BL001, Cabimer, Ibima, LRH-1, transdifferentiation, Type 1 diabetes mellitus
Current therapies in type I diabetes suppress immune attack or neutralize substances that promote inflammation. This is an innovative strategy that decreases the immune process and promotes the survival and function of beta cells, which produce insulin.
Researchers from the Andalusian Center for Molecular Biology and Regenerative Medicine (Cabimer) in Seville and the Biomedical Research Institute of Malaga (Ibima) have identified a molecule that reverses the symptoms of type I diabetes in laboratory mice, published on April 16 in «Nature Communications».
On the surface of the beta cells of pancreatic islets is the LRH-1 protein whose activation is produced by the experimental molecule BL001, supplied by injections, activating LRH-1 favors the inflammatory medium and promotes the regeneration of beta cells. This molecule slows the type I diabetic.
Diabetes mellitus (DM), is a group o metabolic disorders in which there are high blood sugar levels over a prolonged period. Diabetes is due to either pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced.
There are three main types of diabetes mellitus:
a) Type I DM results from the pancreas´s failure to produce enough insulin.
b) Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly.
c) Gestational diabetes is the third main form, and occurs when pregtnant women without a previous history of diabetes develop high blood sugar levels.
As of 2015, an estimated 415 million people had diabetes worldwide, with type 2DM marking up about 90% of the cases, and 10% 1DM.
Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the pancreatic islets, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic, in which a T cell-mediated autoinmune attack leads to the loss of beta cells and thus insulin. Type 1 diabetes can affect children or adults, but was traditionally termed “juvenile diabetes” because a majority of these diabetes cases were in children. Type 1 diabetes is partly inherited, with multiple genes, including certain HLA genotypes, known to influence the risk of diabetes.
Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy.
Liver receptor homologue-1 (LRH-1) is a nuclear receptor that repress inflammation in digestive organs and protects pancreatic islets against apoptosis. BL001 a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of páncreas, while incrasing beta cell mass and insulin secretion.
The liver receptor homolog-1 (LRH-1, or NR5A2) is a memeber of the NR5A family of nuclear receptors, which plays a pivotal role in early embryonic development, and specifies the endodermal lineage. In the páncreas, LRH-1 regulates the expression of genes involved in digestive functions, and protects endocrine islets against cytokine-and streptozotocinglucocorticoids biosynthesis.
Long –term in vivo administration of BL001 prevents the development of diabetes in mice, throught the combined maintenance of a functional islet beta cell mass and the release of antiinflammatory factors. BL001 activates LHR-1 without cytotoxic or metabolic effects. BL001 protects human islets against apoptosis and rescues insulin secretion in islets of type 2 diabetic donors.
The new drug has been successfully tested in mice and human cell cultures, needs to demonstrate the efficacy and safety of clinical trials, to be used in humans, thus preventing and treating the disease. The drug causes the transformation of alpha cells into beta cells, a phenomenon known as «transdifferentiation«.
• LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus; nature comunicationsNature Communicationsvolume 9, Article number: 1488 (2018)
• WHO diabetes mellitus