Inhibition of hyaluronan synthesis prevents β-cell loss in obesity-associated type 2 diabetes.

Autor: Nagy N; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA., Kaber G; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA., Sunkari VG; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA., Marshall PL; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA., Hargil A; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA., Kuipers HF; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA., Ishak HD; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA., Bogdani M; Benaroya Research Institute, Seattle, WA, USA., Hull RL; Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA., Grandoch M; Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., Fischer JW; Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., McLaughlin TL; Department of Medicine, Medicine - Endocrinology, Endocrine Clinic, Stanford School of Medicine, Stanford, CA, USA., Wight TN; Benaroya Research Institute, Seattle, WA, USA., Bollyky PL; Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, 279 Campus Drive, Beckman Center B241A, Stanford, CA 94305, USA. Electronic address: pbollyky@stanford.edu.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2023 Nov; Vol. 123, pp. 34-47. Date of Electronic Publication: 2023 Sep 30.
DOI: 10.1016/j.matbio.2023.09.003
Abstrakt: Pancreatic β-cell dysfunction and death are central to the pathogenesis of type 2 diabetes (T2D). We identified a novel role for the inflammatory extracellular matrix polymer hyaluronan (HA) in this pathophysiology. Low concentrations of HA were present in healthy pancreatic islets. However, HA substantially accumulated in cadaveric islets of T2D patients and islets of the db/db mouse model of T2D in response to hyperglycemia. Treatment with 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, or the deletion of the main HA receptor CD44, preserved glycemic control and insulin concentrations in db/db mice despite ongoing weight gain, indicating a critical role for this pathway in T2D pathogenesis. 4-MU treatment and the deletion of CD44 likewise preserved glycemic control in other settings of β-cell injury including streptozotocin treatment and islet transplantation. Mechanistically, we found that 4-MU increased the expression of the apoptosis inhibitor survivin, a downstream transcriptional target of CD44 dependent on HA/CD44 signaling, on β-cells such that caspase 3 activation did not result in β-cell apoptosis. These data indicated a role for HA accumulation in diabetes pathogenesis and suggested that it may be a viable target to ameliorate β-cell loss in T2D. These data are particularly exciting, because 4-MU is already an approved drug (also known as hymecromone), which could accelerate translation of these findings to clinical studies.
Competing Interests: Declaration of Competing Interest PLB, NN, GK, and HFK have filed intellectual property around 4-MU. PLB, NN and GK hold a financial interest in Halo Biosciences, a company that is developing 4-MU for various indications.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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