Liver Fat and Insulin Sensitivity Define Metabolite Profiles During a Glucose Tolerance Test in Young Adult Twins.
The associations of body mass index (BMI) and liver fat (LF) with circulating prandial metabolomic markers are incompletely understood.



We aimed to characterize circulating metabolite excursions during an oral glucose tolerance test (OGTT) and evaluate whether the metabolomic signatures of BMI discordance coassociate with LF content.



We measured 80 metabolite parameters by nuclear magnetic resonance, together with glucose and insulin, during a 2-hour OGTT in 64 monozygotic (MZ) and 73 dizygotic (DZ) twin pairs (aged 22.8 to 36.2 years). Metabolite excursions during the OGTT were compared within BMI-discordant (intrapair difference, BMI ≥ 3 kg/m2) cotwins separately within MZ and DZ pairs. Insulin-based indices were calculated from the OGTT. LF was measured by magnetic resonance spectroscopy in 25 BMI-discordant MZ pairs. Metabolite profiles were compared with respect to LF discordance (ΔLF% ≥ 2%).



We replicated many previously reported OGTT-induced metabolite excursions in all 274 individuals and report novel lipoprotein excursions. The associations between some metabolite excursions and BMI differed in MZ and DZ twins. In BMI-discordant MZ pairs (mean ΔBMI = 4.9 kg/m2) who were concordant for LF (Δ0.2%), few metabolites differed between the cotwins: very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B were elevated, and high-density lipoprotein size and concentration were decreased in the cotwins with higher BMI. In contrast, in BMI-discordant MZ pairs (ΔBMI = 6.1 kg/m2) who were discordant for LF (Δ6.8%), cotwins with higher BMI exhibited lower insulin sensitivity and widespread metabolomic differences: elevations in small VLDL and low-density lipoprotein particles, fatty acids (FAs), and isoleucine. Within all 64 MZ twin pairs, lower insulin sensitivity associated with higher levels of VLDLs, triglycerides, FAs, and isoleucine.



BMI-discordant MZ twin pairs who also are discordant for LF have more pronounced within-pair differences in metabolomics profiles during an OGTT than BMI-discordant pairs without LF discordance.
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, FI-00029, Helsinki, Finland.|Institute for Molecular Medicine Finland, FI-00014, Helsinki, Finland.
Joel T
JT
Rämö
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, FI-00029, Helsinki, Finland.
Sanna M
SM
Kaye
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, FI-00029, Helsinki, Finland.
Sakari
S
Jukarainen
Department of Public Health, University of Helsinki, FI-00014, Helsinki, Finland.
Leonie H
LH
Bogl
Department of Radiology, HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, FI-00029, Helsinki, Finland.
Antti
A
Hakkarainen
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany.|German Center for Diabetes Research, Partner Düsseldorf, 40225, Düsseldorf, Germany.
Jesper
J
Lundbom
Department of Radiology, HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, FI-00029, Helsinki, Finland.
Nina
N
Lundbom
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, FI-00029, Helsinki, Finland.|Department of Psychiatry, Helsinki University Hospital, and University of Helsinki, 00014, Helsinki, Finland.
Aila
A
Rissanen
Institute for Molecular Medicine Finland, FI-00014, Helsinki, Finland.|Department of Public Health, University of Helsinki, FI-00014, Helsinki, Finland.|Department of Health, National Institute for Health and Welfare, FI-00014, Helsinki, Finland; and.
Jaakko
J
Kaprio
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, FI-00029, Helsinki, Finland.|Endocrinology, Abdominal Center, Helsinki University Hospital, and University of Helsinki, FI-00029, Helsinki, Finland.
Niina
N
Matikainen
Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, FI-00029, Helsinki, Finland.|Institute for Molecular Medicine Finland, FI-00014, Helsinki, Finland.|Endocrinology, Abdominal Center, Helsinki University Hospital, and University of Helsinki, FI-00029, Helsinki, Finland.
Kirsi H
KH
Pietiläinen
D050154:Adiposity; D000328:Adult; D015415:Biomarkers / Q000378:metabolism*; D004200:Diseases in Twins / Q000378:metabolism* / Q000473:pathology; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005951:Glucose Tolerance Test / Q000379:methods*; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011379:Prognosis; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic; D055815:Young Adult
D015415:Biomarkers