Insulin sensitizers in 2023: lessons learned and new avenues for investigation

Introduction: The concept of ‘insulin sensitizers’ originated with discoveries made by Takeda Pharmaceutical Company in the 1970s. Pioglitazone, a thiazolidinedione (TZD), remains the gold standard in this class due to its beneficial pleiotropic effects, though its use is often limited by tolerability issues. Early efforts to expand beyond this class assumed that the primary molecular target of TZDs was the transcription factor PPARγ. However, recent findings over the past decade have revealed additional targets for TZDs, suggesting a shift in the drug discovery paradigm.

Areas Covered: This review explores various structural classes of experimental insulin sensitizer drugs, some of which have received limited approval in select markets. Pioglitazone, initially approved in 1999 as a secondary treatment for type 2 diabetes, has shown therapeutic benefits across a range of conditions, including cardiovascular and neurological disorders. More recent TZDs have been developed to target a newly identified mitochondrial protein, the mitochondrial pyruvate carrier (MPC), which helps reprogram cellular metabolism. These new TZDs offer insulin-sensitizing effects without the tolerability issues associated with earlier compounds.

Expert Opinion: A deeper understanding of the mechanisms underlying insulin-sensitizing drugs could broaden their therapeutic applications and support the development of combination treatments. This knowledge could pave the way for the registration and widespread use of these agents, which have the potential to address the pathophysiology of chronic metabolic diseases, as well as host responses to environmental stressors, including infections. Key concepts in this evolving field include insulin sensitizers, the MPC target,MSDC-0160 mitochondrial reprogramming, and the treatment of both chronic and infectious diseases.