Targeting LRH-1/NR5A2 to treat type 1 diabetes mellitus

Abstract:

Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disease that targets the selective destruction of islet insulin-producing beta cells by infiltrating immune cells (insulitis). As a result, the organism is no longer able to produce insulin and develops hyperglycaemia and, if untreated, death. Despite advances in medical device technology and insulin analogues as well as strives in generating in vitro insulin-producing cells, there is still no robust therapy to substitute and protect beta cells that are lost in T1DM. Clinical trials aimed at blocking the immune-mediated beta cell destruction have had moderate success leaving a gap in our understanding of disease aetiology. Such breach in knowledge may stem from the oversight that inhibiting the immune attack likely impairs beta cell regeneration and emphasizes a fundamental paradigm in the approach to treat the disease: A non-mutually exclusive strategy in which the uncontrolled self-directed inflammatory immune response (and not the global immune system) as well as beta cell regeneration are exquisitely fine tuned in order to successfully regain immunological tolerance and restoration of a functional beta cell mass. As such, defining factors that can guide a pro-inflammatory immune cell destructive environment towards an anti-inflammatory environment facilitating beta cell survival and stimulate regeneration would define an unprecedented class of immune-regenerative therapeutic agents for T1DM. In our recent study we identify the liver receptor homolog 1 (LRH-1, also known as NR5A2) as a ‘druggable’ target that fulfills these criteria restoring glycemic control in various mouse models of T1DM as well as improving human islet survival and function both in vitro and in vivo (Nat Comms, 9:1488).