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An E115A missense variant in CERS2 is associated with increased sleeping energy expenditure and hepatic insulin resistance in American Indians.
Diabetes 73, 1361-1371 (2024)
Genetic determinants of inter-individual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-hour EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (+116 kcal/day) and increased rates of endogenous glucose production during basal (+5%) and insulin-stimulated (+43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and post-absorptive sleeping metabolic rate.
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Publication type
Article: Journal article
Document type
Scientific Article
ISSN (print) / ISBN
0012-1797
e-ISSN
1939-327X
Journal
Diabetes
Quellenangaben
Volume: 73,
Issue: 8,
Pages: 1361-1371
Publisher
American Diabetes Association
Publishing Place
Alexandria, VA.
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)