GLP-1 and GIP Biology: Incretin Signaling

What the molecules are

Both are released from the gut when nutrients are present, and they regulate how the body handles a meal. [2]

The incretin effect

The "incretin effect" is the finding that GLP-1 and GIP account for a major part of the insulin released after a meal. [2] In type 2 diabetes this effect is severely reduced. [2]

Beyond insulin, incretin peptides regulate islet hormone secretion, blood glucose, lipid metabolism, gut movement, appetite, body weight and immune function. [3] Receptors for GLP-1 and GIP sit in many tissues, and some effects are direct while others work through nerves and other hormones. [3]

How GLP-1 and GIP differ

• GLP-1 improves glucose handling mostly indirectly, by raising nutrient-driven insulin release and lowering glucagon secretion. A review of the physiology also calls GLP-1 biology "incompletely understood", with actions both in the body and in the brain. [1]
• GIP is less clear. Studies of GIP on its own as a diabetes treatment have been consistently disappointing, while GIP combined with GLP-1 activity, and GIP-blocking approaches combined with GLP-1 agonists, both appear to help weight and glucose; the molecular reasons are unknown. [2] Label: mixed, with open questions.

The enzyme that clears them

The incretins are broken down by an enzyme, dipeptidyl peptidase-4 (DPP-4). Medicines that block this enzyme exist as a separate class from medicines that mimic GLP-1. [2] This is one example of why a hormone, an analogue and a pill that changes the hormone's lifetime are different things.

Biology versus clinical evidence

1. What does the hormone do in a healthy meal?

   Established physiology [3]

2. Does a finding in mice or cells apply to people?

   Many mechanisms were identified in preclinical studies, and their relevance to human disease is discussed as uncertain [3]

3. Do effects on blood vessels carry over?

   Reviewers compared cell, animal and human data and flagged pitfalls and limits in the literature [4]

Do not read a mechanism as a treatment claim. Knowing that GLP-1 acts on the gut and brain does not tell you whether a given product, in a given person, improves health outcomes.

Medicines are a separate topic

Some medicines are built on these hormones, and the pages above cover them. A medicine can act on one receptor or on both GLP-1 and GIP receptors. The tirzepatide literature, for example, discusses how GIP receptor activity may add to GLP-1-driven weight loss, while describing this as a putative mechanism. [5] Questions about weight goals are covered in weight-loss medications and medical care.