Diabetologie und Stoffwechsel 2023; 18(S 01): S4
DOI: 10.1055/s-0043-1767837
Abstracts | DK 2023
Freie Vorträge
Freie-Vorträge-Symposium I

Missense Variant in Ceramide Synthase 2 (CERS2) is Associated with Higher Overnight Energy Expenditure and Hepatic Insulin Resistance in Healthy Humans

Authors

  • Sascha Heinitz

    1   Universitätsklinikum Leipzig, Klinik für Endokrinologie, Nephrologie und Rheumatologie, Leipzig, Germany

  • Michael Traurig

    2   National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ, United States

  • Jonathan Krakoff

    2   National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ, United States

  • Philipp Rabe

    3   Universität Leipzig, Rudolf Schönheimer Institute of Biochemistry, Leipzig, Germany

  • Claudia Stäubert

    3   Universität Leipzig, Rudolf Schönheimer Institute of Biochemistry, Leipzig, Germany

  • Michael Stumvoll

    1   Universitätsklinikum Leipzig, Klinik für Endokrinologie, Nephrologie und Rheumatologie, Leipzig, Germany

  • Matthias Blüher

    4   Helmholtz Zentrum München, University of Leipzig and University Hospital of Leipzig, Helmholtz Institute for Metabolic, Obesity and Vascular Research, Leipzig, Germany

  • Leslie Baier

    2   National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ, United States

  • Paolo Piaggi

    2   National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix Epidemiology and Clinical Research Branch, Phoenix, AZ, United States
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Research aim Genetic determinants of inter-individual differences in energy expenditure (EE) remain largely unknown. Participating in cellular signaling pathways, ceramides were identified as putative EE regulators. Current study investigated whether genetic variants within enzymes involved in ceramide synthesis and degradation affect EE.

Methods EE was assessed for 24h by whole-room indirect calorimetry in a large cohort of Indigenous Americans informative for genome-wide imputa-tion data, body composition, and glucose disposal rate during euglycemic-hyperinsulinemic clamp. Real time cellular metabolism was measured using a Seahorse Analyzer. Association analyses of imputed genotype dosages with metabolic measurements were performed via linear mixed effects. Differences in mitochondrial respiration were assessed via mixed model analyses of repeated measurements obtained during the Seahorse experiments.

Results Compared to the A allele, heterozygosity for missense variant rs267738 (E115A; A>C) in exon 4 of ceramide synthase 2 (CERS2) was associated with substantially higher sleeping EE (average=+116 kcal/day independent from differences in body composition) and increased rates of endogenous glucose production during insulin-stimulated (mean=+43%) and fasting (mean=+5%) conditions, both being markers of increased hepatic insulin resistance. The C allele for rs267738 did not affect ceramide synthesis in human hepatoma HepG2 cells but led to decreased (mean=−30%) basal mitochondrial respiration in vitro.

Conclusions These findings are in line with previous mice studies that implicate CerS2 in hepatic insulin resistance and impaired mitochondrial respiration. In summary, we provide evidence that rs267738 in CERS2 affect human metabolism and induce hepatic insulin resistance, presumably via impairment of insulin signaling and alteration of mitochondrial function.



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Artikel online veröffentlicht:
02. Mai 2023

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