Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse

Erno Lindfors, Peddinti V. Gopalacharyulu, Eran Halperin, Matej Orešič (Corresponding Author)

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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.
Original languageEnglish
Article numbere7323
Number of pages9
JournalPLoS ONE
Volume4
Issue number10
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed

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Inbred NOD Mouse
insulin-dependent diabetes mellitus
Medical problems
Type 1 Diabetes Mellitus
glycerone-phosphate O-acyltransferase
Lipid Metabolism
lipid metabolism
mice
Phospholipid Ethers
pathogenesis
Lipids
phosphoprotein phosphatase
acyltransferases
Oxidative stress
insulin secretion
Phosphoprotein Phosphatases
amino acid metabolism
Heterogeneous networks
lipids
Metabolism

Cite this

Lindfors, Erno ; Gopalacharyulu, Peddinti V. ; Halperin, Eran ; Orešič, Matej. / Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse. In: PLoS ONE. 2009 ; Vol. 4, No. 10.
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Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse. / Lindfors, Erno; Gopalacharyulu, Peddinti V.; Halperin, Eran; Orešič, Matej (Corresponding Author).

In: PLoS ONE, Vol. 4, No. 10, e7323, 2009.

Research output: Contribution to journalArticleScientificpeer-review

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AB - 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.

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