Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach

Floegel, Anna; Stefan, Norbert; Yu, Zhonghao; Mühlenbruch, Kristin; Drogan, Dagmar; Joost, Hans‐Georg; Fritsche, Andreas; Häring, Hans‐Ulrich; Angelis, Martin Hrabé de; Peters, Annette; Roden, Michael; Prehn, Cornelia; Wang-Sattler, Rui; Illig, Thomas; Schulze, Matthias B.; Adamski, Jerzy; Pischon, Tobias

doi:10.2337/db12-0495

Cited by 871 publications

(892 citation statements)

References 56 publications

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“…Several of these metabolites include classes of lipids (i.e. lysophosphatidylcholines, phosphocholines and sphingomyelins), which have been shown to be associated with insulin secretion 36. This provides further evidence of kisspeptin's modulation of human metabolism, which (with further study) may provide important mechanistic data.…”

Section: Discussionmentioning

confidence: 72%

“…Linear mixed effect modelling27 was used to identify patterns of serum metabolites, which changed significantly between baseline (T = −15 minutes) and steady state (T = 45 minutes) during kisspeptin but not vehicle administration. The profiles of numerous small molecules (Figure S4) and lipid species (Figure 3) were altered, including lysophosphatidylcholine (LPC 18:2), which was reduced by kisspeptin administration and has previously been shown to be negatively correlated with insulin secretion 36. All annotated metabolites that significantly changed during kisspeptin administration (but not vehicle administration) have been collated in Table S4.…”

Section: Resultsmentioning

confidence: 99%

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The effects of kisspeptin on β‐cell function, serum metabolites and appetite in humans

Izzi‐Engbeaya

Comninos

Clarke

et al. 2018

Diabetes Obesity Metabolism

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AimsTo investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans.Materials and methodsIn 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells).ResultsKisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men.ConclusionsCollectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.

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Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

The effects of kisspeptin on β‐cell function, serum metabolites and appetite in humans

Izzi‐Engbeaya

Comninos

Clarke

et al. 2018

Diabetes Obesity Metabolism

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“…Finally, the Biocrates AbsoluteIDQ p150 kit allows for the quantification of hexose, which is ß90-95% glucose (Goek et al, 2012) and this is an important source of energy for the body. Indeed, metabolites as detected using this sample preprocessing kit have been associated previously with various diseases and other conditions (see, e.g., Floegel et al, 2013;He et al, 2012;Jourdan et al, 2012;Mittelstrass et al, 2011;Wang-Sattler et al, 2012;Xu et al, 2013;.…”

mentioning

confidence: 99%

Familial Resemblance for Serum Metabolite Concentrations

et al. 2013

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Metabolomics is the comprehensive study of metabolites, which are the substrates, intermediate, and end products of cellular metabolism. The heritability of the concentrations of circulating metabolites bears relevance for evaluating their suitability as biomarkers for disease. We report aspects of familial resemblance for the concentrations in human serum of more than 100 metabolites, measured using a targeted metabolomics platform. Age-and sex-corrected monozygotic twin correlations, midparent-offspring regression coefficients, and spouse correlations in subjects from two independent cohorts (Netherlands Twin Register and Leiden Longevity Study) were estimated for each metabolite. In the Netherlands Twin Register subjects, who were largely fasting, we found significant monozygotic twin correlations for 121 out of 123 metabolites. Heritability was confirmed by midparent-offspring regression. For most detected metabolites, the correlations between spouses were considerably lower than those between twins, indicating a contribution of genetic effects to familial resemblance. Remarkably high heritability was observed for free carnitine (monozygotic twin correlation 0.66), for the amino acids serine (monozygotic twin correlation 0.77) and threonine (monozygotic twin correlation 0.64), and for phosphatidylcholine acyl-alkyl C40:3 (monozygotic twin correlation 0.77). For octenoylcarnitine, a consistent point estimate of approximately 0.50 was found for the spouse correlations in the two cohorts as well as for the monozygotic twin correlation, suggesting that familiality for this metabolite is explained by shared environment. We conclude that for the majority of metabolites targeted by the used metabolomics platform, the familial resemblance of serum concentrations is largely genetic. Our results contribute to the knowledge of the heritability of fasting serum metabolite concentrations, which is relevant for biomarker research.

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“…Furthermore, it was recently reported that pregnant women with high fasting plasma glucose concentrations also had high fasting concentrations of several amino acids, including leucine [37]. Higher fasting concentrations of BCAAs were also found in individuals with type 2 diabetes and insulin resistance [34,[38][39][40]. These findings indicate that alterations in BCAA metabolism are associated with gestational diabetes, insulin resistance and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 81%

“…Moreover, population-based studies of previously healthy adults revealed that low lyso-PC C18:2 concentrations were associated with an increased risk of pre-type 2 diabetes and type 2 diabetes [30,34], while high concentrations of several diacyl-PCs (C32:1, C36:1, C38:3 and C40:5) were associated with a risk of type 2 diabetes independent of dietary, lifestyle and anthropometric factors. In our study, the total lyso-PC/total PC ratio was significantly increased in women who had lactated for >3 months as a consequence of higher concentrations of several lyso-PCs and lower concentrations of several diacyl-PCs in these women.…”

Section: Discussionmentioning

confidence: 99%

Lactation is associated with altered metabolomic signatures in women with gestational diabetes

et al. 2016

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Aims/hypothesis Lactation for >3 months in women with gestational diabetes is associated with a reduced risk of type 2 diabetes that persists for up to 15 years postpartum. However, the underlying mechanisms are unknown. We examined whether in women with gestational diabetes lactation for >3 months is associated with altered metabolomic signatures postpartum. Methods We enrolled 197 women with gestational diabetes at a median of 3.6 years (interquartile range 0.7-6.5 years) after delivery. Targeted metabolomics profiles (including 156 metabolites) were obtained during a glucose challenge test. Comparisons of metabolite concentrations and ratios between women who lactated for >3 months and women who lactated for ≤3 months or not at all were performed using linear regression with adjustment for age and BMI at the postpartum visit, time since delivery, and maternal education level, and correction for multiple testing. Gaussian graphical modelling was used to generate metabolite networks.Results Lactation for >3 months was associated with a higher total lysophosphatidylcholine/total phosphatidylcholine ratio; in women with short-term follow-up, it was also associated with lower leucine concentrations and a lower total branchedchain amino acid concentration. Gaussian graphical modelling identified subgroups of closely linked metabolites within phosphatidylcholines and branched-chain amino acids that were affected by lactation for >3 months and have been linked to the pathophysiology of type 2 diabetes in previous studies. Conclusions/interpretation Lactation for >3 months in women with gestational diabetes is associated with changes in the metabolomics profile that have been linked to the early pathogenesis of type 2 diabetes.

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Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach

Cited by 871 publications

References 56 publications

The effects of kisspeptin on β‐cell function, serum metabolites and appetite in humans

The effects of kisspeptin on β‐cell function, serum metabolites and appetite in humans

Familial Resemblance for Serum Metabolite Concentrations

Lactation is associated with altered metabolomic signatures in women with gestational diabetes

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