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PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine

Current Diabetes Reports volume 21, Article number: 18 (2021) Cite this article

Abstract

Purpose of Review

Full and partial synthetic agonists targeting the transcription factor PPARγ are contained in FDA-approved insulin-sensitizing drugs and used for the treatment of metabolic syndrome-related dysfunctions. Here, we discuss the association between PPARG genetic variants and drug efficacy, as well as the role of alternative splicing and post-translational modifications as contributors to the complexity of PPARγ signaling and to the effects of synthetic PPARγ ligands.

Recent Findings

PPARγ regulates the transcription of several target genes governing adipocyte differentiation and glucose and lipid metabolism, as well as insulin sensitivity and inflammatory pathways. These pleiotropic functions confer great relevance to PPARγ in physiological regulation of whole-body metabolism, as well as in the etiology of metabolic disorders. Accordingly, PPARG gene mutations, nucleotide variations, and post-translational modifications have been associated with adipose tissue disorders and the related risk of insulin resistance and type 2 diabetes (T2D). Moreover, PPARγ alternative splicing isoforms—generating dominant-negative isoforms mainly expressed in human adipose tissue—have been related to impaired PPARγ activity and adipose tissue dysfunctions. Thus, multiple regulatory levels that contribute to PPARγ signaling complexity may account for the beneficial as well as adverse effects of PPARγ agonists. Further targeted analyses, taking into account all these aspects, are needed for better deciphering the role of PPARγ in human pathophysiology, especially in insulin resistance and T2D.

Summary

The therapeutic potential of full and partial PPARγ synthetic agonists underlines the clinical significance of this nuclear receptor. PPARG mutations, polymorphisms, alternative splicing isoforms, and post-translational modifications may contribute to the pathogenesis of metabolic disorders, also influencing the responsiveness of pharmacological therapy. Therefore, in the context of the current evidence-based trend to personalized diabetes management, we highlight the need to decipher the intricate regulation of PPARγ signaling to pave the way to tailored therapies in patients with insulin resistance and T2D.

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Acknowledgements

We acknowledge EFSD/Boehringer Ingelheim European Research Programme in Microvascular Complications of Diabetes, granted to A.C. and funding M.A. research contract, and PON Ricerca e Innovazione 2014–2020, PON Ars01_01270 “Innovative Device For SHAping the Risk of Diabetes” (IDF SHARID) to V.C.

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  1. Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Via P. Castellino 111, 80131, Naples, Italy

    Simona Cataldi, Valerio Costa, Alfredo Ciccodicola & Marianna Aprile

  2. Department of Science and Technology, University of Naples “Parthenope”, 80131, Naples, Italy

    Alfredo Ciccodicola

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  1. Simona Cataldi
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  2. Valerio Costa
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Correspondence to Alfredo Ciccodicola.

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Cataldi, S., Costa, V., Ciccodicola, A. et al. PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine. Curr Diab Rep 21, 18 (2021). https://doi.org/10.1007/s11892-021-01385-5

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Keywords

  • PPARG genetic variants
  • Dominant-negative isoforms
  • Post-tranlational modifications
  • Adipose tissue dysfunctions
  • Drug responsiveness
  • Type 2 diabetes