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

References

• Colca JR, Tanis SP, McDonald WG, et al. Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic disease. Expert Opin Investig Drugs. 2014;23(1):1–7. doi: 10.1517/13543784.2013.839659
   PubMed Web of Science ®Google Scholar
• Sohda T, Mizuno K, Imamiya E, et al. Studies on antidiabetic agents. II. Synthesis of 5-[4-(1-methylcyclohexylmethoxy)-benzyl]thiazolidine-2,4-dione (ADD-3878) and its derivatives. Chem Pharm Bull (Tokyo). 1982;30(10):3580–3600. doi: 10.1248/cpb.30.3580
   PubMed Web of Science ®Google Scholar
• Sohda T, Meguro K, Kawamatsu Y. Studies on antidiabetic agents. IV. Synthesis and activity of the metabolites of 5-[4-(1-methylcyclohexylmethoxy)benzyl]-2,4-thiazolidinedione (ciglitazone). Chem Pharm Bull (Tokyo). 1984;32(6):2267–2278. doi: 10.1248/cpb.32.2267
   PubMed Web of Science ®Google Scholar
• Sohda T, Momose Y, Meguro K, et al. ChemInform abstract: studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-(4-(Pyridylalkoxy)benzyl)-2,4-thiazolidinediones. ChemInform. 1990;21(23):37–42. doi: 10.1002/chin.199023199
   Google Scholar
• Kletzien RF, Clarke SD, Ulrich RG. Enhancement of adipocyte differentiation by an insulin-sensitizing agent. Mol Pharmacol. 1992;41(2):393–398.
   PubMed Web of Science ®Google Scholar
• Martín JA, Brooks DA, Prieto L, et al. 2-alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents. Bioorg Med Chem Lett. 2005;15(1):51–55. doi: 10.1016/j.bmcl.2004.10.042
   PubMed Web of Science ®Google Scholar
• Haigh SKB, Allen G, Birrell HC, et al. Non-thiazolidinedione antihyperglycaemic agents. Part 3: the effects of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids. Bioorg Med Chem. 1999;7(5):821–830. doi: 10.1016/S0968-0896(99)00034-6
   PubMed Web of Science ®Google Scholar
• Azukizawa S, Kasai M, Takahashi K, et al. Synthesis and biological evaluation of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: a novel series of PPAR gamma agonists. Chem Pharm Bull (Tokyo). 2008;56(3):335–345. doi: 10.1248/cpb.56.335
   PubMed Web of Science ®Google Scholar
• Ferri N, Corsini A, Sirtori C, et al. PPAR-α agonists are still on the rise: an update on clinical and experimental findings. Expert Opin Investig Drugs. 2017;26(5):593–602. doi: 10.1080/13543784.2017.1312339
   PubMed Web of Science ®Google Scholar
• Sakamoto J, Kimura H, Moriyama S, et al. A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator-activated receptor subtypes. Eur J Pharmacol. 2004;495(1):17–26. doi: 10.1016/j.ejphar.2004.05.020
   PubMed Web of Science ®Google Scholar
• Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005 23;294(20):2581–2586. doi: 10.1001/jama.294.20.joc50147
   PubMed Web of Science ®Google Scholar
• Lincoff AM, Tardif JC, Schwartz GG, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA. 2014;311(15):1515–1525. doi: 10.1001/jama.2014.3321
   PubMed Web of Science ®Google Scholar
• Chatterjee S, Majumder A, Ray S. Observational study of effects of Saroglitazar on glycaemic and lipid parameters on Indian patients with type 2 diabetes. Sci Rep. 2015;5(1):7706. doi: 10.1038/srep07706
   PubMedGoogle Scholar
• Gawrieh S, Noureddin M, Loo N, et al. Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: a randomized controlled Double-blind phase 2 trial. Hepatology. 2021;74(4):1809–1824. doi: 10.1002/hep.31843
   PubMed Web of Science ®Google Scholar
• Agrawal R. The first approved agent in the Glitazar’s class: Saroglitazar. Curr Drug Targets. 2014;15(2):151–155. doi: 10.2174/13894501113149990199
   PubMed Web of Science ®Google Scholar
• Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147–1159. doi: 10.1053/j.gastro.2016.01.038
   PubMed Web of Science ®Google Scholar
• Van Meeteren MJ W, Drenth JPH, ETTL T. Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29(2):117–123. doi: 10.1080/13543784.2020.1668375
   PubMed Web of Science ®Google Scholar
• Boubia B, Poupardin O, Barth M, et al. Design, Synthesis, and evaluation of a novel series of indole sulfonamide peroxisome Proliferator Activated receptor (PPAR) α/γ/δ triple activators: discovery of lanifibranor, a new antifibrotic clinical Candidate. J Med Chem. 2018;61(6):2246–2265. doi: 10.1021/acs.jmedchem.7b01285
   PubMed Web of Science ®Google Scholar
• Francque SM, Bedossa P, Ratziu V, et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385(17):1547–1558. doi: 10.1056/NEJMoa2036205
   PubMed Web of Science ®Google Scholar
• Bae J, Park T, Kim H, et al. Lobeglitazone: a novel thiazolidinedione for the management of type 2 diabetes mellitus. Diabetes Metab J. 2021;45(3):326–336. doi: 10.4093/dmj.2020.0272
   PubMed Web of Science ®Google Scholar
• Gangopadhyay KK, Singh AK. Will lobeglitazone rival pioglitazone? A systematic review and critical appraisal. Diabetes Metab Syndr. 2023;17(4):102747. doi: 10.1016/j.dsx.2023.102747
   PubMed Web of Science ®Google Scholar
• Jin S-M, Park C-Y, Cho YM, et al. Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension. Diab Obes Metab. 2015;17(6):599–602. doi: 10.1111/dom.12435
   PubMed Web of Science ®Google Scholar
• Tanis SP, Colca JR, Parker TT, et al. PPARγ-sparing thiazolidinediones as insulin sensitizers. Design, synthesis and selection of compounds for clinical development. Bioorg Med Chem. 2018;26(22):5870–5884. doi: 10.1016/j.bmc.2018.10.033
   PubMed Web of Science ®Google Scholar
• DeFronzo RA, Inzucchi S, Abdul-Ghani M, et al. Pioglitazone: the forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Dis Res. 2019;16(2):133–143. doi: 10.1177/1479164118825376
   PubMed Web of Science ®Google Scholar
• Nesti L, Tricò D, Mengozzi A, et al. Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug. Cardiovasc Diabetol. 2021;20(1):109. doi: 10.1186/s12933-021-01294-7
   PubMed Web of Science ®Google Scholar
• Strongman H, Christopher S, Majak M. Pioglitazone and cause-specific risk of mortality in patients with type 2 diabetes: extended analysis from a European multidatabase cohort study. BMJ Open Diabetes Res Care. 2018;6(1):e000481. doi: 10.1136/bmjdrc-2017-000481
   PubMed Web of Science ®Google Scholar
• Le P, Chaitoff A, Rothberg MB, et al. Trends in pioglitazone use among U.S. adults with type 2 diabetes and suspected nonalcoholic fatty liver disease. Expert Opin Investig Drugs. 2020;29(2):205–208. doi: 10.1080/13543784.2020.1704731
   PubMed Web of Science ®Google Scholar
• Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321–1331. doi: 10.1056/NEJMoa1506930
   PubMed Web of Science ®Google Scholar
• Spence JD, Viscoli CM, Inzucchi SE, et al. Pioglitazone therapy in patients with stroke and prediabetes: a Post Hoc analysis of the IRIS randomized clinical trial. JAMA Neurol. 2019;76(5):526–535. doi: 10.1001/jamaneurol.2019.0079
   PubMed Web of Science ®Google Scholar
• Yaghi S, Furie KL, Viscoli CM, et al. Pioglitazone prevents stroke in patients with a recent transient ischemic attack or ischemic stroke: a planned secondary analysis of the IRIS trial (insulin resistance intervention after stroke). Circulation. 2018;137(5):455–463. doi: 10.1161/CIRCULATIONAHA.117.030458
   PubMed Web of Science ®Google Scholar
• Inzucchi SE, Viscoli CM, Young LH, et al. Pioglitazone prevents diabetes in patients with insulin resistance and cerebrovascular disease. Diabetes Care. 2016 Oct;39(10):1684–1692. doi: 10.2337/dc16-0798
   PubMed Web of Science ®Google Scholar
• Perdigoto AL, Young LH, Inzucchi SE. Pioglitazone and cardiovascular risk reduction: time for a second look? Cardiovasc Endocrinol. 2017;6(2):55–61. doi: 10.1097/XCE.0000000000000110
   PubMedGoogle Scholar
• Heneka MT, Fink A, Doblhammer G. Effect of pioglitazone Medication on the incidence of dementia. Ann Neurol. 2015;78(2):284–294. doi: 10.1002/ana.24439
   PubMed Web of Science ®Google Scholar
• Lu C-H, Yang C-Y, Li CY, et al. Lower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal study. Diabetologia. 2018;61(3):562–573. doi: 10.1007/s00125-017-4499-5
   PubMed Web of Science ®Google Scholar
• Tang X, Brinton RD, Chen Z, et al. Use of oral diabetes medications and the risk of incident dementia in US veterans aged ≥60 years with type 2 diabetes. BMJ Open Diabetes Res Care. 2022;10(5):e002894. doi: 10.1136/bmjdrc-2022-002894
   PubMed Web of Science ®Google Scholar
• Lin HC, Chung CH, Chen LC, et al. Pioglitazone use increases risk of Alzheimer’s disease in patients with type 2 diabetes receiving insulin. Sci Rep. 2023;13(1):6625. doi: 10.1038/s41598-023-33674-2
   PubMed Web of Science ®Google Scholar
• Burns DK, Alexander RC, Welsh-Bohmer KAC, et al. Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer’s disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomized, double-blind, placebo-controlled tria. Lancet Neurol. 2021l;20(7):537–547. doi: 10.1016/S1474-4422(21)00043-0
   PubMed Web of Science ®Google Scholar
• Colca JR. Insulin sensitizers may prevent metabolic inflammation. Biochem Pharmacol 2006. 2006;72(2):125–131. doi: 10.1016/j.bcp.2006.01.002
   Google Scholar
• Colca JR, Kletzien RF. What has prevented the expansion of insulin sensitisers? Expert Opin Investig Drugs. 2006;15(3):205–210. doi: 10.1517/13543784.15.3.205
   PubMed Web of Science ®Google Scholar
• Musso G, Cassader M, Paschetta E, et al. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis a meta analysis. JAMA Intern Med. 2017;177(5):633–640. doi: 10.1001/jamainternmed.2016.9607
   PubMed Web of Science ®Google Scholar
• Colca JR, McDonald WG, Waldon DJ, et al. Identification of a novel mitochondrial protein (“mitoNEET”) cross-linked specifically by a thiazolidinedione photoprobe. Am J Physiol Endocrinol Metab. 2004;286(2):E252–60. doi: 10.1152/ajpendo.00424.2003
   PubMed Web of Science ®Google Scholar
• Colca JR, McDonald WG, Cavey GS, et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)-relationship to newly identified mitochondrial pyruvate carrier proteins. PLoS One. 2013;8(e61551):1–10. doi: 10.1371/journal.pone.0061551
   Google Scholar
• Bricker DK, Taylor EB, Schell JC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, drosophila, and humans. Science. 2012 6;337(6090):96–100. doi: 10.1126/science.1218099
   PubMed Web of Science ®Google Scholar
• Herzig S, Raemy E, Montessuit S, et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science. 2012 Jul 6;337(6090):93–96. doi: 10.1126/science.1218530
   PubMed Web of Science ®Google Scholar
• McCommis KS, I Chen Z, Fu X, et al. Loss of mitochondrial pyruvate carrier 2 in the liver Leads to Defects in gluconeogenesis and compensation via pyruvate-alanine cycling. Cell Metab. 2015;22(4):682–694. doi: 10.1016/j.cmet.2015.07.028
   PubMed Web of Science ®Google Scholar
• McCommis KS, Hodges WT, Brunt EM, et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology. 2017;65(5):1543–1556. doi: 10.1002/hep.29025
   PubMed Web of Science ®Google Scholar
• Divakaruni AS, Wiley SE, Rogers GW, et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Pro Natl Acad Sci USA. 2013;110(14):5422–5427. doi: 10.1073/pnas.1303360110
   PubMed Web of Science ®Google Scholar
• Yiew NKH, Finck BN. The mitochondrial pyruvate carrier at the crossroads of intermediary metabolism. Am J Physiol Endocrinol Metab. 2022;323(1):E33–E52. doi: 10.1152/ajpendo.00074.2022
   PubMed Web of Science ®Google Scholar
• Zangari J, Petrelli F, Maillot B, et al. The multifaceted pyruvate metabolism: role of the mitochondrial pyruvate carrier. Biomolecules. 2020;10(7):1068. doi: 10.3390/biom10071068
   PubMed Web of Science ®Google Scholar
• Tang BL. Targeting the mitochondrial pyruvate carrier for neuroprotection. Brain Sci. 2019 18;9(9):238. doi: 10.3390/brainsci9090238
   PubMed Web of Science ®Google Scholar
• Divakaruni AS, Wallace M, Buren C, et al. Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death. J Cell Bio. 2017;216(4):1091–1105. doi: 10.1083/jcb.201612067
   PubMed Web of Science ®Google Scholar
• Sharma A, Oonthonpan L, Sheldon RD, et al. Impaired skeletal muscle mitochondrial pyruvate uptake rewires glucose metabolism to drive whole-body leanness. Elife. 2019;8:e45873. doi: 10.7554/eLife.45873
   PubMed Web of Science ®Google Scholar
• Yang C, Ko B, Hensley CT, et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell. 2014;56(3):414–424. doi: 10.1016/j.molcel.2014.09.025
   PubMed Web of Science ®Google Scholar
• Gray LR, Sultana MR, Rauckhorst AJ, et al. Hepatic mitochondrial pyruvate carrier 1 is required for Efficient Regulation of gluconeogenesis and whole-body glucose homeostasis. Cell Metab. 2015;22(4):669–681. doi: 10.1016/j.cmet.2015.07.027
   PubMed Web of Science ®Google Scholar
• Ferguson D, Eichler SJ, Yiew NKH, et al. Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism. Mol Metab. 2023;70:101694. doi: 10.1016/j.molmet.2023.101694
   PubMed Web of Science ®Google Scholar
• Hodges WT, Jarasvaraparn C, Ferguson D, et al. Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice. J Biol Chem. 2022;298(2):101554. doi: 10.1016/j.jbc.2021.101554
   PubMed Web of Science ®Google Scholar
• Tompkins SC, Sheldon RD, Rauckhorst AJ, et al. Disrupting mitochondrial pyruvate uptake directs glutamine into the TCA cycle away from glutathione Synthesis and impairs hepatocellular tumorigenesis. Cell Rep. 2019;28(10):2608–2619. doi: 10.1016/j.celrep.2019.07.098
   PubMed Web of Science ®Google Scholar
• Ferguson D, Habibi M, Eichler SJ, et al. Mitochondrial pyruvate carrier inhibition in hepatic stellate cells attenuates fibrosis in nonalcoholic steatohepatitis in mice. bio Rxiv 2023p. 02.13.528384, 10.1101/2023.02.13.528384. Preprint
   Google Scholar
• Zhu B, Wei X, Narasimhan H, et al. Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19. Sci Immunol. 2023 Epub 2023 Apr 14;8(82):eadf0348. 10.1126/sciimmunol.adf0348
   PubMed Web of Science ®Google Scholar
• Colca JR, VanderLugt JT, Adams WJ, et al. Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer. Clin Pharmacol Ther. 2013;93(4):352–359. doi: 10.1038/clpt.2013.10
   PubMed Web of Science ®Google Scholar
• Shah RC, Matthews DC, Andrews RD, et al. An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer’s disease. Curr Alzheimer Res. 2014;11(6):564–573. doi: 10.2174/1567205011666140616113406
   PubMed Web of Science ®Google Scholar
• Ghosh A, Tyson T, George S, et al. Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease. Sci Transl Med. 2016;8(368):368ra174. doi: 10.1126/scitranslmed.aag2210
   PubMed Web of Science ®Google Scholar
• Quansah E, Peelaerts W, Langston JW, et al. Targeting energy metabolism via the mitochondrial pyruvate carrier as a novel approach to attenuate neurodegeneration. Mol Neurodegener. 2018;13(1):28. doi: 10.1186/s13024-018-0260-x
   PubMed Web of Science ®Google Scholar
• Mallet D, Goutaudier R, Barbier EL, et al. Re-routing metabolism by the mitochondrial pyruvate carrier Inhibitor MSDC-0160 attenuates Neurodegeneration in a rat Model of Parkinson’s disease. Mol Neurobiol. 2022;59(10):6170–6182. doi: 10.1007/s12035-022-02962-9
   PubMed Web of Science ®Google Scholar
• Colca JR, Finck BN. Metabolic mechanisms connecting Alzheimer’s and Parkinson’s diseases: potential avenues for novel therapeutic approaches. Front Mol Biosci. 2022;9:929328. doi: 10.3389/fmolb.2022.929328
   PubMed Web of Science ®Google Scholar
• Colca JR, McDonald WG, Adams WJ. MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis Expert Opin Investig Drugs2018. Expert Opin Investig Drugs. 2018;27(7):631–636. doi: 10.1080/13543784.2018.1494153
   PubMed Web of Science ®Google Scholar
• Harrison SA, Alkhouri N, Davidson BA, et al. Insulin sensitizer MSDC-0602K in nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b study. J Hepato. 2020;72(4):613–626. doi: 10.1016/j.jhep.2019.10.023
   PubMed Web of Science ®Google Scholar
• Colca JR, Scherer PE. The metabolic syndrome, thiazolidinediones, and implications for intersection of chronic and inflammatory disease. Mol Metab. 2022;55:101409. doi: 10.1016/j.molmet.2021.101409
   PubMed Web of Science ®Google Scholar
• Jacques V, Bolze S, Hallakou-Bozec S, et al. Deuterium-stabilized (R)-pioglitazone (PXL065) is responsible for pioglitazone efficacy in NASH yet exhibits little to no PPARγ activity. Hepatol Commun. 2021;5(8):1412–1425. doi: 10.1002/hep4.1723
   PubMed Web of Science ®Google Scholar
• Harrison SA, Thang C, Bolze S, et al. Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: a phase II randomized placebo-controlled trial (DESTINY-1). J Hepatol. 2023;78(5):914–925. doi: 10.1016/j.jhep.2023.02.004
   PubMed Web of Science ®Google Scholar
• Monternier PA, Singh J, Parasar P, et al. Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy. J Inherit Metab Dis. 2022 Jul;45(4):832–847. doi: 10.1002/jimd.12510
   PubMed Web of Science ®Google Scholar
• Li J, Kumar S, Miachin K, et al. A dual MTOR/NAD+ acting gerotherapy. bioRxiv. 2023. doi: 2023.01.16.523975
   Google Scholar
• Colca JR, McDonald WG, Adams W. MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis. Expert Opin Investig Drugs. 2018;27(7):631–636. doi: 10.1080/13543784.2018.1494153
   PubMed Web of Science ®Google Scholar
• Kamm DR, Pyles KD, Sharpe MC, et al. Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide. J Biol Chem. 2021;296:100807. doi: 10.1016/j.jbc.2021.100807
   PubMed Web of Science ®Google Scholar
• Bardova K, Funda J, Pohl R, et al. Additive effects of omega-3 fatty acids and thiazolidinediones in mice fed a high-fat diet: Triacylglycerol/fatty acid cycling in adipose tissue. Nutrients. 2020;12(12):3737. doi: 10.3390/nu12123737
   PubMed Web of Science ®Google Scholar
• Bader DA, Hartig SM, Putluri V, et al. Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. Nat Metab. 2019;1(1):70–85. doi: 10.1038/s42255-018-0002-y
   PubMedGoogle Scholar
• Rattigan KM, Brabcova Z, Sarnello D, et al. Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells. Nat Commun. 2023;14(1):4634. doi: 10.1038/s41467-023-40222-z
   PubMedGoogle Scholar
• Armanini D, Boscaro M, Bordin L, et al. Controversies in the Pathogenesis, diagnosis and treatment of PCOS: focus on insulin resistance, inflammation, and hyperandrogenism. Int J Mol Sci. 2022;23(8):4110. doi: 10.3390/ijms23084110
   PubMed Web of Science ®Google Scholar