Incretin

What Are Incretins?

Incretins are hormones that explain the “incretin effect”—the observation that oral glucose produces a greater insulin response than intravenous glucose of the same amount. This is because eating stimulates gut hormones that enhance insulin release.

The Two Main Incretins

GLP-1 (Glucagon-like Peptide-1)

• Produced by L-cells in small intestine
• Stimulates insulin secretion
• Inhibits glucagon release
• Slows gastric emptying
• Reduces appetite

GIP (Glucose-dependent Insulinotropic Polypeptide)

• Produced by K-cells in upper small intestine
• Stimulates insulin secretion
• Promotes fat storage
• Affects bone metabolism
• May have different effects in obesity

How Incretins Work

Food Intake
    ↓
Nutrient contact with gut
    ↓
L-cells and K-cells release incretins (GLP-1, GIP)
    ↓
Incretins travel to pancreas
    ↓
Beta cells: Enhanced insulin release
Alpha cells: Reduced glucagon release
    ↓
Improved blood sugar control

The Incretin Effect

Glucose Source	Insulin Response	Reason
Oral glucose	Higher	Triggers incretin release
IV glucose	Lower	No gut involvement
Difference	~50-70%	The “incretin effect”

In type 2 diabetes, the incretin effect is reduced, contributing to poor glucose control.

Incretin-Based Therapies

GLP-1 Receptor Agonists

• Semaglutide (Ozempic, Wegovy)
• Liraglutide (Victoza, Saxenda)
• Dulaglutide (Trulicity)

Dual Agonists (GLP-1 + GIP)

• Tirzepatide (Mounjaro, Zepbound)
• Activates both incretin receptors
• May provide enhanced efficacy

DPP-4 Inhibitors

• Prevent breakdown of natural incretins
• Oral medications (sitagliptin, etc.)
• Extend endogenous GLP-1 and GIP action

Why Incretin Therapies Work

Natural incretins have very short half-lives:

• GLP-1: ~2 minutes
• GIP: ~5-7 minutes

Both are rapidly degraded by DPP-4 enzyme. Incretin-based medications are either:

• Resistant to DPP-4 breakdown (GLP-1 agonists)
• Inhibitors of DPP-4 (extending natural incretins)

Frequently Asked Questions

What’s the difference between GLP-1 and incretins?

GLP-1 is one type of incretin. “Incretin” is the category that includes both GLP-1 and GIP. When people talk about “incretin mimetics” or “incretin therapies,” they usually mean GLP-1 receptor agonists specifically.

Why do incretin-based drugs help with weight loss?

GLP-1 acts on the brain to reduce appetite and increase satiety. It also slows stomach emptying, helping you feel full longer. These effects lead to reduced food intake and weight loss.

Can incretins cause hypoglycemia?

Incretins work in a glucose-dependent manner—they enhance insulin only when blood sugar is elevated. This is why GLP-1 agonists rarely cause hypoglycemia on their own (though risk increases if combined with insulin or sulfonylureas).