The overall aim of Inga Sileikaite’s PhD project is to provide new data to shed light on the role played by oxidative stress in type 2 diabetes. ‘It may prove to be an important tool in the design of new therapeutic approaches to reducing diabetic mortality’, she says.

What is known today is that oxidative stress, through the production of reactive oxygen species (ROS), plays a key role in the development of insulin resistance, dysfunction in insulin-producing β-cells, impaired glucose tolerance and type 2 diabetes mellitus (T2D). ROS initiate a chain of reactions that promote both the modification of biological molecules and altered signalling, resulting in cellular dysfunction and cell death. Ribonucleic acid (RNA), an important constituent of the cellular machinery of all organisms, is a prospective target for ROS given its structure, its positioning within cells and the absence of RNA repair mechanisms. The nucleobase guanosine is highly sensitive to oxidation, which causes the generation of 8-oxoguanosine (8-oxoGuo).

‘The secretion of 8-oxoGuo in the urine is strongly correlated with T2D morbidity. Despite this, the mechanism of 8-oxoGuo generation in T2D patients is unknown, nor is it known whether 8-oxoGuo is involved in promoting the disease and pancreatic cell dysfunction. This is relevant because a strategy aimed at decreasing RNA oxidation could potentially be of great therapeutic value in patient treatment’, says Inga Sileikaite.  

The hypothesis of her PhD project is that the increased volume of blood-borne fats observed in individuals with T2D promotes inflammation and oxidative stress, causing RNA oxidation to induce deterioration of the function of the insulin-producing βeta-cells and the development of diabetes.

‘We will use in vivo and in vitro approaches to determine: 1) the quantitative significance of RNA oxidation in diabetic models including β-cells; 2) the pathways responsible for both generation and removal of 8-oxoGuo; 3) the role of oxidation in the alteration of β-cell function; and 4) the effect of new targeted antioxidant-based methods of protecting RNA (and  other  targets)  from oxidative  damage  in order to  maintain  β-cell function.

Inga Sileikaite’s project will build on preliminary data showing that 8-oxoGuo and related compounds can alter β-cell function in an in vitro β-cell model.

CONTACT
Inga Sileikaite, MSc
Faculty of Health and Medical Sciences, University of Copenhagen
inga.silei@gmail.com
+45 91800208