In contrast, no significant differences were observed in levels of INFgamma (0.6965??0.0931 versus 0.4989??0.0733 test), TNFalpha (5.925??0.815 versus 6.648??0.659 test), IL1beta (0.5267??0.0913 versus 0.3461??0.0579 test) and IL2 (1.306??0.181 versus 1.111??0.154 test) between immunized untreated and BL001-treated mice at 8 weeks. Open in a separate window Fig. insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus. Introduction Type 1 diabetes mellitus (T1DM) is a CD4+ and CD8+ T-cell-dependent autoimmune disease that targets beta cell destruction, ultimately leading to hyperglycemia and insulin dependence. The collapse in tolerance to self-antigens, such as insulin, is precipitated by genetic and environmental factors1,2. To date, therapies aimed at inhibiting the BAZ2-ICR immune system using anti-CD3 monoclonal antibodies FLJ32792 or at neutralizing pro-inflammatory cytokines, have had limited success3,4. One of the reasons may be that inhibiting the immune and inflammatory reactions in the pancreas impairs the repairing and regeneration capabilities of a functional beta cells mass5,6, as observed during wound healing7. Novel agents that could guide a pro-inflammatory autoimmune destructive environment toward an anti-inflammatory milieu facilitating islet regeneration, would define a novel class of antidiabetic therapies. The liver receptor homolog-1 (LRH-1, or NR5A2) is a member of the NR5A family of nuclear receptors, which plays a pivotal role in early embryonic development, and specifies the endodermal lineage8. In the liver, LRH-1 modulates the expression of genes involved in cholesterol and bile acid metabolism, as well as in glucose homeostasis9, attenuates the hepatic acute phase response, which is triggered upon increases of pro-inflammatory cytokines, and protects against endoplasmic reticulum stress10,11. In the intestine, LRH-1, modulates the enterocyte renewal and regulates the local immune system via production of glucocorticoids12. In the pancreas, LRH-1 regulates the expression of genes involved in digestive functions, and protects the endocrine islets against cytokine- and streptozotocin-induced apoptosis13,14, while stimulating the production of enzymes involved in glucocorticoids biosynthesis14. In view of the above, specifically of the BAZ2-ICR possibility that LRH-1 could elicit an islet-driven anti-inflammatory microenvironment, we posited that upregulating LRH-1 activity could have beneficial therapeutic effects BAZ2-ICR in diabetes mellitus (DM). Natural phospholipids physiologically stimulates LRH-1 activity15,16, decreasing hepatic steatosis and improving glucose homeostasis in animal models of insulin resistance17. Given that LRH-1 can also be activated by smaller, nonpolar bicyclic compounds18, we have synthesized a compound termed BL001, which we have tested in mouse models of T1DM, as well as in pancreatic islets from patients affected by Type 2 DM (T2DM). Here we report that the long-term in vivo administration of BL001 prevents the development of diabetes in mice, through the combined maintenance of a functional islet beta cell mass and the release of anti-inflammatory factors, which contribute to the islet regeneration effect. We further report that BL001 also protects human islet cells from apoptosis and improves impaired insulin secretion as well as beta cell survival in the pancreatic islets of T2DM patients. The data define LRH-1 as a novel therapeutic target for the treatment of T1DM. Results BL001 activates LHR-1 without cytotoxic or metabolic effects The chemical structure of BL001, which specifically binds to and activates LRH-118, is depicted in Supplementary Fig.?1a. The effects of the drug on LRH-1 activity, cell viability, and toxicity are described in Supplementary Fig.?1bCe. Pharmacokinetic and safety profiling of BL001 were studied in C57BL/6 and RIP-B7.1 mice, respectively. An i.p. injection of 10?mg/kg b.w. BL001 led to peak plasma concentrations of 3.6?g/ml (8?M) after 0.2?h, and a half-life of 9.4?h. Daily injections during 24 weeks did not reveal macroscopic organ alterations in BL001-treated RIP-B7.1 mice (Supplementary Fig.?2a, b), which also featured normal plasma levels of total cholesterol and triglycerides up to 8 weeks of treatment (Supplementary Fig.?3a, b). Insulin sensitivity was not altered by this BL001 treatment (Supplementary Fig.?3c). BL001 blunts apoptosis and attenuates diabetes in mice To assess the anti-apoptotic effect of BL001, mouse islets were exposed to 10?M BL001 in the presence of 2?ng/ml IL1beta, 28?ng/ml TNFalpha and 833?ng/ml IFNgamma. BAZ2-ICR The drug prevented the cytokine-induced islet cell death.