#173020 Signaling molecules in diabetes: search for potential targets in intrinsic pathways for prediction and intervention in diabetes

Diabetes mellitus is a complex metabolic disorder that can be presented in two major forms, as type 1 diabetes (T1D) and the much more common type 2 diabetes (T2D). While their etiologies are different, both diabetes types are characterized by hyperglycemia resulting either from insufficient insulin levels in T1D, or an insensitivity of target cells to insulin in T2D. In T1D, the death of insulin-producing pancreatic β-cells in an autoimmune response is a comparatively rapid event, whereas in T2D loss of β-cell mass occurs over years as interactions of extrinsic stressors and intrinsic factors continually impair β-cell functioning. The decline in the total mass of functional β-cells required to provide insulin for maintaining glucose homeostasis underlies diabetes development. Insight into the molecular control mechanisms in β-cells and the pathology of diabetes has laid the foundation for the paradigm for diabetes treatment based on the application of strategies that support functional β-cells by suppressing cytotoxic cell signaling and preventing the activation of cell death pathways. Our research is focused on β-cells as the principal element in diabetes development, and on hepatocytes and cardiomyocytes as the targets of diabetic complications. Our experimental systems include the in vivo model of streptozotocin (STZ)-induced diabetes in the rat, and in vitro models employing different cell lines maintained in culture.

Sub-project: Genetic Prediction of Type 1 Diabetes and Novel Approaches for Preventing Pancreatic β-Cell Dysfunction: Examination of the Different Stages of CXCL12-Mediated Signaling

Sub-Project Leader: Dr. Melita Vidaković, principal research fellow

One area of research in the Department of Molecular Biology is focused on the examination of β-cell physiology with the aim of defining conditions that could improve β-cell survival in the context of chemokine CXCL12, a potent chemotactic and angiogenic factor. Activation of the CXCL12 axis manifests as the expression of the proliferative phenotype that improves the resistance of β-cells to cytotoxic diabetogenic stimuli. Injury of β-cells induces the production and release of CXCL12 that promotes the dedifferentiation of adjacent α-cells into Glucagon-like peptide-1 (GLP-1)- and GLP-1 receptor-producing pro-α-cells, that causes their trans-differentiation into β-cells. The trans-differentiation of pro-α-cells into β-cells provides a potential mechanism for cellular reprogramming and regeneration of the β-cell compartment in individuals with T1D. These findings have positioned CXCL12 as a focal point in strategies for diabetes treatment. Our aim is to elucidate the molecular mechanisms that underlie the positive impact of CXCL12 expression on β-cells. Our research is focused on the crosstalk between the activity of PARP-1, an important contributor to cell homeostasis maintenance and the CXCL12 axis, including the protein regulators of CXCL12 gene transcription and epigenetic mechanisms involved in CXCL12 gene expression in β-cells. Also, we have recently initiated a screening study designed to test whether compounds present in the Epigenetic Compound Library (ECL-COST-TD0905) possess a DNA methyltransferase 1 (DNMT1) inhibitory potential. We are also studying the molecular basis of the potential beneficial actions of novel natural products in β-cells exposed to diabetogenic stimuli and on other tissues, both in vitro and in vivo.

Current Research

Analysis of the DNA methylation pattern of the CXCL12 gene promoter and first intron in rat pancreatic islets during the first four weeks of development of multiple low dose STZ-induced diabetes. Examination of the influence of several synthetic compounds that inhibit PARP-1 activity, on the methylation patterns of the CXCL12 gene promoter and its first intronic region.

Sub-Project team:

Dr. Goran Poznanović

Dr. Mirjana Mihailović

Dr. Svetlana Dinić

Dr. Nevena Grdović

Dr. Aleksandra Uskoković

Dr. Jelena Arambašić Jovanović

Dr. Miloš Đorđević

Dr. Anja Tolić

Jovana Rajić

Marija Đorđević

Sub-project: HMGB1 Expression and Signaling in Diabetic Livers

Sub-Project Leader: dr Ilijana Grigorov, principal research fellow

The pancreas and liver play central functions in glucose homeostasis. Insulin signalling has a critical role in maintaining normal liver function. In diabetes, hypoinsulinemia and the resulting disruption of insulin signalling in hepatocytes lead to progressive hepatic dysfunction, increasing the risk of liver disease. The high mobility group box 1 (HMGB1) protein was originally described as a chromatin-associated protein. When HMGB1 is released from stressed, damaged or dying cells, it behaves as an endogenous extracellular alarm molecule promoting proinflammatory signalling. Our working hypothesis is that HMGB1 plays an important role through a paracrine-like signalling mechanism. Thus, by synergizing with diabetes-activated stress-responses, HMGB1 is expected to exacerbate hepatocyte dysfunction. We are studying the intra-and extra-hepatic effects of HMGB1 on cellular signalling. Diabetic cardiomyopathy refers to a disease process involving the myocardium of diabetic patients. It is characterized by structural abnormalities as a result of multiple alterations at the cellular and molecular levels promoted by the diabetic state which is associated with hyperglycemia, hyperlipidemia and systemic oxidative stress. We are examining the molecular processes that contribute to diabetic cardiomyopathy. Also, we are studying the long-term effects of exogenous supplementation of the hormone melatonin that possesses a powerful antioxidant activity on the described experimental model of diabetes.

Current Research

Examination of the influence of diabetes-related oxidative stress on the expression, sub-cellular localization and post-translational modifications (acetylation, O-GlcNAc glycosylation, phopshorylation) of HMGB1 in rat liver. Establishment of a correlation between dynamic changes in HMGB1 levels in the serum and liver during prolonged diabetes with liver dysfunction, the inflammatory state and activation of apoptosis- and autophagy-related events. Examination of the molecular mechanisms (with a particular focus onNF-κB O-GlcNaC glycosylation) responsible for the downregulation of haptoglobin gene expression during diabetes progression.

Sub-Project team:

Dr. Svetlana Ivanović Matić

Dr. Desanka Bogojević

Dr. Vesna Martinović

Dr. Sofija Jovanović Stojanov

Anja Petrović

Jelena Stevanović

Tatjana Živić

Collaborators:

dr Nebojša M. Lalić

dr Ludwig Wagner

 

Address

Bulevar despota Stefana 142
11060 Belgrade
Serbia

Contact

Telefon: +381 11 20 78 300
Fax: +381 11 27 61 433
Email: ibiss@ibiss.bg.ac.rs

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