The Effects of Yerba Mate (Ilex paraguariensis) in the Development of Type 1 Diabetes in the STZ-induced C57BL/6 and NOD Mouse Models

Type 1 Diabetes (T1D) is a T cell-mediated autoimmune disease that attacks the pancreas\u27 insulin-producing b-cells. As immunotherapies have failed to reverse T1D, the focus has turned to prevention, particularly during the subclinical, pre-stage 1 when auto-reactive T cells are not yet active. Yerba mate (YM) or Ilex paraguariensis has been shown to have anti-inflammatory and hypoglycemic properties that make it a potentially safe and inexpensive therapeutic agent to delay the onset of the disease. This study aimed to evaluate YM\u27s effect on the progression of T1D and T cell populations in two mouse models of T1D: streptozotocin (STZ)-induced C57BL/6 (STZ-B6) strain and non-obese-diabetic/ShiLtj (NOD) strain. YM was given daily as an infusion ad libitum at 4% and 2% w/v. In the STZ-B6 model, YM treatment began before diabetes induction by low-dose STZ and continued daily for a total period of 6 weeks. In the NOD model, YM treatment began at 5 weeks of age and continued daily for 19 weeks. Glycemia and body weights were monitored bi-weekly and weekly for the STZ-B6 mice and NOD mice, respectively. At the endpoint, animals were euthanized to analyze immunological parameters of cell viability, T cell proliferation, T cell immunophenotypes, and related cytokine production in their spleens. An in vitro T cell assay was also conducted on splenocytes from healthy NOD mice directly treated with 0.5-1000 mg/mL YM. YM treatment significantly decreased glycemia and T1D incidence for both concentrations in the STZ-B6 model over 6 weeks while increasing or maintaining body weight with 4% and 2% w/v, respectively. YM at 4%, but not 2%, w/v significantly decreased glycemia in NOD mice over 19 weeks of treatment without affecting T1D onset. However, both concentrations induced body weight loss in NOD mice starting around 14 weeks of treatment. Further ex vivo data showed YM treatment in STZ-B6 mice at both concentrations significantly lowered T cell proliferation, caused transient changes in T cell immunophenotypes, and suppressed both pro-inflammatory and anti-inflammatory cytokine production. In NOD mice, 4% YM (w/v) treatment showed a transient effect at the 12 weeks of age timepoint in lowering T cell, Th, and Tc populations and reducing production of pro-inflammatory cytokines IL-6 and IFN-, However, this anti-inflammatory effect was not evident at 17 weeks of age or the endpoint. YM exposure of T cells in vitro caused a dose-dependent decrease of T cell proliferation. The concentrations of all studied cytokines, IL-2, TNF-a, IFN-, IL-17, IL-4, and IL-10, were suppressed with addition of 1000 g/mL YM, suggesting its toxicity. A dose-dependent reduction and increase of IFN- and IL-2 production, respectively, was observed whereas other studied cytokines were not affected by lower concentrations of YM. In summary, this is the first study to show YM\u27s potential to delay the onset of T1D. Our results corroborate with other studies that tout YM\u27s anti-proliferative and hypoglycemic action, in addition to its immunomodulatory action on T cells