Mechanism of Action of GLP-1 (Glucagon-Like Peptide-1)

Introduction

Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone secreted from the L-cells of the distal ileum and colon in response to food intake. It plays a critical role in regulating glucose homeostasis and energy balance. GLP-1 acts through specific receptors found in the pancreas, gastrointestinal tract, and central nervous system to modulate insulin secretion, suppress glucagon, and slow gastric emptying.

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Step-by-Step Mechanism of Action

1. Secretion from Intestinal L-cells
   GLP-1 is released postprandially from enteroendocrine L-cells in the ileum and colon in response to nutrient ingestion.
2. Binding to GLP-1 Receptors
   It binds to GLP-1 receptors (GLP-1Rs), which are G-protein-coupled receptors found predominantly in pancreatic beta cells, as well as in alpha cells, the brain, and gastrointestinal tract.
3. Enhancement of Glucose-Dependent Insulin Secretion
   In pancreatic beta cells, GLP-1 increases cyclic AMP (cAMP) levels, activating protein kinase A (PKA) and Epac2 pathways to enhance insulin secretion in a glucose-dependent manner.
4. Suppression of Glucagon Secretion
   GLP-1 inhibits glucagon release from pancreatic alpha cells during hyperglycemic states, reducing hepatic glucose output.
5. Slowing of Gastric Emptying
   It delays gastric emptying, prolonging nutrient absorption time and attenuating postprandial blood glucose rise.
6. Appetite Suppression and Satiety
   GLP-1 acts on the hypothalamus to suppress appetite, enhancing satiety and reducing caloric intake.
7. Short Half-Life
   Native GLP-1 has a very short half-life (1–2 minutes) due to rapid degradation by dipeptidyl peptidase-4 (DPP-4) enzyme.

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Pharmacokinetic Parameters

Parameter	Value
Source	Intestinal L-cells
Half-life	1–2 minutes
Degradation	By DPP-4 enzyme
Receptor Type	G-protein-coupled (GLP-1R)
Main Sites of Action	Pancreas, GI tract, brain

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Clinical Uses (Physiological Role)

• Regulation of postprandial glucose levels
• Enhancing glucose-stimulated insulin release
• Reducing glucagon secretion during hyperglycemia
• Slowing gastric emptying
• Promoting satiety and reducing food intake

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Adverse Effects (when mimicked pharmacologically)

• Nausea and vomiting
• Delayed gastric emptying
• Rare pancreatitis (in GLP-1 analog therapy)
• Injection site reactions (from analogs)

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Comparative Analysis

Hormone	Stimulates Insulin	Suppresses Glucagon	Slows Gastric Emptying	Origin
GLP-1	Yes	Yes	Yes	Intestinal L-cells
GIP	Yes	No	No	K-cells of duodenum
Glucagon	No	N/A	No	Pancreatic alpha cells

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MCQs

1. GLP-1 is secreted from which type of cells?
   a) Alpha cells b) Beta cells c) L-cells d) K-cells
   Answer: c) L-cells
2. GLP-1 secretion is stimulated by:
   a) Fasting b) Stress c) Food intake d) Exercise
   Answer: c) Food intake
3. One major function of GLP-1 is to:
   a) Increase glucagon b) Inhibit insulin c) Stimulate glucose-dependent insulin release d) Stimulate lipolysis
   Answer: c) Stimulate glucose-dependent insulin release
4. GLP-1 slows:
   a) Hepatic metabolism b) Gastric emptying c) Renal excretion d) CNS transmission
   Answer: b) Gastric emptying
5. The enzyme that rapidly degrades GLP-1 is:
   a) MAO-B b) COMT c) DPP-4 d) PKA
   Answer: c) DPP-4
6. Which of the following is a central effect of GLP-1?
   a) Hypothermia b) Appetite suppression c) Anxiety d) Euphoria
   Answer: b) Appetite suppression
7. GLP-1 acts via which type of receptor?
   a) Tyrosine kinase b) Ligand-gated ion channel c) GPCR d) Nuclear receptor
   Answer: c) GPCR
8. GLP-1 does not significantly act on:
   a) Pancreas b) Brain c) Gastrointestinal tract d) Skeletal muscle
   Answer: d) Skeletal muscle
9. GLP-1 enhances insulin secretion via:
   a) PIP2 pathway b) IP3/Ca2+ c) cAMP/PKA d) JAK/STAT
   Answer: c) cAMP/PKA
10. Native GLP-1 has a half-life of:
    a) 1–2 minutes b) 10–15 minutes c) 30–60 minutes d) >2 hours
    Answer: a) 1–2 minutes

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FAQs

1. What triggers GLP-1 release?
GLP-1 is secreted in response to carbohydrate, fat, and protein ingestion.

2. Does GLP-1 cause hypoglycemia?
No, it enhances insulin secretion only in the presence of elevated blood glucose.

3. Why is GLP-1 rapidly inactivated?
It is quickly degraded by DPP-4, limiting its physiological duration of action.

4. How does GLP-1 affect appetite?
It promotes satiety by acting on the hypothalamus, reducing food intake.

5. Is GLP-1 used directly as a drug?
No, due to its short half-life. Long-acting GLP-1 receptor agonists are used instead.

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References

• PubMed: Physiology of GLP-1
• DrugBank: GLP-1 biological role
• NCBI Bookshelf: Incretin hormones overview
• StatPearls: GLP-1 physiology
• [Textbook: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed.]