladder and biliary disorders, which have also been reported with other GLP-1 receptor agonists.[49][50] Quantitative partitioning of effects between GIP and GLP-1 in humans has not been definitively established. However, GIP agonism has not been shown to introduce additional adverse effects and may mitigate GLP-1–mediated nausea, thereby improving gastrointestinal tolerability and enabling greater therapeutic exposure.[51]

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Disclosure: Tej Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Marjorie Launico declares no relevant financial relationships with ineligible companies.