TY - JOUR
T1 - Insulin sensitizers in 2023
T2 - lessons learned and new avenues for investigation
AU - Colca, Jerry R.
AU - Tanis, Steven P.
AU - Kletzien, Rolf F.
AU - Finck, Brian N.
N1 - Publisher Copyright:
© 2023 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Insulin sensitizer
KW - MPC
KW - MSDC-0160
KW - chronic and infectious disease
KW - metabolic reprogramming
KW - mitochondrial target
KW - pioglitazone
KW - rosiglitazone
UR - http://www.scopus.com/inward/record.url?scp=85173075467&partnerID=8YFLogxK
U2 - 10.1080/13543784.2023.2263369
DO - 10.1080/13543784.2023.2263369
M3 - Review article
C2 - 37755339
AN - SCOPUS:85173075467
SN - 1354-3784
VL - 32
SP - 803
EP - 811
JO - Expert Opinion on Investigational Drugs
JF - Expert Opinion on Investigational Drugs
IS - 9
ER -