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Tissue inhibitor of metalloproteinase-1 predicts adiposity in humans

Susan Kralisch, Matthias Bluher, Anke Tonjes, Ulrike Lossner, Ralf Paschke, Michael Stumvoll, and Mathias Fasshauer

Objective: Tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated in fat of obese rodents and promotes adipose tissue development in these animals. However, it is unclear whether TIMP-1 independently predicts adiposity in humans and whether serum levels are increased in s.c. and visceral obesity.

Design: Twenty-four lean, 16 s.c. obese, and 20 visceral obese subjects were studied.

Methods: Plasma TIMP-1 concentrations were quantified using ELISAs and correlated to clinical parameters.

Results: Plasma TIMP-1 levels were significantly different between lean (156 ± 42 μg/l), s.c. obese (186 ± 52 μg/l), and visceral obese (198 ± 42 μg/l) subjects (P < 0.01). Furthermore, TIMP-1 correlated positively with body mass index (BMI), waist-to-hip ratio (WHR), % body fat, fasting insulin, free fatty acids, cholesterol, leptin, interleukin-6, and negatively with adiponectin (P < 0.05). Moreover, TIMP-1 serum levels predicted % body fat but not WHR independent of age, sex, and plasma insulin.

Conclusions: We demonstrate that increased TIMP-1 serum levels are found with increased adiposity in humans.

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Serum levels of adipocyte fatty acid binding protein are increased in gestational diabetes mellitus

Susan Kralisch, Holger Stepan, Jürgen Kratzsch, Michael Verlohren, Hans-Joachim Verlohren, Kathrin Drynda, Ulrike Lössner, Matthias Blüher, Michael Stumvoll, and Mathias Fasshauer

Objective

Adipocyte fatty acid binding protein (AFABP) was recently introduced as a novel adipokine, serum levels of which independently correlate with the development of the metabolic syndrome and cardiovascular disease in humans. In the current study, we investigated serum concentrations of AFABP in patients with gestational diabetes mellitus (GDM) as compared with healthy pregnant controls matched for gestational age and fasting insulin.

Design and methods

AFABP was determined by ELISA in controls (n=80) and GDM patients (n=40) and correlated to clinical and biochemical measures of renal function, glucose and lipid metabolism, as well as inflammation, in both groups.

Results

Median serum AFABP concentrations were significantly elevated in subjects with GDM (22.9 μg/l) as compared with healthy pregnant controls (18.3 μg/l; P<0.05). Furthermore, GDM was independently associated with AFABP concentrations in multiple regression analysis (P<0.05). In addition, markers of adiposity (body mass index, serum leptin), triglycerides and serum creatinine were independently associated with circulating AFABP (P<0.05).

Conclusions

Maternal AFABP concentrations are significantly increased in GDM. The adipokine might contribute to the increased metabolic and cardiovascular risk of the disease.

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Gene expression of PPARγ and PGC-1α in human omental and subcutaneous adipose tissues is related to insulin resistance markers and mediates beneficial effects of physical training

Karen Ruschke, Lauren Fishbein, Arne Dietrich, Nora Klöting, Anke Tönjes, Andreas Oberbach, Mathias Fasshauer, Jost Jenkner, Michael R Schön, Michael Stumvoll, Matthias Blüher, and Christos S Mantzoros

Objective

Obesity and type 2 diabetes (T2D) are reaching epidemic proportions in Western societies, and they contribute to substantial morbidity and mortality. The peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) system plays an important role in the regulation of efficient energy utilization and oxidative phosphorylation, both of which are decreased in obesity and insulin resistance.

Design and methods

We measured the metabolic parameters and the expression of PPARγ and PGC-1α mRNA using quantitative real-time PCR in omental and subcutaneous (SC) adipose tissues in an observational study of 153 individuals as well as in SC fat and skeletal muscle in an interventional study of 60 subjects (20 each with normal glucose tolerance, impaired glucose tolerance, and T2D) before and after intensive physical training for 4 weeks.

Results

PPARγ and PGC-1α mRNA expression in both fat depots as well as in skeletal muscle is associated with markers of insulin resistance and cardiovascular risk. PGC-1α mRNA expression is significantly higher in SC fat than in omental fat, whereas PPARγ mRNA expression is not significantly different between these fat depots. Skeletal muscle and SC fat PPARγ and PGC-1α mRNA expression increased significantly in response to physical training.

Conclusions

Gene expression of PPARγ and PGC-1α in human adipose tissue is related to markers of insulin resistance and cardiovascular risk. Increased muscle and adipose tissue PPARγ and PGC-1α expression in response to physical training may mediate the beneficial effects of exercise on insulin sensitivity.

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Long-term exercise training decreases interleukin-6 (IL-6) serum levels in subjects with impaired glucose tolerance: effect of the −174G/C variant in IL-6 gene

Andreas Oberbach, Stefanie Lehmann, Katharina Kirsch, Joanna Krist, Melanie Sonnabend, Axel Linke, Anke Tönjes, Michael Stumvoll, Matthias Blüher, and Peter Kovacs

Objective

Exercise training has been shown to have anti-inflammatory effects in patients with type 2 diabetes. Changes in interleukin-6 (IL-6) serum concentrations in response to training could contribute to these beneficial effects. However, there are heterogeneous data on whether circulating IL-6 is altered by exercise training. We therefore hypothesize that genetic factors modify the individual changes in IL-6 levels after long-term training.

Research design and methods

The −174G/C variant in the IL-6 gene was genotyped in 60 subjects with impaired glucose tolerance. For a 12-month interventional study, patients were randomized into three groups: a control group (n=16) was compared with one group, which underwent a standardized training program (n=24) and another group, which was treated with 4 mg rosiglitazone once daily (n=20). At baseline, after 1, 6, and 12 months, we measured anthropometric parameters and serum concentration of IL-6 and, at baseline and after 12 months, we determined glucose tolerance and fitness level.

Results

Only in subjects carrying the SNP −174C allele did long-term exercise training result in significantly reduced IL-6 serum concentrations. Multivariate linear regression analysis identified the IL-6 genotype as a significant predictor of changes in IL-6 serum concentrations independent of age, gender and improvement in body mass index, hemoglobin (Hb)A1c, and fitness level in response to training.

Conclusions

Genetic variants in the IL-6 gene significantly modify changes in IL-6 serum concentrations in response to long-term exercise training programs. Our data suggest that genetic factors are important determinants for the individual response to anti-inflammatory effects of exercise training.

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Betatrophin levels are increased in women with gestational diabetes mellitus compared to healthy pregnant controls

Thomas Ebert, Susan Kralisch, Ulrike Wurst, Ulrike Lössner, Jürgen Kratzsch, Matthias Blüher, Michael Stumvoll, Anke Tönjes, and Mathias Fasshauer

Objective

Betatrophin has recently been introduced as a novel adipokine/hepatokine, which promotes pancreatic β cell proliferation and improves glucose tolerance in several mouse models of insulin resistance. However, regulation of betatrophin in gestational diabetes mellitus (GDM), as well as its association with markers of obesity, such as glucose and lipid metabolism, inflammation, and renal function, have not been elucidated.

Design and methods

Circulating betatrophin was quantified in 74 women with GDM and 74 healthy and gestational age-matched controls by ELISA. In a subset of the study population comprising of 85 patients (41 previous controls, 44 previous women with GDM), postpartum betatrophin levels were measured in a follow-up study.

Results

Median (interquartile range) serum betatrophin levels were higher in women with GDM (1.79 (0.53) μg/l) as compared to non-diabetic pregnant controls (1.58 (0.44) μg/l) (P=0.002). In multivariate analysis, GDM status was an independent and positive predictor of circulating betatrophin (P=0.001). Furthermore, betatrophin levels were significantly higher during gestation (1.70 (0.53) μg/l) as compared to postpartum levels (1.55 (0.66) μg/l) (P=0.028). Moreover, postpartum irisin remained a positive and independent predictor of postpartum betatrophin concentrations.

Conclusions

Women with GDM have significantly higher betatrophin levels as compared to healthy pregnant controls and GDM status positively predicts circulating betatrophin. Furthermore, postpartum levels are significantly lower as compared to betatrophin concentrations during pregnancy. Moreover, irisin is a significant predictor of postpartum betatrophin levels.

Free access

Circulating high-molecular-weight adiponectin is upregulated in preeclampsia and is related to insulin sensitivity and renal function

Mathias Fasshauer, Theresa Waldeyer, Jeannette Seeger, Susanne Schrey, Thomas Ebert, Jürgen Kratzsch, Ulrike Lössner, Matthias Blüher, Michael Stumvoll, Renaldo Faber, and Holger Stepan

Objective

Preeclampsia (PE) is a serious cardiovascular complication in pregnancy which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, a paradoxical upregulation of the insulin-sensitizing and anti-atherogenic adipokine adiponectin has been shown in PE. Furthermore, high-molecular-weight (HMW) adiponectin has been suggested as the biologically active form of this adipokine.

Design and methods

HMW adiponectin and total adiponectin serum concentrations were quantified by ELISA in PE (n=16) patients and pregnant control women without PE (n=20). Furthermore, HMW adiponectin and total adiponectin were correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation.

Results

Median maternal HMW adiponectin and total adiponectin levels were significantly and independently upregulated almost twofold in PE when compared with controls. HMW adiponectin and total adiponectin correlated positively with creatinine and negatively with fasting insulin in univariate and multivariate analyses.

Conclusions

We show that maternal HMW adiponectin and total adiponectin serum concentrations are significantly increased in PE and are positively associated with markers of insulin sensitivity and renal dysfunction. Adiponectin might be part of a physiological feedback mechanism improving insulin sensitivity and cardiovascular health in PE.

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Effect of a 4 week physical training program on plasma concentrations of inflammatory markers in patients with abnormal glucose tolerance

Andreas Oberbach, Anke Tönjes, Nora Klöting, Mathias Fasshauer, Jürgen Kratzsch, Martin W Busse, Ralf Paschke, Michael Stumvoll, and Matthias Blüher

Objective: Subclinical chronic inflammation could be a unifying factor linking type 2 diabetes (T2D) and atherosclerosis. The beneficial effects of physical activity on a reduced risk of coronary heart disease could at least in part be mediated by improved markers of inflammation.

Research design and methods: The aim of this study was to determine the effect of 4 weeks of physical training on plasma concentrations of interleukin (IL)-6, C-reactive protein (CRP), adiponectin and IL-10 in 60 individuals with normal glucose tolerance, impaired glucose tolerance (IGT) or T2D.

Results: In patients with IGT and T2D, significant improvement in body fat, fitness level, glucose metabolism and insulin sensitivity after 4 weeks of physical training was associated with significantly improved plasma concentrations of adiponectin and CRP, but not IL-6. Regression analysis demonstrated only for the anti-inflammatory parameters adiponectin and IL-10 a significant relationship with the decrease in fasting plasma glucose, whereas changes in IL-6 and CRP were not significantly related to changes in fasting plasma glucose, body fat, maximal oxygen uptake, or insulin sensitivity. In a multivariate linear regression analysis, only changes in circulating adiponectin, fasting plasma glucose and percentage body fat were determinants of changes in insulin sensitivity.

Conclusions: Physical training was associated with a near normalization of adiponectin and CRP plasma concentrations in subjects with IGT and T2D. Increased insulin sensitivity after training was most strongly related to changes in adiponectin plasma concentrations, in fasting plasma glucose and percentage body fat, whereas changes in IL-6, IL-10 and CRP plasma concentrations did not significantly contribute to improved insulin sensitivity.

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Serum levels of the myokine irisin in relation to metabolic and renal function

Thomas Ebert, Denise Focke, David Petroff, Ulrike Wurst, Judit Richter, Anette Bachmann, Ulrike Lössner, Susan Kralisch, Jürgen Kratzsch, Joachim Beige, Ingolf Bast, Matthias Anders, Matthias Blüher, Michael Stumvoll, and Mathias Fasshauer

Objective

Irisin has recently been introduced as a novel myokine which reverses visceral obesity and improves glucose metabolism in mice. However, regulation of irisin in humans in relation to renal and metabolic disease has not been comprehensively studied.

Design and methods

Serum irisin levels were quantified by ELISA and correlated with anthropometric and biochemical parameters of renal function, glucose and lipid metabolism, as well as inflammation, in 532 patients with stages 1–5 of chronic kidney disease (CKD).

Results

Median serum irisin levels adjusted for age, gender, and BMI significantly decreased with increasing CKD stage and lowest concentrations were seen in patients with CKD stage 5. Furthermore, irisin concentrations were associated with facets of the metabolic syndrome including diastolic blood pressure, markers of impaired glucose tolerance, and dyslipidemia in univariate analysis. Moreover, markers of renal function, e.g. glomerular filtration rate, and insulin resistance, e.g. homeostasis model assessment of insulin resistance, remained independently associated with circulating irisin levels in robust multivariate analysis.

Conclusions

We show that irisin serum concentrations decrease with increasing CKD stage and are independently and positively predicted by renal function and insulin resistance. The physiological relevance of our findings, as well as the factors contributing to irisin regulation in humans, needs to be further defined in future experiments.

Free access

Prospective evaluation of aldosterone LC-MS/MS-specific cutoffs for the saline infusion test

Charlotte Michaela Fries, Yoon Ju Bae, Nada Rayes, Benjamin Sandner, Berend Isermann, Michael Stumvoll, Valentina Fagotto, Martin Reincke, Martin Bidlingmaier, Vogel Mandy, Jürgen Kratzsch, and Wiebke Kristin Fenske

Objective

Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has become state of the art for the quantitative analysis of steroid hormones. Although method comparisons show that aldosterone measurement using LC-MS/MS yields considerably lower levels than immunoassays (IAs), method-specific cutoff values for primary aldosteronism (PA) are largely missing. Objective of this study was to analyze the diagnostic accuracy of proposed LC-MS/MS-specific cutoff values for the saline infusion test (SIT).

Design and methods

From 2016 to 2019, 104 consecutive patients suspected of PA underwent the SIT and captopril challenge test in the tertiary medical center at the University Hospital of Leipzig, Germany. Patients with positive case confirmation underwent adrenal imaging and adrenal venous sampling for subtype classification.

Results

Overall, proposed assay-specific PACLC-MS/MS cutoff values for the SIT achieved higher diagnostic accuracy than established PACIA values with a sensitivity and specificity of 87.5% (95% CI: 71.0–96.5) and 97% (95% CI: 89.6–99.6) for a cutoff of 120 pmol/L and 93.8% (95% CI: 79.2–99.2) and 92.5% (95% CI: 83.4–97.5) for a cutoff of 94 pmol/L. The most accurate post-SIT PACLC-MS/MS cutoff value in this study was 83 pmol/L, yielding a sensitivity and specificity of 96.9% (95% CI: 83.8–99.9) and 92.5% (95% CI: 83.4–97.5), respectively.

Conclusions

The present data confirm the need for the implication of lower method-specific aldosterone cutoff values for the diagnosis of PA with LC-MS/MS based aldosterone measurement.

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The brown fat-secreted adipokine neuregulin 4 is decreased in human and murine chronic kidney disease

Susan Kralisch, Annett Hoffmann, Nora Klöting, Armin Frille, Hartmut Kuhn, Marcin Nowicki, Sabine Paeschke, Anette Bachmann, Matthias Blüher, Ming-Zhi Zhang, Raymond C Harris, Michael Stumvoll, Mathias Fasshauer, and Thomas Ebert

Objective

Neuregulin 4 (NRG4) has recently been introduced as a novel brown adipose tissue (BAT)-secreted adipokine with beneficial metabolic effects in mice. However, regulation of Nrg4 in end-stage kidney disease (ESKD) and type 2 diabetes mellitus (T2DM) has not been elucidated, so far.

Design/methods

Serum NRG4 levels were quantified by ELISA in 60 subjects with ESKD on chronic hemodialysis as compared to 60 subjects with an estimated glomerular filtration rate >50 mL/min/1.73 m2 in a cross-sectional cohort. Within both groups, about half of the patients had a T2DM. Furthermore, mRNA expression of Nrg4 was determined in two mouse models of diabetic kidney disease (DKD) as compared to two different groups of non-diabetic control mice. Moreover, mRNA expression of Nrg4 was investigated in cultured, differentiated mouse brown and white adipocytes, as well as hepatocytes, after treatment with the uremic toxin indoxyl sulfate.

Results

Median serum NRG4 was significantly lower in patients with ESKD compared to controls and the adipokine was independently associated with a beneficial renal, glucose and lipid profile. In mice with DKD, Nrg4 mRNA expression was decreased in all adipose tissue depots compared to control mice. The uremic toxin indoxyl sulfate did not significantly alter Nrg4 mRNA expression in adipocytes and hepatocytes, in vitro.

Conclusions

Circulating NRG4 is independently associated with a preserved renal function and mRNA expression of -Nrg4 is reduced in adipose tissue depots of mice with DKD. The BAT-secreted adipokine is further associated with a beneficial glucose and lipid profile supporting NRG4 as potential treatment target in metabolic and renal disease states.