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The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI dIrECT study (vol 63, pg 744, 2020)

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dIABETOLOGIA 2021年第1期64卷 260-261页

作者： Koivula, robert W. Atabaki-Pasdar, Naeimeh Giordano, Giuseppe N. White, Tom Adamski, Jerzy Bell, Jimmy d. Beulens, Joline Brage, Soren Brunak, Soren de Masi, Federico dermitzakis, Emmanouil T. Forgie, Ian M. Frost, Gary Hansen, Torben Hansen, Tue H. Hattersley, Andrew Kokkola, Tarja Kurbasic, Azra Laakso, Markku Mari, Andrea Mcdonald, Timothy J. Pedersen, Oluf rutters, Femke Schwenk, Jochen M. Teare, Harriet J. A. Thomas, E. Louise Vinuela, Ana Mahajan, Anubha McCarthy, Mark I. ruetten, Hartmut Walker, Mark Pearson, Ewan Pavo, Imre Franks, Paul W. Lund Univ Skane Univ Hosp Malmo Dept Clin Sci Genet & Mol Epidemiol CRC Bldg 91Level 12Jan Waldenstroms Gata 35 SE-20502 Malmo Sweden Univ Oxford Radcliffe Dept Med Oxford Ctr Diabet Endocrinol & Metab Oxford England Univ Cambridge Sch Clin Med MRC Epidemiol Unit Cambridge England German Res Ctr Environm Hlth Helmholtz Zentrum Munchen Genome Anal Ctr Res Unit Mol Endocrinol & Metab Neuherberg Germany Tech Univ Munich Lehrstuhl Expt Genet Freising Weihenstephan Germany Natl Univ Singapore Yong Loo Lin Sch Med Dept Biochem Singapore Singapore Univ Westminister Dept Life Sci Res Ctr Optimal Hlth London England Univ Amsterdam Locat VU Univ Amsterdam Publ Hlth Res Inst Dept Epidemiol & BiostatMed Ctr Amsterdam Netherlands Univ Southern Denmark Fac Hlth Sci Odense Denmark Univ Copenhagen Novo Nordisk Fdn Ctr Prot Res Copenhagen Denmark Tech Univ Denmark Dept Bio & Hlth Informat Lyngby Denmark Univ Geneva Med Sch Dept Genet Med & Dev Geneva Switzerland Univ Geneva Inst Genet & Genom Geneva iGE3 Geneva Switzerland Swiss Inst Bioinformat Geneva Switzerland Univ Dundee Ninewells Hosp Sch Med Populat Hlth & Genom Dundee Scotland Imperial Coll London Div Diabet Endocrinol & Metab Dept Med Nutr & Dietet Res Grp Hammersmith Campus London England Univ Copenhagen Fac Hlth & Med Sci Novo Nordisk Fdn Ctr Basic Metab Res Copenhagen Denmark Univ Exeter Med Sch NIHR Exeter Clin Res Facil Exeter Devon England Univ Exeter Med Sch Inst Biomed & Clin Sci Exeter Devon England Univ Eastern Finland Dept ofMedicine Kuopio Finland Kuopio Univ Hosp Kuopio Finland CNR Inst Neurosci Padua Italy KTH Royal Inst Technol Affin Prote Sci Life Lab Stockholm Sweden Univ Oxford Nuffield Dept Populat Hlth HeLEX Old Rd Campus Oxford England Univ Oxford Wellcome Ctr Human Genet Oxford England Churchill Hosp NIHR Oxford Biomed Res Ctr Oxford England Genentech Inc Human Genet South San Francisco CA USA Sanofi Aventis Deutschland GmbH R&D Frankfurt G

Unfortunately, 'Present address' was omitted from one of the addresses provided for Mark I. McCarthy (#26).

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Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI dIrECT study

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CELL rEPOrTS MEdICINE 2022年第1期3卷 100477-100477页

作者： Wesolowska-Andersen, Agata Brorsson, Caroline A. Bizzotto, roberto Mari, Andrea Tura, Andrea Koivula, robert Mahajan, Anubha Vinuela, Ana Tajes, Juan Fernandez Sharma, Sapna Haid, Mark Prehn, Cornelia Artati, Anna Hong, Mun-Gwan Musholt, Petra B. Kurbasic, Azra de Masi, Federico Tsirigos, Kostas Pedersen, Helle Krogh Gudmundsdottir, Valborg Thomas, Cecilia Engel Banasik, Karina Jennison, Chrisopher Jones, Angus Kennedy, Gwen Bell, Jimmy Thomas, Louise Frost, Gary Thomsen, Henrik Allin, Kristine Hansen, Tue Haldor Vestergaard, Henrik Hansen, Torben rutters, Femke Elders, Petra T'Hart, Leen Bonnefond, Amelie Canouil, Mickael Brage, Soren Kokkola, Tarja Heggie, Alison McEvoy, donna Hattersley, Andrew Mcdonald, Timothy Teare, Harriet ridderstrale, Martin Walker, Mark Forgie, Ian Giordano, Giuseppe N. Froguel, Philippe Pavo, Imre ruetten, Hartmut Pedersen, Oluf dermitzakis, Emmanouil Franks, Paul W. Schwenk, Jochen M. Adamski, Jerzy Pearson, Ewan McCarthy, Mark, I Brunak, Soren Univ Oxford Wellcome Ctr Human Genet Oxford England Tech Univ Denmark Dept Hlth Technol Lyngby Denmark Univ Copenhagen Novo Nordisk Fdn Fac Hlth & Med Sci Ctr Prot Res Copenhagen Denmark CNR Inst Neurosci Padua Italy Univ Geneva Dept Genet Med & Dev Med Sch Geneva Switzerland German Res Ctr Environm Hlth GmbH Res Unit Mol Endocrinol & Metab Helmholtz Zentrum Muenchen Neuherberg Germany KTH Royal Inst Technol Sch Engn Sci Chem Biotechnol & Hlth Sci Life Lab Affin Prote Solna Sweden Sanofi Aventis Deutschland GmbH Translat Med & Clin Pharmacol TMCP R&D Global Dev Frankfurt Germany Lund Univ Clin Sci Malmo Sweden Univ Bath Dept Math Sci Bath Avon England Univ Exeter Med Sch Exeter Devon England Univ Dundee Immunoassay Biomarker Core Lab Shool Med Dundee Scotland Univ Westminster Res Ctr Optimal Hlth Dept Life Sci London Scotland Imperial Coll London Fac Med Sect Nutr Res Hammersmith Campus London Scotland Univ Copenhagen Novo Nordisk Fdn Fac Hlth & Med Sci Ctr Basic Metab Res Copenhagen Denmark Amsterdam UMC Locat VUmc Dept Epidemiol & Biostat Amsterdam Publ Hlth Res Inst Amsterdam Netherlands Amsterdam UMC Locat VUmc Dept Gen Practice Amsterdam Publ Hlth Res Inst Amsterdam Netherlands Leiden Univ Med Ctr Dept Cell & Chem Biol Leiden Netherlands Univ Lille Lille Univ Hosp European Genom Inst Diabet EGID Inst Pasteur LilleINSERM UMR 1283CNRS UMR 8199 Lille France Univ Cambridge MRC Epidemiol Unit Sch Clin Med Cambridge England Univ Eastern Finland Dept Med Kuopio Finland Newcastle Univ Inst Cellular Med Newcastle England Royal Victoria Infirm Diabet Res Network Newcastle England Univ Oxford Fac Law Ctr Hlth Law & Emerging Technol HeLEX Oxford England Newcastle Univ Fac Med Sci Translat & Clin Res Inst Newcastle England Univ Dundee Dundee Scotland Eli Lilly Reg Operat GmbH Vienna Austria Tech Univ Munich Lehrstuhl Expt Genet Freising Weihenstephan Germany Natl Univ Singapore Yong Loo Lin Sch Med Dept Biochem 8 M

The presentation and underlying pathophysiology of type 2 diabetes (T2d) is complex and heterogeneous. recent studies attempted to stratify T2d into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2d based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2d etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired 1 beta cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2d can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments.

关键词： type 2 diabetes patient stratification patient clustering soft-clustering archetypes multi-omics disease progression glycaemic deterioration precision medicine

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The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI dIrECT study

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dIABETOLOGIA 2020年第4期63卷 744-756页

作者： Koivula, robert W. Atabaki-Pasdar, Naeimeh Giordano, Giuseppe N. White, Tom Adamski, Jerzy Bell, Jimmy d. Beulens, Joline Brage, Soren Brunak, Soren de Masi, Federico dermitzakis, Emmanouil T. Forgie, Ian M. Frost, Gary Hansen, Torben Hansen, Tue H. Hattersley, Andrew Kokkola, Tarja Kurbasic, Azra Laakso, Markku Mari, Andrea Mcdonald, Timothy J. Pedersen, Oluf rutters, Femke Schwenk, Jochen M. Teare, Harriet J. A. Thomas, E. Louise Vinuela, Ana Mahajan, Anubha McCarthy, Mark I. ruetten, Hartmut Walker, Mark Pearson, Ewan Pavo, Imre Franks, Paul W. Lund Univ Genet & Mol Epidemiol Skane Univ Hosp Malmo Dept Clin SciCRC Bldg 91Level 12Jan Waldenstroms Gata 35 SE-20502 Malmo Sweden Univ Oxford Radcliffe Dept Med Oxford Ctr Diabet Endocrinol & Metab Oxford England Univ Cambridge Sch Clin Med MRC Epidemiol Unit Cambridge England German Res Ctr Environm Hlth Helmholtz Zentrum Munchen Genome Anal Ctr Res Unit Mol Endocrinol & Metab Neuherberg Germany Tech Univ Munich Lehrstuhl Expt Genet Freising Weihenstephan Germany Natl Univ Singapore Yong Loo Lin Sch Med Dept Biochem Singapore Singapore Univ Westminister Dept Life Sci Res Ctr Optimal Hlth London England Amsterdam Univ Med Ctr Locat VU Univ Med Ctr Amsterdam Publ Hlth Res Inst Dept Epidemiol & Biostat Amsterdam Netherlands Univ Southern Denmark Fac Hlth Sci Odense Denmark Univ Copenhagen Novo Nordisk Fdn Ctr Prot Res Copenhagen Denmark Tech Univ Denmark Dept Bio & Hlth Informat Lyngby Denmark Univ Geneva Sch Med Dept Genet Med & Dev Geneva Switzerland Univ Geneva IGE3 Geneva Switzerland Swiss Inst Bioinformat Geneva Switzerland Univ Dundee Ninewells Hosp Populat Hlth & Genom Sch Med Dundee Scotland Imperial Coll London Nutr & Dietet Res Grp Dept Med Div Diabet Endocrinol & Metab Hammersmith Campus London England Univ Copenhagen Novo Nordisk Fdn Ctr Basic Metab Res Fac Hlth & Med Sci Copenhagen Denmark Univ Exeter Sch Med NIHR Exeter Clin Res Facil Exeter Devon England Univ Exeter Sch Med Inst Biomed & Clin Sci Exeter Devon England Univ Eastern Finland Dept Med Kuopio Finland Kuopio Univ Hosp Kuopio Finland CNR Inst Neurosci Padua Italy KTH Royal Inst Technol Affin Prote Sci Life Lab Stockholm Sweden Univ Oxford Nuffield Dept Populat Hlth HeLEX Old Rd Campus Oxford England Univ Oxford Wellcome Ctr Human Genet Oxford England Churchill Hosp NIHR Oxford Biomed Res Ctr Oxford England Genentech Inc Human Genet San Francisco CA USA Sanofi Aventis Deutschland GmbH R&D Frankfurt Germany Newcastle Univ Inst C

Aims/hypothesis It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative diabetes research on Patient Stratification (IMI dIrECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N <= 920) or with recently diagnosed type 2 diabetes (cohort 2: N <= 435). Methods We defined a structural equation model that describes the TC and fitted this within the IMI dIrECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MrI, and physical activity through wrist-worn triaxial accelerometry. results are presented as standardised beta coefficients, SE and p values, respectively. results The TC and TC-PA models showed better fit than null models (TC: chi(2) = 242, p = 0.004 and chi(2) = 63, p = 0.001 in cohort 1 and 2, respectively;TC-PA: chi(2) = 180, p = 0.041 and chi(2) = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. Conclusions/interpretation These analyses partially support

关键词： Beta cell function Ectopic fat Glycaemic control Insulin sensitivity Physical activity Prediabetes Structural equation modelling Type 2 diabetes

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differences in the timing and magnitude of Pkd1 gene deletion determine the severity of polycystic kidney disease in an orthologous mouse model of AdPKd

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PHYSIOLOGICAL rEPOrTS 2016年第12期4卷 12846-12846页

作者： rogers, Kelly A. Moreno, Sarah E. Smith, Laurie A. Husson, Herve Bukanov, Nikolay O. Ledbetter, Steven r. Budman, Yeva Lu, Yuefeng Wang, Bing Ibraghimov-Beskrovnaya, Oxana Natoli, Thomas A. Sanofi Genzyme R&D Ctr Dept Rare Renal Dis Res 49 New York Ave Framingham MA 02151 USA Sanofi Corp Dept Analyt Res & Dev Waltham MA USA Sanofi Genzyme R&D Ctr Dept Biostat & Programming Framingham MA USA

development of a disease-modifying therapy to treat autosomal dominant polycystic kidney disease (AdPKd) requires well-characterized preclinical models that accurately reflect the pathology and biochemical changes associated with the disease. Using a Pkd1 conditional knockout mouse, we demonstrate that subtly altering the timing and extent of Pkd1 deletion can have a significant impact on the origin and severity of kidney cyst formation. Pkd1 deletion on postnatal day 1 or 2 results in cysts arising from both the cortical and medullary regions, whereas deletion on postnatal days 3-8 results in primarily medullary cyst formation. Altering the extent of Pkd1 deletion by modulating the tamoxifen dose produces dose-dependent changes in the severity, but not origin, of cystogenesis. Limited Pkd1 deletion produces progressive kidney cystogenesis, accompanied by interstitial fibrosis and loss of kidney function. Cyst growth occurs in two phases: an early, rapid growth phase, followed by a later, slow growth period. Analysis of biochemical pathway changes in cystic kidneys reveals dysregulation of the cell cycle, increased proliferation and apoptosis, activation of Mek-Erk, Akt-mTOr, and Wnt-beta-catenin signaling pathways, and altered glycosphingolipid metabolism that resemble the biochemical changes occurring in human AdPKd kidneys. These pathways are normally active in neonatal mouse kidneys until repressed around 3 weeks of age;however, they remain active following Pkd1 deletion. Together, this work describes the key parameters to accurately model the pathological and biochemical changes associated with AdPKd in a conditional mouse model.

关键词： Cell cycle progression cyst growth glycosphingolipid mouse model polycystic kidney disease

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Efficacy and Safety of Alirocumab in Japanese Subjects (Phase 1 and 2 Studies)

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AMErICAN JOUrNAL OF CArdIOLOGY 2016年第1期118卷 56-63页

作者： Teramoto, Tamio Kobayashi, Masahiko Uno, Kiyoko Takagi, Yoshiharu Matsuoka, Osamu Sugimoto, Masayuki Inoue, Satoshi Minami, Fumiko Baccara-dinet, Marie Therese Teikyo Acad Res Ctr Tokyo Japan Sanofi Therapeut Strategy Unit Asia Pacific R&D Tokyo Japan Sanofi Med Operat Primary & Consumer Hlth Care Med Tokyo Japan Sanofi Clin Sci & Operat Biostat & Programming R&DBiostat Tokyo Japan Heishinkai Med Grp Inc ToCROM Clin Tokyo Japan Koganeibashi Sakura Clin Tokyo Japan Heishinaki Med Grp Inc OCROM Clin Osaka Japan Daiwa Hosp Osaka Japan Sanofi Dev & Launch Unit PCSK9 Montpellier France

We assessed the safety and tolerability of ascending single doses of alirocumab in healthy Japanese subjects and evaluated the effect of alirocumab at 3 doses (50, 75, 150 mg) on low density lipoprotein cholesterol (LdL-C) reduction in patients with primary hypercholesterolemia on atorvastatin. A randomized, single ascending-dose study of alirocumab (100, 150, 250, or 300 mg) or placebo (3:1 ratio), administered subcutaneously, was conducted in 32 healthy Japanese men. The phase 2, randomized, double-blind, placebo-controlled, parallel-group study was performed in patients with primary hypercholesterolemia (defined as calculated LdL-C >= 100 mg/dl [2.6 mmol/l]) who were on a stable dose of atorvastatin (5 to 20 mg). Patients were randomized to alirocumab (50, 75, or 150 mg) or placebo (in single 1.0-m1 injection volumes) administered every 2 weeks (Q2W) for 12 weeks;the primary outcome was the mean percent change in calculated LdL-C from baseline to week 12. Single subcutaneous administration of alirocumab in healthy subjects was well tolerated over 15 weeks and resulted in highest mean percent reductions in LdL-C from baseline of approximately 40% to 60%. In the multiple-dose study, least-square mean (SE) changes in calculated LdL-C concentrations from baseline to week 12 were -54.8% (3.1%) for alirocumab 50 mg, -62.3% (3.1%) for alirocumab 75 mg, and -71.7% (3.1%) for alirocumab 150 mg, with a least-square mean (SE) difference versus placebo of -52.2% (4.3%), -59.6% (4.3%), and -69.1% (4.3%), respectively (all p <0.0001). In conclusion, alirocumab was well tolerated and significantly reduced LdL-C concentrations in Japanese patients with primary hypercholesterolemia on atorvastatin. (C) 2016 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-Nd license (http://***/licenses/by-nc-nd/4.0/). (Am J Cardiol 2016;118:56-63)

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discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI dIrECT Consortium

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dIABETOLOGIA 2019年第9期62卷 1601-1615页

作者： Koivula, robert W. Forgie, Ian M. Kurbasic, Azra Vinuela, Ana Heggie, Alison Giordano, Giuseppe N. Hansen, Tue H. Hudson, Michelle Koopman, Anitra d. M. rutters, Femke Siloaho, Maritta Allin, Kristine H. Brage, Soren Brorsson, Caroline A. dawed, Adem Y. de Masi, Federico Groves, Christopher J. Kokkola, Tarja Mahajan, Anubha Perry, Mandy H. rauh, Simone P. ridderstrale, Martin Teare, Harriet J. A. Thomas, E. Louise Tura, Andrea Vestergaard, Henrik White, Tom Adamski, Jerzy Bell, Jimmy d. Beulens, Joline W. Brunak, Soren dermitzakis, Emmanouil T. Froguel, Philippe Frost, Gary Gupta, ramneek Hansen, Torben Hattersley, Andrew Jablonka, Bernd Kaye, Jane Laakso, Markku Mcdonald, Timothy J. Pedersen, Oluf Schwenk, Jochen M. Pavo, Imre Mari, Andrea McCarthy, Mark I. ruetten, Hartmut Walker, Mark Pearson, Ewan Franks, Paul W. Lund Univ Skane Univ Hosp Malmo Genet & Mol Epidemiol Unit Dept Clin SciDiabet CtrCRC Bldg 91Level 10Jan Waldenstroms Gata 35 SE-20502 Malmo Sweden Univ Oxford Radcliffe Dept Med Oxford Ctr Diabet Endocrinol & Metab Oxford England Univ Dundee Med Res Inst Populat Hlth & Genom Dundee DD1 9SY Scotland Univ Geneva Med Sch Dept Genet Med & Dev Geneva Switzerland Univ Geneva Inst Genet & Genom Geneva iGE3 Geneva Switzerland Swiss Inst Bioinformat Geneva Switzerland Newcastle Univ Inst Cellular Med Diabet Newcastle Upon Tyne Tyne & Wear England Univ Copenhagen Fac Hlth & Med Sci Novo Nordisk Fdn Ctr Basic Metab Res Copenhagen Denmark Univ Exeter Med Sch NIHR Exeter Clin Res Facil Exeter Devon England Vrije Univ Amsterdam Med Ctr Amsterdam Publ Hlth Res Inst Dept Epidemiol & Biostat Amsterdam Netherlands Univ Eastern Finland Dept Med Kuopio Finland Kuopio Univ Hosp Kuopio Finland Bispebjerg & Frederiksberg Hosp Dept Clin Epidemiol Copenhagen Denmark Univ Cambridge Sch Clin Med MRC Epidemiol Unit Cambridge England Univ Southern Denmark Fac Hlth Sci Odense Denmark Tech Univ Denmark Dept Bio & Hlth Informat Lyngby Denmark Univ Oxford Wellcome Ctr Human Genet Oxford England Lund Univ Skane Univ Hosp Malmo Clin Obes Dept Clin Sci Malmo Sweden Novo Nordisk AS Soborg Denmark Univ Oxford Nuffield Dept Populat Hlth HeLEX Old Rd Campus Oxford England Univ Westminster Dept Life Sci Res Ctr Optimal Hlth London England CNR Inst Neurosci Padua Italy German Res Ctr Environm Hlth GmbH Helmholtz Zentrum Muenchen Inst Epidemiol 2 Neuherberg Germany Univ Copenhagen Novo Nordisk Fdn Ctr Prot Res Copenhagen Denmark Imperial Coll London Sch Publ Hlth Dept Genom Common Dis London England Univ Lille CNRS Pasteur Inst Lille Lille France Imperial Coll London Div Diabet Endocrinol & Metab Dept Med Nutr & Dietet Res Grp Hammersmith Campus London England Univ Exeter Med Sch Inst Biomed & Clin Sci Exeter Devon England Sanofi Aventis Deuts

Aims/hypothesis Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) diabetes research on Patient Stratification (dIrECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). Methods From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. results Using AdA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- Sd) at baseline: age 62 (6.2) years;BMI 27.9 (4.0) kg/m(2);fasting glucose 5.7 (0.6) mmol/l;2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l;2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following charact

关键词： diet Ectopic fat Genome Glycaemic control Insulin secretion Insulin sensitivity Personalised medicine Physical activity Prediabetes Type 2 diabetes

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Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-dIrECT study

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GENOME MEdICINE 2020年第1期12卷 109-109页

作者： Gudmundsdottir, Valborg Pedersen, Helle Krogh Mazzoni, Gianluca Allin, Kristine H. Artati, Anna Beulens, Joline W. Banasik, Karina Brorsson, Caroline Cederberg, Henna Chabanova, Elizaveta de Masi, Federico Elders, Petra J. Forgie, Ian Giordano, Giuseppe N. Grallert, Harald Gupta, ramneek Haid, Mark Hansen, Torben Hansen, Tue H. Hattersley, Andrew T. Heggie, Alison Hong, Mun-Gwan Jones, Angus G. Koivula, robert Kokkola, Tarja Laakso, Markku Longreen, Peter Mahajan, Anubha Mari, Andrea Mcdonald, Timothy J. McEvoy, donna Musholt, Petra B. Pavo, Imre Prehn, Cornelia ruetten, Hartmut ridderstrale, Martin rutters, Femke Sharma, Sapna Slieker, roderick C. Syed, Ali Tajes, Juan Fernandez Thomas, Cecilia Engel Thomsen, Henrik S. Vangipurapu, Jagadish Vestergaard, Henrik Vinuela, Ana Wesolowska-Andersen, Agata Walker, Mark Adamski, Jerzy Schwenk, Jochen M. McCarthy, Mark, I Pearson, Ewan dermitzakis, Emmanouil Franks, Paul W. Pedersen, Oluf Brunak, Soren Tech Univ Denmark Dept Bio & Hlth Informat Lyngby Denmark Univ Copenhagen Novo Nordisk Fdn Ctr Basic Metab Res Fac Hlth & Med Sci Copenhagen Denmark Univ Copenhagen Novo Nordisk Fdn Ctr Prot Res Fac Hlth & Med Sci Copenhagen Denmark Bispebjerg & Frederiksberg Hosp Ctr Clin Res & Prevent Capital Reg Copenhagen Denmark German Res Ctr Environm Hlth Res Unit Mol Endocrinol & Metab Helmholtz Zentrum Muenchen Neuherberg Germany Amsterdam UMC Dept Epidemiol & Biostat VUmc Amsterdam Publ Hlth Res Inst Amsterdam Netherlands Univ Med Ctr Utrecht Julius Ctr Hlth Sci & Primary Care Utrecht Netherlands Helsinki Univ Hosp Abdominal Ctr Dept Endocrinol Helsinki Finland Copenhagen Univ Hosp Herlev Gentofte Dept Diagnost Radiol Herlev Denmark Amsterdam UMC Dept Gen Practice Locat VUmc Amsterdam Publ Hlth Res Inst Amsterdam Netherlands Univ Dundee Ninewells Hosp Sch Med Dundee Scotland Lund Univ Skane Univ Hosp Lund Univ Diabet Ctr Clin Res CtrGenet & Mol Epidemiol UnitDept Clin Malmo Sweden German Ctr Diabet Res DZD eV Neuherberg Germany Helmholtz Zentrum Munchen Res Unit Mol Epidemiol Inst Epidemiol Neuherberg Germany Helmholtz Zentrum Munchen Clin Cooperat Grp Type 2 Diabet Munich Germany Ludwig Maximilians Univ Munchen Munich Germany Helmholtz Zentrum Munchen Clin Cooperat Grp Nutrigen & Type 2 Diabet Munich Germany Tech Univ Munich Munich Germany Novo Nordisk Res Ctr Oxford Oxford England Univ Southern Denmark Fac Hlth Sci Odense Denmark Slagelse Hosp Dept Cardiol & Endocrinol Slagelse Denmark Univ Exeter Coll Med & Hlth Inst Clin & Biol Sci Exeter Devon England Newcastle Univ Inst Cellular Med Diabet Newcastle Upon Tyne Tyne & Wear England KTH Royal Inst Technol Sch Engn Sci Chem Biotechnol & Hlth Sci Life Lab Affin Prote Solna Sweden Univ Oxford Churchill Hosp Oxford Ctr Diabet Endocrinol & Metab Oxford England Univ Eastern Finland Inst Clin Med Internal Med Kuopio Finland Univ Oxford Wellcome Ctr Human Genet Oxford England CN

Background The rising prevalence of type 2 diabetes (T2d) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2d can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2d. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2d from the IMI-dIrECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2d. Methods Clusters of co-expressed genes were identified in the non-diabetic IMI-dIrECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2d. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-dIrECT cohorts. results We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2d status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals f

关键词： Type 2 diabetes Transcriptomics Co-expression modules Omics data integration

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Analytical and statistical comparability of generic enoxaparins from the US market with the originator product

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JOUrNAL OF PHArMACEUTICAL ANd BIOMEdICAL ANALYSIS 2015年 115卷 431-442页

作者： Mourier, Pierre A. J. Agut, Christophe Souaifi-Amara, Hajer Herman, Frederic Viskov, Christian Sanofi F-94403 Vitry Sur Seine France Sanofi R&D F-34184 Montpellier France Experis IT Life Sci F-92723 Nanterre France Sanofi CMC Biostat & Programming Ctr Rech Vitry Sur Seine F-94403 Vitry Sur Seine France

Low-molecular-weight heparins (LMWHs) are complex anticoagulant drugs, made from heparin porcine mucosa starting material. Enoxaparin sodium manufactured by sanofi is one of the most widely prescribed LMWHs and has been used since 1993 in the USA. In 2010, US Food and drug Administration approval for supplying generic enoxaparin was granted to Sandoz and subsequently to Amphastar. Little is known, however, of the differences in composition of these preparations. In this study, samples from several batches of generic enoxaparins were purchased on the US market and analyzed with state of the art methodologies, including disaccharide building blocks quantification, nuclear magnetic resonance (NMr), and a combination of orthogonal separation techniques. direct high-performance liquid chromatography analysis of the different enoxaparin batches revealed distinct process fingerprints associated with each manufacturer. disaccharide building block analysis showed differences in the degree of sulfation, the presence of glycoserine derivatives, as well as in proportions of disaccharides. results were compared by statistical approaches using multivariate analysis with a partial least squares discriminant analysis methodology. The variations were statistically significant and allowed a clear distinction to be made between the enoxaparin batches according to their manufacturer. These results were further confirmed by orthogonal analytical techniques, including NMr, which revealed compositional differences of oligosaccharides both in low- and high-affinity antithrombin fractions of enoxaparin. (C) 2015 The Authors. Published by Elsevier B.V.

关键词： Analytical comparability disaccharide quantification Enoxaparin Generic Chemometrics Nuclear magnetic resonance

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diabetes as a risk factor for hepatic encephalopathy in cirrhosis patients

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JOUrNAL OF HEPATOLOGY 2015年第5期63卷 1133-1138页

作者： Jepsen, Peter Watson, Hugh Andersen, Per Kragh Vilstrup, Hendrik Aarhus Univ Hosp Dept Gastroenterol & Hepatol DK-8000 Aarhus Denmark Aarhus Univ Hosp Dept Clin Epidemiol DK-8000 Aarhus Denmark Sanofi Aventis R&D Paris France Univ Copenhagen Inst Publ Hlth Dept Biostat Copenhagen Denmark

Background & Aims: It remains unclear whether diabetes increases the risk for hepatic encephalopathy (HE) in cirrhotic patients. We examined this question using data from three randomized trials of satavaptan, a vasopressin receptor antagonist that does not affect HE risk, in cirrhotic patients with ascites. Methods: The trials included 1198 patients, and we excluded those with HE before or at randomization and followed the remaining patients for the one year duration of the trials. They were examined for HE regularly, and we compared rates of first-time overt HE between diabetics and non-diabetic patients using Cox regression, adjusting for gender, age, ascites severity, cirrhosis etiology, Child-Pugh class, creatinine, bilirubin, INr, sodium, potassium, albumin, platelets, lactulose use, benzodiazepine/barbiturate use, spironolactone dose, furosemide dose, potassium-sparing diuretic dose, and CirCom comorbidity score. results: We included 862 patients of whom 193 (22%) had diabetes. In total, they experienced 115 first-time episodes of overt HE during the follow-up. Fewer diabetics than non-diabetic patients were in Child-Pugh class C at baseline (13% vs. 23%), yet they had higher cumulative risk of first-time overt HE (26.0% vs. 15.8% after 1 year), and their episodes of first-time overt HE were more likely to progress beyond grade 2 (64% vs. 42% of episodes progressed to grade 3 or 4, p = 0.01 for independence between diabetes and highest HE grade). After the confounder adjustment, the hazard ratio of first-time overt HE for diabetics vs. non-diabetic patients was 1.86 (95% CI 1.20-2.87). Conclusions: diabetes increased the risk of first-time overt HE among cirrhotic patients with ascites. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

关键词： Hepatic encephalopathy Cirrhosis diabetes mellitus End-stage liver disease Prognosis

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dose-finding studies, MCP-Mod, model selection, and model averaging: Two applications in the real world

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CLINICAL TrIALS 2014年第4期11卷 476-484页

作者： Verrier, dominique Sivapregassam, Sindou Solente, Anne-Catherine Sanofi R&D Biostat & Programming Dept F-34184 Montpellier France Inserm DGOS CIE 802 Ctr Invest Clin Epidemiol Clin Antilles Guyane Guyane France Sanofi R&D Dept Biostat & Programming Paris France

Background Phase II clinical trials are important milestones to determine whether a dose-effect exists and to decide on future doses to use in confirmatory studies. To take into account the overall shape of the dose response curve, modeling the relationship by linear or non-linear models is preferable to the classical pair-wise comparisons of the effect of each dose versus the placebo or the comparator. The multiple comparisons and modeling approach has been developed within the last 10 years to address this important question in the clinical development of drugs. despite some recent publications referring to this methodology, few detailed applications have been shown so far and several practical questions remain to be addressed. Methods Starting from a set of candidate models, model selection using classical methods criteria is possible. However, it suffers some limitations, not taking into account the uncertainty of the selection process itself. An attractive solution is to use model averaging, which applies appropriate weights to the parameters (e.g., the minimum effective dose) obtained from each model. results A discussion of the selection criteria is first presented. Through two real examples, how to proceed with model selection and model averaging is presented and discussed. Limitations The first multiple comparisons and modeling approach papers addressed normal responses. More recently, an extension of this methodology has been proposed to deal with other types of responses, in particular binary, time-to-event and longitudinal data. Questions that remain are concerned with the choice of the candidate models and of their parameters' guesstimates. Conclusions The analysis of clinical dose-finding studies using a modeling of the entire curve offers a promising alternative as compared with the classical multiple comparisons methods, while not compromising the necessary rigor of the analysis.

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