MOA of Biguanides

Mechanism of Action of Biguanides

by

Introduction

Biguanides are a class of oral antihyperglycemic drugs, with metformin being the only widely used agent today. Metformin is the first-line therapy for type 2 diabetes mellitus due to its excellent safety profile, weight-neutral effect, and strong efficacy in lowering blood glucose without causing hypoglycemia.

Mechanism of Action of Biguanides centers on decreasing hepatic glucose production, increasing insulin sensitivity, and enhancing peripheral glucose uptake. Biguanides act primarily through activation of AMPK (AMP-activated protein kinase) and inhibition of mitochondrial complex I, leading to reductions in gluconeogenesis and improvements in metabolic efficiency.

Mechanism of action of Biguanides
Metformin pharmacology mechanism
Metformin pharmacology mechanism
AMPK activation mechanism

Mechanism of Action (Step-wise)

1. Activation of AMPK (AMP-activated protein kinase) – Primary Mechanism

  • Biguanides (metformin) activate AMPK, the key metabolic “energy-sensing” enzyme in liver and muscle.
  • AMPK activation leads to:
    • ↓ Hepatic gluconeogenesis
    • ↑ Peripheral glucose uptake
    • ↑ Fatty acid oxidation
    • ↓ Lipogenesis

Effect: Lower blood glucose levels and improved insulin sensitivity.

2. Inhibition of Hepatic Gluconeogenesis

Biguanides reduce hepatic glucose output by inhibiting several gluconeogenic pathways:

  • ↓ Conversion of lactate, amino acids, and glycerol into glucose
  • ↓ Expression of gluconeogenic enzymes including:
    • PEPCK (phosphoenolpyruvate carboxykinase)
    • G6Pase (glucose-6-phosphatase)

Effect: Significant reduction in fasting plasma glucose.

3. Inhibition of Mitochondrial Complex I

  • Metformin partially inhibits mitochondrial respiratory-chain complex I, leading to:
    • ↓ ATP production
    • ↑ AMP levels

This increases the AMP:ATP ratio, which further activates AMPK and suppresses gluconeogenesis.

4. Increased Peripheral Glucose Uptake (Muscle and Fat)

AMPK activation promotes translocation of GLUT-4 transporters to the cell membrane in skeletal muscle.

Effects:

  • ↑ Glucose uptake
  • ↑ Insulin sensitivity
  • ↓ Postprandial glucose spikes

5. Reduction of Intestinal Glucose Absorption

Biguanides mildly reduce glucose absorption from the gut.

Effect: Lower post-meal glucose levels.

6. Changes in Gut Microbiota

Emerging evidence suggests that metformin:

  • Favors beneficial microbiota populations
  • Improves incretin (GLP-1) secretion

Effect: Additional mild glucose-lowering and appetite regulation.

7. Summary of Biguanide Mechanism

Action SiteMechanismEffect
LiverAMPK activation → ↓ gluconeogenesis↓ Fasting glucose
Muscle↑ GLUT-4 translocation↑ Glucose uptake
MitochondriaComplex I inhibition↑ AMP → AMPK activation
Gut↓ Glucose absorption, ↑ GLP-1↓ Postprandial glucose
Systemic↑ Insulin sensitivityBetter glycemic control
AMPK activation mechanism flowchart
Biguanides MOA Flowchart

Pharmacokinetics

  • Absorption: Incomplete and slow from GI tract
  • Distribution: Not protein bound
  • Metabolism: Not metabolized
  • Excretion: Renal (unchanged drug)
  • Half-life: 4–8 hours

Clinical Uses

  • Type 2 diabetes mellitus
  • Prediabetes
  • Polycystic ovarian syndrome (PCOS)
  • Non-alcoholic fatty liver disease
  • Weight management (adjunct in insulin resistance)

Adverse Effects

  • GI upset (nausea, diarrhea, metallic taste)
  • Vitamin B12 deficiency (long-term use)
  • Lactic acidosis (rare but serious; risk increases in renal failure, liver disease, hypoxia)
  • Anorexia and mild weight loss

Contraindications

  • Renal impairment
  • Severe hepatic disease
  • Heart failure with hypoxia
  • Alcohol abuse
  • History of lactic acidosis

Comparative Analysis

FeatureBiguanides (Metformin)SulfonylureasThiazolidinediones
Hypoglycemia riskNoneHighLow
Weight effectNeutral/↓↑↑
Mechanism↓ Glucose production, ↑ sensitivity↑ Insulin release↑ Insulin sensitivity
Primary siteLiver + musclePancreasAdipose + muscle

MCQs

1. Biguanides primarily reduce blood glucose by:
a) Increasing insulin secretion
b) Decreasing hepatic gluconeogenesis
c) Blocking GLUT-2 receptors
d) Stimulating pancreatic beta cells
Answer: b) Decreasing hepatic gluconeogenesis

2. Activation of which enzyme is central to metformin’s action?
a) PEPCK
b) Adenylate cyclase
c) AMPK
d) Tyrosine kinase
Answer: c) AMPK

3. Biguanides inhibit which mitochondrial component?
a) Complex IV
b) Complex II
c) Complex I
d) ATP synthase
Answer: c) Complex I

4. Metformin’s effect on muscle involves:
a) Blocking insulin receptors
b) Increasing GLUT-4 translocation
c) Stimulating cortisol release
d) Inhibiting cAMP
Answer: b) Increasing GLUT-4 translocation

5. A rare but serious adverse effect of biguanides is:
a) Ketoacidosis
b) Lactic acidosis
c) Hyperkalemia
d) Hypoglycemia
Answer: b) Lactic acidosis

FAQs

Q1. Do biguanides cause hypoglycemia?
No. They do not increase insulin secretion, so hypoglycemia risk is minimal.

Q2. Why is metformin first-line for type 2 diabetes?
It is safe, effective, weight-neutral, and reduces cardiovascular risk.

Q3. Can metformin cause weight loss?
A mild reduction occurs due to appetite suppression and better insulin sensitivity.

Q4. Why must kidney function be monitored?
Because metformin is renally excreted and accumulation increases lactic acidosis risk.

Q5. Does metformin improve PCOS?
Yes, by reducing insulin resistance and improving ovulatory function.

References

Goodman & Gilman’s Pharmacological Basis of Therapeutics
Katzung Basic & Clinical Pharmacology
Tripathi Essentials of Medical Pharmacology
Harrison’s Principles of Internal Medicine

Leave a Comment