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1. De effecten van een PPAR-α-agonist (ciprofibraat) op de weefselspecifieke glucoseopname in insulineresistentie; resultaten van een gerandomiseerde dubbelblinde placebogecontroleerde cross-overstudie

Author

de Wit-Verheggen, Vera, Vanweert, Froukje, Raiko, Juho, Liénard, Viktor, Schaart, Gert, Gemmink, Anne, Nascimento, Emmani, Hesselink, Matthijs, Wildberger, Joachim, Wierts, Roel, Joris, Peter, Haas, Joel, Montaigne, David, Staels, Bart, Phielix, Esther, Schrauwen, Patrick, Schrauwen-Hinderling, Vera, and van de Weijer, Tineke

Published
2024
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2. Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes

Author

Parker, Victoria E. R., Robertson, Darren, Erazo-Tapia, Edmundo, Havekes, Bas, Phielix, Esther, de Ligt, Marlies, Roumans, Kay H. M., Mevenkamp, Julian, Sjoberg, Folke, Schrauwen-Hinderling, Vera B., Johansson, Edvin, Chang, Yi-Ting, Esterline, Russell, Smith, Kenneth, Wilkinson, Daniel J., Hansen, Lars, Johansson, Lars, Ambery, Philip, Jermutus, Lutz, and Schrauwen, Patrick

Published
2023
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4. Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: A randomized, double-blind crossover trial

Author

Veelen, Anna, Andriessen, Charlotte, Op den Kamp, Yvo, Erazo-Tapia, Edmundo, de Ligt, Marlies, Mevenkamp, Julian, Jörgensen, Johanna A., Moonen-Kornips, Esther, Schaart, Gert, Esterline, Russell, Havekes, Bas, Oscarsson, Jan, Schrauwen-Hinderling, Vera B., Phielix, Esther, and Schrauwen, Patrick

Published
2023
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5. Effects of SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes on skeletal muscle cellular metabolism

Author

op den Kamp, Yvo J.M., Gemmink, Anne, de Ligt, Marlies, Dautzenberg, Bas, Kornips, Esther, Jorgensen, Johanna A., Schaart, Gert, Esterline, Russell, Pava, Diego A., Hoeks, Joris, Schrauwen-Hinderling, Vera B., Kersten, Sander, Havekes, Bas, Koves, Timothy R., Muoio, Deborah M., Hesselink, Matthijs K.C., Oscarsson, Jan, Phielix, Esther, and Schrauwen, Patrick

Published
2022
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10. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans

Author

Remie, Carlijn ME, Roumans, Kay HM, Moonen, Michiel PB, Connell, Niels J, Havekes, Bas, Mevenkamp, Julian, Lindeboom, Lucas, de Wit, Vera HW, van de Weijer, Tineke, Aarts, Suzanne ABM, Lutgens, Esther, Schomakers, Bauke V, Elfrink, Hyung L, Zapata-Pérez, Rubén, Houtkooper, Riekelt H, Auwerx, Johan, Hoeks, Joris, Schrauwen-Hinderling, Vera B, Phielix, Esther, and Schrauwen, Patrick

Published
2020
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11. One-leg inactivity induces a reduction in mitochondrial oxidative capacity, intramyocellular lipid accumulation and reduced insulin signalling upon lipid infusion: a human study with unilateral limb suspension

Author

Bilet, Lena, Phielix, Esther, van de Weijer, Tineke, Gemmink, Anne, Bosma, Madeleen, Moonen-Kornips, Esther, Jorgensen, Johanna A., Schaart, Gert, Zhang, Dongyan, Meijer, Kenneth, Hopman, Maria, Hesselink, Matthijs K. C., Ouwens, D. Margriet, Shulman, Gerald I., Schrauwen-Hinderling, Vera B., and Schrauwen, Patrick

Published
2020
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12. Metabolic responses to mild cold acclimation in type 2 diabetes patients

Author

Remie, Carlijn M. E., Moonen, Michiel P. B., Roumans, Kay H. M., Nascimento, Emmani B. M., Gemmink, Anne, Havekes, Bas, Schaart, Gert, Kornips, Esther, Joris, Peter J., Schrauwen-Hinderling, Vera B., Hoeks, Joris, Kersten, Sander, Hesselink, Matthijs K. C., Phielix, Esther, Lichtenbelt, Wouter D. van Marken, and Schrauwen, Patrick

Published
2021
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16. The tissue‐specific metabolic effects of the PPARα agonist ciprofibrate in insulin‐resistant male individuals: a double‐blind, randomized, placebo‐controlled crossover study

Author

de Wit‐Verheggen, Vera H. W., primary, Vanweert, Froukje, additional, Raiko, Juho, additional, Liénard, Viktor, additional, Schaart, Gert, additional, Gemmink, Anne, additional, Nascimento, Emmani B. M., additional, Hesselink, Matthijs K. C., additional, Wildberger, Joachim E., additional, Wierts, Roel, additional, Joris, Peter J., additional, Haas, Joel, additional, Montaigne, David, additional, Staels, Bart, additional, Phielix, Esther, additional, Schrauwen, Patrick, additional, Schrauwen‐Hinderling, Vera B., additional, and van de Weijer, Tineke, additional

Published
2023
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17. Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

Author

Roumans, Kay H. M., Lindeboom, Lucas, Veeraiah, Pandichelvam, Remie, Carlijn M. E., Phielix, Esther, Havekes, Bas, Bruls, Yvonne M. H., Brouwers, Martijn C. G. J., Ståhlman, Marcus, Alssema, Marjan, Peters, Harry P. F., de Mutsert, Renée, Staels, Bart, Taskinen, Marja-Riitta, Borén, Jan, Schrauwen, Patrick, and Schrauwen-Hinderling, Vera B.

Published
2020
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20. The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity

Author

Vanweert, Froukje, Boone, Sebastiaan C., Brouwers, Bram, Mook-Kanamori, Dennis O., de Mutsert, Renée, Rosendaal, Frits R., Lamb, Hildo J., Schrauwen-Hinderling, Vera B., Schrauwen, Patrick, Hesselink, Matthijs K. C., and Phielix, Esther

Abstract

Aims: To evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a conventional exercise training program, a subcategory of physical activity, could lower plasma BCAA along with alterations in IHL content in patients with type 2 diabetes (T2DM) and people with nonalcoholic fatty liver (NAFL). Methods: To investigate the effect of physical activity on the association between plasma BCAA and IHL content, linear regression analyses were performed in 1983 individuals from the Netherlands Epidemiology of Obesity (NEO) stratified by physical activity frequency. Furthermore, the effect of a 12-week supervised combined aerobic resistance-exercise program on plasma BCAA, insulin sensitivity (hyperinsulinemic–euglycemic clamp), and IHL (proton-magnetic resonance spectroscopy (1H-MRS)) was investigated in seven patients with T2DM, seven individuals with NAFL and seven BMI-matched control participants (CON). Results: We observed positive associations between plasma valine, isoleucine and leucine level, and IHL content (1.29 (95% CI: 1.21, 1.38), 1.52 (95% CI: 1.43, 1.61), and 1.54 (95% CI: 1.44, 1.64) times IHL, respectively, per standard deviation of plasma amino acid level). Similar associations were observed in less active versus more active individuals. Exercise training did not change plasma BCAA levels among groups, but reduced IHL content in NAFL (from 11.6 ± 3.0% pre-exercise to 8.1 ± 2.0% post exercise, p< 0.05) and CON (from 2.4 ± 0.6% pre-exercise to 1.6 ± 1.4% post exercise, p< 0.05), and improved peripheral insulin sensitivity in NAFL as well by ~23% (p< 0.05). Conclusions: The association between plasma BCAA levels and IHL is not affected by physical activity level. Exercise training reduced IHL without affecting plasma BCAA levels in individuals with NAFL and CON. We conclude that exercise training-induced reduction in IHL content is not related to changes in plasma BCAA levels. Trial registration: Trial registry number: NCT01317576.

Published
2024
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23. Dietary lipid droplet structure in postnatal life improves hepatic energy and lipid metabolism in a mouse model for postnatal programming

Author

Jelenik, Tomas, primary, Kodde, Andrea, additional, Pesta, Dominik, additional, Phielix, Esther, additional, Oosting, Annemarie, additional, Rohbeck, Elisabeth, additional, Dewidar, Bedair, additional, Mastrototaro, Lucia, additional, Trenkamp, Sandra, additional, Keijer, Jaap, additional, van der Beek, Eline M., additional, and Roden, Michael, additional

Published
2022
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25. Dietary lipid droplet structure in postnatal life improves hepatic energy and lipid metabolism in a mouse model for postnatal programming

Author

Jelenik, Tomas, Kodde, Andrea, Pesta, Dominik, Phielix, Esther, Oosting, Annemarie, Rohbeck, Elisabeth, Dewidar, Bedair, Mastrototaro, Lucia, Trenkamp, Sandra, Keijer, Jaap, van der Beek, Eline M., Roden, Michael, Jelenik, Tomas, Kodde, Andrea, Pesta, Dominik, Phielix, Esther, Oosting, Annemarie, Rohbeck, Elisabeth, Dewidar, Bedair, Mastrototaro, Lucia, Trenkamp, Sandra, Keijer, Jaap, van der Beek, Eline M., and Roden, Michael

Abstract

Early-life diets may have a long-lasting impact on metabolic health. This study tested the hypothesis that an early-life diet with large, phospholipid-coated lipid droplets (Concept) induces sustained improvements of hepatic mitochondrial function and metabolism. Young C57BL/6j mice were fed Concept or control (CTRL) diet from postnatal day 15 (PN15) to PN42, followed by western style (WSD) or standard rodent diet (AIN) until PN98. Measurements comprised body composition, insulin resistance (HOMA-IR), tricarboxylic acid (TCA) cycle and beta-oxidation-related hepatic oxidative capacity using high-resolution respirometry, mitochondrial dynamics, mediators of insulin resistance (diacylglycerols, DAG) or ceramides) in subcellular compartments as well as systemic oxidative stress. Concept feeding increased TCA cycle-related respiration by 33% and mitochondrial fusion protein-1 by 65% at PN42 (both p 0.05). At PN98, CTRL, but not Concept, mice developed hyperinsulinemia (CTRL/AIN 0.22 +/- 0.44 vs. CTRL/WSD 1.49 +/- 0.53 nmol/l, p 0.05 and Concept/AIN 0.20 +/- 0.38 vs. Concept/WSD 1.00 +/- 0.29 nmol/l, n.s.) and insulin resistance after WSD (CTRL/AIN 107 +/- 23 vs. CTRL/WSD 738 +/- 284, p 0.05 and Concept/AIN 109 +/- 24 vs. Concept/WSD 524 +/- 157, n.s.). WSD-induced liver weight was 18% lower in adult Concept-fed mice and beta-oxidation-related respiration was 69% higher (p 0.05; Concept/WSD vs. Concept/AIN) along with lower plasma lipid peroxides (CTRL/AIN 4.85 +/- 0.28 vs. CTRL/WSD 5.73 +/- 0.47 mu mol/l, p 0.05 and Concept/AIN 4.49 +/- 0.31 vs. Concept/WSD 4.42 +/- 0.33 mu mol/l, n.s.) and were in part protected from WSD-induced increase in hepatic cytosolic DAG C16:0/C18:1. Early-life feeding of Concept partly protected from WSD-induced insulin resistance and systemic oxidative stress, potentially via changes in specific DAG and mitochondrial function, highlighting the role of early life diets on metabolic health later in life.

Published
2022

27. Erratum. Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial. Diabetes Care 2021;44:1334–1343

Author

Kamp, Yvo J.M. Op den, primary, Ligt, Marlies de, additional, Dautzenberg, Bas, additional, Kornips, Esther, additional, Esterline, Russell, additional, Hesselink, Matthijs K.C., additional, Hoeks, Joris, additional, Schrauwen-Hinderling, Vera B., additional, Havekes, Bas, additional, Oscarsson, Jan, additional, Phielix, Esther, additional, and Schrauwen, Patrick, additional

Published
2022
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28. Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection

Author

Lindeboom, Lucas, Nabuurs, Christine I., Hoeks, Joris, Brouwers, Bram, Phielix, Esther, Kooi, M. Eline, Hesselink, Matthijs K.C., Wildberger, Joachim E., Stevens, Robert D., Koves, Timothy, Muoio, Deborah M., Schrauwen, Patrick, and Schrauwen-Hinderling, Vera B.

Subjects
Acetyl-L-carnitine -- Physiological aspects -- Research, Nuclear magnetic resonance spectroscopy -- Usage, Muscles -- Physiological aspects -- Research, Health care industry
Abstract

Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. Here, we investigated the use of long-echo time (TE) proton magnetic resonance spectroscopy (¹H-MRS) to measure skeletal muscle acetylcarnitine concentrations on a clinical 3T scanner. We applied long-TE 1H-MRS to measure acetylcarnitine in endurance-trained athletes, lean and obese sedentary subjects, and type 2 diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE ¹H-MRS protocol was implemented for successful detection of skeletal muscle acetylcarnitine in these individuals. There were pronounced differences in insulin sensitivity, as measured by hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial function, as measured by phosphorus-MRS ([sup.31]P-MRS), across groups. Insulin sensitivity and mitochondrial function were highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with mean acetylcarnitine concentration correlating with mean insulin sensitivity in each group. These results demonstrate that measuring acetylcarnitine concentrations with ¹H-MRS is feasible on clinical MR scanners and support the hypothesis that T2DM patients are characterized by a decreased formation of acetylcarnitine, possibly underlying decreased insulin sensitivity., Introduction The use of proton magnetic resonance spectroscopy ('H-MRS) in human skeletal muscle has been instrumental in establishing the importance of ectopic fat accumulation in the development of type 2 [...]

Published
2014
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30. Evidence for a Direct Effect of the NAD+ Precursor Acipimox on Muscle Mitochondrial Function in Humans

Author

van de Weijer, Tineke, Phielix, Esther, Bilet, Lena, Williams, Evan G., Ropelle, Eduardo R., Bierwagen, Alessandra, Livingstone, Roshan, Nowotny, Peter, Sparks, Lauren M., Paglialunga, Sabina, Szendroedi, Julia, Havekes, Bas, Moullan, Norman, Pirinen, Eija, Hwang, Jong-Hee, Schrauwen-Hinderling, Vera B., Hesselink, Matthijs K.C., Auwerx, Johan, Roden, Michael, and Schrauwen, Patrick

Published
2015
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34. Athletes feature greater rates of muscle glucose transport and glycogen synthesis during lipid infusion

Author

Phielix, Esther, Phielix, Esther, Begovatz, Paul, Gancheva, Sofiya, Bierwagen, Alessandra, Kornips, Esther, Schaart, Gert, Hesselink, Matthijs K. C., Schrauwen, Patrick, Roden, Michael, Phielix, Esther, Phielix, Esther, Begovatz, Paul, Gancheva, Sofiya, Bierwagen, Alessandra, Kornips, Esther, Schaart, Gert, Hesselink, Matthijs K. C., Schrauwen, Patrick, and Roden, Michael

Abstract

BACKGROUND. Insulin resistance results from impaired skeletal muscle glucose transport/phosphorylation, linked to augmented lipid availability. Despite greater intramuscular lipids, athletes are highly insulin sensitive, which could result from higher rates of insulin-stimulated glycogen synthesis or glucose transport/phosphorylation and oxidation. Thus, we examined the time course of muscle glycogen and glucose-6-phosphate concentrations during low and high systemic lipid availability.METHODS. Eight endurance-trained and 9 sedentary humans (VO2 peak: 56 +/- 2 vs. 33 +/- 2 mL/kg/min, P <0.05) underwent 6-hour hyperinsulinemic-isoglycemic clamp tests with infusions of triglycerides or saline in a randomized crossover design. Glycogen and glucose-6-phosphate concentrations were monitored in vastus lateralis muscles using C-13/P-31 magnetic resonance spectroscopy.RESULTS. Athletes displayed a 25% greater (P<0.05) insulin-stimulated glucose disposal rate (Rd) than sedentary participants. During Intralipid infusion, insulin sensitivity remained higher in the athletes (Delta Rd: 25 +/- 3 vs.17 +/- 3 mu mol/kg/min, P<0.05), supported by higher glucose transporter type 4 protein expression than in sedentary humans. Compared to saline infusion, AUC of glucose-6-phosphate remained unchanged during Intralipid infusion in athletes (1.6 +/- 0.2 mmol/L vs.1.4 +/- 0.2 [mmol/L] x h, P = n.s.) but tended to decrease by 36% in sedentary humans (1.7 +/- 0.4 vs.1.1 +/- 0.1 [mmol/L] x h, P<0.059). This drop was accompanied by a 72% higher rate of net glycogen synthesis in the athletes upon Intralipid infusion (47 +/- 9 vs.13 +/- 3 mu mol/kg/min, P <0.05).CONCLUSION. Athletes feature higher skeletal muscle glucose disposal and glycogen synthesis during increased lipid availability, which primarily results from maintained insulin-stimulated glucose transport with increased myocellular glucose-6-phosphate levels for subsequent glycogen synthesis.

Published
2019

35. Metabolic responses to mild cold acclimation in type 2 diabetes patients

Author

Remie, Carlijn M.E., Moonen, Michiel P.B., Roumans, Kay H.M., Nascimento, Emmani B.M., Gemmink, Anne, Havekes, Bas, Schaart, Gert, Kornips, Esther, Joris, Peter J., Schrauwen-Hinderling, Vera B., Hoeks, Joris, Kersten, Sander, Hesselink, Matthijs K.C., Phielix, Esther, van Marken Lichtenbelt, Wouter D., Schrauwen, Patrick, Remie, Carlijn M.E., Moonen, Michiel P.B., Roumans, Kay H.M., Nascimento, Emmani B.M., Gemmink, Anne, Havekes, Bas, Schaart, Gert, Kornips, Esther, Joris, Peter J., Schrauwen-Hinderling, Vera B., Hoeks, Joris, Kersten, Sander, Hesselink, Matthijs K.C., Phielix, Esther, van Marken Lichtenbelt, Wouter D., and Schrauwen, Patrick

Abstract

Mild cold acclimation for 10 days has been previously shown to markedly improve insulin sensitivity in patients with type 2 diabetes. Here we show in a single-arm intervention study (Trialregister.nl ID: NL4469/NTR5711) in nine patients with type 2 diabetes that ten days of mild cold acclimation (16–17 °C) in which observable, overt shivering was prevented, does not result in improved insulin sensitivity, postprandial glucose and lipid metabolism or intrahepatic lipid content and only results in mild effects on overnight fasted fat oxidation, postprandial energy expenditure and aortic augmentation index. The lack of marked metabolic effects in this study is associated with a lack of self-reported shivering and a lack of upregulation of gene expression of muscle activation or muscle contraction pathways in skeletal muscle and suggests that some form of muscle contraction is needed for beneficial effects of mild cold acclimation.

Published
2021

36. Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial

Author

Op den Kamp, Yvo J.M., primary, de Ligt, Marlies, additional, Dautzenberg, Bas, additional, Kornips, Esther, additional, Esterline, Russell, additional, Hesselink, Matthijs K.C., additional, Hoeks, Joris, additional, Schrauwen-Hinderling, Vera B., additional, Havekes, Bas, additional, Oscarsson, Jan, additional, Phielix, Esther, additional, and Schrauwen, Patrick, additional

Published
2021
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42. Therapeutic Efficiency of Lowering Branched-Chain Amino Acid Levels in Patients with Type 2 Diabetes Using Sodium-Phenylbutyrate: A Randomized Placebo Controlled Clinical Intervention Study

Author

Vanweert, Froukje, primary, Neinast, Michael, additional, Tapia, Edmundo Erazo, additional, van de Weijer, Tineke, additional, Hoeks, Joris, additional, Schrauwen-Hinderling, Vera B., additional, Blair, Megan C., additional, Bornstein, Marc R., additional, Hesselink, Matthijs K.C., additional, Schrauwen, Patrick, additional, Arany, Zoltan, additional, and Phielix, Esther, additional

Published
2021
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45. L-carnitine infusion does not alleviate lipid-induced insulin resistance and metabolic inflexibility

Author

Bruls, Yvonne M. H., primary, op den Kamp, Yvo J. M., additional, Phielix, Esther, additional, Lindeboom, Lucas, additional, Havekes, Bas, additional, Schaart, Gert, additional, Moonen-Kornips, Esther, additional, Wildberger, Joachim E., additional, Hesselink, Matthijs K. C., additional, Schrauwen, Patrick, additional, and Schrauwen-Hinderling, Vera B., additional

Published
2020
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46. 1263-P: Nutritional Reprogramming of Hepatic Metabolism by Feeding a Diet Containing Large, Phospholipid-Coated Lipid Droplets in Early Life Protects against Western Style Diet–Induced Insulin Resistance in Adult Mice

Author

JELENIK, TOMAS, primary, KODDE, ANDREA, additional, PESTA, DOMINIK, additional, ROHBECK, ELISABETH, additional, DEWIDAR, BEDAIR, additional, PHIELIX, ESTHER, additional, OOSTING, ANNEMARIE, additional, VAN DER BEEK, ELINE M., additional, and RODEN, MICHAEL, additional

Published
2020
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50. Postexercise changes in myocellular lipid droplet characteristics of young lean individuals are affected by circulatory nonesterified fatty acids.

Author

Daemen, Sabine, van Polanen, Nynke, Bilet, Lena, Phielix, Esther, Moonen-Kornips, Esther, Schrauwen-Hinderling, Vera B., Schrauwen, Patrick, and Hesselink, Matthijs K. C.

Subjects
FREE fatty acids, ACTIVE recovery, LIPIDS, SURFACE coatings, CONFOCAL microscopy
Abstract

Intramyocellular lipid (IMCL) content is an energy source during acute exercise. Nonesterified fatty acid (NEFA) levels can compete with IMCL utilization during exercise. IMCL content is stored as lipid droplets (LDs) that vary in size, number, subcellular distribution, and in coating with LD protein PLIN5. Little is known about how these factors are affected during exercise and recovery. Here, we aimed to investigate the effects of acute exercise with and without elevated NEFA levels on intramyocellular LD size and number, intracellular distribution and PLIN5 coating, using high-resolution confocal microscopy. In a crossover study, 9 healthy lean young men performed a 2-h moderate intensity cycling protocol in the fasted (high NEFA levels) and glucose-fed state (low NEFA levels). IMCL and LD parameters were measured at baseline, directly after exercise and 4 h postexercise. We found that total IMCL content was not changed directly after exercise (irrespectively of condition), but IMCL increased 4 h postexercise in the fasting condition, which was due to an increased number of LDs rather than changes in size. The effects were predominantly detected in type I muscle fibers and in LDs coated with PLIN5. Interestingly, subsarcolemmal, but not intermyofibrillar IMCL content, was decreased directly after exercise in the fasting condition and was replenished during the 4 h recovery period. In conclusion, acute exercise affects IMCL storage during exercise and recovery, particularly in type I muscle fibers, in the subsarcolemmal region and in the presence of PLIN5. Moreover, the effects of exercise on IMCL content are affected by plasma NEFA levels. [ABSTRACT FROM AUTHOR]

Published
2021
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