The incretin effect describes how eating food triggers a much stronger insulin response than receiving glucose directly into the bloodstream, even when blood sugar levels are the same. This remarkable difference—accounting for 50–70% of insulin released after a meal in healthy people—is driven by gut hormones called incretins. In type 2 diabetes, this effect is substantially reduced, contributing to poor blood sugar control. Understanding the incretin effect has revolutionised diabetes treatment, leading to new medications that restore this natural mechanism and are now recommended by NICE for specific patient groups.

What Is the Incretin Effect?

The incretin effect refers to the phenomenon whereby oral glucose intake stimulates a significantly greater insulin response compared to intravenous glucose administration, even when blood glucose concentrations are identical. This difference accounts for approximately 50–70% of total insulin secretion following a meal in healthy individuals, highlighting the crucial role of gut-derived hormones in glucose homeostasis.

The term 'incretin' reflects these hormones' primary function of enhancing pancreatic beta-cell insulin release in a glucose-dependent manner. This physiological mechanism represents an elegant feedback system linking nutrient absorption in the gastrointestinal tract with metabolic regulation. When food enters the digestive system, specialised enteroendocrine cells release incretin hormones into the bloodstream, which then act on pancreatic beta cells to amplify insulin secretion.

In individuals with type 2 diabetes mellitus, the incretin effect is substantially diminished, contributing to postprandial hyperglycaemia and overall glycaemic dysregulation. This impairment occurs through multiple mechanisms: whilst GLP-1 secretion may be modestly reduced, the most significant defect is the markedly diminished insulinotropic response to GIP in type 2 diabetes, alongside decreased beta-cell responsiveness to incretin signalling. Understanding these defects has proven pivotal in developing novel therapeutic strategies.

The discovery and characterisation of the incretin effect has advanced diabetes management over the past two decades. Recognition that this physiological pathway is compromised in type 2 diabetes has led to the development of incretin-based therapies, which are now widely used under specific criteria recommended by NICE and other international guidelines.

How Incretin Hormones Regulate Blood Sugar

Two principal incretin hormones mediate glucose regulation: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), formerly known as gastric inhibitory polypeptide. These peptides are secreted by enteroendocrine L-cells and K-cells respectively, located predominantly in the distal small intestine and duodenum.

Following meal ingestion, these hormones are rapidly released in response to nutrient detection, particularly glucose, fatty acids, and amino acids. GLP-1 and GIP bind to specific G-protein coupled receptors on pancreatic beta cells, triggering intracellular signalling cascades that enhance glucose-dependent insulin secretion. Crucially, this insulinotropic effect only occurs when blood glucose levels are elevated, thereby minimising hypoglycaemia risk—a significant advantage over some traditional diabetes medications.

Beyond insulin secretion, incretin hormones—particularly GLP-1—exert multiple complementary effects on glucose homeostasis:

• Suppression of glucagon secretion from pancreatic alpha cells (primarily a GLP-1 effect), reducing hepatic glucose output

• Delayed gastric emptying (primarily a GLP-1 effect), which slows carbohydrate absorption and attenuates postprandial glucose excursions

• Promotion of satiety through central nervous system pathways (primarily a GLP-1 effect), potentially reducing caloric intake

• Potential preservation of beta-cell function through anti-apoptotic and proliferative effects demonstrated in animal models, though evidence in humans remains limited

GIP shares the insulinotropic action but does not suppress glucagon or delay gastric emptying to the same extent as GLP-1, and may even increase glucagon secretion under certain glycaemic conditions.

Under physiological conditions, incretin hormones have an extremely short half-life, typically less than two minutes for GLP-1, due to rapid enzymatic degradation by dipeptidyl peptidase-4 (DPP-4). This swift inactivation ensures tight temporal regulation of the incretin response but also presents challenges for therapeutic exploitation, which has been addressed through pharmaceutical innovation in incretin-based medications.

Incretin-Based Therapies and Treatment Options

The therapeutic manipulation of the incretin system has yielded two distinct classes of medications now widely used in type 2 diabetes management: GLP-1 receptor agonists (also called GLP-1 analogues or incretin mimetics) and DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors, also known as gliptins).

GLP-1 receptor agonists are synthetic analogues or modified versions of human GLP-1 that resist DPP-4 degradation, providing sustained receptor activation. Available formulations in the UK include exenatide, lixisenatide, liraglutide, dulaglutide, and semaglutide, administered via subcutaneous injection with varying frequencies from twice daily to once weekly. Oral semaglutide represents the first orally administered GLP-1 receptor agonist. These agents typically produce HbA1c reductions of 1.0–1.5% (11–16 mmol/mol) alongside significant weight loss (average 2–5 kg), making them particularly valuable for overweight patients.

NICE NG28 recommends considering GLP-1 receptor agonists for adults with type 2 diabetes when triple therapy with metformin and two other oral drugs is not effective, not tolerated, or contraindicated, and the person has:

• a body mass index (BMI) of 35 kg/m² or above (adjust accordingly for people from Black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity, or

• a BMI lower than 35 kg/m² and for whom insulin therapy would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities.

Continue GLP-1 receptor agonist therapy only if there is a beneficial metabolic response (a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss of at least 3% of initial body weight at 6 months).

DPP-4 inhibitors, including sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin, work by preventing the enzymatic breakdown of endogenous GLP-1 and GIP, thereby prolonging their activity. These oral medications produce more modest glycaemic improvements (HbA1c reduction ~0.5–0.8% [5–9 mmol/mol]) and are weight-neutral but offer excellent tolerability and low hypoglycaemia risk.

Common adverse effects of GLP-1 receptor agonists include gastrointestinal disturbances—particularly nausea, vomiting, and diarrhoea—which typically diminish with continued use. Serious safety concerns include pancreatitis (reported with both GLP-1 receptor agonists and DPP-4 inhibitors), gallbladder disease including cholelithiasis and cholecystitis, and a potential increased risk of diabetic retinopathy complications with semaglutide in patients with pre-existing retinopathy. DPP-4 inhibitors generally demonstrate favourable safety profiles, with nasopharyngitis and headache being the most frequently reported side effects; rare but serious adverse reactions include pancreatitis, severe arthralgia, and bullous pemphigoid.

Both drug classes are not indicated for type 1 diabetes or for the treatment of diabetic ketoacidosis. Dose adjustments or caution are required for some agents in patients with renal impairment; consult individual Summary of Product Characteristics (SmPC) for specific guidance. Patients should be advised to report suspected side effects via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk or via the Yellow Card app.

The Role of GLP-1 and GIP in Glucose Control

Glucagon-like peptide-1 (GLP-1) represents the more extensively studied and therapeutically exploited incretin hormone. Secreted primarily by intestinal L-cells in response to nutrient ingestion, GLP-1 exerts potent glucose-lowering effects through multiple complementary mechanisms. Its glucose-dependent insulinotropic action ensures insulin secretion is appropriately matched to metabolic demand, whilst simultaneous glucagon suppression reduces inappropriate hepatic glucose production during the postprandial period. Importantly, the insulinotropic effect of GLP-1 is relatively preserved in type 2 diabetes, making it an attractive therapeutic target.

GLP-1's extrapancreatic effects contribute substantially to its therapeutic value. Gastric emptying delay reduces the rate of glucose appearance in the circulation, directly attenuating postprandial glycaemic spikes. Central appetite regulation through hypothalamic GLP-1 receptors promotes satiety and reduces food intake, explaining the weight loss observed with GLP-1-based therapies. Emerging evidence suggests potential cardiovascular benefits, with several GLP-1 receptor agonists (including liraglutide, semaglutide injection, and dulaglutide) demonstrating reduced major adverse cardiovascular events in outcome trials; some UK-licensed products now include cardiovascular risk reduction indications in their SmPCs.

Glucose-dependent insulinotropic polypeptide (GIP), secreted by duodenal and jejunal K-cells, was historically considered the dominant incretin but has received less therapeutic attention. GIP shares GLP-1's insulinotropic properties but differs in several important respects: it does not suppress glucagon secretion or delay gastric emptying, and may even increase glucagon under certain conditions. Critically, in type 2 diabetes, the insulinotropic effect of GIP is markedly reduced, contrasting with GLP-1's relatively preserved activity. This differential impairment explains the therapeutic focus on GLP-1 pathways.

Recent pharmaceutical developments have explored dual GLP-1/GIP receptor agonists, such as tirzepatide, which harness the complementary actions of both incretins. Early clinical data suggest superior glycaemic control and weight reduction compared to selective GLP-1 agonists. Tirzepatide is licensed in the UK for the treatment of adults with insufficiently controlled type 2 diabetes mellitus; consult NICE guidance and the MHRA SmPC for current recommendations and safety information.

Patients experiencing severe or persistent abdominal pain, unexplained nausea, vomiting, or other concerning symptoms whilst taking incretin-based therapies should contact their GP promptly for clinical assessment. Severe abdominal pain radiating to the back may indicate pancreatitis and requires urgent medical attention; patients should seek immediate help via NHS 111 or attend A&E if symptoms are severe.

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