TY - JOUR
T1 - Metabolic profiling of tissue-specific insulin resistance in human obesity
T2 - results from the Diogenes study and the Maastricht Study
AU - Vogelzangs, Nicole
AU - van der Kallen, Carla J. H.
AU - van Greevenbroek, Marleen M. J.
AU - van der Kolk, Birgitta W.
AU - Jocken, Johan W. E.
AU - Goossens, Gijs H.
AU - Schaper, Nicolaas C.
AU - Henry, Ronald M. A.
AU - Eussen, Simone J. P. M.
AU - Valsesia, Armand
AU - Hankemeier, Thomas
AU - Astrup, Arne
AU - Saris, Wim H. M.
AU - Stehouwer, Coen D. A.
AU - Blaak, Ellen E.
AU - Arts, Ilja C. W.
AU - CODAM study
N1 - Funding Information:
World’s Best Diet (Penguin, Australia). EEB receives grant support from food industry, such as DSM, Danone, Friesland Campina, Avebe, and Sensus, partly within the context of public–private consortia and has received funding from pharmaceutical companies like Novartis. She is involved in several task forces/expert groups related to the International Life Science Institute, ILSI Europe. All other authors report no possible conflicts of interest.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/6
Y1 - 2020/6
N2 - Background: Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. Methods: This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m
2) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m
2; 40–65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. Results: Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. Conclusions: In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.
AB - Background: Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. Methods: This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m
2) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m
2; 40–65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. Results: Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. Conclusions: In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.
KW - AMINO-ACID CATABOLISM
KW - BRANCHED-CHAIN
KW - MUSCLE
KW - LIVER
KW - SERUM
KW - HYPERGLYCEMIA
KW - DETERMINANTS
KW - INFLAMMATION
KW - EXPRESSION
KW - INDEXES
U2 - 10.1038/s41366-020-0565-z
DO - 10.1038/s41366-020-0565-z
M3 - Article
C2 - 32203114
SN - 0307-0565
VL - 44
SP - 1376
EP - 1386
JO - International Journal of Obesity
JF - International Journal of Obesity
IS - 6
ER -