6.3 Complications and Treatment
Dysregulation of T-cell homeostasis resulting from the progression of diabetes mellitus can affect all vital organs in the body, resulting in a variety of chronic complications. The adipose tissue is an endocrine organ that plays an important role in regulating glucose metabolism and fatty acid oxidation. Under physiological conditions, adipokines (such as leptin) continually activate effector T cells, which leads to the generation of cytokines that suppress inflammation; the liver first undergoes steatosis, and the secretion of chemokines by hepatocytes and Kupffer cells eventually leads to inflammation and fibrosis58,115. A study on T2DM and cardiovascular risk found increased immune activation in individuals with T2DM and cardiovascular disease116 and that signaling by inducible T cell costimulator and its ligand (ICOS/ICOSL), a co-stimulatory immune checkpoint, induces cytotoxic effects, such as activation of cytotoxic T lymphocytes, and inhibits Treg activity117. High glucose levels and AGEs may cause T-cell inflammatory responses and vascular endothelial dysfunction by upregulating ICOS signaling118. In addition, diabetic nephropathy100 and retinopathy119exhibit varying degrees of T cell homeostasis disruption, exacerbating inflammation and dysfunction.
A growing body of research is exploring immunotherapies for T2DM to reduce disease progression and complications. Conventional oral hypoglycemic agents such as glucagon-like peptide (GLP)-1 agonists have been shown to help inhibit T cell proliferation, promote Th2 transition, and reduce the IL-1/IFN-γ ratio to reduce renal and cardiovascular deterioration120,121. Patients with newly diagnosed T2DM who have a short course of rigorous insulin treatment have substantial reductions in inflammatory markers such as IL-6, TNF-α, and chemokines and increases in activating factors that govern proper T cell production and secreted chemokines122, further suggesting that insulin regulates T cell immune homeostasis in addition to its glucose-lowering effects. However, the effects of these factors on the inflammatory signaling pathway in blood glucose levels are understudied. Additionally, the role of immunomodulation in the treatment of T2DM goes far beyond that. Adult stem cells from individuals with obesity and T2DM inhibit CD4+ T cell proliferation, modulate T cell activation markers (CD69 and CD25), and increase Treg frequency123 thereby facilitating immunotherapy.
Researchers are currently exploring the development of a diabetes vaccine that modulates immune cell subsets in T2DM. A vaccine targeting IL-1β with polylactic acid particles as an adjuvant targets and inhibits IL-1β and blocks NF-κB activation by decreasing the levels of IKKβ and phosphorylated RelA124 and blocking the release of pro-inflammatory factors. The PD-1 pathway is important for regulating T-cell activation, tolerance, and exhaustion. There have been opposing findings regarding whether PD-1 is upregulated110,111or downregulated114 in T2DM, but it has been suggested that PD-1-deficient Tregs may protect non-obese diabetic mice from diabetes by inhibiting the PI3K/AKT pathway125. Therefore, the use of PD-1 as an immune checkpoint inhibitor may be beneficial in restoring immune function in patients with T2DM.