Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Karacay, C.
Autophagy Induction as a Therapeutic Intervention
in Type 1 Diabetes
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 164
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kotzbeck Petra
- Pieber Thomas
- Strobl Herbert
- Altmetrics:
- Abstract:
- Physiological autophagy is crucial for maintenance of healthy functional beta cells and autophagy deficiency results in exacerbated diabetes in mice. Induction of autophagy has shown protective effects on beta cells in type 2 diabetes models. Spermidine is a natural polyamine and an autophagy inducer. The polyamine spermidine was shown to prolong lifespan of many organisms and to enhance cognitive and cardiac functions in aging mice. Spermidine was also reported to reduce inflammation and to modulate immune cell populations such as T cells, B cells, macrophages, and dendritic cells. The effect of spermidine on progression of type 1 diabetes has yet to be explored. The aim of this thesis was to study the role of autophagy induction by daily oral spermidine treatment in type 1 diabetes pathogenesis in NOD mice. We investigated three spermidine concentrations (1 mM, 3 mM, and 10 mM) in two studies employing male NOD mice. These studies were designed to observe the effect of spermidine on polyamine metabolism and on vital parameters of mice such as body weight, food, and water consumption. Later we investigated the effect of 3 mM and 10 mM spermidine on diabetes incidence, immune cell populations, islet insulitis, insulin granule pool, and autophagy in female NOD mice in two prevention studies. Supplementation of 3 mM and 10 mM spermidine in drinking water was tolerable in male and female NOD mice, indicated by similar BW and water and food consumption between the control and spermidine groups. 10 mM spermidine affected polyamine metabolism in several relevant organs of male NOD mice. In the prevention study, 3 mM spermidine in drinking water did not significantly change diabetes incidence in female NOD mice. The changes in CD8+ T cells, Tregs and NKT cells were inconclusive. 3 mM spermidine did not alter islet insulitis and plasma cytokine levels in nondiabetic survivors and diabetic mice. In the prevention study, 10 mM spermidine in drinking water increased the diabetes incidence in NOD mice and elevated pro-inflammatory CD8+ T cells in pLN of diabetic mice. Additionally, 10 mM spermidine affected Tregs both in nondiabetic survivors and diabetic mice and dendritic cell populations and NK cells in nondiabetic survivors. 10 mM spermidine significantly reduced IL-6 plasma cytokine levels in nondiabetic survivors but it did not affect other measured plasma cytokines (IFN-ɣ, IL-1β, TNF-α, IL-2, IL-5, and IL-10) both in nondiabetic survivors and diabetic mice. 10 mM spermidine did not change insulitis and the thymic T cell populations both in nondiabetic survivors and diabetic mice. Additionally, 10 mM spermidine increased the autophagy levels in total pancreas in late-onset diabetic mice. Last but not least, 10 mM spermidine did not change the insulin granule pool and autophagy-dependent insulin granule digestion. Altogether these results suggest that 10 mM spermidine treatment increased diabetes incidence and increased pro-inflammatory T cells in NOD mice, possibly via autophagy induction.