Incretins are naturally occurring gut hormones that play a vital role in regulating blood glucose levels after meals. Produced by specialised cells in the intestinal lining, these peptide hormones coordinate the body's metabolic response to food intake by enhancing insulin secretion and suppressing glucagon release. The two main incretins—glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)—account for approximately 50–70% of postprandial insulin secretion. Understanding incretin physiology has transformed diabetes management, leading to the development of incretin-based therapies now recommended in NICE guidance for type 2 diabetes treatment.

What Are Incretins and Where Are They Produced?

Incretins are naturally occurring hormones produced in the gastrointestinal tract that play a crucial role in regulating blood glucose levels, particularly after eating. These peptide hormones are secreted by specialised cells in the intestinal lining in response to nutrient intake, forming part of the body's sophisticated metabolic control system.

The primary sites of incretin production are enteroendocrine cells scattered throughout the small intestine and colon. These specialised cells act as nutrient sensors, detecting the presence of glucose, fats, and proteins in the digestive tract. When food enters the intestine, these cells release incretins into the bloodstream, where they travel to various organs to coordinate the body's metabolic response to feeding. Specifically, glucose-dependent insulinotropic polypeptide (GIP) is produced mainly by K-cells in the duodenum and jejunum (proximal small intestine), whilst glucagon-like peptide-1 (GLP-1) is secreted by L-cells located predominantly in the ileum (distal small intestine) and colon.

The incretin system represents an elegant example of gut-pancreas communication, often referred to as the 'enteroinsular axis'. This physiological pathway ensures that insulin secretion is appropriately matched to nutrient absorption, helping to maintain blood glucose within normal ranges. Understanding incretin physiology has proven particularly valuable in diabetes management, as it has led to the development of incretin-based therapies that mimic or enhance the action of these natural hormones.

Incretins account for a substantial portion of insulin secretion after meals—research suggests they are responsible for approximately 50–70% of postprandial insulin release, though this estimate varies by population and methodology. This phenomenon, known as the 'incretin effect', demonstrates that oral glucose intake stimulates far greater insulin secretion than intravenous glucose administration, even when blood glucose levels are identical. This discovery has fundamentally shaped our understanding of glucose homeostasis and metabolic regulation. It is important to note that incretin measurements are not used in routine clinical practice in the NHS.

The Two Main Types of Incretin Hormones

The human body produces two principal incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), formerly known as gastric inhibitory polypeptide. Whilst both contribute to glucose regulation, they differ in their sites of production, duration of action, and additional physiological effects.

GLP-1 is primarily secreted by L-cells located predominantly in the distal small intestine (ileum) and colon. This hormone has a very short half-life of approximately 2–3 minutes in circulation, as it is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4). Beyond its glucose-lowering effects, GLP-1 exerts several beneficial actions including:

• Slowing gastric emptying, which moderates the rate of nutrient absorption

• Reducing appetite and promoting satiety through central nervous system effects

• Suppressing inappropriate glucagon secretion from pancreatic alpha cells

• Potentially preserving pancreatic beta-cell function, though this effect is mainly supported by preclinical and short-term human studies and has not been confirmed as a durable clinical outcome

GIP is produced by K-cells, which are concentrated in the proximal small intestine (duodenum and jejunum). GIP is released earlier in the digestive process compared to GLP-1, as nutrients first encounter the upper intestine. Like GLP-1, GIP is also degraded by DPP-4, though it has a slightly longer half-life of approximately 5–7 minutes.

Both incretins stimulate insulin secretion in a glucose-dependent manner, meaning they only enhance insulin release when blood glucose levels are elevated. This important safety feature significantly reduces the risk of hypoglycaemia when incretin-based therapies are used alone. However, the risk of hypoglycaemia may increase when these medicines are used in combination with insulin or sulfonylureas. The complementary actions of GLP-1 and GIP create a coordinated response to food intake, optimising metabolic control throughout the postprandial period.

How Incretin Function Changes in Type 2 Diabetes

In people with type 2 diabetes, the incretin system demonstrates significant dysfunction, contributing to impaired glucose control. Research has consistently shown that the incretin effect is substantially reduced in individuals with type 2 diabetes compared to people without diabetes. This defect appears relatively early in the disease process and may even be present in some individuals with prediabetes, though the extent and timing vary between individuals.

The mechanisms underlying incretin dysfunction in type 2 diabetes are complex and multifactorial. Whilst GIP secretion generally remains normal or may even be elevated, the pancreatic beta-cells become resistant to its insulinotropic effects. This means that despite adequate GIP levels, the hormone fails to stimulate appropriate insulin release. In contrast, GLP-1 secretion is often reduced in people with type 2 diabetes, though the degree of impairment varies between individuals. Some research suggests this may relate to the chronic hyperglycaemia itself, creating a vicious cycle of metabolic dysfunction.

Importantly, despite reduced incretin effect, the beta-cells in type 2 diabetes typically retain some responsiveness to GLP-1, particularly when pharmacological doses are administered. This preserved sensitivity forms the basis for incretin-based therapies, which have become important treatment options under NICE guidance (NG28). The observation that exogenous GLP-1 can still stimulate insulin secretion in people with type 2 diabetes has led to the development of GLP-1 receptor agonists and DPP-4 inhibitors.

The incretin defect in type 2 diabetes appears to be largely acquired rather than inherited, though the evidence is evolving and some early defects may occur in individuals at risk. Clear, clinically relevant genetic determinants of incretin dysfunction have not been established, and research in this area continues.

How Incretins Regulate Blood Sugar Levels

Incretins employ multiple complementary mechanisms to maintain glucose homeostasis, creating a coordinated metabolic response to nutrient intake. The primary mechanism involves glucose-dependent insulin secretion from pancreatic beta-cells. When incretins bind to their specific receptors on beta-cells, they trigger intracellular signalling pathways that enhance insulin synthesis and release, but only when glucose concentrations are elevated. This glucose-dependency is a critical safety feature that minimises hypoglycaemia risk.

Beyond insulin stimulation, incretins—particularly GLP-1—suppress glucagon secretion from pancreatic alpha cells. Glucagon is a counter-regulatory hormone that raises blood glucose by promoting hepatic glucose production. In type 2 diabetes, glucagon levels are often inappropriately elevated, contributing to hyperglycaemia. By suppressing excessive glucagon release, GLP-1 helps reduce hepatic glucose output, particularly in the postprandial state.

GLP-1 also slows gastric emptying, which moderates the rate at which nutrients enter the small intestine and are absorbed into the bloodstream. This effect helps prevent rapid postprandial glucose excursions by spreading nutrient absorption over a longer period. Additionally, GLP-1 acts on appetite centres in the hypothalamus, promoting satiety and reducing food intake. This effect contributes to weight management with GLP-1 receptor agonists, though it is important to note that DPP-4 inhibitors are generally weight-neutral. Weight management is an important consideration given the strong association between obesity and type 2 diabetes.

The incretin system also appears to have protective effects on pancreatic beta-cells in animal studies, where GLP-1 may promote beta-cell proliferation and inhibit apoptosis (programmed cell death). However, durable beta-cell preservation in humans remains uncertain and is not a proven clinical outcome. This represents an important area of ongoing research.

Safety advice for patients using incretin-based medicines: Contact your GP if you experience persistent nausea, vomiting, or abdominal discomfort, as these may indicate adverse effects requiring medical review. Seek urgent medical help (via NHS 111 or 999) if you develop severe, persistent abdominal pain, especially if it radiates to your back, with or without vomiting, as this may indicate pancreatitis—a rare but serious side effect. If you experience any suspected side effects from your diabetes medication, you can report them via the MHRA Yellow Card scheme at yellowcard.mhra.gov.uk.

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