Insulin sensitizers such as pioglitazone, which act via the transcription factor PPARγ, have been limited by poor understanding of their mechanism and lack of new approvals since 1999. We hypothesized that minimizing direct PPARγ interaction while maintaining activity on a recently identified mitochondrial target (mitochondrial pyruvate carrier, MPC) could retain insulin-sensitizing efficacy without PPARγ-related side effects. We designed thiazolidinedione (TZD) analogs to reduce PPARγ binding, synthesized compounds (including ketones 5–8 and enantiomeric alcohols 11–14), and evaluated their PPARγ binding affinity (IC50), transactivation activity (EC50), and antihyperglycemic efficacy in obese, hyperglycemic KKAy mice. Compounds like ketones 6/7 and alcohols 12/14 showed significantly diminished PPARγ binding/activation (e.g., 6 had PPARγ IC50 = 22.30 μM vs pioglitazone's 1.79 μM) but retained full antihyperglycemic activity (T/C values ~0.5–0.6, comparable to pioglitazone). They also competed with a photoprobe targeting MPC, supporting a mitochondrial mechanism. This work demonstrates that reducing PPARγ interaction does not compromise antihyperglycemic efficacy, validates the MPC as a potential target, and provides TZD analogs for clinical development as PPARγ-sparing insulin sensitizers.