Pathology of type 1 diabetes and new therapeutic approaches – an update

As recent as a decade ago, the pathology of human diabetes had been poorly understood, predominantly because of limited access to well-preserved human pancreata. This has also hampered therapeutic progress. Through the pancreatic organ donor consortium (nPOD), we are now gaining unprecedented knowledge about features of the human disease. For example, while there appears to be little immune infiltration in multiple antibody-positive individuals before disease onset, beta cells already exhibit early abnormalities that could point towards defects in proinsulin processing and their overall metabolic health. Therefore, therapies that 'strengthen' beta cells might be important, in addition to those modulating the immune system. We will discuss such combination therapies that show synergy between dampening immune function (either islet antigen specifically or systemic) and supporting beta-cell function. Strategies to further mechanistic understanding and refining such combinatorial approaches with suitable biomarkers, in vitro whole islet stress assays and preclinical studies will form cornerstones for future 'smarter' immune therapies.