Monash University

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Advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in pancreatic beta cell dysfunction

posted on 2017-02-28, 01:09 authored by Yap, Yih Teng
It is widely accepted that advanced glycation end products (AGEs) are pathological contributors to diabetic complications, nonetheless, whether they impact directly on the pathogenesis of diabetes per se remains to be elucidated. There is growing evidence indicating that AGEs can affect β-cell function as well as insulin sensitivity, though these studies were primarily performed in acute settings. Hence within this thesis, the relationship between AGEs and β-cell dysfunction was investigated as the primary focus. Firstly, the direct effects of AGEs on insulin secretory function in both in vitro and in vivo studies (Chapter 2) were investigated. The in vitro study employing a pancreatic β cell line, MIN6N8 suggested that AGEs could recruit known pathways of damage resulting in insulin secretory abnormalities which were also seen in rats chronically exposed to either high AGE diets or regular injections of AGEs. Furthermore, these defects were shown to be prevented with pharmacological inhibition of AGE pathway, which also reduced the incidence of autoimmune diabetes in the non-obese diabetic (NODLt) mouse model. In addition, circulating AGE concentrations in children at risk of diabetes were elevated at birth in those children who subsequently developed type 1 diabetes. Given that AGEs can exert their biological effects via receptors such as receptor for AGEs (RAGE), it was then investigated whether RAGE expression was altered in the NODLt mouse model as well as if changes in RAGE in humans associated with type 1 diabetes (Chapter 3). Interestingly, NODLt mice showed a decrease in circulating and islet RAGE expression at seroconversion to autoantibody positivity. Also within the same chapter, we identified three single nucleotide polymorphisms (SNPs) in the RAGE gene (AGER) that predicted the risk of T1D in susceptible children, as well as their circulating levels of soluble RAGE. Taken together, this chapter suggested that RAGE could be an interface between genetic susceptibility and environmental contributors such as AGEs in the development of T1D. In order to examine if excessive dietary AGE intake could exacerbate injury to β cells contributing to the development of T1D, the effects of diets low or high in AGE content were investigated using two models of autoimmune diabetes, the NODLt mouse and the T-cell receptor (TCR) transgenic model, NOD8.3+ mouse (Chapter 4). Firstly, long term intervention with a low AGE diet was identified to significantly lower the incidence of autoimmune diabetes in NODLt mice, despite concomitant decline in insulin sensitivity. Since circulating AGEs appear to be elevated in newborn samples taken from susceptible children, NOD8.3+ mothers were then fed with diets either low or high in AGE content during pregnancy which demonstrated that pups were already showing abnormalities in islet insulin secretion and changes in the profile of immune cells present in the pancreatic lymph nodes. Lastly, the physiological role of RAGE in β-cell secretory function was investigated by using a RAGE knockout (RAGE-/-) mouse model (Chapter 5). This study demonstrated that RAGE within the islets is required for insulin secretion. Interestingly, however decreasing RAGE expression in isolated pancreatic β-cells did not produce the same effects on insulin secretion as seen isolated RAGE-/- islets suggesting that another islet cell may be involved in this phenomenon such as β-cells which have very high RAGE expression. Taken together, my thesis has highlighted that the AGE-RAGE pathway may have important physiological roles in insulin secretion which are worth investigating as potential sites for therapeutic intervention to prevent T1D.


Principal supervisor

Josephine Forbes

Year of Award


Department, School or Centre

Immunology - Alfred

Campus location



Doctor of Philosophy

Degree Type



Faculty of Medicine Nursing and Health Sciences