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.