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  • Review Article
  • Published:

PPARα: an emerging therapeutic target in diabetic microvascular damage

Nature Reviews Endocrinology volume 6, pages 454–463 (2010)Cite this article

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A Correction to this article was published on 01 September 2010

Abstract

The global pandemic of diabetes mellitus portends an alarming rise in the prevalence of microvascular complications, despite advanced therapies for hyperglycemia, hypertension and dyslipidemia. Peroxisome proliferator-activated receptor α (PPARα) is expressed in organs affected by diabetic microvascular disease (retina, kidney and nerves), and its expression is regulated specifically in these tissues. Experimental evidence suggests that PPARα activation attenuates or inhibits several mediators of vascular damage, including lipotoxicity, inflammation, reactive oxygen species generation, endothelial dysfunction, angiogenesis and thrombosis, and thus might influence intracellular signaling pathways that lead to microvascular complications. PPARα has emerged as a novel target to prevent microvascular disease, via both its lipid-related and lipid-unrelated actions. Despite strong experimental evidence of the potential benefits of PPARα agonists in the prevention of vascular damage, the evidence from clinical studies in patients with diabetes mellitus remains limited. Promising findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study on microvascular outcomes are countered by elevations in participants' homocysteine and creatinine levels that might potentially attenuate the benefits of PPARα activation. This Review focuses on the role of PPARα activation in diabetic microvascular disease and highlights the available experimental and clinical evidence from studies of PPARα agonists.

Key Points

  • Activation of peroxisome proliferator-activated receptor α (PPARα) alleviates dyslipidemia and might slow the progression of diabetic microvascular complications through both lipid-related and lipid-unrelated mechanisms

  • Substantial experimental evidence shows that PPARα activation decreases reactive oxygen species generation and inflammatory cytokine expression through both lipid-related and lipid-unrelated effects

  • The influence of PPARα activation on endothelial function remains unresolved, probably owing to species-related differences in PPARα activity and the diversity of regulators of endothelial function

  • Although fenofibrate reduced the need for amputations and laser treatment (albeit without preserving visual acuity) in patients with retinopathy, fibrates cannot yet be recommended for prevention of diabetic microvascular complications

  • Increased serum levels of creatinine, cystatin C and homocysteine during fibrate therapy might reflect a transient impairment of renal function, potentially related to effects of fibrates on renal hemodynamics

  • Large-scale, prospective, randomized trials to evaluate the efficacy of fibrates on microvascular outcomes as primary end points in patients with diabetes mellitus are urgently needed

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Figure 1: Diabetes-induced microvascular damage and potential protective actions of PPARα agonists.

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Acknowledgements

M. Maranghi holds a fellowship from Sapienza University, Rome, Italy. We thank Laura Impivaara for excellent technical assistance.

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Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Helsinki University Central Hospital and Biomedicum, Haartmaninkatu 8, Helsinki, 00029, Finland

    Anne Hiukka & Marja-Riitta Taskinen

  2. Division of Endocrinology and Diabetes, Department of Medicine, Helsinki University Central Hospital and Biomedicum, Haartmaninkatu 8, Helsinki, 00029, Finland

    Niina Matikainen

  3. Department of Clinical Science, Sapienza University, Viale del Policlinico 155, Rome, 00161, Italy

    Marianna Maranghi

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  1. Anne Hiukka
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Correspondence to Marja-Riitta Taskinen.

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Competing interests

N. Matikainen declares that she has acted as a consultant for Novartis and Orion. M.-R.Taskinen declares that she has acted as a consultant for Kowa, Merck Sharpe & Dohme, and Novartis, received grant or research support from Eli Lilly, Merck Sharpe & Dohme, Sanofi-Aventis and Takeda, and is a member of the speakers' bureau or has received honoraria from Merck Sharpe & Dohme and Merck Schering-Plough. The other authors declare no competing interests.

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Hiukka, A., Maranghi, M., Matikainen, N. et al. PPARα: an emerging therapeutic target in diabetic microvascular damage. Nat Rev Endocrinol 6, 454–463 (2010). https://doi.org/10.1038/nrendo.2010.89

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