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

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.

KEYWORDS:

• Insulin sensitizer
• MPC
• mitochondrial target
• metabolic reprogramming
• chronic and infectious disease
• pioglitazone
• rosiglitazone
• MSDC-0160

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.

Additional information

Funding

This paper was not funded.