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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.

In response to environmental challenges, biological systems respond with dynamic adaptive changes in order to maintain the functionality of the system. Such adaptations may lead to cumulative stress over time, possibly leading to global failure of the system. When studying such systems responses, it is therefore important to understand them in system-wide and dynamic context. Here we hypothesize that dynamic changes in the topology of functional modules of integrated biological networks reflect their activity under specific environmental challenges. We introduce topological enrichment analysis of functional subnetworks (TEAFS), a method for the analysis of integrated molecular profile and interactome data, which we validated by comprehensive metabolomic analysis of dynamic yeast response under oxidative stress. TEAFS identified activation of multiple stress response related mechanisms, such as lipid metabolism and phospholipid biosynthesis. We identified, among others, a fatty acid elongase IFA38 as a hub protein which was absent at all time points under oxidative stress conditions. The deletion mutant of the IFA38 encoding gene is known for the accumulation of ceramides. By applying a comprehensive metabolomic analysis, we confirmed the increased concentrations over time of ceramides and palmitic acid, a precursor of de novoceramide biosynthesis. Our results imply that the connectivity of the system is being dynamically modulated in response to oxidative stress, progressively leading to the accumulation of (lipo)toxic lipids such as ceramides. Studies of local network topology dynamics can be used to investigate as well as predict the activity of biological processes and the system’s responses to environmental challenges and interventions.

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., Author Summary We have recently found that distinct metabolic disturbances precede β-cell autoimmunity in children who later progress to type 1 diabetes (T1D). Here we performed a murine study using non-obese diabetic (NOD) mice that recapitulated the protocol used in human, followed up by independent studies where NOD mice were studied in relation to risk of diabetes progression. We found that young 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, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum subgroup. The metabolic phenotypes observed in our study could be relevant as end points for studies investigating T1D pathogenesis and/or responses to interventions. By proceeding from a clinical study via metabolomics and modeling to an experimental model using a similar study design, then evolving further to tissue-specific studies, we hereby also present a conceptually novel approach to reversed translation that may be useful in future therapeutic studies in the context of prevention and treatment of T1D as well as of other diseases characterized by long prodromal periods.