title: Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes.
abstract: Type 1 diabetes has been recently linked to nonalcoholic fatty liver disease (NAFLD), which is known to associate with insulin resistance, obesity, and type 2 diabetes. However, the role of insulin resistance and hyperglycemia for hepatic energy metabolism is yet unclear. To analyze early abnormalities in hepatic energy metabolism, we examined 55 patients with recently diagnosed type 1 diabetes. They underwent hyperinsulinemic-normoglycemic clamps with [6,6-(2)H2]glucose to assess whole-body and hepatic insulin sensitivity. Hepatic γATP, inorganic phosphate (Pi), and triglyceride concentrations (hepatocellular lipid content [HCL]) were measured with multinuclei magnetic resonance spectroscopy ((31)P/(1)H-MRS). Glucose-tolerant humans served as control (CON) (n = 57). Whole-body insulin sensitivity was 44% lower in patients than in age- and BMI-matched CON. Hepatic γATP was 15% reduced (2.3 ± 0.6 vs. 2.7 ± 0.6 mmol/L, P < 0.001), whereas hepatic Pi and HCL were similar in patients when compared with CON. Across all participants, hepatic γATP correlated negatively with glycemia and oxidized LDL. Carriers of the PPARG G allele (rs1801282) and noncarriers of PPARGC1A A allele (rs8192678) had 21 and 13% lower hepatic ATP concentrations. Variations in genes controlling oxidative metabolism contribute to a reduction in hepatic ATP in the absence of NAFLD, suggesting that alterations in hepatic mitochondrial function may precede diabetes-related liver diseases.
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Sofiya
authors.initials: S
authors.lastname: Gancheva
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bierwagen
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Kirti
authors.initials: K
authors.lastname: Kaul
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nowotny
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kahl
authors.affiliation: German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Giani
authors.affiliation: German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Klueppelholz
authors.affiliation: German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Knebel
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Begovatz
authors.affiliation: German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Strassburger
authors.affiliation: German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Hadi
authors.initials: H
authors.lastname: Al-Hasani
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany.
authors.forename: Jesper
authors.initials: J
authors.lastname: Lundbom
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Szendroedi
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany michael.roden@ddz.uni-duesseldorf.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000483:Alleles; D015992:Body Mass Index; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics; D010710:Phosphates / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010710:Phosphates; D014280:Triglycerides; D000255:Adenosine Triphosphate