Metabolic dysfunction and insulin sensitizers in acute and chronic disease.

Introduction: The concept of insulin resistance has been a major topic for more than 5 decades. While there are several treatments that may impact insulin resistance, this pathology is uniquely addressed by mitochondrially directed thiazolidinedione (TZD) insulin sensitizers. Understanding of this mechanism of action and consideration of 'insulin resistance' as a consequence of metabolic inflammation allows a new paradigm for approaching chronic diseases.

Areas covered: We review evolving understanding of the mitochondrial pyruvate carrier (MPC) as a mitochondrial mechanism of action of the TZD insulin sensitizers and discuss how reprogramming of mitochondrial metabolism impacts pleotropic pharmacology in multiple tissues. Additional lines of investigation are proposed.

Expert opinion: A change in paradigm can facilitate rethinking of insulin sensitizers in clinical trials, specifically beyond the treatment of frank type 2 diabetes. There should be broader clinical evaluation of insulin sensitizers in combination with weight loss and lifestyle approaches across diseases/syndromes associated with insulin resistance. Finally, 'connecting all the dots' to unwind the interconnectedness of cell biology involved in the syndromes impacted by metabolic dysfunction and the efficacy of TZD insulin sensitizers may also uncover new molecular targets. New studies should facilitate the discovery and development of novel pharmacologic agents.