Mechanism of Action of Thiazolidinediones

Introduction

Thiazolidinediones (TZDs), also known as glitazones, are oral antidiabetic drugs used to improve insulin sensitivity in patients with type 2 diabetes mellitus. Unlike insulin secretagogues, TZDs do not stimulate insulin release—they enhance the body’s response to insulin.

Common examples include:

• Pioglitazone
• Rosiglitazone

They act by binding to PPAR-γ (peroxisome proliferator-activated receptor gamma) and modulating gene transcription, leading to improved glucose uptake in peripheral tissues. TZDs are frequently asked about in USMLE, GPAT, NCLEX, and NIPER pharmacology modules.

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Stepwise Mechanism of Action of Thiazolidinediones

1. Binding to PPAR-γ
   TZDs bind to PPAR-γ, a nuclear receptor primarily found in adipose tissue, muscle, and liver.
2. PPAR-γ activation and gene modulation
   Activated PPAR-γ forms a heterodimer with retinoid X receptor (RXR), regulating the transcription of insulin-responsive genes.
3. Enhanced insulin sensitivity
   Gene activation increases GLUT4 expression, adiponectin, and other insulin-sensitizing proteins in skeletal muscle and adipose tissue.
4. Reduced hepatic glucose production
   In the liver, TZDs reduce gluconeogenesis, contributing to lower fasting blood glucose levels.
5. Redistribution of fat
   TZDs promote subcutaneous fat storage over visceral fat accumulation, reducing insulin resistance.
6. No stimulation of insulin release
   Unlike sulfonylureas or glinides, TZDs do not induce hypoglycemia when used alone.

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Pharmacokinetic Parameters of TZDs

Drug	Absorption	Half-life	Metabolism	Excretion
Pioglitazone	~80%	3–7 hrs (active metabolite: 16–24 hrs)	Hepatic (CYP2C8)	Fecal and renal
Rosiglitazone	~99%	~3–4 hrs	Hepatic (CYP2C8, CYP2C9)	Renal/Fecal

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Clinical Uses of TZDs

• Type 2 diabetes mellitus (monotherapy or with metformin, sulfonylureas, or insulin)
• Insulin resistance syndromes
• Polycystic ovarian syndrome (PCOS) – off-label use
• Non-alcoholic fatty liver disease (NAFLD) – under research

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Adverse Effects of TZDs

• Weight gain (due to fluid retention and adipose accumulation)
• Edema and fluid retention → may exacerbate heart failure
• Increased risk of fractures (especially in women)
• Anemia
• Bladder cancer risk (pioglitazone – debated)
• Hepatotoxicity – monitor liver function
• Macular edema (rare)

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Comparative Analysis: Pioglitazone vs Rosiglitazone

Feature	Pioglitazone	Rosiglitazone
Lipid profile effect	↑ HDL, ↓ TGs	Neutral or ↑ LDL
Cardiovascular safety	Better profile	Higher risk (restricted use in some countries)
Bladder cancer concern	Reported (controversial)	Not associated
CYP metabolism	CYP2C8	CYP2C8 and CYP2C9
Insulin sensitivity	Improves	Improves

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Practice MCQs

Q1. TZDs act by activating which receptor?
a. GLP-1 receptor
b. Insulin receptor
c. PPAR-γ ✅
d. SGLT2

Q2. PPAR-γ activation leads to:
a. Insulin secretion
b. Increased glucose absorption
c. Increased insulin sensitivity ✅
d. Beta-cell destruction

Q3. Which of the following is TRUE about TZDs?
a. They stimulate insulin release
b. They cause hypoglycemia
c. They reduce insulin resistance ✅
d. They block glucagon receptors

Q4. Which adverse effect is associated with TZD use?
a. Hypokalemia
b. Edema ✅
c. Bradycardia
d. Renal stones

Q5. Pioglitazone affects lipid profile by:
a. Increasing LDL
b. Decreasing HDL
c. Decreasing triglycerides ✅
d. Causing hyperlipidemia

Q6. TZDs should be avoided in:
a. Liver cirrhosis
b. Congestive heart failure ✅
c. Gout
d. Hypothyroidism

Q7. What is the effect of TZDs on glucose uptake?
a. Decrease uptake
b. No effect
c. Increase via GLUT4 induction ✅
d. Block SGLT1

Q8. Rosiglitazone has been restricted in some countries due to:
a. Hepatotoxicity
b. Cardiotoxicity ✅
c. Nephrotoxicity
d. GI upset

Q9. How do TZDs affect insulin secretion?
a. Increase secretion
b. Inhibit secretion
c. No direct effect ✅
d. Destroy beta cells

Q10. TZDs are most useful in:
a. Type 1 diabetes
b. Type 2 diabetes with insulin resistance ✅
c. Gestational diabetes
d. DKA

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FAQs

Q1: Can TZDs be used in type 1 diabetes?
No. They require insulin presence and are ineffective in type 1 diabetes.

Q2: Do TZDs cause hypoglycemia?
Not when used alone. However, risk increases if combined with insulin or sulfonylureas.

Q3: Are TZDs safe in heart failure?
No. They can cause fluid retention and are contraindicated in NYHA Class III/IV heart failure.

Q4: Do TZDs affect lipid profile?
Yes. Pioglitazone increases HDL and decreases triglycerides.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• ADA Guidelines
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK544294/