Browsing by Author "Yetukuri, Laxman"

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    High Density Lipoprotein structural changes and drug response in lipidomic profiles following the long-term fenofibrate therapy in the FIELD substudy
    (2011) Yetukuri, Laxman; Huopaniemi, Ilkka; Koivuniemi, Artturi; Maranghi, Marianna; Hiukka, Anne; Nygren, Heli; Kaski, Samuel; Taskinen, Marja-Riitta; Vattulainen, Ilpo; Jauhiainen, Matti; Oresic, Matej; Helsinki Insititute for Information Technology HIIT; Tietojenkäsittelytieteen laito; Department of Applied Physics
    In a recent FIELD study the fenofibrate therapy surprisingly failed to achieve significant benefit over placebo in the primary endpoint of coronary heart disease events. Increased levels of atherogenic homocysteine were observed in some patients assigned to fenofibrate therapy but the molecular mechanisms behind this are poorly understood. Herein we investigated HDL lipidomic profiles associated with fenofibrate treatment and the drug-induced Hcy levels in the FIELD substudy. We found that fenofibrate leads to complex HDL compositional changes including increased apoA-II, diminishment of lysophosphatidylcholines and increase of sphingomyelins. Ethanolamine plasmalogens were diminished only in a subgroup of fenofibrate-treated patients with elevated homocysteine levels. Finally we performed molecular dynamics simulations to qualitatively reconstitute HDL particles in silico. We found that increased number of apoA-II excludes neutral lipids from HDL surface and apoA-II is more deeply buried in the lipid matrix than apoA-I. In conclusion, a detailed molecular characterization of HDL may provide surrogates for predictors of drug response and thus help identify the patients who might benefit from fenofibrate treatment.
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    Metabolic regulation in progression to autoimmune diabetes
    (2011) Sysi-Aho, Marko; Ermolov, Andrey; Gopalacharyulu, Peddinti V.; Tripathi, Abhishek; Seppänen-Laakso, Tuulikki; Maukonen, Johanna; Mattila, Ismo; Ruohonen, Suvi T.; Vähätalo, Laura; Yetukuri, Laxman; Härkönen, Taina; Lindfors, Erno; Nikkilä, Janne; Ilonen, Jorma; Simell, Olli; Saarela, Maria; Knip, Mikael; Kaski, Samuel; Savontaus, Eriika; Oresic, Matej; Helsinki Insititute for Information Technology HIIT; Tietojenkäsittelytieteen laito
    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.