High Glucose in Diabetic Hyperglycemia Perturbs Lymphocyte SERCA-Regulated Ca<sup>2+</sup> Stores with Accompanying ER Stress and Signaling Dysfunction
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 funct...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
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| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/7/987 |
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| Summary: | 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) Ca<sup>2+</sup> 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 Ca<sup>2+</sup>-ATPase (SERCA) Ca<sup>2+</sup> ion pumps, which are the major enzymatic ion transporters maintaining replenished TCR-sensitive Ca<sup>2+</sup> pools. We conducted companion experiments using Jurkat T lymphocytes exposed to high glucose which allowed finer resolution of early disruptions to ER Ca<sup>2+</sup> store integrity and greater clarity on SERCA isoform-specific roles in diabetes-induced Ca<sup>2+</sup> 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 Ca<sup>2+</sup> stores and culminating in T cell and immune dysfunction. |
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| ISSN: | 2218-273X |