06 May New Focus for Inflammatory Skin Disease and Psoriasis: Topical Glucose Transport Inhibitors
MedicalResearch.com Interview with:
Richard Wang, M.D., Ph.D.
Assistant Professor Dermatology
UT Southwestern Medical Center
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Targeting cellular metabolism is currently being explored as a new way to diagnose and treat diseases. In particular, there has been increasing interest in specifically targeting metabolic pathways are preferentially altered in disease states, like cancer. Although an increased dependence on glucose transport and metabolism has been well established for rapidly proliferating cells, attempts to target this conserved pathway have been limited by concerns about the high potential for side effects from the systemic inhibition of glucose transport.
To investigate the feasibility of targeting glucose transport in skin diseases, we investigated the effect of inhibiting glucose transport in the skin by deleting the primary glucose transporter in the skin, Glut1, in mouse keratinocytes. We confirmed that the Glut1-deficient keratinocytes showed metabolic and oxidative stress and impaired proliferation. However, the keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and barrier function. Metabolomic profiling revealed sphingolipid, hexose, amino acid, and nucleotide adaptations in Glut1-deficient keratinocytes. However, Glut1 deficient skin did show defects in both proliferation and migration after physiologically relevant stressors like excisional wounds and UV-B irradiation.
Given its importance during stressors, we further tested whether Glut1 was important in the pathogenesis of psoriasis models. Notably, both the genetic and pharmacological inhibition of Glut1 decreased hyperplasia in mouse and human organic models of psoriasis. Moreover, the topical application of a Glut1 inhibitor further decreased inflammation in these models. The ability to deliver glucose transport inhibitors specifically to the skin may limit the adverse effects from the systemic inhibition of glucose transport and suggests that the topical inhibition of glucose transport may be a novel approach to treat hyperproliferative and inflammatory skin diseases.
MedicalResearch.com: What should readers take away from your report?
Response: While glucose is important for the skin during injury or stress, it is not necessary for skin development and normal barrier function. Both the genetic and chemical inhibition of glucose transport in keratinocytes suggests that it could be a novel treatment option for psoriasis and other hyperproliferative skin diseases.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: We are interested in optimizing the topical inhibition of glucose transport using more potent inhibitors of glucose transport. It would also be interesting to assess the effect of inhibiting glucose transport on other hyperproliferative skin diseases including non-melanoma skin cancers, like cutaneous squamous cell carcinoma.
Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis
Zhuzhen Zhang, Zhenzhen Zi, Eunice E. Lee, Jiawei Zhao, Diana C. Contreras, Andrew P. South, E. Dale Abel, Benjamin F. Chong, Travis Vandergriff, Gregory A. Hosler, Philipp E. Scherer, Marcel Mettlen, Jeffrey C. Rathmell, Ralph J. DeBerardinis & Richard C. Wang
Nature Medicine (2018)
Published: 16 April 2018
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