High Glucose in Diabetic Hyperglycemia Perturbs Lymphocyte SERCA-Regulated Ca2+ Stores with Accompanying ER Stress and Signaling Dysfunction

Authors

• Md N. Uddin, University of the PacificFollow
• James L. Graham, University of California, Davis
• Peter J. Havel, University of California, Davis
• Roshanak Rahimian, University of the PacificFollow
• David W. Thomas, University of the PacificFollow

Document Type

Article

Publication Title

Biomolecules

Department

Pharmacy

ISSN

2218273X

Volume

15

Issue

7

DOI

10.3390/biom15070987

First Page

1

Last Page

26

Publication Date

7-11-2025

Abstract

It is well recognized that patients with type 2 diabetes mellitus (T2DM) exhibit significant impairment of immune function resulting in a higher frequency of infections. We hypothesize in this study that a likely contributor to immune dysfunction in T2DM is alteration of T lymphocyte signaling functions induced by chronic hyperglycemia. In this study we have utilized the established UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model of human T2DM to investigate whether progressive hyperglycemia diminishes T cell receptor (TCR)-releasable endoplasmic reticulum (ER) Ca²⁺ stores, an essential early antigen-stimulated signal driving T cell activation. Furthermore, results from this study demonstrate that chronic hyperglycemia markedly alters the expression profile of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) Ca²⁺ ion pumps, which are the major enzymatic ion transporters maintaining replenished TCR-sensitive Ca²⁺ pools. We conducted companion experiments using Jurkat T lymphocytes exposed to high glucose which allowed finer resolution of early disruptions to ER Ca²⁺ store integrity and greater clarity on SERCA isoform-specific roles in diabetes-induced Ca²⁺ signal dysregulation. In summary, these experiments suggest that hyperglycemia in T2DM drives an ER stress state manifesting in reduced expression of the SERCA pumps, erosion of ER Ca²⁺ stores and culminating in T cell and immune dysfunction.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Uddin, Md N.; Graham, James L.; Havel, Peter J.; Rahimian, Roshanak; and Thomas, David W., "High Glucose in Diabetic Hyperglycemia Perturbs Lymphocyte SERCA-Regulated Ca2+ Stores with Accompanying ER Stress and Signaling Dysfunction" (2025). Pacific Faculty Work. 62.
https://scholarlycommons.pacific.edu/all-faculty/62