GLP-1, GIP, and Glucagon: What These Pathways Actually Do

Three receptor systems sit at the center of the most active area in metabolic drug research right now: GLP-1, GIP, and glucagon. Compounds targeting one or more of these pathways have generated more clinical trial activity, pharmaceutical investment, and public interest in the past five years than almost any other class of drugs. Understanding what each system actually does is useful context for following that research.

All three are hormones, and all three play roles in how the body manages blood glucose, energy storage, and appetite. They are part of a broader system called the incretin axis, which coordinates metabolic responses to food intake. But they are not interchangeable, and understanding the distinctions matters for understanding why researchers are studying combinations.

The Incretin System: Background

When food is eaten and nutrients begin entering the small intestine, specialized cells in the gut wall release hormones into the bloodstream. These hormones signal to the pancreas, brain, and other tissues that nutrients are arriving, triggering a coordinated response. The hormones are called incretins because their original discovery was tied to their ability to potentiate insulin release in response to food, an effect that does not occur when glucose is administered directly into the bloodstream.

GLP-1 and GIP are the two primary incretin hormones. They are secreted by different cell types, act on overlapping but distinct receptor systems, and have somewhat different physiological roles. Glucagon is not technically an incretin, but its receptor pathway interacts meaningfully with both GLP-1 and GIP signaling, which is why it is studied together with them in the context of multi-receptor agonist research.

GLP-1: Glucagon-Like Peptide-1

GLP-1 is produced by L-cells in the small intestine and colon, as well as by neurons in the brainstem. It is secreted in response to nutrient ingestion, with levels rising within minutes of a meal and declining within 10 to 20 minutes due to rapid degradation by the enzyme DPP-4.

GLP-1 receptors (GLP-1R) are expressed in the pancreas, brain, heart, kidneys, lungs, and gastrointestinal tract. The most studied effects of GLP-1 receptor activation are:

Insulin secretion. GLP-1R activation in pancreatic beta cells stimulates insulin release, but only when blood glucose is elevated. This glucose-dependent mechanism means GLP-1 pathway activation does not typically cause hypoglycemia on its own, which is a meaningful safety distinction compared to some other insulin-stimulating mechanisms.

Glucagon suppression. GLP-1 suppresses glucagon release from pancreatic alpha cells during hyperglycemia. Since glucagon raises blood glucose, suppressing it during a meal helps moderate the post-meal glucose rise.

Gastric emptying. GLP-1 slows the rate at which the stomach empties its contents into the small intestine. This extends the period over which nutrients enter circulation, moderating glucose spikes, and also contributes to satiety.

Appetite regulation. GLP-1 receptors in the hypothalamus and brainstem mediate satiety signaling. GLP-1 receptor agonists reduce food intake in both animal models and human clinical trials, which is the mechanism underlying their studied weight loss effects.

GIP: Glucose-Dependent Insulinotropic Polypeptide

GIP is produced by K-cells in the upper small intestine and is the earlier-discovered of the two incretin hormones. Like GLP-1, it is released in response to food and stimulates insulin secretion in a glucose-dependent manner.

For many years, GIP was considered a less interesting research target than GLP-1, partly because early GIP receptor agonist compounds did not show the robust weight loss effects seen with GLP-1 agonism. The picture became more complicated with tirzepatide, the dual GLP-1/GIP receptor agonist approved by the FDA in 2022, which showed weight loss outcomes exceeding those of GLP-1 agonists alone. That clinical result redirected significant research attention toward understanding what GIP receptor activation contributes to the combination.

Current research suggests GIP receptor activation may:

Amplify the GLP-1 pathway. Evidence from clinical trials indicates that GIP and GLP-1 receptor co-activation produces weight-related outcomes greater than either pathway alone. The mechanism behind this amplification is not fully resolved, but hypotheses involve complementary effects on adipose tissue metabolism and central appetite circuits.

Modulate adipose tissue. GIP receptors are expressed on fat cells, and GIP signaling appears to influence both fat storage and fat oxidation depending on context. In the setting of dual agonism, researchers have observed net reductions in fat mass, suggesting the combined receptor signaling shifts the balance toward fat utilization.

Affect bone metabolism. GIP receptors are expressed in bone tissue, and preclinical data has linked GIP signaling to bone formation and maintenance. This is an area of active research with no established clinical conclusion.

Glucagon

Glucagon is produced by alpha cells in the pancreatic islets and is secreted in response to low blood glucose, fasting, and exercise. Its primary function is to raise blood glucose by signaling the liver to break down glycogen and release glucose into the bloodstream, a process called glycogenolysis. It also stimulates gluconeogenesis, the production of new glucose from non-carbohydrate precursors.

On the surface, activating glucagon receptors alongside insulin-stimulating pathways like GLP-1 and GIP seems counterproductive, because glucagon raises blood glucose while those pathways lower it. The research rationale for including glucagon receptor agonism in the triple-receptor compounds like retatrutide rests on a different set of effects:

Thermogenesis and energy expenditure. Glucagon receptor activation in brown adipose tissue and the liver has been shown to increase energy expenditure. This is a mechanism neither GLP-1 nor GIP agonism directly addresses, and researchers have proposed it contributes to the additional weight reduction seen with triple agonists compared to dual agonists.

Liver fat reduction. Glucagon receptor activation in the liver has been associated with reduced hepatic fat accumulation in preclinical models. This is part of the rationale for studying triple receptor agonists in metabolic dysfunction-associated steatotic liver disease.

The challenge of glucagon receptor agonism is that, used alone or in excess relative to the insulin-stimulating pathways, it would produce hyperglycemia. The triple agonist strategy is built on the premise that the three pathways can be balanced such that the glucagon-mediated energy expenditure effects are captured without the hyperglycemic consequence. Whether that balance holds across diverse patient populations is a key question in the ongoing Phase 3 research.

Why Researchers Study the Pathways Together

The progression from single to dual to triple receptor agonism in metabolic research reflects a broader shift toward multi-target pharmacology. The rationale is that metabolic dysregulation is not a single-pathway problem. Insulin resistance, obesity, and related conditions involve dysregulation across multiple hormonal systems simultaneously. Engaging several of those systems at once, at appropriate relative strengths, may produce outcomes that sequential single-pathway interventions cannot match.

The clinical data from tirzepatide's approval and the retatrutide Phase 2 trial support this hypothesis at least preliminarily. Whether the additional complexity of triple agonism translates to better long-term outcomes, with an acceptable safety profile, is what the ongoing trials are designed to answer.