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  • 1.
    Barbarroja, Nuria
    et al.
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Rodriguez-Cuenca, Sergio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Camargo, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Lipids and Atherosclerosis Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Pirraco, Ana
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
    Relat, Joana
    Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
    Cuadrado, Irene
    Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.
    Pellegrinelli, Vanessa
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lopez-Pedrera, Chary
    Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
    Tinahones, Francisco J.
    CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Investigación Biomédica de Málaga, Hospital Virgen de la Victoria, Malaga, Spain.
    Symons, J. David
    College of Health, University of Utah, Salt Lake City UT, United States; Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City UT, United States.
    Summers, Scott A.
    Program in Cardiovascular and Metabolic Disorders, Duke-National University, Singapore Graduate Medical School, Singapore, Singapore.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center, Gentofte, Denmark.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 4, p. 1180-1192Article in journal (Refereed)
    Abstract [en]

    Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

  • 2. Barker, Adam
    et al.
    Sharp, Stephen J.
    Timpson, Nicholas J.
    Bouatia-Naji, Nabila
    Warrington, Nicole M.
    Kanoni, Stavroula
    Beilin, Lawrence J.
    Brage, Soren
    Deloukas, Panos
    Evans, David M.
    Grontved, Anders
    Hassanali, Neelam
    Lawlor, Deborah A.
    Lecoeur, Cecile
    Loos, Ruth J. F.
    Lye, Stephen J.
    McCarthy, Mark I.
    Mori, Trevor A.
    Ndiaye, Ndeye Coumba
    Newnham, John P.
    Ntalla, Ioanna
    Pennell, Craig E.
    St Pourcain, Beate
    Prokopenko, Inga
    Ring, Susan M.
    Sattar, Naveed
    Visvikis-Siest, Sophie
    Dedoussis, George V.
    Pahner, Lyle J.
    Froguel, Philippe
    Smith, George Davey
    Ekelund, Ulf
    Örebro University, School of Health and Medical Sciences.
    Wareham, Nicholas J.
    Langenberg, Claudia
    Association of genetic loci with glucose levels in childhood and adolescence a meta-analysis of over 6,000 children2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 6, p. 1805-1812Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-To investigate whether associations of common genetic variants recently identified for fasting glucose or insulin levels in nondiabetic adults are detectable in healthy children and adolescents. RESEARCH DESIGN AND METHODS-A total of 16 single nucleotide polymorphisms (SNPs) associated with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were associated with glucose levels in healthy children and adolescents, with four of these associations reported in previous studies and five reported here for the first time (GLIS3, PROX1, SLC2A2, ADCY5, and CRY2). Effect sizes were similar to those in adults, suggesting age-independent effects of these fasting glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level of 0.026 mrnol/L (0.021-0.031) for each unit increase in the score. CONCLUSIONS-Novel fasting glucose loci identified in genome-wide association studies of adults are associated with altered fasting glucose levels in healthy children and adolescents with effect sizes comparable to adults. In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011

  • 3.
    Carobbio, Stefania
    et al.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Hagen, Rachel M.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lelliott, Christopher J.
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Slawik, Marc
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Endocrine Research Unit, Medizinische Klinik-Innenstadt, Ludwig-Maximilians University, Munich, Germany.
    Medina-Gomez, Gema
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Departamento de Bioquímica, Fisiología y Genética Molecular, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, , Madrid, Spain.
    Tan, Chong-Yew
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Sicard, Audrey
    Laboratory of Obesity, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse, France.
    Atherton, Helen J.
    MRC Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Barbarroja, Nuria
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Hospital Virgen de la Victoria, CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Malaga, Spain.
    Bjursell, Mikael
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Bohlooly-Y, Mohammad
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Virtue, Sam
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Tuthill, Antoinette
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Lefai, Etienne
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Laville, Martine
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Wu, Tingting
    Department of Biosciences, CVGI IMED, AstraZeneca Research and Development, Mölndal, Sweden.
    Considine, Robert V.
    Division of Endocrinology and Metabolism, School of Medicine, Indiana University, Indianapolis IN, United States.
    Vidal, Hubert
    Lyon CarMeN Laboratory, Human Nutrition Research Center, Lyon1 University, Lyon, France.
    Langin, Dominique
    Laboratory of Obesity, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse, France; Laboratory of Clinical Biochemistry, Toulouse, France.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Department of Medicine, Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland.
    Tinahones, Francisco J.
    Departamento de Bioquímica, Fisiología y Genética Molecular, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Madrid, Spain.
    Fernandez-Real, Jose Manuel
    Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, CIBERobn Fisiopatología de la Obesidad y Nutrición, Girona, Spain.
    Griffin, Julian L.
    MRC Human Nutrition Research, Elsie Widdowson Laboratory, University of Cambridge, Cambridge, United Kingdom.
    Sethi, Jaswinder K.
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    López, Miguel
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
    Vidal-Puig, Antonio
    Metabolic Research Laboratories, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 11, p. 3697-3708Article in journal (Refereed)
    Abstract [en]

    The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.

  • 4.
    den Hoed, Marcel
    et al.
    Epidemiol Unit, Inst Metab Sci, Medical Research Council (MRC), Cambridge, England.
    Ekelund, Ulf
    Örebro University, School of Health and Medical Sciences. Epidemiol Unit, Inst Metab Sci, Medical Research Council (MRC), Cambridge, England.
    Brage, Soren
    Epidemiol Unit, Inst Metab Sci, Medical Research Council (MRC), Cambridge, England.
    Grontved, Anders
    Inst Sport Sci & Clin Biomech, Univ So Denmark, Odense, Denmark.
    Zhao, Jing Hua
    Epidemiol Unit, Inst Metab Sci, Medical Research Council (MRC), Cambridge, England.
    Sharp, Stephen J.
    Epidemiol Unit, Inst Metab Sci, Medical Research Council (MRC), Cambridge, England.
    Ong, Ken K.
    Epidemiol Unit, Inst Metab Sci, Medical Research Council (MRC), Cambridge, England.
    Wareham, Nicholas J.
    Epidemiol Unit, Inst Metab Sci, Medical Research Council (MRC), Cambridge, England.
    Loos, Ruth J. F.
    Epidemiol Unit, Inst Metab Sci, Medical Research Council (MRC), Cambridge, England.
    Genetic susceptibility to obesity and related traits in childhood and adolescence influence of loci identified by genome-wide association studies2010In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 11, p. 2980-2988Article in journal (Refereed)
    Abstract [en]

    Objective: Large-scale genome-wide association (GWA) studies have thus far identified 16 loci incontrovertibly associated with obesity-related traits in adults. We examined associations of variants in these loci with anthropometric traits in children and adolescents.

    Research design and methods: Seventeen variants representing 16 obesity susceptibility loci were genotyped in 1,252 children (mean +/- SD age 9.7 +/- 0.4 years) and 790 adolescents (15.5 +/- 0.5 years) from the European Youth Heart Study (EYHS). We tested for association of individual variants and a genetic predisposition score (GPS-17), calculated by summing the number of effect alleles, with anthropometric traits. For 13 variants, summary statistics for associations with BMI were meta-analyzed with previously reported data (N-total = 13,071 children and adolescents).

    Results: In EYHS, 15 variants showed associations or trends with anthropometric traits that were directionally consistent with earlier reports in adults. The meta-analysis showed directionally consistent associations with BMI for all 13 variants, of which 9 were significant (0.033-0.098 SD/allele; P < 0.05). The near-TMEM18 variant had the strongest effect (0.098 SD/allele P = 8.5 x 10(-11)). Effect sizes for BMI tended to be more pronounced in children and adolescents than reported earlier in adults for variants in or near SEC16B, TMEM18, and KCTD15, (0.028-0.035 SD/allele higher) and less pronounced for rs925946 in BDNF (0.028 SD/allele lower). Each additional effect allele in the GPS-17 was associated with an increase of 0.034 SD in BMI (P = 3.6 x 10(-5)), 0.039 SD, in sum of skinfolds (P = 1.7 x 10(-7)), and 0.022 SD in waist circumference (P = 1.7 X 10(-4)), which is comparable with reported results in adults (0.039 SD/allele for BMI and 0.033 SD/allele for waist circumference).

    Conclusions: Most obesity susceptibility loci identified by GWA studies in adults are already associated with anthropometric traits in children/adolescents. Whereas the association of some variants may differ with age, the cumulative effect size is similar. Diabetes 59:2980-2988, 2010

  • 5.
    Goodyear, Laurie J.L
    et al.
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States; Metabolism Section, Joslin Diabetes Center, One Joslin Place, Boston MA, United States.
    Hershman, Michael F.
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States.
    Napoli, Raffaele
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States.
    Calles, Jorge
    Division of Endocrinology, Department of Medicine, University of Vermont, Burlington VT, United States.
    Markuns, Jeffrey F.
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States.
    Ljungqvist, Olle
    Örebro University, School of Medical Sciences. Department of Surgery, Karolinska Hospital and Institute, Stockholm, Sweden.
    Horton, Edward S.
    Research Division, Brigham and Women's Hospital, New England Deaconess Hospital, Boston MA, United States.
    Glucoseingestion causes GLUT4 translocation in human skeletal muscle1996In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 45, no 8, p. 1051-1056Article in journal (Refereed)
    Abstract [en]

    In humans, ingestion of carbohydrates causes an increase in blood glucose concentration, pancreatic insulin release, and increased glucose disposal into skeletal muscle. The underlying molecular mechanism for the increase in glucose disposal in human skeletal muscle after carbohydrate ingestion is not known. We determined whether glucoseingestion increases glucose uptake in human skeletal muscle by increasing the number of glucose transporter proteins at the cell surface and/or by increasing the activity of the glucose transporter proteins in the plasma membrane. Under local anesthesia, approximately 1 g of vastus lateralis muscle was obtained from six healthy subjects before and 60 min after ingestion of a 75-g glucose load. Plasma membranes were isolated from the skeletal muscle and used to measure GLUT4 and GLUT1 content and glucosetransport in plasma membrane vesicles. Glucose ingestion increased the plasma membrane content of GLUT4 per gram muscle (3,524 +/- 729 vs. 4,473 +/- 952 arbitrary units for basal and 60 min, respectively; P < 0.005). Transporter-mediated glucosetransport into plasma membrane vesicles was also significantly increased (130 +/- 11 vs. 224 +/- 38 pmol.mg-1.s-1; P < 0.017), whereas the calculated ratio of glucose transport to GLUT4, an indication of transporter functional activity, was not significantly increased 60 min after glucose ingestion (2.3 +/- 0.4 vs. 3.0 +/- 0.5 pmol.GLUT4 arbitrary units-1.s-1; P < 0.17). These results demonstrate that oral ingestion of glucose increases the rate of glucose transport across the plasma membrane and causes GLUT4 translocation in human skeletal muscle. These findings suggest that under physiological conditions the translocation of GLUT4 is an important mechanism for the stimulation of glucose uptake in human skeletal muscle.

  • 6.
    Hiukka, Anne
    et al.
    Department of Medicine, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland.
    Ståhlman, Marcus
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Pettersson, Camilla
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Levin, Malin
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Adiels, Martin
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Teneberg, Susanne
    Department of Medical Biochemistry and Cell Biology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Leinonen, Eeva S.
    Department of Medicine, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland.
    Hultén, Lillemor Mattsson
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Wiklund, Olov
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Oresic, Matej
    Technical Research Centre of Finland VTT, Espoo, Finland.
    Olofsson, Sven-Olof
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Taskinen, Marja-Riitta
    Department of Medicine, Helsinki University Central Hospital and Biomedicum, Helsinki, Finland.
    Ekroos, Kim
    Zora Biosciences, Espoo, Finland.
    Borén, Jan
    Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory and the Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan2009In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, no 9, p. 2018-2026Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Apolipoprotein CIII (apoCIII) is an independent risk factor for cardiovascular disease, but the molecular mechanisms involved are poorly understood. We investigated potential proatherogenic properties of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes.

    RESEARCH DESIGN AND METHODS: LDL was isolated from control subjects, subjects with type 2 diabetes, and apoB transgenic mice. LDL-biglycan binding was analyzed with a solid-phase assay using immunoplates coated with biglycan. Lipid composition was analyzed with mass spectrometry. Hydrolysis of LDL by sphingomyelinase was analyzed after labeling plasma LDL with [(3)H]sphingomyelin. ApoCIII isoforms were quantified after isoelectric focusing. Human aortic endothelial cells were incubated with desialylated apoCIII or with LDL enriched with specific apoCIII isoforms.

    RESULTS: We showed that enriching LDL with apoCIII only induced a small increase in LDL-proteoglycan binding, and this effect was dependent on a functional site A in apoB100. Our findings indicated that intrinsic characteristics of the diabetic LDL other than apoCIII are responsible for further increased proteoglycan binding of diabetic LDL with high-endogenous apoCIII, and we showed alterations in the lipid composition of diabetic LDL with high apoCIII. We also demonstrated that high apoCIII increased susceptibility of LDL to hydrolysis and aggregation by sphingomyelinases. In addition, we demonstrated that sialylation of apoCIII increased with increasing apoCIII content and that sialylation of apoCIII was essential for its proinflammatory properties.

    CONCLUSIONS: We have demonstrated a number of features of apoCIII-containing LDL from hypertriglyceridemic patients with type 2 diabetes that could explain the proatherogenic role of apoCIII.

  • 7.
    Hyysalo, Jenni
    et al.
    Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Bian, Hua
    Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Leivonen, Marja
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Jaser, Nabil
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Juuti, Anne
    Department of Surgery, Helsinki University Central Hospital, Vantaa, Finland.
    Honka, Miikka-Juhani
    Turku PET Centre, University of Turku, Turku, Finland.
    Nuutila, Pirjo
    Turku PET Centre, University of Turku, Turku, Finland.
    Olkkonen, Vesa M.
    Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Yki-Järvinen, Hannele
    Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
    Circulating triacylglycerol signatures in nonalcoholic fatty liver disease associated with the I148M variant in PNPLA3 and with obesity2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 1, p. 312-322Article in journal (Refereed)
    Abstract [en]

    We examined whether relative concentrations of circulating triacylglycerols (TAGs) between carriers compared with noncarriers of PNPLA3(I148M) gene variant display deficiency of TAGs, which accumulate in the liver because of defective lipase activity. We also analyzed the effects of obesity-associated nonalcoholic fatty liver disease (NAFLD) independent of genotype, and of NAFLD due to either PNPLA3(I148M) gene variant or obesity on circulating TAGs. A total of 372 subjects were divided into groups based on PNPLA3 genotype or obesity. Absolute and relative deficiency of distinct circulating TAGs was observed in the PNPLA3(148MM/148MI) compared with the PNPLA3(148II) group. Obese and 'nonobese' groups had similar PNPLA3 genotypes, but the obese subjects were insulin-resistant. Liver fat was similarly increased in obese and PNPLA3(148MM/148MI) groups. Relative concentrations of TAGs in the obese subjects versus nonobese displayed multiple changes. These closely resembled those between obese subjects with NAFLD but without PNPLA3(I148M) versus those with the I148M variant and NAFLD. The etiology of NAFLD influences circulating TAG profiles. 'PNPLA3 NAFLD' is associated with a relative deficiency of TAGs, supporting the idea that the I148M variant impedes intrahepatocellular lipolysis rather than stimulates TAG synthesis. 'Obese NAFLD' is associated with multiple changes in TAGs, which can be attributed to obesity/insulin resistance rather than increased liver fat content per se.

  • 8. Kelliny, Clara
    et al.
    Ekelund, Ulf
    Örebro University, School of Health and Medical Sciences.
    Andersen, Lars Bo
    Brage, Sören
    Loos, Ruth J. F.
    Wareham, Nicholas J.
    Langenberg, Claudia
    Common genetic determinants of glucose homeostasis in healthy children: the European youth heart study2009In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, no 12, p. 2939-2945Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-The goal of this study was to investigate whether the effects of common genetic variants associated with fasting glucose in adults are detectable in healthy children. RESEARCH DESIGN AND METHODS-Single nucleotide polymorphisms in MTNR1B (rs10830963), G6PC2 (rs560887), and GCK (rs4607517) were genotyped in 2,025 healthy European children aged 9-11 and 14-16 years. Associations with fasting glucose, insulin, homeostasis model assessment (HOMA)-insulin resistance (IR) and HOMA-B were investigated along with those observed for type 2 diabetes variants available in this study (CDKN2A/B, IGF2BP2, CDKAL1, SLC30A8, HHEX-IDE, and Chr 11p12). RESULTS-Strongest associations were observed for G6PC2 and MTNR1B, with mean fasting glucose levels (95% Cl) being 0.084 (0.06-0.11) mmol/l, P = 7.9 x 10(-11) and 0.069 (0.04-0.09) mmol/l, p = 1.9 x 10(-7) higher per risk allele copy, respectively. A similar but weaker trend was observed for GCK (0.028 [-0.006 to 0.06] mmol/l, P = 0.11). All three variants were associated with lower P-cell function (HOMA-B P = 9.38 x 10(-5), 0.004, and 0.04, respectively). SLC30A8 (rs13266634) was the only type 2 diabetes variant associated with higher fasting glucose (0.033 mmol/l [0.01-0.06], P = 0.01). Calculating a genetic predisposition score adding the number of risk alleles of G6PC2, MTNR1B, GCK, and SLC30A8 showed that glucose levels were successively higher in children carrying a greater number of risk alleles (P = 7.1 x 10(-17)), with mean levels of 5.34 versus 4.91 mmol/l comparing children with seven alleles (0.6% of all children) to those with none (0.5%). No associations were found for fasting insulin or HOMA-IR with any of the variants. CONCLUSIONS-The effects of common polymorphisms influencing fasting glucose are apparent in healthy children, whereas the presence of multiple risk alleles amounts to a difference of >1 SD of fasting glucose. Diabetes 58:2939-2945, 2009

  • 9.
    Kolak, Maria
    et al.
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Westerbacka, Jukka
    Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland.
    Velagapudi, Vidya R.
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Wågsäter, Dick
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Makkonen, Janne
    Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Medical Research Institute, Helsinki, Finland.
    Rissanen, Aila
    Obesity Research Unit, University of Helsinki, Helsinki, Finland.
    Häkkinen, Anna-Maija
    Department of Oncology, University of Helsinki, Helsinki, Finland.
    Lindell, Monica
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Bergholm, Robert
    Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland; Minerva Medical Research Institute, Helsinki, Finland.
    Hamsten, Anders
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Fisher, Rachel M.
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Yki-Järvinen, Hannele
    Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden; Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland.
    Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity2007In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, no 8, p. 1960-1968Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.

    RESEARCH DESIGN AND METHODS: A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.

    RESULTS: Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.

    CONCLUSIONS: Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.

  • 10.
    Kotronen, Anna
    et al.
    Department of Medicine, Division of Diabetes, Helsinki, Finland; Minerva Medical Research Institute, Helsinki, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Westerbacka, Jukka
    Department of Medicine, Division of Diabetes, Helsinki, Finland.
    Kiviluoto, Tuula
    Department of Surgery, University of Helsinki, Helsinki, Finland.
    Arola, Johanna
    Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
    Ruskeepää, Anna-Liisa
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Yki-Järvinen, Hannele
    Department of Medicine, Division of Diabetes, Helsinki, Finland.
    Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver2009In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, no 1, p. 203-208Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine whether 1) hepatic ceramide and diacylglycerol concentrations, 2) SCD1 activity, and 3) hepatic lipogenic index are increased in the human nonalcoholic fatty liver.

    RESEARCH DESIGN AND METHODS: We studied 16 subjects with (n = 8) and without (n = 8) histologically determined nonalcoholic fatty liver (NAFL(+) and NAFL(-)) matched for age, sex, and BMI. Hepatic concentrations of lipids and fatty acids were quantitated using ultra-performance liquid chromatography coupled to mass spectrometry and gas chromatography.

    RESULTS: The absolute (nmol/mg) hepatic concentrations of diacylglycerols but not ceramides were increased in the NAFL(+) group compared with the NAFL(-) group. The livers of the NAFL(+) group contained proportionally less long-chain polyunsaturated fatty acids as compared with the NAFL(-) group. Liver fat percent was positively related to hepatic stearoyl-CoA desaturase 1 (SCD1) activity index (r = 0.70, P = 0.003) and the hepatic lipogenic index (r = 0.54, P = 0.030). Hepatic SCD1 activity index was positively related to the concentrations of diacylglycerols (r = 0.71, P = 0.002) but not ceramides (r = 0.07, NS).

    CONCLUSIONS: We conclude that diacylglycerols but not ceramides are increased in NAFL. The human fatty liver is also characterized by depletion of long polyunsaturated fatty acids in the liver and increases in hepatic SCD1 and lipogenic activities.

  • 11.
    Krämer, David Kitz
    et al.
    Department of Surgical Science, Karolinska Institute, Stockholm, Sweden; Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden .
    Al-Khalili, Lubna
    Department of Surgical Science, Karolinska Institute, Stockholm, Sweden; Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Perrini, Sebastio
    Department of Surgical Science, Karolinska Institute, Stockholm, Sweden; Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Skogsberg, Josefin
    Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden .
    Wretenberg, Per
    Department of Surgical Science, Karolinska Institute, Stockholm, Sweden.
    Kannisto, Katja
    Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden .
    Wallberg-Henriksson, Harriet
    Department of Surgical Science, Karolinska Institute, Stockholm, Sweden; Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Ehrenborg, Ewa
    Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden .
    Zierath, Juleen R.
    Department of Surgical Science, Karolinska Institute, Stockholm, Sweden; Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Krook, Anna
    Department of Surgical Science, Karolinska Institute, Stockholm, Sweden; Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; Integrative Physiology, Dept. of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden .
    Direct activation of glucose transport in primary human myotubes after activation of peroxisome proliferator-activated receptor delta2005In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, no 4, p. 1157-1163Article in journal (Refereed)
    Abstract [en]

    Activators of peroxisome proliferator-activated receptor (PPAR)gamma have been studied intensively for their insulin-sensitizing properties and antidiabetic effects. Recently, a specific PPARdelta activator (GW501516) was reported to attenuate plasma glucose and insulin levels when administered to genetically obese ob/ob mice. This study was performed to determine whether specific activation of PPARdelta has direct effects on insulin action in skeletal muscle. Specific activation of PPARdelta using two pharmacological agonists (GW501516 and GW0742) increased glucose uptake independently of insulin in differentiated C2C12 myotubes. In cultured primary human skeletal myotubes, GW501516 increased glucose uptake independently of insulin and enhanced subsequent insulin stimulation. PPARdelta agonists increased the respective phosphorylation and expression of AMP-activated protein kinase 1.9-fold (P < 0.05) and 1.8-fold (P < 0.05), of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) 2.2-fold (P < 0.05) and 1.7-fold (P < 0.05), and of p38 MAPK 1.2-fold (P < 0.05) and 1.4-fold (P < 0.05). Basal and insulin-stimulated protein kinase B/Akt was unaltered in cells preexposed to PPARdelta agonists. Preincubation of myotubes with the p38 MAPK inhibitor SB203580 reduced insulin- and PPARdelta-mediated increase in glucose uptake, whereas the mitogen-activated protein kinase kinase inhibitor PD98059 was without effect. PPARdelta agonists reduced mRNA expression of PPARdelta, sterol regulatory element binding protein (SREBP)-1a, and SREBP-1c (P < 0.05). In contrast, mRNA expression of PPARgamma, PPARgamma coactivator 1, GLUT1, and GLUT4 was unaltered. Our results provide evidence to suggest that PPARdelta agonists increase glucose metabolism and promote gene regulatory responses in cultured human skeletal muscle. Moreover, we provide biological validation of PPARdelta as a potential target for antidiabetic therapy.

  • 12.
    La Torre, Daria
    et al.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Larsson, Helena E.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Ivarsson, Sten A.
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Lernmark, Åke
    Department of Clinical Sciences, Lund University Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Decreased cord-blood phospholipids in young age-at-onset type 1 diabetes2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 11, p. 3951-3956Article in journal (Refereed)
    Abstract [en]

    Children developing type 1 diabetes may have risk markers already in their umbilical cord blood. It is hypothesized that the risk for type 1 diabetes at an early age may be increased by a pathogenic pregnancy and be reflected in altered cord-blood composition. This study used metabolomics to test if the cord-blood lipidome was affected in children diagnosed with type 1 diabetes before 8 years of age. The present case-control study of 76 index children diagnosed with type 1 diabetes before 8 years of age and 76 healthy control subjects matched for HLA risk, sex, and date of birth, as well as the mother's age and gestational age, revealed that cord-blood phosphatidylcholines and phosphatidylethanolamines were significantly decreased in children diagnosed with type 1 diabetes before 4 years of age. Reduced levels of triglycerides correlated to gestational age in index and control children and to age at diagnosis only in the index children. Finally, gestational infection during the first trimester was associated with lower cord-blood total lysophosphatidylcholines in index and control children. In conclusion, metabolomics of umbilical cord blood may identify children at increased risk for type 1 diabetes. Low phospholipid levels at birth may represent key mediators of the immune system and contribute to early induction of islet autoimmunity.

  • 13.
    Medina-Gomez, Gema
    et al.
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Virtue, Sam
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Lelliott, Christopher
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Boiani, Romina
    Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy .
    Campbell, Mark
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Christodoulides, Constantinos
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Perrin, Christophe
    Centre National de la Recherche Scientifique, Paul Sabatier University, Toulouse, France .
    Jimenez-Linan, Mercedes
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Blount, Margaret
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Dixon, John
    Paradigm Therapeutics, Cambridge, U.K.
    Zahn, Dirk
    Paradigm Therapeutics, Cambridge, U.K.
    Thresher, Rosemary R.
    Paradigm Therapeutics, Cambridge, U.K.
    Aparicio, Sam
    Paradigm Therapeutics, Cambridge, U.K.
    Carlton, Mark
    Paradigm Therapeutics, Cambridge, U.K.
    Colledge, William H.
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Kettunen, Mikko I.
    Department of Biochemistry, University of Cambridge, Cambridge, U.K..
    Seppänen-Laakso, Tuulikki
    VTT: Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland.
    Sethi, Jaswinder K.
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    O'Rahilly, Stephen
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    Brindle, Kevin
    Department of Biochemistry, University of Cambridge, Cambridge, U.K..
    Cinti, Saverio
    Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy .
    Oresic, Matej
    VTT: Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland.
    Burcelin, Remy
    Centre National de la Recherche Scientifique, Paul Sabatier University, Toulouse, France .
    Vidal-Puig, Antonio
    Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
    The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-gamma2 isoform2005In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, no 6, p. 1706-1716Article in journal (Refereed)
    Abstract [en]

    The nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) is critically required for adipogenesis. PPARgamma exists as two isoforms, gamma1 and gamma2. PPARgamma2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues, where it is regulated more by nutritional state than PPARgamma1. To elucidate the relevance of the PPARgamma2 in vivo, we generated a mouse model in which the PPARgamma2 isoform was specifically disrupted. Despite similar weight, body composition, food intake, energy expenditure, and adipose tissue morphology, male mice lacking the gamma2 isoform were more insulin resistant than wild-type animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPARgamma2 is not the result of lipodystrophy and suggests a specific role for PPARgamma2 in maintaining insulin sensitivity independently of its effects on adipogenesis. Furthermore, PPARgamma2 knockout mice fed a high-fat diet did not become more insulin resistant than those on a normal diet, despite a marked increase in their mean adipocyte cell size. These findings suggest that PPARgamma2 is required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPARgamma2 may be necessary for the adverse effects of a high-fat diet on carbohydrate metabolism.

  • 14.
    Musi, N.
    et al.
    Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Boston, MA, United States.
    Fujii, N.
    Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Boston, MA, United States.
    Hirschman, M.
    Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Boston, MA, United States.
    Ekberg, I.
    Karolinska Institute, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden.
    Fröberg, S.
    Karolinska Institute, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden.
    Ljungqvist, Olle
    Karolinska Institute, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden; Department of Surgery, Huddinge University Hospital, Huddinge, Sweden.
    Thorell, A.
    Karolinska Institute, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden.
    Goodyear, L.
    Research Division, Joslin Diabetes Center, Brigham and Women's Hospital, Boston, MA, United States; Research Division, Joslin Diabetes Center, One Joslin Place, Boston, United States.
    AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise2001In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 50, no 5, p. 921-927Article in journal (Refereed)
    Abstract [en]

    Insulin-stimulated GLUT4 translocation is impaired in people with type 2 diabetes. In contrast, exercise results in a normal increase in GLUT4 translocation and glucose uptake in these patients. Several groups have recently hypothesized that exercise increases glucose uptake via an insulin-independent mechanism mediated by the activation of AMP-activated protein kinase (AMPK). If this hypothesis is correct, people with type 2 diabetes should have normal AMPK activation in response to exercise. Seven subjects with type 2 diabetes and eight matched control subjects exercised on a cycle ergometer for 45 min at 70% of maximum workload. Biopsies of vastus lateralis muscle were taken before exercise, after 20 and 45 min of exercise, and at 30 min postexercise. Blood glucose concentrations decreased from 7.6 to 4.77 mmol/l with 45 min of exercise in the diabetic group and did not change in the control group. Exercise significantly increased AMPK α2 activity 2.7-fold over basal at 20 min in both groups and remained elevated throughout the protocol, but there was no effect of exercise on AMPK α1 activity. Subjects with type 2 diabetes had similar protein expression of AMPK α1, α2, and β1 in muscle compared with control subjects. AMPK α2 was shown to represent approximately two-thirds of the total a mRNA in the muscle from both groups. In conclusion, people with type 2 diabetes have normal exercise-induced AMPK α2 activity and normal expression of the α1, α2 and β1 isoforms. Pharmacological activation of AMPK may be an attractive target for the treatment of type 2 diabetes.

  • 15.
    Musi, N.
    et al.
    Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
    Hirschman, M. F.
    Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
    Nygren, J.
    Karolinska Institute, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden.
    Svanfeldt, M.
    Department of Surgery, Huddinge University Hospital, Huddinge, Sweden.
    Båvenholm, P.
    Division of Medicine, Karolinska Hospital and Institute, Stockholm, Sweden; Department of Emergency and Cardiovascular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden.
    Rooyackers, O.
    Department of Anesthesiology and Intensive Care, Huddinge University Hospital, Huddinge, Sweden.
    Zhou, G.
    Department of Meta Bolic Disorders, Merck Research Laboratories, Rahway, NJ, United States.
    Williamsson, J. M.
    Department of Meta Bolic Disorders, Merck Research Laboratories, Rahway, NJ, United States.
    Ljungqvist, Olle
    Örebro University, School of Medical Sciences. Örebro University Hospital. Karolinska Institute, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden; Department of Surgery, Huddinge University Hospital, Huddinge, Sweden.
    Efendic, S.
    Division of Molecular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden; Department of Endocrinology, Karolinska Hospital and Institute, Stockholm, Sweden.
    Moller, D. E.
    Department of Meta Bolic Disorders, Merck Research Laboratories, Rahway, NJ, United States.
    Thorell, A.
    Karolinska Institute, Centre of Gastrointestinal Disease, Ersta Hospital, Stockholm, Sweden.
    Goodyear, L. J.
    Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Research Division, Joslin Diabetes Center, One Joslin Place, Boston, United States.
    Metformin increases AMP-activated-protein-kinase activity in skeletal of subjects with type 2 diabetes2002In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 51, no 7, p. 2074-2081Article in journal (Refereed)
    Abstract [en]

    Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK α2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK α2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK α2.

  • 16.
    Oresic, Matej
    et al.
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Gopalacharyulu, Peddinti
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mykkänen, Juha
    Department of Pediatrics, University of Turku, Turku, Finland; Hospital District of Southwest Finland, Turku, Finland.
    Lietzen, Niina
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Mäkinen, Marjaana
    Department of Pediatrics, University of Turku, Turku, Finland; Hospital District of Southwest Finland, Turku, Finland.
    Nygren, Heli
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Simell, Satu
    Department of Pediatrics, University of Turku, Turku, Finland; Hospital District of Southwest Finland, Turku, Finland.
    Simell, Ville
    Department of Pediatrics, University of Turku, Turku, Finland; Hospital District of Southwest Finland, Turku, Finland.
    Hyöty, Heikki
    Department of Virology, School of Medicine, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Veijola, Riitta
    Institute of Clinical Medicine, University of Oulu, Oulu, Finland.
    Ilonen, Jorma
    Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland; Immunogenetics Laboratory, University of Turku, Turku, Finland.
    Sysi-Aho, Marko
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Knip, Mikael
    Children’s Hospital, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland; Folkhälsan Research Center, Helsinki, Finland.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Simell, Olli
    Department of Pediatrics, University of Turku, Turku, Finland; Hospital District of Southwest Finland, Turku, Finland.
    Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes2013In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 9, p. 3268-3274Article in journal (Refereed)
    Abstract [en]

    Previous studies show that children who later progress to type 1 diabetes (T1D) have decreased preautoimmune concentrations of multiple phospholipids as compared with nonprogressors. It is still unclear whether these changes associate with development of β-cell autoimmunity or specifically with clinical T1D. Here, we studied umbilical cord serum lipidome in infants who later developed T1D (N = 33); infants who developed three or four (N = 31) islet autoantibodies, two (N = 31) islet autoantibodies, or one (N = 48) islet autoantibody during the follow-up; and controls (N = 143) matched for sex, HLA-DQB1 genotype, city of birth, and period of birth. The analyses of serum molecular lipids were performed using the established lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry. We found that T1D progressors are characterized by a distinct cord blood lipidomic profile that includes reduced major choline-containing phospholipids, including sphingomyelins and phosphatidylcholines. A molecular signature was developed comprising seven lipids that predicted high risk for progression to T1D with an odds ratio of 5.94 (95% CI, 1.07-17.50). Reduction in choline-containing phospholipids in cord blood therefore is specifically associated with progression to T1D but not with development of β-cell autoimmunity in general.

  • 17. Ortega, Francisco B.
    et al.
    Ruiz, Jonatan R.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health and Medical Sciences.
    Meirhaeghe, Aline
    Gonzalez-Gross, Marcela
    Moreno, Luis A.
    Molnar, Denes
    Kafatos, Anthony
    Gottrand, Frederic
    Widhalm, Kurt
    Labayen, Idoia
    Sjöström, Michael
    Physical Activity Attenuates the Effect of Low Birth Weight on Insulin Resistance in Adolescents Findings From Two Observational Studies2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 9, p. 2295-2299Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-To examine whether physical activity influences the association between birth weight and insulin resistance in adolescents. RESEARCH DESIGN AND METHODS-The study comprised adolescents who participated in two cross-sectional studies: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study (n = 520, mean age = 14.6 years) and the Swedish part of the European Youth Heart Study (EYHS) (n = 269, mean age = 15.6 years). Participants had valid data on birth weight (parental recall), BMI, sexual maturation, maternal education, breastfeeding, physical activity (accelerometry, counts/minute), fasting glucose, and insulin. Insulin resistance was assessed by homeostasis model assessment-insulin resistance (HOMA-IR). Maternal education level and breastfeeding duration were reported by the mothers. RESULTS-There was a significant interaction of physical activity in the association between birth weight and HOMA-IR (logarithmically transformed) in both the HELENA study and the EYHS (P = 0.05 and P = 0.03, respectively), after adjusting for sex, age, sexual maturation, BMI, maternal education level, and breastfeeding duration. Stratified analyses by physical activity levels (below/above median) showed a borderline inverse association between birth weight and HOMA-IR in the low-active group (standardized beta = -0.094, P = 0.09, and standardized beta = -0.156, P = 0.06, for HELENA and EYHS, respectively), whereas no evidence of association was found in the high-active group (standardized beta = -0.031, P = 0.62, and standardized beta = 0.053, P = 0.55, for HELENA and EYHS, respectively). CONCLUSIONS-Higher levels of physical activity may attenuate the adverse effects of low birth weight on insulin sensitivity in adolescents. More observational data, from larger and more powerful studies, are required to test these findings. Diabetes 60:2295-2299, 2011

  • 18.
    Pflueger, Maren
    et al.
    Forschergruppe Diabetes e.V., Helmholtz Center Munich, Neuherberg, Germany.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Suortti, Tapani
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology. VTT Technical Research Centre of Finland, Espoo, Finland.
    Achenbach, Peter
    Forschergruppe Diabetes e.V., Helmholtz Center Munich, Neuherberg, Germany; Institute of Diabetes Research, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
    Bonifacio, Ezio
    Deutsche Forschungsgemeinschaft (DFG), Center for Regenerative Therapies Dresden (CRTD)-Cluster of Excellence, Biotechnologisches Zentrum, Dresden, Germany.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Ziegler, Anette-G
    Forschergruppe Diabetes e.V., Helmholtz Center Munich, Neuherberg, Germany; Institute of Diabetes Research, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
    Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 11, p. 2740-2747Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Islet autoimmunity precedes type 1 diabetes and often initiates in childhood. Phenotypic variation in islet autoimmunity relative to the age of its development suggests heterogeneous mechanisms of autoimmune activation. To support this notion, we examined whether serum metabolite profiles differ between children with respect to islet autoantibody status and the age of islet autoantibody development.

    RESEARCH DESIGN AND METHODS: The study analyzed 29 metabolites of amino acid metabolism and 511 lipids assigned to 12 lipid clusters in children, with a type 1 diabetic parent, who first developed autoantibodies at age 2 years or younger (n = 13), at age 8 years or older (n = 22), or remained autoantibody-negative, and were matched for age, date of birth, and HLA genotypes (n = 35). Ultraperformance liquid chromatography and mass spectroscopy were used to measure metabolites and lipids quantitatively in the first autoantibody-positive and matched autoantibody-negative serum samples and in a second sample after 1 year of follow-up.

    RESULTS: Differences in the metabolite profiles were observed relative to age and islet autoantibody status. Independent of age-related differences, autoantibody-positive children had higher levels of odd-chain triglycerides and polyunsaturated fatty acid-containing phospholipids than autoantibody-negative children and independent of age at first autoantibody appearance (P < 0.0001). Consistent with our hypothesis, children who developed autoantibodies by age 2 years had twofold lower concentration of methionine compared with those who developed autoantibodies in late childhood or remained autoantibody-negative (P < 0.0001).

    CONCLUSIONS: Distinct metabolic profiles are associated with age and islet autoimmunity. Pathways that use methionine are potentially relevant for developing islet autoantibodies in early infancy.

  • 19.
    Prawitt, Janne
    et al.
    University of Lille Nord de France, Lille, France; Institut national de la santé et de la recherche médicale (INSERM), unité mixte de recherche (UMR)1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Abdelkarim, Mouaadh
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Stroeve, Johanna H. M.
    Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen, Netherlands.
    Popescu, Iuliana
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Duez, Helene
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Velagapudi, Vidya R
    Dumont, Julie
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Bouchaert, Emmanuel
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    van Dijk, Theo H.
    Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen, Netherlands.
    Lucas, Anthony
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Dorchies, Emilie
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Daoudi, Mehdi
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Lestavel, Sophie
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Gonzalez, Frank J
    Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda MD, United States.
    Oresic, Matej
    Örebro University, School of Medical Sciences. VTT Technical Research Centre of Finland, Espoo, Finland.
    Cariou, Bertrand
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France; NSERM U915, Nantes, France; Faculty of Medicine, University of Nantes, Thorax Institute, Nantes, France; Clinic of Endocrinology, University Hospital Center Nantes, Nantes, France.
    Kuipers, Folkert
    Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen, Netherlands.
    Caron, Sandrine
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Staels, Bart
    University of Lille Nord de France, Lille, France; INSERM UMR1011, Lille, France; UDSL, Lille, France; Institut Pasteur de Lille, Lille, France.
    Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 7, p. 1861-1871Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.

    RESEARCH DESIGN AND METHODS: Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity.

    RESULTS: FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism.

    CONCLUSIONS: Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.

  • 20.
    Prieur, Xavier
    et al.
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Institut du Thorax, Institut National de la Santé et de la Recherche Médicale U915, Nantes, France.
    Mok, Crystal Y. L.
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Velagapudi, Vidya R
    Technical Research Centre of Finland (VTT), Espoo, Finland.
    Núñez, Vanessa
    Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Fuentes, Lucía
    Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Montaner, David
    Department of Bioinformatics and Genomics, Functional Genomics Node (INB) at CIPF, Centro de Investigación Príncipe Felipe (CIFP), Valencia, Spain.
    Ishikawa, Ko
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Camacho, Alberto
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Barbarroja, Nuria
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    O'Rahilly, Stephen
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Sethi, Jaswinder K
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Dopazo, Joaquin
    Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Oresic, Matej
    Örebro University, School of Medical Sciences. Technical Research Centre of Finland (VTT), Espoo, Finland.
    Ricote, Mercedes
    Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
    Vidal-Puig, Antonio
    Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
    Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 3, p. 797-809Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response.

    RESEARCH DESIGN AND METHODS: We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment.

    RESULTS: We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization.

    CONCLUSIONS: Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

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