Mode of Action of Rosiglitazone
Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist that primarily improves insulin sensitivity by reducing hepatic glucose production and enhancing peripheral glucose uptake in skeletal muscle. 1
Primary Mechanism
Rosiglitazone functions as a synthetic ligand for the nuclear transcription factor PPAR-γ, which has broad effects on glucose and lipid metabolism, vascular biology, and inflammation. 1 This receptor activation alters the transcription of multiple genes involved in glucose and lipid metabolism, including those coding for:
Tissue-Specific Effects
Adipose Tissue (Primary Site)
PPAR-γ is predominantly expressed in adipose tissue, where rosiglitazone exerts its primary effects. 1, 2 The drug modifies adipocyte function by:
- Increasing subcutaneous adipose tissue while decreasing visceral fat 1
- Altering the release of adipocyte-derived mediators of insulin resistance, including free fatty acids and tumor necrosis factor-alpha 2
- Promoting redistribution of fat from visceral to subcutaneous depots 1
Skeletal Muscle
Rosiglitazone enhances insulin-stimulated glucose uptake in skeletal muscle by 38%, with whole-body glucose uptake improving by 44%. 3 Notably, it doubles the exercise-induced increment in glucose uptake during insulin stimulation (99% increase). 3 While PPAR-γ expression is lower in muscle than adipose tissue, the drug improves muscle insulin sensitivity likely through both direct effects and indirect signaling from adipocytes. 2
Liver
The drug reduces hepatic glucose production, contributing to improved glycemic control. 1, 4 This hepatic effect, combined with peripheral insulin sensitization, accounts for the approximately 1% reduction in HbA1c observed with monotherapy. 5
Clinical Pharmacology
Metabolic Effects
- Does not increase hypoglycemia risk (non-insulin secretagogue mechanism) 1
- May preserve pancreatic beta-cell function 4
- Reduces plasma free fatty acid levels by approximately 25% at highest doses 1
Cardiovascular and Fluid Effects
The PPAR-γ activation produces plasma volume expansion of approximately 1.8 mL/kg, resulting in:
- Hemoglobin decreases of 0.8-1.1 g/dL 1, 6
- Hematocrit reductions of 2.3-3.6% 1, 6
- Pedal edema in 4.8% of monotherapy patients (versus 1.2% placebo) 1, 6
These changes reflect hemodilution from increased plasma volume rather than effects on erythropoiesis. 1
Important Clinical Caveat
Rosiglitazone is no longer widely available due to concerns about increased myocardial infarction risk, and its prescribing remains severely restricted. 1 The cardiovascular safety concerns have limited its clinical utility despite its effective insulin-sensitizing mechanism. 4, 7