Incretin hormones are peptides released from the gut into the bloodstream immediately following a meal. These hormones act as a communication link between the digestive system and the pancreas, signaling that nutrients have been consumed and blood sugar levels will soon rise. Their primary function is to augment the secretion of insulin from pancreatic beta cells, thereby preventing excessive post-meal spikes in glucose concentration. This mechanism ensures the body’s response to food intake is rapid and proportional.
The Core Mechanism of Action
The physiological impact of these gut hormones is demonstrated by the “incretin effect.” This phenomenon occurs when consuming glucose by mouth stimulates a significantly higher insulin response compared to receiving the same amount intravenously. In healthy individuals, the insulin secreted after an oral glucose load can be two to three times greater than the response from an intravenous infusion. Incretin hormones are responsible for an estimated 50% to 70% of the total insulin released after nutrient ingestion.
Once released from the gut, incretins travel to the pancreas, where they act on two distinct cell types. They stimulate the insulin-producing beta cells, promoting the release of stored insulin into circulation. Simultaneously, they act on the alpha cells to suppress the release of glucagon, a hormone that raises blood sugar by signaling the liver to produce glucose.
This dual action works only in a glucose-dependent manner. When blood sugar levels are elevated, incretins are highly active, but their effect diminishes significantly as blood sugar returns to a normal range. This built-in safeguard prevents the hormones from causing dangerously low blood sugar, a complication known as hypoglycemia.
Identifying the Key Incretins: GLP-1 and GIP
The body relies on two primary hormones to facilitate the incretin effect: Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP). GIP is secreted by K-cells, found predominantly in the upper small intestine (duodenum and jejunum). GLP-1 is secreted by L-cells, located in the more distal portions of the small intestine and the colon.
While both hormones stimulate insulin secretion in a glucose-dependent manner, GLP-1 possesses additional functions that distinguish it from GIP. GLP-1 acts on the stomach to slow the rate at which food empties, helping to moderate the influx of glucose into the bloodstream.
GLP-1 also travels to the brain, where it promotes feelings of fullness and reduces appetite. GIP, in contrast, primarily focuses on augmenting insulin release without these effects on satiety or gastric motility. This difference in secondary actions contributes to the distinct therapeutic profiles of drugs that target each hormone.
The Role of DPP-4 in Deactivation
The naturally occurring incretin hormones are designed to be rapidly deactivated, ensuring their effects on insulin secretion are temporary and tightly controlled. The primary mechanism for this limitation is the enzyme Dipeptidyl peptidase-4 (DPP-4), a circulating protein. DPP-4 rapidly cleaves the structure of both GLP-1 and GIP, rendering them inactive almost immediately after release.
This enzymatic degradation results in native GLP-1 and GIP having short half-lives in the bloodstream, often lasting only minutes. DPP-4 acts as a molecular brake, preventing the hormones from overstimulating the pancreas. This rapid inactivation is a crucial part of metabolic regulation, but it posed a challenge for researchers seeking to harness the hormones’ beneficial effects therapeutically.
Therapeutic Applications in Diabetes Management
The discovery of the incretin system and the role of DPP-4 provided a new target for medications treating Type 2 Diabetes, which often involves impaired insulin secretion and an ineffective incretin response. This knowledge led to the development of two major classes of pharmacological agents designed to enhance the activity of these gut hormones. The first class, known as DPP-4 inhibitors (gliptins), works by blocking the action of the DPP-4 enzyme itself.
By inhibiting DPP-4, these oral medications allow the body’s own naturally released GLP-1 and GIP to remain active for a longer period. This results in a modest, physiological increase in incretin levels, which helps to improve glucose-dependent insulin secretion and suppress glucagon. DPP-4 inhibitors are generally considered weight-neutral and carry a low risk of hypoglycemia.
The second class is the GLP-1 Receptor Agonists (GLP-1 RAs), synthetic compounds designed to mimic the action of GLP-1. These drugs are engineered to resist degradation by DPP-4, giving them a much longer half-life, ranging from hours to a week. GLP-1 RAs deliver high levels of the hormone’s action, boosting insulin secretion and glucagon suppression.
GLP-1 RAs achieve greater reductions in average blood sugar levels (HbA1c) compared to DPP-4 inhibitors. Because they mimic GLP-1’s secondary effects, these agents often lead to weight loss, averaging between 1 and 4 kilograms. Several GLP-1 RAs have also demonstrated a protective effect against major adverse cardiovascular events. While GLP-1 RAs offer stronger benefits, they are associated with a higher incidence of gastrointestinal side effects, such as nausea.