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Sigrid Bjerge Gribsholt Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark

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Morten Schmidt Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

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Eskild Bendix Kristiansen Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark

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Bjørn Richelsen Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

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Henrik Toft Sørensen Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

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-0452 . Declaration of interest SBG has received speaking fees from Novo Nordisk A/S. All other authors declare they have no conflicts of interest. Funding This research was supported by Department of Clinical Epidemiology at Aarhus University Hospital, the

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Yanmei Lou Department of Health Management, Beijing Xiaotangshan Hospital, Beijing, People’s Republic of China

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Yanyan Zhang Department of Epidemiology and Health Statistics, Shenzhen University Health Science Center, Shenzhen, Guangdong, People’s Republic of China

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Ping Zhao Department of Health Management, Beijing Xiaotangshan Hospital, Beijing, People’s Republic of China

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Pei Qin Department of Epidemiology and Health Statistics, Shenzhen University Health Science Center, Shenzhen, Guangdong, People’s Republic of China

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Changyi Wang Department of Non-communicable Disease Prevention and Control, Shenzhen Nanshan Center for Chronic Disease, Shenzhen, Guangdong, People’s Republic of China

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Jianping Ma Department of Non-communicable Disease Prevention and Control, Shenzhen Nanshan Center for Chronic Disease, Shenzhen, Guangdong, People’s Republic of China

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Xiaolin Peng Department of Non-communicable Disease Prevention and Control, Shenzhen Nanshan Center for Chronic Disease, Shenzhen, Guangdong, People’s Republic of China

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Hongen Chen Department of Non-communicable Disease Prevention and Control, Shenzhen Nanshan Center for Chronic Disease, Shenzhen, Guangdong, People’s Republic of China

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Dan Zhao Department of Non-communicable Disease Prevention and Control, Shenzhen Nanshan Center for Chronic Disease, Shenzhen, Guangdong, People’s Republic of China

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Shan Xu Department of Non-communicable Disease Prevention and Control, Shenzhen Nanshan Center for Chronic Disease, Shenzhen, Guangdong, People’s Republic of China

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Li Wang Department of Non-communicable Disease Prevention and Control, Shenzhen Nanshan Center for Chronic Disease, Shenzhen, Guangdong, People’s Republic of China

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Ming Zhang Department of Epidemiology and Health Statistics, Shenzhen University Health Science Center, Shenzhen, Guangdong, People’s Republic of China

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Dongsheng Hu Department of Epidemiology and Health Statistics, Shenzhen University Health Science Center, Shenzhen, Guangdong, People’s Republic of China

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Fulan Hu Department of Epidemiology and Health Statistics, Shenzhen University Health Science Center, Shenzhen, Guangdong, People’s Republic of China

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regression dilution in long-term follow-up of prospective studies . American Journal of Epidemiology 1999 150 341 – 353 . ( https://doi.org/10.1093/oxfordjournals.aje.a010013 ) 19 Geva M Shlomai G Berkovich A Maor E Leibowitz A Tenenbaum A

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Yunyi Ding Department of Nephrology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou, China

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Siyao Lv Department of Gastroenterology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, Hangzhou, China

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Ruijie Xie Division of Clinical Epidemiology and Aging Research, University of Heidelberg, Heidelberg, Germany

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Wei Ye Department of Gastroenterology, Hangzhou TCM Hospital, Hangzhou, China

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Yichen Luo School of Mechanical Engineering, Zhejiang University, Hangzhou, China

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Yayu Li Department of Nephrology, Hangzhou TCM Hospital, Hangzhou, China

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levels equal to or surpassing 6.5%, or the administration of pharmacological agents for diabetes management. The eGFR was ascertained by employing the Chronic Kidney Disease Epidemiology Collaboration algorithm ( 30 ). DKD is defined as diabetes with the

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Clemens Kamrath Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany

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Alexander Eckert German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University, Ulm, Germany

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Birgit Rami-Merhar Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria

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Sebastian Kummer Department of General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich Heine University, Medical Faculty, Duesseldorf, Germany

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Martin Wabitsch Center for Rare Endocrine Diseases, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, Ulm University Medical Centre, Ulm, Germany

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Katharina Laubner Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany

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Florian Kopp Forth Clinical Department of Medicine, Academic Teaching Hospital Augsburg, Augsburg, Germany

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Silvia Müther Center for Pediatric Diabetology, DRK-Kliniken-Berlin Westend, Berlin, Germany

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Steffen Mühldorfer Department for Gastroenterology, Endocrinology and Metabolic Diseases, Bayreuth University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Bayreuth, Germany

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Reinhard W Holl German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany
Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University, Ulm, Germany

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software (clinical data managers, Institute of Epidemiology and Medical Biometry (ZIBMT), Ulm University, Ulm, Germany). The authors wish to thank all centers contributing to this analysis: Augsburg IV. Med. Uni-Klinik, Bad Mergentheim

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Marie Auzanneau Institute of Epidemiology and Medical Biometry, ZIBMT, Medical Faculty of Ulm University, Ulm, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany

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Alexander J Eckert Institute of Epidemiology and Medical Biometry, ZIBMT, Medical Faculty of Ulm University, Ulm, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany

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Andreas Fritsche German Center for Diabetes Research (DZD), Neuherberg, Germany
Department of Internal Medicine IV, University Hospital Tübingen, Germany
Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany

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Martin Heni Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
Division of Endocrinology and Diabetology, Department of Internal Medicine 1, University Hospital Ulm, Ulm, Germany
Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany

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Andrea Icks German Center for Diabetes Research (DZD), Neuherberg, Germany
Institute of Health Services Research and Health Economics, Center for Health and Society, Faculty of Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Institute of Health Services Research and Health Economics, German Diabetes Center (DDZ), Leibniz Centre for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

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Annabel S Mueller-Stierlin Department of General Practice and Primary Care, University Hospital Ulm, Um, Germany
Department of Psychiatry and Psychotherapy II, University Hospital Ulm, Um, Germany

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Ana Dugic Department of Gastroenterology, Klinikum Bayreuth, Medizincampus Oberfranken der Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Bayreuth, Germany

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Alexander Risse Diabetes Center at Sophie-Charlotte-Platz, Diabetes Foot Unit, Berlin, Germany

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Stefanie Lanzinger Institute of Epidemiology and Medical Biometry, ZIBMT, Medical Faculty of Ulm University, Ulm, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany

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Reinhard W Holl Institute of Epidemiology and Medical Biometry, ZIBMT, Medical Faculty of Ulm University, Ulm, Germany
German Center for Diabetes Research (DZD), Neuherberg, Germany

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, Institute of Epidemiology and Medical Biometry, University of Ulm) and Mrs J. Loske (Research Data Center of the German Federal Statistical Office, Destatis). References 1 Sun H Saeedi P Karuranga S Pinkepank M Ogurtsova K Duncan BB

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Chengnan Guo Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Yixi Xu Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Yange Ma Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Xin Xu Wenzhou Medical University, Wenzhou, Zhejiang, China

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Fang Peng Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Hui-hui Li Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Dongzhen Jin Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Shu-zhen Zhao Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Zhezheng Xia Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Mengyuan Lai Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Mingzhu Che Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Ruogu Huang Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Yanan Wang Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Depeng Jiang Department of Community Health Sciences, College of Medicine, University of Manitoba, Winnipeg, Canada

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Chao Zheng The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

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Guangyun Mao Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China
Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
National Clinical Research Center for Ocular Diseases, Wenzhou, Zhejiang, China

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Although previous studies demonstrate that trehalose can help maintain glucose homeostasis in healthy humans, its role and joint effect with glutamate on diabetic retinopathy (DR) remain unclear. We aimed to comprehensively quantify the associations of trehalose and glutamate with DR. This study included 69 pairs of DR and matched type 2 diabetic (T2D) patients. Serum trehalose and glutamate were determined via ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry system. Covariates were collected by a standardized questionnaire, clinical examinations and laboratory assessments. Individual and joint association of trehalose and glutamate with DR were quantified by multiple conditional logistic regression models. The adjusted odds of DR averagely decreased by 86% (odds ratio (OR): 0.14; 95% CI: 0.06, 0.33) with per interquartile range increase of trehalose. Comparing with the lowest quartile, adjusted OR (95% CI) were 0.20 (0.05, 0.83), 0.14 (0.03, 0.63) and 0.01 (<0.01, 0.05) for participants in the second, third and fourth quartiles of trehalose, respectively. In addition, as compared to their counterparts, T2D patients with lower trehalose (<median) and higher glutamate (≥median) had the highest odds of DR (OR: 36.81; 95% CI: 6.75, 200.61). An apparent super-multiplicative effect of trehalose and glutamate on DR was observed, whereas relative excess risk due to interaction was not significant. The study suggests that trehalose is beneficial to inhibit the occurrence of DR and synergistically decreases the risk of DR with reduced glutamate. Our findings also provide new insights into the mechanisms of DR and further longitudinal studies are required to confirm these findings.

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Robert Maidstone Oxford Centre for Diabetes, Endocrinology and Metabolism, and Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

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Martin K Rutter Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK

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Thomas Marjot Oxford Centre for Diabetes, Endocrinology and Metabolism, and Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
Oxford Liver Unit, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, UK

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David W Ray Oxford Centre for Diabetes, Endocrinology and Metabolism, and Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
NIHR Oxford Health Biomedical Research Centre, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK

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Matthew Baxter Oxford Centre for Diabetes, Endocrinology and Metabolism, and Oxford Kavli Centre for Nanoscience Discovery, University of Oxford, Oxford, UK
NIHR Oxford Health Biomedical Research Centre, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK

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Fazel Y Henry L & Wymer M . Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes . Hepatology 2016 64 73 – 84 . ( https://doi.org/10.1002/hep.28431 ) 2 European Association

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Wang-shu Liu Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China

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Ling-yan Hua Department of Ophthalmology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China

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Su-xiang Zhu Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China

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Feng Xu Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China

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Xue-qin Wang Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China

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Chun-feng Lu Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China

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Jian-bin Su Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China

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Feng Qi Emergency Intensive Care Unit, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China

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-based HPLC method in a hemoglobin analysis system (D-10, Bio-Rad) was adopted to measure glycosylated hemoglobin (HbA1c) levels. The estimated glomerular filtration rate (eGFR) was calculated based on the Chronic Kidney Disease Epidemiology Collaboration

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Yi Chen Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

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Wen Zhang Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

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Chi Chen Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

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Yuying Wang Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

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Ningjian Wang Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

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Yingli Lu Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

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using the following equations according to a previous study ( 18 ): BMI was calculated as weight in kilograms divided by height in meters squared. The eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation

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Philippe Jean-Luc Gradidge Centre for Exercise Science and Sports Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

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Nicole G Jaff Department of Chemical Pathology, National Health Laboratory Service, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

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Shane A Norris SAMRC/Wits Developmental Pathways for Health Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
Global Health Research Institute, School of Human Development and Health, University of Southampton, Southampton, UK

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Marketa Toman Department of Chemical Pathology, National Health Laboratory Service, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

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Nigel J Crowther Department of Chemical Pathology, National Health Laboratory Service, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

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-induced hypoadiponectinaemia: the opposite influences of central and peripheral fat compartments . International Journal of Epidemiology 2017 46 2044 – 2055 . ( https://doi.org/10.1093/ije/dyx022 ) 12 Turer AT Khera A Ayers CR Turer CB Grundy SM Vega GL Scherer

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