The heterozygous N291S mutation in the lipoprotein lipase gene impairs whole-body insulin sensitivity and affects a distinct set of plasma metabolites in humans

Sofia Mikkelsen Berg, Jesper Foged Havelund, Harald Hasler-Sheetal, Vibeke Hedeholm Kongstad Kruse, Andreas James Thestrup Pedersen, Aleksander Bill Hansen, Mads Nybo, Henning Beck-Nielsen, Kurt Højlund, Nils J. Færgeman

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Background Mutations in the lipoprotein lipase gene causing decreased lipoprotein lipase activity are associated with surrogate markers of insulin resistance and the metabolic syndrome in humans. Objective We investigated the hypothesis that a heterozygous lipoprotein lipase mutation (N291S) induces whole-body insulin resistance and alterations in the plasma metabolome. Methods In 6 carriers of a heterozygous lipoprotein lipase mutation (N291S) and 11 age-matched and weight-matched healthy controls, we examined insulin sensitivity and substrate metabolism by euglycemic-hyperinsulinemic clamps combined with indirect calorimetry. Plasma samples were taken before and after the clamp (4 hours of physiological hyperinsulinemia), and metabolites were measured enzymatically or by gas chromatography-mass spectrometry. Results Compared with healthy controls, heterozygous carriers of a defective lipoprotein lipase allele had elevated fasting plasma levels triglycerides (P < .006), and markedly impaired insulin-stimulated glucose disposal rates (P < .024) and nonoxidative glucose metabolism (P < .015). Plasma metabolite profiling demonstrated lower circulating levels of pyruvic acid and α-tocopherol in the N291S carriers than in controls both before and after stimulation with insulin (all >1.5-fold change and P < .05). Conclusion Heterozygous carriers with a defective lipoprotein lipase allele are less insulin sensitive and have increased plasma levels of nonesterified fatty acids and triglycerides. The heterozygous N291S carriers also have a distinct plasma metabolomic signature, which may serve as a diagnostic tool for deficient lipoprotein lipase activity and as a marker of lipid-induced insulin resistance.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Lipidology
Vol/bind11
Udgave nummer2
Sider (fra-til)515-523.e6
ISSN1933-2874
DOI
StatusUdgivet - 16. maj 2017

Fingeraftryk

Lipoprotein Lipase
Insulin Resistance
Mutation
Alleles
Glucose Clamp Technique
Hyperinsulinism
Nonesterified Fatty Acids
Gas Chromatography-Mass Spectrometry
Fasting
Insulin
Lipids
Weights and Measures

Citer dette

@article{cd1b9393553b4d85a15048a8f9059932,
title = "The heterozygous N291S mutation in the lipoprotein lipase gene impairs whole-body insulin sensitivity and affects a distinct set of plasma metabolites in humans",
abstract = "Background Mutations in the lipoprotein lipase gene causing decreased lipoprotein lipase activity are associated with surrogate markers of insulin resistance and the metabolic syndrome in humans. Objective We investigated the hypothesis that a heterozygous lipoprotein lipase mutation (N291S) induces whole-body insulin resistance and alterations in the plasma metabolome. Methods In 6 carriers of a heterozygous lipoprotein lipase mutation (N291S) and 11 age-matched and weight-matched healthy controls, we examined insulin sensitivity and substrate metabolism by euglycemic-hyperinsulinemic clamps combined with indirect calorimetry. Plasma samples were taken before and after the clamp (4 hours of physiological hyperinsulinemia), and metabolites were measured enzymatically or by gas chromatography-mass spectrometry. Results Compared with healthy controls, heterozygous carriers of a defective lipoprotein lipase allele had elevated fasting plasma levels triglycerides (P < .006), and markedly impaired insulin-stimulated glucose disposal rates (P < .024) and nonoxidative glucose metabolism (P < .015). Plasma metabolite profiling demonstrated lower circulating levels of pyruvic acid and α-tocopherol in the N291S carriers than in controls both before and after stimulation with insulin (all >1.5-fold change and P < .05). Conclusion Heterozygous carriers with a defective lipoprotein lipase allele are less insulin sensitive and have increased plasma levels of nonesterified fatty acids and triglycerides. The heterozygous N291S carriers also have a distinct plasma metabolomic signature, which may serve as a diagnostic tool for deficient lipoprotein lipase activity and as a marker of lipid-induced insulin resistance.",
keywords = "Gas chromatography-mass spectrometry, Gene mutation, Heterozygous N291S mutation, Insulin sensitivity, Lipoprotein lipase deficiency, α-tocopherol, Humans, Middle Aged, Male, Insulin Resistance/genetics, Lipoprotein Lipase/genetics, Female, Heterozygote, Mutation, Plasma/metabolism",
author = "Berg, {Sofia Mikkelsen} and Havelund, {Jesper Foged} and Harald Hasler-Sheetal and Kruse, {Vibeke Hedeholm Kongstad} and Pedersen, {Andreas James Thestrup} and Hansen, {Aleksander Bill} and Mads Nybo and Henning Beck-Nielsen and Kurt H{\o}jlund and F{\ae}rgeman, {Nils J.}",
year = "2017",
month = "5",
day = "16",
doi = "10.1016/j.jacl.2017.02.009",
language = "English",
volume = "11",
pages = "515--523.e6",
journal = "Journal of Clinical Lipidology",
issn = "1933-2874",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - The heterozygous N291S mutation in the lipoprotein lipase gene impairs whole-body insulin sensitivity and affects a distinct set of plasma metabolites in humans

AU - Berg, Sofia Mikkelsen

AU - Havelund, Jesper Foged

AU - Hasler-Sheetal, Harald

AU - Kruse, Vibeke Hedeholm Kongstad

AU - Pedersen, Andreas James Thestrup

AU - Hansen, Aleksander Bill

AU - Nybo, Mads

AU - Beck-Nielsen, Henning

AU - Højlund, Kurt

AU - Færgeman, Nils J.

PY - 2017/5/16

Y1 - 2017/5/16

N2 - Background Mutations in the lipoprotein lipase gene causing decreased lipoprotein lipase activity are associated with surrogate markers of insulin resistance and the metabolic syndrome in humans. Objective We investigated the hypothesis that a heterozygous lipoprotein lipase mutation (N291S) induces whole-body insulin resistance and alterations in the plasma metabolome. Methods In 6 carriers of a heterozygous lipoprotein lipase mutation (N291S) and 11 age-matched and weight-matched healthy controls, we examined insulin sensitivity and substrate metabolism by euglycemic-hyperinsulinemic clamps combined with indirect calorimetry. Plasma samples were taken before and after the clamp (4 hours of physiological hyperinsulinemia), and metabolites were measured enzymatically or by gas chromatography-mass spectrometry. Results Compared with healthy controls, heterozygous carriers of a defective lipoprotein lipase allele had elevated fasting plasma levels triglycerides (P < .006), and markedly impaired insulin-stimulated glucose disposal rates (P < .024) and nonoxidative glucose metabolism (P < .015). Plasma metabolite profiling demonstrated lower circulating levels of pyruvic acid and α-tocopherol in the N291S carriers than in controls both before and after stimulation with insulin (all >1.5-fold change and P < .05). Conclusion Heterozygous carriers with a defective lipoprotein lipase allele are less insulin sensitive and have increased plasma levels of nonesterified fatty acids and triglycerides. The heterozygous N291S carriers also have a distinct plasma metabolomic signature, which may serve as a diagnostic tool for deficient lipoprotein lipase activity and as a marker of lipid-induced insulin resistance.

AB - Background Mutations in the lipoprotein lipase gene causing decreased lipoprotein lipase activity are associated with surrogate markers of insulin resistance and the metabolic syndrome in humans. Objective We investigated the hypothesis that a heterozygous lipoprotein lipase mutation (N291S) induces whole-body insulin resistance and alterations in the plasma metabolome. Methods In 6 carriers of a heterozygous lipoprotein lipase mutation (N291S) and 11 age-matched and weight-matched healthy controls, we examined insulin sensitivity and substrate metabolism by euglycemic-hyperinsulinemic clamps combined with indirect calorimetry. Plasma samples were taken before and after the clamp (4 hours of physiological hyperinsulinemia), and metabolites were measured enzymatically or by gas chromatography-mass spectrometry. Results Compared with healthy controls, heterozygous carriers of a defective lipoprotein lipase allele had elevated fasting plasma levels triglycerides (P < .006), and markedly impaired insulin-stimulated glucose disposal rates (P < .024) and nonoxidative glucose metabolism (P < .015). Plasma metabolite profiling demonstrated lower circulating levels of pyruvic acid and α-tocopherol in the N291S carriers than in controls both before and after stimulation with insulin (all >1.5-fold change and P < .05). Conclusion Heterozygous carriers with a defective lipoprotein lipase allele are less insulin sensitive and have increased plasma levels of nonesterified fatty acids and triglycerides. The heterozygous N291S carriers also have a distinct plasma metabolomic signature, which may serve as a diagnostic tool for deficient lipoprotein lipase activity and as a marker of lipid-induced insulin resistance.

KW - Gas chromatography-mass spectrometry

KW - Gene mutation

KW - Heterozygous N291S mutation

KW - Insulin sensitivity

KW - Lipoprotein lipase deficiency

KW - α-tocopherol

KW - Humans

KW - Middle Aged

KW - Male

KW - Insulin Resistance/genetics

KW - Lipoprotein Lipase/genetics

KW - Female

KW - Heterozygote

KW - Mutation

KW - Plasma/metabolism

UR - http://www.sciencedirect.com/science/article/pii/S1933287417300375

U2 - 10.1016/j.jacl.2017.02.009

DO - 10.1016/j.jacl.2017.02.009

M3 - Journal article

C2 - 28502509

VL - 11

SP - 515-523.e6

JO - Journal of Clinical Lipidology

JF - Journal of Clinical Lipidology

SN - 1933-2874

IS - 2

ER -