PPAR-Gamma Selective Modulators for Insulin Resistance: Metabolic Outcomes Without Thiazolidinedione Adverse Effects

Mugisha Emmanuel K.

Faculty of Science and Technology Kampala International University Uganda

                                                                                              ABSTRACT
Peroxisome proliferator-activated receptor gamma (PPAR-γ) played a central role in regulating glucose and lipid metabolism, making it a critical target for combating insulin resistance and type 2 diabetes mellitus. Traditional PPAR-γ agonists, notably thiazolidinediones (TZDs), effectively improved insulin sensitivity but were limited by adverse effects such as weight gain, edema, and cardiovascular risks. Recent developments focus on synthetic PPARγ modulators that selectively activate beneficial pathways while minimizing harmful side effects. This review aimed to critically evaluate the molecular mechanisms of selective PPAR-γ modulators (SPARMs), their impact on metabolic outcomes, and their potential to overcome adverse effects associated with TZDs. An extensive literature search identified preclinical and clinical studies assessing the efficacy and safety profiles of SPARMs, with inclusion criteria emphasizing mechanistic insights and metabolic endpoints. Emerging evidence indicated that SPARMs induced favorable improvements in insulin sensitivity, lipid profiles, and inflammatory markers comparable to TZDs but with reduced or absent adverse effects such as weight gain and edema. Structural modifications that influenced coactivator recruitment appeared pivotal for these outcomes. However, variability in clinical responses and limited long-term data highlight ongoing challenges. Selective PPAR-γ modulators held promise as therapeutic agents capable of delivering metabolic benefits without the adverse effects characteristic of TZDs. Nonetheless, further detailed mechanistic studies and extended clinical assessments were required to fully delineate their safety and efficacy profiles.

Keywords: PPAR-gamma, Selective modulators, Insulin resistance, Metabolic outcomes, Thiazolidinediones.

CITE AS: Mugisha Emmanuel K. (2026). PPAR-Gamma Selective Modulators for Insulin Resistance: Metabolic Outcomes Without Thiazolidinedione Adverse Effects. Research Output Journal of Engineering and Scientific Research 5(1): 9-13. https://doi.org/10.59298/ROJESR/2026/5.1913