14 research outputs found
Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse
Recent clinical evidence suggests important role of lipid and amino acid metabolism in early pre-autoimmune stages of type 1 diabetes pathogenesis. We study the molecular paths associated with the incidence of insulitis and type 1 diabetes in the Non-Obese Diabetic (NOD) mouse model using available gene expression data from the pancreatic tissue from young pre-diabetic mice. We apply a graph-theoretic approach by using a modified color coding algorithm to detect optimal molecular paths associated with specific phenotypes in an integrated biological network encompassing heterogeneous interaction data types. In agreement with our recent clinical findings, we identified a path downregulated in early insulitis involving dihydroxyacetone phosphate acyltransferase (DHAPAT), a key regulator of ether phospholipid synthesis. The pathway involving serine/threonine-protein phosphatase (PP2A), an upstream regulator of lipid metabolism and insulin secretion, was found upregulated in early insulitis. Our findings provide further evidence for an important role of lipid metabolism in early stages of type 1 diabetes pathogenesis, as well as suggest that such dysregulation of lipids and related increased oxidative stress can be tracked to beta cells
Metabolic Regulation in Progression to Autoimmune Diabetes
Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese prediabetic (NOD) mice which recapitulated the design of the human study and derived the metabolic states from longitudinal lipidomics data. We show that female NOD mice who later progress to autoimmune diabetes exhibit the same lipidomic pattern as prediabetic children. These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, normoglycemia, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum group. Together, the findings indicate that autoimmune diabetes is preceded by a state of increased metabolic demands on the islets resulting in elevated insulin secretion and suggest alternative metabolic related pathways as therapeutic targets to prevent diabetes
NETWORKBASED REPRESENTATIONÂ OFÂ BIOLOGICALÂ DATA FOR ENABLINGÂ CONTEXTBASEDÂ MINING
Biological phenomena are usually described by relational model of interactions and dependencies between different entities. Therefore, a networkbased knowledge representation of biological knowledge seems to be an obvious choice. In this paper, we propose such a representation when integrating data from heterogeneous life science data sources, including information extracted from biomedical literature. We show that such a representation enables explanatory analysis in a context dependent manner. The context is enabled by a judicious assignment of weights on the quality dimensions. Analysis of clusters of nodes and links in the context of underlying biological questions may provide emergence of new concepts and understanding. Results are obtained with our megNet software, an integrative platform based on a multitier architecture using a native XML database. 1