Glucose-dependent insulinotropic polypeptide (GIP) is definitively classified as an incretin hormone, playing a crucial role in glucose homeostasis alongside glucagon-like peptide-1 (GLP-1). Incretins are gastrointestinal hormones that enhance insulin secretion from pancreatic beta cells in response to food intake, accounting for 50–70% of the total insulin response following oral glucose. GIP, secreted by K-cells in the proximal small intestine, stimulates insulin release in a glucose-dependent manner, minimising hypoglycaemia risk. Recent therapeutic advances, particularly dual GIP/GLP-1 receptor agonists such as tirzepatide, have revolutionised type 2 diabetes management, demonstrating superior glycaemic control and substantial weight loss. Understanding GIP's incretin properties is essential for clinicians managing diabetes and optimising contemporary treatment strategies.

What Are Incretins and How Do They Work?

Incretins are a group of gastrointestinal hormones released from specialised enteroendocrine cells in the intestinal mucosa in response to nutrient ingestion, particularly glucose and other carbohydrates. These hormones play a crucial role in glucose homeostasis by enhancing insulin secretion from pancreatic beta cells in a glucose-dependent manner—a phenomenon known as the incretin effect. In healthy individuals, this effect accounts for approximately 50–70% of the total insulin response following oral glucose intake, compared with intravenous glucose administration, though the precise contribution varies across studies and methodologies.

The primary mechanism of action involves binding to specific G-protein-coupled receptors on pancreatic beta cells, which triggers a cascade of intracellular signalling pathways. This results in increased cyclic adenosine monophosphate (cAMP) levels, enhanced calcium influx, and ultimately potentiation of glucose-stimulated insulin secretion. Importantly, incretin hormones exhibit glucose-dependent activity, meaning they stimulate insulin release only when blood glucose levels are elevated, thereby minimising the risk of hypoglycaemia.

The two principal incretin hormones identified in humans are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Beyond their insulinotropic effects, GLP-1 exerts multiple metabolic actions including potent suppression of glucagon secretion from pancreatic alpha cells (which reduces hepatic glucose output), marked slowing of gastric emptying to moderate postprandial glucose excursions, and effects on satiety and body weight regulation. GIP's effects on glucagon and gastric emptying are more variable and context-dependent. Both hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), limiting their physiological half-life to just a few minutes.

Understanding incretin physiology has revolutionised diabetes management, leading to the development of incretin-based therapies including GLP-1 receptor agonists and DPP-4 inhibitors, which are now established treatment options recommended by NICE (NG28) for type 2 diabetes mellitus.

Is GIP an Incretin Hormone?

Yes, glucose-dependent insulinotropic polypeptide (GIP) is definitively classified as an incretin hormone. Originally discovered in 1973 and initially termed gastric inhibitory polypeptide due to its effects on gastric acid secretion, GIP was subsequently recognised as a potent insulin secretagogue and renamed to reflect its primary physiological role. GIP is a 42-amino acid peptide hormone secreted by enteroendocrine K-cells, which are predominantly located in the proximal small intestine, particularly the duodenum and jejunum.

GIP secretion is rapidly stimulated following food intake, with nutrients such as glucose, fatty acids, and amino acids serving as potent secretagogues. Plasma GIP concentrations rise within minutes of eating, reaching peak levels approximately 30–60 minutes postprandially. The hormone then binds to GIP receptors (GIPR), which are expressed not only on pancreatic beta cells but also in adipose tissue, bone, and the central nervous system, suggesting pleiotropic metabolic effects beyond glucose regulation.

The insulinotropic action of GIP represents a major contributor to the incretin effect in healthy individuals, though the relative contributions of GIP and GLP-1 vary across studies and physiological conditions. Like other incretin hormones, GIP's insulin-releasing properties are strictly glucose-dependent, providing an inherent safety mechanism against hypoglycaemia. The hormone also influences lipid metabolism, with effects on triglyceride storage in adipocytes observed in preclinical models; the clinical significance of these effects in humans requires further investigation. Similarly, whilst GIP receptors are expressed in bone, the role of GIP in human bone metabolism remains an area of active research.

However, the incretin effect mediated by GIP appears to be significantly impaired in individuals with type 2 diabetes mellitus. Research indicates that whilst GIP secretion may be preserved or even elevated in these patients, the insulinotropic response to GIP is markedly reduced, a phenomenon termed 'GIP resistance'. This observation initially led to therapeutic strategies focusing predominantly on GLP-1 pathways, though recent evidence has prompted re-evaluation of GIP's therapeutic potential.

Clinical Evidence for GIP-Based Therapies

For many years, the therapeutic exploitation of GIP was considered less promising than GLP-1-based approaches, primarily due to the observed GIP resistance in type 2 diabetes and concerns that GIP receptor activation might promote weight gain through its adipogenic effects. However, recent clinical developments have dramatically altered this perspective, particularly with the emergence of dual GIP/GLP-1 receptor agonists such as tirzepatide.

Tirzepatide (Mounjaro), approved by the MHRA in 2023 for type 2 diabetes management, represents a novel therapeutic class that simultaneously activates both GIP and GLP-1 receptors. Landmark clinical trials including SURPASS-1 through SURPASS-5 have demonstrated that tirzepatide produces superior glycaemic control compared with selective GLP-1 receptor agonists, with HbA1c reductions of up to approximately 27 mmol/mol (2.5%) from baseline. Remarkably, these trials also showed substantial weight loss, with reductions exceeding 10 kg in many participants—contradicting earlier concerns about GIP's potential obesogenic effects.

The mechanisms underlying these impressive clinical outcomes remain an area of active investigation. Current evidence suggests that GIP receptor activation may enhance the beneficial effects of GLP-1 through synergistic actions on insulin secretion. Some research indicates that GIP may influence central appetite pathways and potentially promote energy expenditure when combined with GLP-1 receptor activation, though these mechanistic hypotheses require further elucidation and should be interpreted cautiously.

NICE guidance (TA928) recommends tirzepatide as an option for adults with type 2 diabetes in circumstances where a GLP-1 receptor agonist would otherwise be considered under the treatment algorithms in NG28. This typically includes patients with inadequate glycaemic control on metformin-based therapy, often in combination with other oral agents or insulin, and where specific HbA1c and BMI criteria are met. Treatment should be continued only if a clinically meaningful response is achieved—for example, a reduction in HbA1c of at least 11 mmol/mol (1.0%) and weight loss of at least 3% of initial body weight at around 6 months, as per NG28 continuation criteria for GLP-1 receptor agonists.

Common adverse effects mirror those of GLP-1 agonists and include gastrointestinal symptoms such as nausea, vomiting, and diarrhoea, which are usually transient and dose-dependent. Patients should be counselled about these potential effects and advised to contact their GP if symptoms persist or worsen. Severe gastrointestinal symptoms may lead to dehydration; patients should maintain adequate fluid intake and seek medical advice if they develop signs of dehydration or acute kidney injury (reduced urine output, dizziness, confusion). Additional important safety considerations include: risk of hypoglycaemia when used with insulin or sulfonylureas (dose adjustments of these agents may be required); potential for gallbladder disease (cholelithiasis, cholecystitis); injection-site reactions; and, as with rapid HbA1c reductions from any cause, potential worsening of diabetic retinopathy in susceptible individuals. Whilst there are theoretical concerns regarding pancreatitis risk with incretin-based therapies, causality remains unestablished; patients experiencing severe, persistent abdominal pain should seek immediate medical attention. Patients should report any suspected side effects via the MHRA Yellow Card scheme (available at yellowcard.mhra.gov.uk or via the Yellow Card app).

How GIP Differs from GLP-1

Whilst both GIP and GLP-1 are classified as incretin hormones sharing the common function of glucose-dependent insulin secretion, they exhibit important physiological and pharmacological differences that have significant therapeutic implications. Understanding these distinctions helps explain why dual agonist approaches may offer advantages over selective GLP-1 therapies.

Anatomical distribution and secretion patterns differ substantially between the two hormones. GIP is secreted primarily from K-cells in the proximal small intestine (duodenum and jejunum), with secretion triggered rapidly by nutrient absorption, particularly fats and carbohydrates. In contrast, GLP-1 is produced by L-cells located predominantly in the distal ileum and colon, with a somewhat delayed secretory response. This spatial separation suggests complementary roles in coordinating the body's metabolic response to feeding throughout the digestive process.

Regarding metabolic effects beyond insulin secretion, notable differences emerge. GLP-1 consistently and potently suppresses glucagon secretion, markedly slows gastric emptying, and reduces appetite through central mechanisms—effects that collectively contribute to weight loss. GIP's effects on glucagon are more complex, variable, and context-dependent, and its influence on gastric emptying appears less pronounced or inconsistent. Importantly, GIP receptors are abundantly expressed in adipose tissue where they may promote lipid storage in certain contexts, leading to initial concerns about weight gain. However, emerging evidence suggests that in the context of dual agonism, GIP may facilitate metabolic benefits including potential effects on fat oxidation and energy expenditure, though these mechanisms remain under investigation and require further validation.

The preservation of GIP secretion but loss of insulinotropic response in type 2 diabetes represents another key distinction. Whilst GLP-1's effects are diminished but not abolished in diabetes, GIP's insulin-releasing capacity is more severely compromised. Paradoxically, this 'GIP resistance' may be partially overcome through pharmacological receptor activation with synthetic agonists, particularly when combined with GLP-1 receptor stimulation.

Clinical implications of these differences are increasingly recognised. Patients prescribed dual GIP/GLP-1 agonists should be monitored for glycaemic control and weight changes according to standard diabetes care protocols outlined in NICE NG28. Those experiencing inadequate response or intolerable side effects should discuss alternative treatment options with their healthcare provider, as individual responses to incretin-based therapies can vary considerably.

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