The PTGS2/COX2-PGE2 signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus.

Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling. The main product derived from PTGS2/COX2 expression and activation is Prostaglandin E2 (PGE2), which promotes a wide variety of tissue-specific effects, pending environmental inputs. One of the major sources of PGE2 are infiltrating inflammatory cells - the production of this molecule increases drastically in damaged tissues. Immune infiltration is a hallmark of type 1 diabetes mellitus, a multifactorial disease that leads to autoimmune-mediated pancreatic beta cell destruction. Controversial effects for the PTGS2/COX2-PGE2 signaling cascade in pancreatic islet cells subjected to diabetogenic conditions have been reported, allocating PGE2 as both, cause and consequence of inflammation. Herein, we review the main effects of this molecular pathway in a tissue-specific manner, with a special emphasis on beta cell mass protection/destruction and its potential role in the prevention or development of T1DM. We also discuss strategies to target this pathway for future therapies.

Active surveillance of atypical cartilaginous tumours of bone: short term quality of life measurements.

BACKGROUND: In the recent years active surveillance has been introduced for atypical cartilaginous tumours (ACT). This is the first study on the impact of this new treatment approach on patients' quality-of-life. We evaluated general health-related quality of life (HRQL) in patients diagnosed with enchondroma or ACT. METHODS: In this prospective study, patients recently diagnosed with enchondroma and ACT of the long bones were asked to participate. Health-related quality of life (HRQL) was assessed at diagnosis and at six month follow-up, using the 36-item Short Form Health Survey (SF-36) and Numeric Pain Rating Scale (NRS). HRQL of the active surveillance group was compared to the Dutch population and a Dutch sample with locoregional cancer. RESULTS: In total, 45 patients were included in the study, of which four patients underwent curettage and cryosurgery, 41 patients were under active surveillance. The HRQL of the active surveillance group seemed lower compared to the Dutch population, but similar to patients suffering locoregional cancers. No comparison between the surgery and the active surveillance group could be made. In the active surveillance group no statistical difference was found between baseline and six months follow-up regarding HRQL and pain during rest and activities. CONCLUSION: Patients diagnosed with non-malignant chondroid tumours have lower HRQL compared to the healthy population. Active surveillance had no adverse effect on patients well-being, after six months active surveillance the HRQL remained unchanged. Interestingly, in our study no impact on mental health was seen, implicating that diagnosed but untreated chondroid tumours do not seem to influence patients anxiety.

Pericentromeric satellite lncRNAs are induced in cancer-associated fibroblasts and regulate their functions in lung tumorigenesis.

The abnormal tumor microenvironment (TME) often dictates the therapeutic response of cancer to chemo- and immuno-therapy. Aberrant expression of pericentromeric satellite repeats has been reported for epithelial cancers, including lung cancer. However, the transcription of tandemly repetitive elements in stromal cells of the TME has been unappreciated, limiting the optimal use of satellite transcripts as biomarkers or anti-cancer targets. We found that transcription of pericentromeric satellite DNA (satDNA) in mouse and human lung adenocarcinoma was observed in cancer-associated fibroblasts (CAFs). In vivo, lung fibroblasts expressed pericentromeric satellite repeats HS2/HS3 specifically in tumors. In vitro, transcription of satDNA was induced in lung fibroblasts in response to TGFß, IL1α, matrix stiffness, direct contact with tumor cells and treatment with chemotherapeutic drugs. Single-cell transcriptome analysis of human lung adenocarcinoma confirmed that CAFs were the cell type with the highest number of satellite transcripts. Human HS2/HS3 pericentromeric transcripts were detected in the nucleus, cytoplasm, extracellularly and co-localized with extracellular vesicles in situ in human biopsies and activated fibroblasts in vitro. The transcripts were transmitted into recipient cells and entered their nuclei. Knock-down of satellite transcripts in human lung fibroblasts attenuated cellular senescence and blocked the formation of an inflammatory CAFs phenotype which resulted in the inhibition of their pro-tumorigenic functions. In sum, our data suggest that satellite long non-coding (lnc) RNAs are induced in CAFs, regulate expression of inflammatory genes and can be secreted from the cells, which potentially might present a new element of cell-cell communication in the TME.

NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function.

LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglycemia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE2 levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist-ONO-8130-negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE2/PTGER1 signaling axis as a key pathway mediating BL001 survival properties.

Shared decision making: Does a decision aid support patients with an atypical cartilaginous tumor in making a decision about treatment.

Objective: Due to new insights, atypical cartilaginous tumors (ACTs) of the long bones are no longer considered malignant and treatment is shifting from surgery to active surveillance. We developed a decision aid in order to support in shared decision making on treatment.The aim of this study is to evaluate the treatment preferences of patients with an ACT in the long bones. Methods: During thirty-four months, patients received a decision aid digitally with information about the disease, the treatment options, and the risks and benefits of active surveillance and surgical treatment. The given answers to patients' preference questions were evaluated qualitatively in relation to the final choice of treatment. Results: Eighty-four patients were included. None of the patients who preferred active surveillance later underwent surgery. Only four patients underwent surgery based on patient preference. Conclusion: In our experience the decision aid is useful for shared decision making as it provides the patient with information and the clinician with insight into patient's preferences. The preference for treatment generally corresponds to the eventual treatment. Innovation: When treatment changes, due to new insights, a decision aid seems helpful for both patients and clinicians to discuss the treatment that best suits the patient's situation.

The metabesity factor HMG20A potentiates astrocyte survival and reactive astrogliosis preserving neuronal integrity.

Rationale: We recently demonstrated that the 'Metabesity' factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes. The impact of ORY1001, an inhibitor of the LSD1-CoREST complex, on HMG20A expression, reactive astrogliosis and glucose metabolism was evaluated in vitro and in vivo in high-fat high-sucrose fed mice. Results: We show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. HMG20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and reactive astrogliosis. Hmg20a transcript levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways which are hallmarks of reactive astrogliosis. Accordingly, HMG20A depleted astrocytes exhibited reduced mitochondrial bioenergetics and increased susceptibility to apoptosis. Neuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. ORY1001 treatment rescued expression of reactive astrogliosis-linked genes in HMG20A ablated astrocytes while enhancing cell surface area, GFAP intensity and STAT3 expression in healthy astrocytes, mimicking the effect of HMG20A. Furthermore, ORY1001 treatment protected against obesity-associated glucose intolerance in mice correlating with a regression of hypothalamic HMG20A expression, indicative of reactive astrogliosis attenuation with improved health status. Conclusion: HMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce reactive astrogliosis in an attempt to preserve the neuronal network and re-establish glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote reactive astrogliosis and increase susceptibility of neurons to stress-induced apoptosis. Such effects could be reversed by ORY1001 treatment both in vitro and in vivo, paving the way for a new therapeutic approach for Type 2 Diabetes Mellitus.

The Hygiene Hypothesis - Learning From but Not Living in the Past.

Postulated by Strachan more than 30 years ago, the Hygiene Hypothesis has undergone many revisions and adaptations. This review journeys back to the beginnings of the Hygiene Hypothesis and describes the most important landmarks in its development considering the many aspects that have refined and generalized the Hygiene Hypothesis over time. From an epidemiological perspective, the Hygiene Hypothesis advanced to a comprehensive concept expanding beyond the initial focus on allergies. The Hygiene Hypothesis comprise immunological, microbiological and evolutionary aspects. Thus, the original postulate developed into a holistic model that explains the impact of post-modern life-style on humans, who initially evolved in close proximity to a more natural environment. Focusing on diet and the microbiome as the most prominent exogenous influences we describe these discrepancies and the resulting health outcomes and point to potential solutions to reestablish the immunological homeostasis that frequently have been lost in people living in developed societies.

Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes?

Diabetes is a chronic metabolic disease caused by an absolute or relative deficiency in functional pancreatic ß-cells that leads to defective control of blood glucose. Current treatments for diabetes, despite their great beneficial effects on clinical symptoms, are not curative treatments, leading to a chronic dependence on insulin throughout life that does not prevent the secondary complications associated with diabetes. The overwhelming increase in DM incidence has led to a search for novel antidiabetic therapies aiming at the regeneration of the lost functional ß-cells to allow the re-establishment of the endogenous glucose homeostasis. Here we review several aspects that must be considered for the development of novel and successful regenerative therapies for diabetes: first, the need to maintain the heterogeneity of islet ß-cells with several subpopulations of ß-cells characterized by different transcriptomic profiles correlating with differences in functionality and in resistance/behavior under stress conditions; second, the existence of an intrinsic islet plasticity that allows stimulus-mediated transcriptome alterations that trigger the transdifferentiation of islet non-ß-cells into ß-cells; and finally, the possibility of using agents that promote a fully functional/mature ß-cell phenotype to reduce and reverse the process of dedifferentiation of ß-cells during diabetes.

Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.

Molecular Modelling of Islet ß-Cell Adaptation to Inflammation in Pregnancy and Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM), a metabolic disease that develops with the increase in insulin resistance during late pregnancy, is currently one of the most common complications affecting pregnancy. The polygenic nature of GDM, together with the interplay between different genetic variants with nutritional and environmental factors has hindered the full understanding of the etiology of this disease. However, an important genetic overlap has been found with type 2 diabetes mellitus (T2DM) and, as in the case of T2DM, most of the identified loci are associated with ß-cell function. Early detection of GDM and adequate interventions to control the maternal glycemia are necessary to avoid the adverse outcomes for both the mother and the offspring. The in utero exposure to the diabetic milieu predispose these children for future diseases, among them T2DM, originating a vicious circle implicated in the increased prevalence of both GDM and T2DM. The involvement of inflammatory processes in the development of GDM highlights the importance of pancreatic ß-cell factors able to favor the adaptation processes required during gestation, concomitantly with the protection of the islets from an inflammatory milieu. In this regard, two members of the Pax family of transcription factors, PAX4 and PAX8, together with the chromatin remodeler factor HMG20A, have gained great relevance due to their involvement in ß-cell mass adaptation together with their anti-inflammatory properties. Mutations in these factors have been associated with GDM, highlighting these as novel candidates for genetic screening analysis in the identification of women at risk of developing GDM.

Dissecting the Brain/Islet Axis in Metabesity.

The high prevalence of type 2 diabetes mellitus (T2DM), together with the fact that current treatments are only palliative and do not avoid major secondary complications, reveals the need for novel approaches to treat the cause of this disease. Efforts are currently underway to identify therapeutic targets implicated in either the regeneration or re-differentiation of a functional pancreatic islet ß-cell mass to restore insulin levels and normoglycemia. However, T2DM is not only caused by failures in ß-cells but also by dysfunctions in the central nervous system (CNS), especially in the hypothalamus and brainstem. Herein, we review the physiological contribution of hypothalamic neuronal and glial populations, particularly astrocytes, in the control of the systemic response that regulates blood glucose levels. The glucosensing capacity of hypothalamic astrocytes, together with their regulation by metabolic hormones, highlights the relevance of these cells in the control of glucose homeostasis. Moreover, the critical role of astrocytes in the response to inflammation, a process associated with obesity and T2DM, further emphasizes the importance of these cells as novel targets to stimulate the CNS in response to metabesity (over-nutrition-derived metabolic dysfunctions). We suggest that novel T2DM therapies should aim at stimulating the CNS astrocytic response, as well as recovering the functional pancreatic ß-cell mass. Whether or not a common factor expressed in both cell types can be feasibly targeted is also discussed.

Quality of postoperative pain management in Ethiopia: A prospective longitudinal study.

BACKGROUND: The annual number of surgical operations performed is increasing throughout the world. With this rise in the number of surgeries performed, so too, the challenge of effectively managing postoperative pain. In Africa, there are scanty data available that make use of multi-center data to characterize the quality of postoperative pain management. In this study using a longitudinal data, we have attempted to characterize the quality of postoperative pain management; among patients scheduled for major elective orthopedic, gynecologic and general surgery. METHODS: This prospective longitudinal study evaluated the quality of postoperative pain management in patients undergoing elective general, gynecologic, and orthopedic surgery. We quantified the prevalence of moderate to severe postoperative pain with the International Pain Outcome Questionnaire and the corresponding adequacy of treatment with the pain management index. At four time points after surgery, we estimated pain severity, its physical and emotional interference, and patient satisfaction. RESULTS: Moderate to severe postoperative pain was present in 88.2% of patients, and pain was inadequately treated in 58.4% of these patients. Chronic pain (ß = 0.346, 95% CI: 0.212, 0.480) predicted patients' worst pain intensity. Gender was not associated with the worst pain intensity or percentage of time spent in severe pain. Patient's pain intensity did not predicted the level of satisfaction. CONCLUSIONS: The prevalence of moderate to severe postoperative pain and its functional interference is high in Ethiopian patients. The treatment provided to patients is inadequate and not in line with international recommendations and standards.

The views of patients, healthcare professionals and hospital officials on barriers to and facilitators of quality pain management in Ethiopian hospitals: A qualitative study.

BACKGROUND: Postoperative pain remains a challenge in the developed world, but the consequences of inadequately treated postoperative pain are particularly severe in low- and middle-income countries. Since 2011, reports have drawn attention to the poor quality of postoperative pain management in Ethiopia; however, our multicenter qualitative study was the first to attempt to understand the factors that are barriers to and facilitators of quality pain managment in the country. To this aim, the study explored the perspectives of patients, healthcare professionals, and hospital officials. We expected that the results of this study would inform strategies to improve the provision of quality pain management in Ethiopia and perhaps even in other low- and middle-income countries. METHODS: This study used a qualitative, descriptive approach in which nine healthcare professionals, nine patients, and six hospital officials (i.e. executives in a managerial or leadership position in administration, nursing, or education) participated in face-to-face, semi-structured interviews. Thematic data analysis was conducted, and patterns were explained with the help of a theoretical framework. FINDINGS: The barriers identified ranged from healthcare professionals' lack of empathy to a positive social appraisal of patients' ability to cope with pain. They also included a lack of emphasis on pain and its management during early medical education, together with the absence of available resources. Enhancing the ability of healthcare professionals to create favorable rapport with patients and increasing the cultural competence of professionals are essential ingredients of future pain education interventions. CONCLUSIONS: Barriers to and facilitators of postoperative pain management do not exist independently but are reciprocally linked. This finding calls for holistic and inclusive interventions targeting healthcare professionals, patients, and hospital officials. The current situation is unlikely to improve if only healthcare professionals are educated about pain physiology, pharmacology, and management. Patients should also be educated, and the hospital environment should be modified to provide high-quality postoperative pain management.

Transient PAX8 Expression in Islets During Pregnancy Correlates With ß-Cell Survival, Revealing a Novel Candidate Gene in Gestational Diabetes Mellitus.

Transient Pax8 expression was reported in mouse islets during gestation, whereas a genome-wide linkage and admixture mapping study highlighted PAX8 as a candidate gene for diabetes mellitus (DM). We sought the significance of PAX8 expression in mouse and human islet biology. PAX8 was induced in gestating mouse islets and in human islets treated with recombinant prolactin. Global gene expression profiling of human and mouse islets overexpressing the corresponding species-specific PAX8 revealed the modulation of distinct genetic pathways that converge on cell survival. Accordingly, apoptosis was reduced in PAX8-overexpressing islets. These findings support that PAX8 could be a candidate gene for the study of gestational DM (GDM). PAX8 was genotyped in patients with GDM and gestational thyroid dysfunction (GTD), a pathology commonly found in patients with mutations on PAX8 A novel missense PAX8 mutation (p.T356M, c.1067C>T) was identified in a female diagnosed with GDM and GTD as well as in her father with type 2 DM but was absent in control patients. The p.T356M variant did not alter protein stability or cellular localization, whereas its transactivation activity was hindered. In parallel, a retrospective clinical analysis uncovered that a pregnant female harboring a second PAX8 mutation (p.P25R, c.74C>G) previously reported to cause congenital hypothyroidism also developed GDM. These data indicate that increased expression of PAX8 affects islet viability and that PAX8 could be considered as a candidate gene for the study of GDM.

Therapeutic potential of pancreatic PAX4-regulated pathways in treating diabetes mellitus.

The high prevalence of diabetes mellitus (DM) in our society, together with the fact that current treatments are only palliative and do not prevent the development of life threatening side effects, highlights the urgent need for novel therapies targeting the root cause of the disease. Independent of the etiology of DM, the definitive therapeutic approach will imply the restitution of an adequate functional ß-cell mass capable of compensating for the insulin demand of the organism. The recent demonstration of heterogeneity within the islets as well as their innate plasticity has encouraged the development of studies aiming at potentiation of the regenerative capacity of islets. In this regard, factors implicated in pancreas ontogeny as well as in the adaptation processes that take place in the islets under situations of increased insulin demand have gained much interest. One of these factors is the transcription factor PAX4, required for ß-cell formation during embryonic development and implicated in adult ß-cell adaptation under stress situations. Here we review the therapeutic potential of PAX4 as well as its downstream targets for the development of novel treatments for DM.

LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and 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.

The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity.

HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the HMG20A gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that HMG20A is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased HMG20A transcript levels, a result also observed in islets of gestating mice. In contrast, HMG20A expression was not altered in islets from diet-induced obese and pre-diabetic mice. The T2DM-associated rs7119 SNP, located in the 3' UTR of the HMG20A transcript reduced the luciferase activity of a reporter construct in the human beta 1.1E7 cell line. Depletion of Hmg20a in the rat INS-1E cell line resulted in decreased expression levels of its neuronal target gene NeuroD whereas Rest and Pax4 were increased. Chromatin immunoprecipitation confirmed the interaction of HMG20A with the Pax4 gene promoter. Expression levels of Mafa, Glucokinase, and Insulin were also inhibited. Furthermore, glucose-induced insulin secretion was blunted in HMG20A-depleted islets. In summary, our data demonstrate that HMG20A expression in islet is essential for metabolism-insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as NeuroD and Mafa and that depletion induces expression of genes such as Pax4 and Rest implicated in beta cell de-differentiation. More importantly we assign to the T2DM-linked rs7119 SNP the functional consequence of reducing HMG20A expression likely translating to impaired beta cell mature function.

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

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).