Abstract
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.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease that results in destruction of insulin-producing beta cells of the pancreas [1]
The early stages of T1D pathogenesis are characterized by insulitis, an inflammation of the islets of Langerhans of the pancreas caused by the lymphocyte infiltration
In order to better understand the early diabetes pathogenesis, it would have been of great importance to study the molecular mechanisms behind the early metabolic dysregulation as related to the autoimmune response, an area so far neglected in T1D research
Summary
Type 1 diabetes (T1D) is an autoimmune disease that results in destruction of insulin-producing beta cells of the pancreas [1]. The seroconversion to islet autoantibody positivity has been the first detectable signal for the onset of autoimmunity and progression towards diabetes [2], the initiators of autoimmune response, mechanisms regulating progress toward beta cell failure and factors determining time of presentation of clinical diabetes are poorly understood. We detected multiple changes related to dysregulation of lipid and amino acid metabolism preceding the autoimmunity and overt T1D [3]. In order to better understand the early diabetes pathogenesis, it would have been of great importance to study the molecular mechanisms behind the early metabolic dysregulation as related to the autoimmune response, an area so far neglected in T1D research
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