Efekat primene etil-piruvata na razvoj dijabetesa tipa 1 kod C57BL/6 miševa
Effects of ethyl pyruvate on the development of type 1 diabetes in C57BL/6 mice
Abstract:
Type 1 diabetes (T1D) is an autoimmune disease which triggers inflammation in the pancreas and the death of pancreatic β-cells, resulting in a decrease in insulin levels and increase of blood glucose levels. Since a cure for T1D still hasn’t been found and patients with T1D rely on a life-long insulin treatment, constant efforts are invested to develop new therapeutical approaches. To that end, this doctoral thesis was devoted to testing the effects of ethyl pyruvate, known to have anti-inflammatory properties, on the development of T1D, induced by multiple low-doses of streptozotocin, in C57BL/6 mice. Its prophylactic application in the aforementioned T1D model resulted in decreased disease incidence, accompanied by lessened immune cell infiltration into the pancreatic islets and reduced expression of the primary target molecule of ethyl pyruvate, HMGB1 (High Mobility Group Box 1). Ethyl pyruvate accomplished its protective influence by stimulating the regulatory arm of the immune response, namely by increasing the proportion of tolerogenic dendritic cells and regulatory T (Treg) cells. It also exerted its effects on Treg cells by increasing their proliferation, differentiation, migration and suppressive function, primarily towards effector T-bet+ T cells. Aside from its effects on Treg cells in pathological conditions, ethyl pyruvate stimulated Treg cells in homeostatic conditions, whether applied orally or intraperitoneally. Complementary in vitro experiments showed that ethyl pyruvate potentiates Treg cell proliferation, which is achieved through the modulation of cell metabolism, by stimulating glycolysis and suppressing fatty acid β-oxidation, while there is no effect on the citric acid cycle or oxidative phosphorylation. The results of this doctoral thesis indicate a notable potential of ethyl pyruvate to inhibit inflammation, a key part of T1D pathology, and that its application in T1D therapy can be further explored in preclinical and clinical studies.
Keywords:
Type 1 diabetes; Ethyl pyruvate; Streptozotocin; Inflammation; Regulatory T cellsSource:
University of Belgrade, Faculty of Biology, 2020, 1-119Funding / projects:
- Molecular mechanisms of physiological and pharmacological control of inflammation and cancer (RS-MESTD-Basic Research (BR or ON)-173013)