ABSTRACT
Introduction
‘Insulin sensitizers’ derived discoveries of the Takeda Company in 1970s. Pioglitazone remains the best in class with beneficial pleiotropic pharmacology, although use is limited by tolerability issues. Various attempts to expand out of this class assumed the primary molecular target was the transcription factor, PPARγ. Findings over the last 10 years have identified new targets of thiazolidinediones (TZDs) that should alter the drug discovery paradigm.
Areas covered
We review structural classes of experimental insulin sensitizer drugs, some of which have attained limited approval in some markets. The TZD pioglitazone, originally approved in 1999 as a secondary treatment for type 2 diabetes, has demonstrated benefit in apparently diverse spectrums of disease from cardiovascular to neurological issues. New TZDs modulate a newly identified mitochondrial target (the mitochondrial pyruvate carrier) to reprogram metabolism and produce insulin sensitizing pharmacology devoid of tolerability issues.
Expert opinion
Greater understanding of the mechanism of action of insulin sensitizing drugs can expand the rationale for the fields of treatment and potential for treatment combinations. This understanding can facilitate the registration and broader use of agents with that impact the pathophysiology that underlies chronic metabolic diseases as well as host responses to environmental insults including pathogens, insulin sensitizer, MPC, mitochondrial target, metabolic reprogramming, chronic and infectious disease.
Article highlights
Pioglitazone remains the most useful insulin sensitizer in clinical use, although its use is still limited by side effects mediated by direct activation of the transcription factor Peroxisome Proliferator Proliferator-Activated Receptor gamma (PPARγ).
Clinical development of new agents has proceeded along two 180 degree divergent pathways – selection of direct binding and activation of a group of PPAR transcription factors and elimination of this binding in favor of newly identified mitochondrial target.
Several new PPAR-activating compounds have been discovered and have achieved market approval for limited use in limited jurisdictions.
The elucidation of the new mitochondrial target as the mitochondrial pyruvate carrier (MPC) has allowed the development of several MPC-modulating TZDs.
These new agents and the elucidation of their mechanism of action outline a new paradigm for the discovery and development of insulin sensitizing agents.
Abbreviations
AD | = | Alzheimer’s disease |
ALS | = | amyotrophic lateral sclerosis |
ETC | = | electron transport chain |
HCC | = | hepatocellular carcinoma |
mTOR | = | mammalian target of rapamycin |
MPC | = | mitochondrial pyruvate transporter |
PD | = | Parkinson’s disease |
PPAR | = | peroxisome proliferator-activated receptor |
TZD | = | thiazolidinedione |
Declaration of interest
JR Colca is the founder and part owner of MSDC and Cirius Therapeutics who are developing relevant compounds, S Tanis is patent holder on MSDC-0602K compound mentioned in the paper. R Kletzien is cofounder and part owner of MSDC and owner of Cirius stock. B Finck is the owner of Cirius stock.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.