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Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes

ABSTRACT: Type 2 diabetes (T2D) patients are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that both COVID-19-infected T2D patients and influenza-infected T2D mice exhibit a defective Th1 response, which is an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4+T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4+T cells. These abnormalities promote lipid peroxidation (LPO), which drives the carbonylation of STAT4, a crucial Th1 lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates these Th1 defects in T2D patients with poor glycemic control, and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274826 | GEO | 2024/11/02

REPOSITORIES: GEO

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Project description:Objective: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells (PBMCs) due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency and hyperglycemia. Research Design and Methods: Microarray analysis was performed on PBMCs from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D) and 24 healthy controls. One and four month follow-up samples were obtained from 20 of the T1D patients. Results: Microarray analysis identified 282 genes differing in expression between newlydiagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of interleukin-1Î² (IL1B), early growth response gene 3 (EGR3), and prostaglandin-endoperoxide; synthase 2 (PTGS2) resolved within four months of insulin therapy and were also observed in T2D suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81/282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly-connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D. Conclusion: T1D and T2D likely share a final common pathway for beta cell dysfunction that includes secretion of interleukin-1Î² and prostaglandins by immune effector cells, exacerbating existing beta cell dysfunction, and causing further hyperglycemia. The results identify several targets for disease-modifying therapy of diabetes and potential biomarkers for monitoring treatment efficacy. Experiment Overall Design: We obtained blood samples from 24 healthy volunteers, 43 newly diagnosed T1D patients and 12 newly diagnosed T2D patients. All study participants were between the ages of 2 and 18 years. We collected samples one and four months after diagnosis from the last 20 of the T1D patients. For each time point one sample did not pass quality control and was dropped from the analysis. Patients with T2D were distinguished from T1D on the basis of age, body habitus, Experiment Overall Design: presence (11/12 patients) of acanthosis nigricans, family history of type 2 diabetes (11/12 patients), and absence of autoantibodies to insulin, IA-2, and GAD65. We allowed low titers of insulin antibodies in T2D patients (< 4 U/mL), which have been previously reported. All but two Experiment Overall Design: of the T1D patients with positive anti-insulin antibodies were also positive for at least one additional autoantibody.

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Hyperglycemia-triggered lipid peroxidation destabilizes STAT4 and impairs anti-viral Th1 responses in type 2 diabetes

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