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- Chorell, Elin, et al.
(författare)
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Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes
- 2017
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Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 72, s. 27-36
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Tidskriftsartikel (refereegranskat)abstract
- Context. Gestational diabetes is commonly linked to development of type 2 diabetes mellitus (T2DM). There is a need to characterize metabolic changes associated with gestational diabetes in order to find novel biomarkers for T2DM. Objective. To find potential pathophysiological mechanisms and markers for progression from gestational diabetes mellitus to T2DM by studying the metabolic transition from pregnancy to postpartum. Design. The metabolic transition profile from pregnancy to postpartum was characterized in 56 women by mass spectrometry-based metabolomics; 11 women had gestational diabetes mellitus, 24 had normal glucose tolerance, and 21 were normoglycaemic but at increased risk for gestational diabetes mellitus. Fasting serum samples collected during trimester 3 (gestational week 32 +/- 0.6) and postpartum (10.5 +/- 0.4 months) were compared in diagnosis-specific multivariate models (orthogonal partial least squares analysis). Clinical measurements (e.g., insulin, glucose, lipid levels) were compared and models of insulin sensitivity and resistance were calculated for the same time period. Results. Women with gestational diabetes had significantly increased postpartum levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and their circulating lipids did not return to normal levels after pregnancy. The increase in BCAAs occurred postpartum since the BCAAs did not differ during pregnancy, as compared to normoglycemic women. Conclusions. Postpartum levels of specific BCAAs, notably valine, are related to gestational diabetes during pregnancy. (C) 2017 Elsevier Inc. All rights reserved.
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- Foerster, Jana, et al.
(författare)
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Serum Lipid and Serum Metabolite Components in relation to anthropometric parameters in EPIC-Potsdam participants
- 2015
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Ingår i: Metabolism. - Maryland Heights, MO, United States : Saunders Elsevier. - 0026-0495 .- 1532-8600. ; 64:10, s. 1348-58
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIM: Lipidomic and metabolomic techniques become more and more important in human health research. Recent developments in analytical techniques enable the investigation of high amounts of substances. The high numbers of metabolites and lipids that are detected with among others mass spectrometric techniques challenge in most cases the statistical processes to bring out stable and interpretable results. This study targets to use the novel non-established statistical method treelet transform (TT) to investigate high numbers of metabolites and lipids and to compare the results with the established method principal component analysis (PCA). Serum lipid and metabolite profiles are investigated regarding their association to anthropometric parameters associated to obesity.METHODS: From 226 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Potsdam study blood samples were investigated with an untargeted metabolomics approach regarding serum metabolites and lipids. Additionally, participants were surveyed anthropometrically to assess parameters of obesity, such as body mass index (BMI), waist-to-hip-ratio (WHR) and body fat mass. TT and PCA are used to generate treelet components (TCs) and factors summarizing serum metabolites and lipids in new, latent variables without too much loss of information. With partial correlations TCs and factors were associated to anthropometry under the control for relevant parameters, such as sex and age.RESULTS: TT with metabolite variables (p=121) resulted in 5 stable and interpretable TCs explaining 18.9% of the variance within the data. PCA on the same variables generated 4 quite complex, less easily interpretable factors explaining 37.5% of the variance. TT on lipidomic data (p=353) produced 3 TCs as well as PCA on the same data resulted in 3 factors; the proportion of explained variance was 17.8% for TT and 39.8% for PCA. In both investigations TT ended up with stable components that are easier to interpret than the factors from the PCA. In general, the generated TCs and factors were similar in their structure when the factors are considered regarding the original variables loading high on them. Both TCs and factors showed associations to anthropometric measures.CONCLUSIONS: TT is a suitable statistical method to generate summarizing, latent variables in data sets with more variables than observations. In the present investigation it resulted in similar latent variables compared to the established method of PCA. Whereby less variance is explained by the summarizing constructs of TT compared to the factors of PCA, TCs are easier to interpret. Additionally the resulting TCs are quite stable in bootstrap samples.
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| 6. |
- Fryk, Emanuel, et al.
(författare)
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Microdialysis and proteomics of subcutaneous interstitial fluid reveals increased galectin-1 in type 2 diabetes patients
- 2016
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Ingår i: Metabolism-Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:7, s. 998-1006
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To identify a potential therapeutic target for type 2 diabetes by comparing the subcutaneous interstitial fluid from type 2 diabetes patients and healthy men. Methods. Proteomics was performed on the interstitial fluid of subcutaneous adipose tissue obtained by microdialysis from 7 type 2 diabetes patients and 8 healthy participants. 851 proteins were detected, of which 36 (including galectin-1) showed significantly altered expression in type 2 diabetes. We also measured galectin-1 expression in: (1) adipocytes isolated from adipose tissue biopsies from these participants; (2) subcutaneous adipose tissue of 24 obese participants before, during and after 16 weeks on a very low calorie diet (VLCD); and (3) adipocytes isolated from 6 healthy young participants after 4 weeks on a diet and lifestyle intervention to promote weight gain. We also determined the effect of galectin-1 on glucose uptake in human adipose tissue. Results. Galectin-1 protein levels were elevated in subcutaneous dialysates from type 2 diabetes compared with healthy controls (p < 0.05). In agreement, galectin-1 mRNA expression was increased in adipocytes from the type 2 diabetes patients (p < 0.05). Furthermore, galectin-1 mRNA expression was decreased in adipose tissue after VLCD (p < 0.05) and increased by overfeeding (p < 0.05). Co-incubation of isolated human adipocytes with galectin-1 reduced glucose uptake (p < 0.05) but this was independent of the insulin signal. Conclusion. Proteomics of the interstitial fluid in subcutaneous adipose tissue in vivo identified a novel adipokine, galectin-1, with a potential role in the pathophysiology of type 2 diabetes. (C) 2016 Elsevier Inc. All rights reserved.
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- Kurko, Johanna, et al.
(författare)
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Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI)
- 2016
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Ingår i: Metabolism. - : Saunders Elsevier. - 0026-0495 .- 1532-8600. ; 65:9, s. 1361-1375
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lysinuric protein intolerance (LPI [MIM 222700]) is an aminoaciduria with defective transport of cationic amino acids in epithelial cells in the small intestine and proximal kidney tubules due to mutations in the SLC7A7 gene. LPI is characterized by protein malnutrition, failure to thrive and hyperammonemia. Many patients also suffer from combined hyperlipidemia and chronic kidney disease (CKD) with an unknown etiology.METHODS: Here, we studied the plasma metabolomes of the Finnish LPI patients (n=26) and healthy control individuals (n=19) using a targeted platform for analysis of amino acids as well as two analytical platforms with comprehensive coverage of molecular lipids and polar metabolites.RESULTS: Our results demonstrated that LPI patients have a dichotomy of amino acid profiles, with both decreased essential and increased non-essential amino acids. Altered levels of metabolites participating in pathways such as sugar, energy, amino acid and lipid metabolism were observed. Furthermore, of these metabolites, myo-inositol, threonic acid, 2,5-furandicarboxylic acid, galactaric acid, 4-hydroxyphenylacetic acid, indole-3-acetic acid and beta-aminoisobutyric acid associated significantly (P<0.001) with the CKD status. Lipid analysis showed reduced levels of phosphatidylcholines and elevated levels of triacylglycerols, of which long-chain triacylglycerols associated (P<0.01) with CKD.CONCLUSIONS: This study revealed an amino acid imbalance affecting the basic cellular metabolism, disturbances in plasma lipid composition suggesting hepatic steatosis and fibrosis and novel metabolites correlating with CKD in LPI. In addition, the CKD-associated metabolite profile along with increased nitrite plasma levels suggests that LPI may be characterized by increased oxidative stress and apoptosis, altered microbial metabolism in the intestine and uremic toxicity.
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- Nikolaou, Nikolaos, et al.
(författare)
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AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease.
- 2019
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Ingår i: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 99, s. 67-80
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroid hormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes a fundamental step in bile acid synthesis.Human liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels were measured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver cell lines. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clinical biochemistry, and enzyme immunoassays.In human liver biopsies, AKR1D1 expression decreased with advancing steatosis, fibrosis and inflammation. Expression was decreased in patients with type 2 diabetes. In human liver cell lines, AKR1D1 knockdown decreased primary bile acid biosynthesis and steroid hormone clearance. RNA-sequencing identified disruption of key metabolic pathways, including insulin action and fatty acid metabolism. AKR1D1 knockdown increased hepatocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increased de novo lipogenesis and decreased β-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bile acid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the observed metabolic phenotype is driven through bile acid rather than steroid hormone availability.Genetic manipulation of AKR1D1 regulates the metabolic phenotype of human hepatoma cell lines, driving steatosis and inflammation. Taken together, the observation that AKR1D1 mRNA is down-regulated with advancing NAFLD suggests that it may have a crucial role in the pathogenesis and progression of the disease.
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- Pereira, Maria J., et al.
(författare)
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Impaired adipose tissue lipid storage, but not altered lipolysis, contributes to elevated levels of NEFA in type 2 diabetes. Degree of hyperglycemia and adiposity are important factors
- 2016
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:12, s. 1768-1780
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Tidskriftsartikel (refereegranskat)abstract
- Background Elevated levels of circulating non-esterified fatty acids (NEFA) mediate many adverse metabolic effects. In this work we aim to determine the impact of type 2 diabetes (T2D), glycemic control and obesity on lipolysis regulation. Design and Participants 20 control and 20 metformin-treated T2D subjects were matched for sex (10M/10 F), age (58±11 vs 58±9 y) and BMI (30.8±4.6 vs 30.7±4.9kg/m2). In vivo lipolysis was assessed during a 3h-OGTT with plasma glycerol and NEFA levels. Subcutaneous adipose tissue (SAT) biopsies were obtained to measure mRNA and metabolite levels of factors related to lipolysis and lipid storage and to assess in vitro lipolysis in isolated subcutaneous adipocytes. Results Plasma NEFA AUC during the OGTT where higher 30% (P=0.005) in T2D than in control subjects, but plasma glycerol AUC and subcutaneous adipocyte lipolysis in vitro were similar, suggesting that adipose tissue lipolysis is not altered. Expression in SAT of genes involved in lipid storage (FABP4, DGAT1, FASN) were reduced in T2D subjects compared with controls, but no differences were seen for genes involved in lipolysis. T2D subjects had elevated markers of beta-oxidation, α-hydroxybutyrate (1.4-fold, P<0.01) and β-hydroxybutyrate (1.7-fold, P<0.05) in plasma. In multivariate analysis, HbA1c, visceral adipose tissue volume and sex (male) were significantly associated with NEFA AUC in T2D subjects. Conclusions In T2D subjects, NEFA turnover is impaired, but not due to defects in lipolysis or lipid beta-oxidation. Impaired adipose NEFA re-esterification or de novo lipogenesis is likely to contribute to higher NEFA plasma levels in T2D. The data suggest that hyperglycemia and adiposity are important contributing factors for the regulation of plasma NEFA concentrations. © 2016 Elsevier Inc.
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