**1. Introduction**

Type 1 diabetes (T1DM) is a complex autoimmune disorder resulting from the destruction of pancreatic insulin producing β-cells due to the loss of self-tolerance. There has been a rapid increase in disease incidence worldwide and T1DM is increasingly being diagnosed in even younger individuals and in those from diverse cultural backgrounds. Insulin replacement therapy remains the only viable option for individuals with T1DM. Ensuring any new therapies are meeting a very high safety bar and are superior to insulin replacement therapy remains a challenge. Indeed, treatment with global immunosuppression, while somewhat effective, has significant side effects and is not a practical solution to prevent T1DM which commonly develops in early life. Also, despite insulin's excellent safety profile, management of insulin replacement therapy involves multiple daily injections, pumps and continuous blood glucose monitoring or closed loop systems which are costly and complex to maintain, particularly in younger children. These therapies also bring increased risk for life-threatening high (hyperglycemia) or low (hypoglycemia) blood glucose concentrations as well as increased risk for chronic complications and shortened lifespan. Despite significant progress made in the development of therapeutics for T1DM and some remarkable results in the pre-clinical models, a successful translation into clinic is yet to occur. Due to the T1DM's multifactorial nature, the necessity to find links between genetic predisposition, immune system abnormalities and environmental triggers is becoming increasingly apparent. Therefore, exploring relationships between these contributing factors is necessary for better understanding of the disease progression and for design of the best therapeutic approaches. More recently, multiple studies have focused on the complex biology and involvement of the receptor for advanced glycation end products (RAGE) and its ligands in inflammation, autoimmunity, diabetes complications, apoptosis, and endoplasmic reticulum stress including the exploration of various ways to alleviate these. This presents an exciting new avenue for the development of targeted RAGE-related therapeutics and their translational potential from pre-clinical models to humans.
