The incidence of type 1 diabetes (T1D) in youth, historically higher in Nordic countries, is now rising across many European nations, China, India and the Middle East.1, 2., 3 While insulin pumps and continuous glucose monitoring systems have improved the clinical management of young individuals with diabetes, the elevated risk of progression to vascular complications remains a significant clinical challenge. T1D is characterized by the autoimmune destruction of pancreatic beta-cells, and both immune markers and poor metabolic control have been associated with the advancement of vascular complications in individuals with T1D.3 In contrast, clinical indicators such as improved glucose control, normotension and reduced levels of lipids, and the presence of growth factors have consistently been linked to a lower incidence of vascular complications across various ethnicities1,2,4, 5., 6 Additionally, the patterns of organ damage in long-standing T1D may differ among patients, and there have been some attempts to classify these into parenchymal and non-parenchymal origin for better understanding of clinical outcomes.4

However, despite the prolonged exposure to hyperglycaemia, it remains unclear why some patients with long-term T1D do not develop major diabetic complications at a systemic level. Drawing an analogy to the morbidity profiles of centenarians,7 Edwin Gale, a former editor of Diabetologia, has classified long-lived patients with type 1 diabetes with no signs of major complications (micro- or macrovascular, including diabetic nephropathy) as “escapers”.8 Several studies have been conducted to investigate molecular mechanisms and to illuminate contributing factors to a beneficial clinical profile of long-standing T1D. They suggest potential roles of enhanced mitochondrial function, efficient glycolytic pathways, signaling regulated by PK2 kinase, reactive oxygen species (ROS), DNA damage responses, and immune system activity in mediating resilience against the progression of diabetic complications.4,5,9 Improved understanding of protective mechanisms against disease progression to complications is particularly important in the light of recent reports of significant increase in incidence of type 1 diabetes after the COVID-19 pandemic worldwide.10

In the present study, we aimed to expand blood RNA sequencing analyses from our previous Scandinavian Swedish-Danish PROLONG study5 to participants of the Norwegian Dialong study with a long diabetes duration of >45 years.6 Our findings highlight the consistent and central role of DNA repair and damage mechanisms, as well as inflammatory response genes, in conferring protection against major vascular complications in patients with long-standing T1D.