Incretins are metabolic hormones that help manage the body’s energy and nutrient levels. These hormones are released from cells within the gut shortly after food is consumed. Their primary purpose is to regulate blood glucose (blood sugar) by responding to nutrients entering the digestive system. This process ensures the body can efficiently use or store energy from a meal, preventing drastic fluctuations in blood sugar.
The Biological Role of Incretins
The two main incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). They are produced by different cells in the intestinal lining. The release of both hormones happens within minutes of food intake, particularly in response to carbohydrates and fats, signaling that nutrients are being absorbed into the bloodstream.
Once in circulation, these hormones perform several coordinated actions. A principal function is stimulating the pancreas to release insulin, but only when blood glucose levels are elevated. This glucose-dependent mechanism ensures insulin is secreted at the appropriate time to help cells absorb sugar from the blood for energy. GLP-1 and GIP bind to specific receptors on the insulin-producing beta cells of the pancreas, initiating a signaling cascade that promotes insulin synthesis and release.
GLP-1 also helps regulate blood sugar by suppressing the secretion of glucagon. This pancreatic hormone normally tells the liver to produce and release glucose, which is counterproductive after a meal when sugar levels are already rising. This action is specific to GLP-1, as GIP can, under certain conditions, stimulate glucagon release.
Beyond the pancreas, GLP-1 influences digestion and appetite. It slows gastric emptying, the process by which food moves from the stomach to the small intestine, which helps smooth out nutrient absorption and prevent a sudden blood sugar surge. GLP-1 also acts on the brain to promote a feeling of fullness (satiety), helping to regulate food intake.
The Incretin Effect and Its Impairment
The importance of gut hormones in managing blood sugar was first understood through the “incretin effect.” Researchers observed that when a person consumes glucose orally, the resulting insulin secretion is much greater than when an identical amount of glucose is administered intravenously.
This enhanced insulin release from oral glucose is attributed to the actions of GIP and GLP-1. When food enters the digestive tract, these hormones are released and signal the pancreas to prepare for the incoming glucose. In healthy individuals, the incretin effect accounts for an estimated 50% to 70% of the total insulin secreted after a meal.
In individuals with type 2 diabetes, this system is compromised. The incretin effect is significantly reduced or even absent, a characteristic feature of the condition. While incretin secretion may be slightly altered, the primary issue is the pancreatic cells’ diminished response to them. The insulin-stimulating action of GIP is almost completely lost. While the response to GLP-1 is better preserved, it is not enough to compensate for the impairment, which contributes to high blood sugar levels after meals.
Therapeutic Use of Incretins
The understanding of the incretin system has led to medications that target these pathways for type 2 diabetes and obesity. These therapies amplify the body’s natural incretin actions. One class, DPP-4 inhibitors, are oral drugs that block the enzyme dipeptidyl peptidase-4 (DPP-4), which breaks down GLP-1 and GIP. By inhibiting this enzyme, the drugs allow incretins to remain active longer, enhancing their glucose-lowering effects.
Another approach uses molecules that mimic the GLP-1 hormone, called GLP-1 receptor agonists. These are synthetic versions of GLP-1 engineered to resist breakdown by the DPP-4 enzyme, giving them a longer duration of action than the natural hormone. Administered by injection, these agonists activate GLP-1 receptors, resulting in insulin release, glucagon suppression, slowing of gastric emptying, and appetite reduction. These effects lead to improved blood sugar control and weight loss.
A newer class of medication, dual GIP and GLP-1 receptor agonists, combines the actions of both incretin hormones. These therapies are single molecules designed to activate the receptors for both GIP and GLP-1. This dual-agonist approach leverages the complementary benefits of each hormone. The combination produces a synergistic effect, resulting in greater improvements in blood sugar management and more weight loss than is achieved with GLP-1 receptor agonists alone.