Abstract
Chronic inflammation is a driving force for the development of metabolic disease including diabetes and obesity. However, the functional characteristics of T-cell senescence in the abnormal glucose homeostasis are not fully understood. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity. Human senescent (CD28−CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans. Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.
Highlights
Chronic inflammation is strongly associated with metabolic diseases, including diabetes and atherosclerosis[1,2]
Genes that were significantly upregulated in the peripheral blood mononuclear cells (PBMCs) of normal controls and patients with prediabetes were analyzed for genelist enrichment with gene set libraries created from level 4 of the MGI mouse phenotype ontology using Network2Canvas. g PBMCs isolated from controls (n = 6) and patients (n = 6) with prediabetes were subjected to real-time PCR
We found that the 10 representative terms Gene Ontology Biological Process and Cellular Component and Molecular Function were enriched in PBMCs from drug-naive patients with type 2 diabetes (Supplementary Fig. 1a–c)
Summary
Chronic inflammation is strongly associated with metabolic diseases, including diabetes and atherosclerosis[1,2]. (see figure on previous page) Fig. 1 Identification of differentially expressed genes in PBMCs from normoglycemic controls and patients with prediabetes. A Hierarchical clustering and heatmap based on genes that were differentially expressed in PBMCs from patients with prediabetes (n = 4) (≥ 2-fold change in expression compared with normoglycemic controls (n = 4)). Genes that were significantly upregulated in the PBMCs of normal controls and patients with prediabetes were analyzed for genelist enrichment with gene set libraries created from level 4 of the MGI mouse phenotype ontology using Network2Canvas. The chronic inflammatory environment that is a characteristic of metabolic diseases may be induced by augmented secretion of proinflammatory cytokines, including TNF-α and IL-6, reactive oxygen species (ROS), and acute-phase reactants released from senescent immune cells. Any relationship between the immunosenescence of T cells and abnormal glucose homeostasis remains to be elucidated
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