Extracellular metallothionein as a therapeutic target in the early progression of Type 1 Diabetes

Authors

Clare K. Melchiorre, Department of Molecular and Cell Biology, University of Connecticut; Storrs, CT, USA.
Matthew D. Lynes, Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, ME 04074, USA.
Sadikshya Bhandari, Department of Molecular and Cell Biology, University of Connecticut; Storrs, CT, USA.
Sheng-Chiang Su, Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School; Boston, MA, USA; Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Christian M. Potts, Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, ME 04074, USA.
Amy V. Thees, Department of Molecular and Cell Biology, University of Connecticut; Storrs, CT, USA.
Carol E. Norris, Department of Molecular and Cell Biology, University of Connecticut; Storrs, CT, USA.
Lucy Liaw, Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, ME 04074, USA.
Yu-Hua Tseng, Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School; Boston, MA, USA.
Michael A. Lynes, Department of Molecular and Cell Biology, University of Connecticut; Storrs, CT, USA. Electronic address: michael.lynes@uconn.edu.

Document Type

Article

Publication Date

3-13-2024

Institution/Department

MaineHealth Institute for Research, Center for Molecular Medicine

Journal Title

Cell stress & chaperones

Abstract

Type 1 diabetes (T1D) is characterized by lymphocyte infiltration into the pancreatic islets of Langerhans, leading to the destruction of insulin-producing beta cells and uncontrolled hyperglycemia. In the non-obese diabetic (NOD) murine model of T1D, onset of this infiltration starts several weeks before glucose dysregulation and overt diabetes. Recruitment of immune cells to the islets is mediated by several chemotactic cytokines, including CXCL10, while other cytokines, including SDF-1α, can confer protective effects. Global gene expression studies of the pancreas from prediabetic NOD mice and single cell sequence analysis of human islets from prediabetic, autoantibody positive patients showed an increased expression of metallothionein (MT), a small molecular weight, cysteine-rich metal binding stress response protein. We have shown that beta cells can release MT into the extracellular environment, which can subsequently enhance the chemotactic response of Th1 cells to CXCL10 and interfere with the chemotactic response of Th2 cells to SDF-1α. These effects can be blocked in vitro with a monoclonal anti-MT antibody, clone UC1MT. When administered to NOD mice before the onset of diabetes, UC1MT significantly reduces the development of T1D. Manipulation of extracellular MT may be an important approach to preserving beta cell function and preventing the development of T1D.

Recommended Citation

Melchiorre, Clare K.; Lynes, Matthew D.; Bhandari, Sadikshya; Su, Sheng-Chiang; Potts, Christian M.; Thees, Amy V.; Norris, Carol E.; Liaw, Lucy; Tseng, Yu-Hua; and Lynes, Michael A., "Extracellular metallothionein as a therapeutic target in the early progression of Type 1 Diabetes" (2024). Maine Medical Center. 3632.
https://knowledgeconnection.mainehealth.org/mmc/3632