Incretin hormones, particularly glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are central to glucose regulation and pancreatic beta cell function. These gastrointestinal hormones, released after eating, account for up to 70% of insulin secretion following meals in healthy individuals. In type 2 diabetes, this incretin effect is markedly reduced, contributing to impaired glucose control. Understanding incretin beta cell function has transformed diabetes treatment, leading to therapies that enhance insulin secretion, support beta cell health, and improve metabolic outcomes. This article examines how incretins influence beta cell function, their role in diabetes pathophysiology, and the clinical evidence for incretin-based treatments in preserving pancreatic function.

What Are Incretins and How Do They Work?

Incretins are gastrointestinal hormones released in response to nutrient ingestion, playing a crucial role in glucose homeostasis. The two principal incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is secreted from L-cells and GIP from K-cells, both located in enteroendocrine tissue of the small intestine following food intake. These hormones account for approximately 50–70% of postprandial insulin secretion in healthy individuals, a phenomenon known as the incretin effect.

The mechanism of action involves binding to specific G-protein-coupled receptors on pancreatic beta cells. When GLP-1 binds to its receptor (GLP-1R), it activates adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels. This cascade amplifies glucose-stimulated insulin secretion in a glucose-dependent manner, meaning insulin release only occurs when blood glucose concentrations are elevated. This glucose-dependency significantly reduces the risk of hypoglycaemia compared to other insulin secretagogues such as sulphonylureas.

Beyond their insulinotropic effects, incretins exert multiple metabolic actions. GLP-1 suppresses glucagon secretion from pancreatic alpha cells, slows gastric emptying, and promotes satiety through central nervous system pathways. GIP also stimulates insulin secretion and may influence lipid metabolism and bone turnover. Importantly, both hormones are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), with plasma half-lives of approximately 2 minutes for GLP-1 and 7 minutes for GIP.

Understanding incretin physiology has revolutionised diabetes management, leading to the development of therapeutic agents that either mimic incretin action (GLP-1 receptor agonists) or prevent incretin degradation (DPP-4 inhibitors). These medications harness the body's natural glucose-regulating mechanisms. Whilst preclinical studies suggest potential benefits for beta cell health, evidence for durable beta cell preservation in humans remains limited, with observed improvements in beta cell function largely reflecting functional enhancement during active treatment rather than permanent structural changes.

The Role of Incretins in Beta Cell Function

Incretins play a multifaceted role in maintaining pancreatic beta cell health, extending beyond acute insulin secretion to encompass beta cell survival and functional capacity. Preclinical studies in animal models and cell culture have demonstrated that GLP-1 receptor activation may promote beta cell mass through several mechanisms, including stimulation of beta cell proliferation, enhancement of beta cell neogenesis from progenitor cells, and inhibition of apoptosis (programmed cell death). However, it is important to note that these findings are predominantly from experimental models and their translation to adult humans remains uncertain.

The cytoprotective effects of incretins observed in preclinical research involve multiple intracellular signalling pathways. GLP-1 receptor activation triggers the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which promotes cell survival by inhibiting pro-apoptotic proteins. Additionally, incretin signalling enhances the expression of genes involved in beta cell differentiation and function, including pancreatic and duodenal homeobox 1 (PDX-1) and insulin gene transcription factors. These molecular effects suggest that incretins may help maintain the beta cell phenotype and functional identity in experimental settings.

Incretins may also protect beta cells from various metabolic stresses encountered in diabetes. Glucotoxicity (damage from chronic hyperglycaemia) and lipotoxicity (damage from elevated free fatty acids) contribute to beta cell dysfunction and death in type 2 diabetes. Experimental evidence indicates that GLP-1 can mitigate oxidative stress and endoplasmic reticulum stress within beta cells, both of which are implicated in diabetes pathogenesis. Laboratory studies have also shown that incretins may improve glucose sensing through upregulation of glucose transporter expression and glucokinase activity, and facilitate proper insulin biosynthesis, processing, and granule formation.

Whilst these preclinical data are promising, the extent to which incretin-based therapies achieve similar beta cell preservation or regeneration in humans is not established. Current evidence suggests that incretin therapies improve beta cell function during treatment, but whether they fundamentally alter the progressive nature of type 2 diabetes or provide lasting structural benefits to beta cells remains an area of ongoing research.

Incretin Effect in Type 2 Diabetes

The incretin effect is markedly diminished in individuals with type 2 diabetes, representing a significant pathophysiological defect contributing to impaired glucose control. Whilst healthy individuals exhibit a 50–70% incretin contribution to postprandial insulin secretion, this effect is reduced to approximately 20–30% in people with type 2 diabetes. This reduction occurs despite normal or even elevated GIP secretion, suggesting incretin resistance rather than deficiency.

The mechanisms underlying impaired incretin effect in type 2 diabetes remain incompletely understood but appear multifactorial. Beta cell dysfunction is central, as the capacity to respond to incretin stimulation diminishes with progressive beta cell failure. Research suggests there may be reduced GLP-1 receptor expression and impaired downstream signalling in diabetic beta cells, though the evidence in humans is limited. Additionally, chronic hyperglycaemia itself may desensitise beta cells to incretin action, creating a cycle of metabolic deterioration.

GIP resistance is particularly pronounced in type 2 diabetes, with the insulinotropic effect of GIP being substantially blunted even at supraphysiological doses. In contrast, the response to GLP-1, whilst reduced, is generally better preserved. This differential response has important therapeutic implications, as GLP-1-based therapies can partially restore glucose-dependent insulin secretion even in established diabetes. The reasons for selective GIP resistance are unclear but may involve receptor downregulation or post-receptor signalling defects.

Interestingly, the incretin defect appears early in the natural history of type 2 diabetes, being present in individuals with impaired glucose tolerance and potentially in some first-degree relatives of people with diabetes. This observation suggests that incretin dysfunction may be both a consequence of metabolic abnormalities and a contributing factor to diabetes development. Weight loss and improved glycaemic control can partially restore the incretin effect, indicating some degree of reversibility. Understanding these mechanisms has informed the rationale for incretin-based therapeutic approaches in diabetes management.

Incretin-Based Therapies and Beta Cell Preservation

Incretin-based therapies comprise two main classes: GLP-1 receptor agonists and DPP-4 inhibitors. GLP-1 receptor agonists available in the UK include exenatide, liraglutide, semaglutide (injectable and oral formulations), dulaglutide, and lixisenatide. Tirzepatide (Mounjaro) is a newer dual GIP/GLP-1 receptor agonist licensed in the UK for type 2 diabetes. DPP-4 inhibitors include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. GLP-1 receptor agonists provide pharmacological receptor stimulation, whilst DPP-4 inhibitors prevent endogenous incretin degradation, thereby increasing physiological incretin levels.

The potential for these agents to preserve or restore beta cell function has generated considerable research interest. Preclinical studies in animal models have consistently demonstrated that GLP-1 receptor agonists can increase beta cell mass, reduce apoptosis, and improve beta cell function. However, evidence for durable beta cell preservation or regeneration in humans is not established, and observed improvements in beta cell function markers largely reverse upon treatment discontinuation.

In clinical practice, incretin-based therapies improve glycaemic control through multiple mechanisms. GLP-1 receptor agonists reduce HbA1c by 0.8–1.5%, promote weight loss (typically 2–5 kg), and carry minimal hypoglycaemia risk when used without insulin or sulphonylureas. NICE guideline NG28 recommends GLP-1 receptor agonists as an option for people with type 2 diabetes, particularly when additional weight loss would benefit other comorbidities. Importantly, GLP-1 receptor agonists with proven cardiovascular benefit (liraglutide, semaglutide, dulaglutide) may be considered earlier in treatment pathways for people with established cardiovascular disease or at high cardiovascular risk, alongside or as an alternative to SGLT2 inhibitors depending on individual clinical circumstances and comorbidities such as chronic kidney disease or heart failure.

DPP-4 inhibitors offer more modest glycaemic improvements (HbA1c reduction of 0.5–0.8%) but are weight-neutral and well-tolerated with low hypoglycaemia risk. They represent a suitable option for individuals unable to tolerate or inject GLP-1 receptor agonists. Both drug classes are licensed by the MHRA for type 2 diabetes management and are available through NHS prescription.

Important safety information: GLP-1 receptor agonists commonly cause gastrointestinal symptoms (nausea, vomiting, diarrhoea), which typically improve over several weeks. Rare but serious adverse effects include acute pancreatitis and gallbladder disease (cholecystitis, cholelithiasis). Severe gastrointestinal losses may lead to dehydration and acute kidney injury; maintain adequate hydration. Semaglutide has been associated with worsening of diabetic retinopathy in people with pre-existing retinopathy, particularly with rapid HbA1c reduction; ophthalmological monitoring is advised in at-risk individuals. Injection-site reactions may occur. Most DPP-4 inhibitors require dose adjustment in renal impairment (linagliptin does not); exenatide is not recommended in severe renal impairment. DPP-4 inhibitors have been associated with acute pancreatitis, severe arthralgia, and bullous pemphigoid (a rare skin condition). Saxagliptin and alogliptin carry a caution regarding heart failure risk in susceptible individuals. Patients should be counselled about these risks and advised to seek urgent medical assessment if they experience severe persistent abdominal pain, symptoms of gallstones, or visual changes. Report suspected side effects via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or the Yellow Card app). These medications should be used as part of comprehensive diabetes management including dietary modification, physical activity, and cardiovascular risk factor management as recommended by NICE guidelines.

Clinical Evidence for Incretin Effects on Beta Cells

Assessing beta cell preservation in humans presents significant methodological challenges, as direct measurement of beta cell mass requires pancreatic biopsy or post-mortem examination. Consequently, clinical studies rely on surrogate markers of beta cell function, including homeostatic model assessment of beta cell function (HOMA-B), proinsulin-to-insulin ratio (elevated ratios suggest beta cell stress), and acute insulin response to glucose. These measures provide indirect evidence of beta cell health and functional capacity.

Several clinical trials have examined whether incretin-based therapies improve beta cell function markers. Studies with GLP-1 receptor agonists, including the DURATION trials with exenatide and the LEAD programme with liraglutide, have demonstrated improvements in HOMA-B and first-phase insulin secretion, suggesting enhanced beta cell responsiveness. These improvements were sustained over 1–3 years of treatment. However, these improvements largely reverse upon treatment discontinuation, raising questions about whether true structural beta cell preservation occurs or whether the benefits reflect functional enhancement of existing cells during active therapy.

DPP-4 inhibitor studies have yielded similar findings, with improvements in beta cell function measures during active treatment that diminish after drug withdrawal. The VERIFY trial investigated early combination therapy with vildagliptin and metformin versus sequential intensification, demonstrating delayed time to treatment failure with early combination therapy. Whilst this suggests potential disease-modifying effects, the study could not definitively prove structural beta cell preservation.

Importantly, there is no established evidence that incretin therapy leads to permanent beta cell regeneration in humans. Imaging studies using techniques such as positron emission tomography with beta cell-specific tracers have not conclusively demonstrated increased beta cell mass with incretin therapy. The current evidence suggests that incretin-based treatments improve beta cell function and may slow functional decline during treatment, but whether they fundamentally alter the progressive nature of type 2 diabetes remains uncertain.

Patient monitoring and safety: Individuals prescribed incretin-based therapies should be monitored for adverse effects and treatment response. Contact your GP or seek urgent medical assessment if you experience persistent severe abdominal pain (which may indicate pancreatitis or gallbladder disease), symptoms of gallstones (right upper abdominal pain, particularly after eating), visual changes (especially if you have pre-existing diabetic retinopathy and are taking semaglutide), or signs of dehydration. Regular HbA1c monitoring (typically every 3–6 months as per NICE NG28, individualised to your circumstances) helps assess treatment efficacy and guide therapy adjustments. These medications should be used as part of comprehensive diabetes management including dietary modification, physical activity, and cardiovascular risk factor management. Report any suspected side effects via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk or through the Yellow Card app.

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