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Childhood obesity: increased risk for cardiometabolic disease and cancer in adulthood

Published:December 05, 2018DOI:https://doi.org/10.1016/j.metabol.2018.12.001

      Highlights

      • Prevalence of childhood obesity has doubled in many countries since 1980.
      • Effects of preventive or therapeutic approaches have been rather small to date.
      • Childhood/adolescent obesity leads to markedly increased morbidity and mortality due to cardiometabolic disease in adulthood.
      • Evidence for strong association between higher body mass index during adolescence and increased cancer risk in adulthood
      • Obesity induces major changes in the cytokine and hormone status of the growing organism.

      Abstract

      Prevalence of childhood obesity has worldwide more than doubled since 1980. Underlying factors are complex and are far from completely understood. Strategies to prevent childhood obesity have mainly focused on behavioral intervention; and obesity therapy was mainly based on lifestyle modification to date. However, effects for both have been quite limited so far and no country has succeeded in fighting the obesity epidemy we are facing.
      Normalization of body weight before onset of puberty is crucial for several reasons: First, obese children and adolescents frequently stay obese until adulthood. Second, obesity during adolescence is significantly associated with increased risk for cardiovascular and metabolic disease such as type 2 diabetes in adulthood. And third, recent data have shown a strong association between higher body mass index (BMI) during adolescence and increased risk for several malignancies such as leukemia, Hodgkin's disease, colorectal cancer, breast cancer and others in adulthood.
      This review summarizes our current understanding of epidemiology, underlying factors, concomitant disease, as well as available intervention strategies and gives an overview of what has been reached so far and what measures should be undertaken to counteract the obesogenic environment.

      Keywords

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      References

        • Eurostat database
        • GBD 2015 Risk Factors Collaborators
        Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015.
        Lancet. 2016; 388: 1659-1724
        • GBD 2015 Obesity Collaborators
        Health effects of overweight and obesity in 195 countries over 25 years.
        N Engl J Med. 2017; 377: 13-26
        • Ng M.
        • Fleming T.
        • Robinson M.
        • et al.
        Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013.
        Lancet. 2014; 384: 766-781
        • Olds T.
        • Maher C.
        • Zumin S.
        • et al.
        Evidence that the prevalence of childhood overweight is plateauing: data from nine countries.
        Int J Pediatr Obes. 2011; 6: 342-360
        • Blüher S.
        • Meigen C.
        • Gausche R.
        • et al.
        Age-specific stabilization in obesity prevalence in German children: a cross-sectional study from 1999 to 2008.
        Int J Pediatr Obes. 2011; 6: e199-e206
        • Lennerz B.S.
        • Moss A.
        • von Schnurbein J.
        • Bickenbach A.
        • Bollow E.
        • Brandt S.
        • et al.
        Do adolescents with extreme obesity differ according to previous treatment seeking behavior? The Youth with Extreme obesity Study (YES) cohort.
        Int J Obes (Lond). 2018; ([Epub ahead of print])https://doi.org/10.1038/s41366-018-0237-4
        • Maximova K.
        • Kuhle S.
        • Davidson Z.
        • Fung C.
        • Veugelers P.J.
        Cardiovascular risk factor profiles of normal and overweight children and adolescents: insights from the Canadian Health Measures Survey.
        Can J Cardiol. 2012; 29: 976-982
        • Berenson G.S.
        Bogalusa Heart Study group. Health consequences of obesity.
        Pediatr Blood Cancer. 2012; 58: 117-121
        • Lauby-Secretan B.
        • Scoccianti C.
        • Loomis D.
        • Grosse Y.
        • Bianchini F.
        • Straif K.
        Body fatness and cancer – viewpoint of the IARC working group.
        N Engl J Med. 2016; 375: 794-798
        • Shamriz O.
        • Leiba M.
        • Levine H.
        • Derazne E.
        • Keinan-Boker L.
        • Kark J.D.
        Higher body mass index in 16–19 year-old Israeli adolescents of North African, Middle Eastern, and European origins is a predictor of acute myeloid leukemia: a cohort of 2.3 million Israelis.
        Cancer Causes Control. 2017; 28: 331-339
        • O'Rahilly S.
        • Farooqi S.I.
        The genetics of obesity in humans. Endotext.com 2005, chapter 8.
        • Mudd L.M.
        • Pivarnik J.M.
        • Pfeiffer K.A.
        • Paneth N.
        • Chung H.
        • Holzman C.
        Maternal physical activity during pregnancy, child leisure-time activity, and child weight status at 3 to 9 years.
        J Phys Act Health. 2015; 12: 506-514
        • Rayfield S.
        • Plugge E.
        Systematic review and meta-analysis of the association between maternal smoking in pregnancy and childhood overweight and obesity.
        J Epidemiol Community Health. 2017; 71: 162-173
        • Tie H.T.
        • Xia Y.Y.
        • Zeng Y.S.
        • Zhang Y.
        • Dai C.L.
        • Guo J.J.
        • et al.
        Risk of childhood overweight or obesity associated with excessive weight gain during pregnancy: a meta-analysis.
        Arch Gynecol Obstet. 2014; 289: 247-257
        • Mamun A.A.
        • Mannan M.
        • Doi S.A.
        Gestational weight gain in relation to offspring obesity over the life course: a systematic review and bias-adjusted meta-analysis.
        Obes Rev. 2014; 15: 338-347
        • Yu Z.B.
        • Han S.P.
        • Zhu G.Z.
        • Zhu C.
        • Wang X.J.
        • Cao X.G.
        • et al.
        Birth weight and subsequent risk of obesity: a systematic review and meta-analysis.
        Obes Rev. 2011; 12: 525-542
        • Oken E.
        • Levitan E.B.
        • Gillman M.W.
        Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis.
        Int J Obes (Lond). 2008; 32: 201-210
        • Lagisz M.
        • Blair H.
        • Kenyon P.
        • Uller T.
        • Raubenheimer D.
        • Nakagawa S.
        • et al.
        Little appetite for obesity: meta-analysis of the effects of maternal obesogenic diets on offspring food intake and body mass in rodents.
        Int J Obes (Lond). 2015; 39: 1669-1678
        • Kuhle S.
        • Tong O.S.
        • Woolcott C.G.
        Association between caesarean section and childhood obesity: a systematic review and meta-analysis.
        Obes Rev. 2015; 16: 295-303
        • Wang J.
        • Wu Y.
        • Xiong G.
        • Chao T.
        • Jin Q.
        • Liu R.
        • et al.
        Introduction of complementary feeding before 4 months of age increases the risk of childhood overweight or obesity: a meta-analysis of prospective cohort studies.
        Nutr Res. 2016; 36: 759-770
        • Lifschitz C.
        Early life factors influencing the risk of obesity.
        Pediatr Gastroenterol Hepatol Nutr. 2015; 18: 217-223
        • Miller S.A.
        • Wu R.K.S.
        • Oremus M.
        The association between antibiotic use in infancy and childhood overweight or obesity: a systematic review and meta-analysis.
        Obes Rev. 2018; 19: 1463-1475
        • Rasmussen S.H.
        • Shrestha S.
        • Bjerregaard L.G.
        • Ängquist L.H.
        • Baker J.L.
        • Jess T.
        • et al.
        Antibiotic exposure in early life and childhood overweight and obesity: a systematic review and meta-analysis.
        Diabetes Obes Metab. 2018; 20: 1508-1514
        • Zhou J.
        • Zhang L.
        • Xuan P.
        • Fan Y.
        • Yang L.
        • Hu C.
        • et al.
        The relationship between famine exposure during early life and body mass index in adulthood: a systematic review and meta-analysis.
        PLoS One. 2018; 13e0192212
        • Li C.
        • Lumey L.H.
        Exposure to the Chinese famine of 1959–61 in early life and long-term health conditions: a systematic review and meta-analysis.
        Int J Epidemiol. 2017; 46: 1157-1170
        • Jerrett M.
        • McConnell R.
        • Wolch J.
        • Chang R.
        • Lam C.
        • Dunton G.
        • et al.
        Traffic-related air pollution and obesity formation in children: a longitudinal, multilevel analysis.
        Environ Health. 2014; 13: 49
        • Swinburn B.A.
        • Sacks G.
        • Hall K.D.
        • et al.
        The global obesity pandemic: shaped by global drivers and local environments.
        Lancet. 2011; 378: 804-814
        • Mei H.
        • Xiong Y.
        • Xie S.
        • Guo S.
        • Li Y.
        • Guo B.
        • et al.
        The impact of long-term school-based physical activity interventions on body mass index of primary school children - a meta-analysis of randomized controlled trials.
        BMC Public Health. 2016; 16: 205
        • Cespedes Feliciano E.M.
        • Quante M.
        • Rifas-Shiman S.L.
        • Redline S.
        • Oken E.
        • Taveras E.M.
        Objective sleep characteristics and cardiometabolic health in young adolescents.
        Pediatrics. 2018; 142
        • Lebourgeois M.K.
        • Hale L.
        • Chang A.M.
        • Akacem L.D.
        • Montgomery-Downs H.E.
        • Buxton O.M.
        Digital media and sleep in childhood and adolescence.
        Pediatrics. 2017; 140: S92-S96
        • Fatima Y.
        • Doi S.A.
        • Mamun A.A.
        Sleep quality and obesity in young subjects: a meta-analysis.
        Obes Rev. 2016; 17: 1154-1166
        • Wu Y.
        • Gong Q.
        • Zou Z.
        • Li H.
        • Zhang X.
        Short sleep duration and obesity among children: a systematic review and meta-analysis of prospective studies.
        Obes Res Clin Pract. 2017; 11: 140-150
        • Thamer C.
        • Machann J.
        • Stefan N.
        • Haap M.
        • Schäfer S.
        • Brenner S.
        • et al.
        High visceral fat mass and high liver fat are associated with resistance to lifestyle intervention.
        Obesity (Silver Spring). 2007; 15: 531-538
        • Schwarz P.E.
        • Greaves C.J.
        • Lindström J.
        • Yates T.
        • Davies M.J.
        Nonpharmacological interventions for the prevention of type 2 diabetes mellitus.
        Nat Rev Endocrinol. 2012; 8: 363-373
        • Polyzos S.A.
        • Kountouras J.
        • Mantzoros C.S.
        Adipokines in nonalcoholic fatty liver disease.
        Metabolism. 2016; 65: 1062-1079
        • Stefan N.
        • Haring H.U.
        The role of hepatokines in metabolism.
        Nat Rev Endocrinol. 2013; 9: 144-152
        • Boutari C.
        • Mantzoros C.S.
        Inflammation: a key player linking obesity with malignancies.
        Metabolism. 2018; 81 ([Epub 2018 Jan]): A3-A6https://doi.org/10.1016/j.metabol.2017.12.015
        • Boutari C.
        • Perakakis N.
        • Mantzoros C.S.
        Association of adipokines with development and progression of nonalcoholic fatty liver disease.
        Endocrinol Metab (Seoul). 2018; 33: 33-43
        • Wiegand S.
        • Keller K.
        • Röbl M.
        • et al.
        Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16,390 overweight or obese children and adolescents.
        Int J Obes (Lond). 2010; 34: 1468-1474
        • Zimmet P.
        • Alberti G.
        • Kaufman F.
        • et al.
        The metabolic syndrome in children and adolescents.
        Lancet. 2007; 369: 2059-2061
        • Blüher S.
        • Molz E.
        • Wiegand S.
        • et al.
        Body mass index, waist circumference, and waist-to-height ratio as predictors of cardiometabolic risk in childhood obesity depending on pubertal development.
        J Clin Endocrin Metab. 2013; 98: 3384-3393
        • Bjerregaard L.F.
        • Jensen B.W.
        • Ängquist L.
        • Osler M.
        • Sorensen T.
        • Baker J.L.
        Change in overweight from childhood to early adulthood and risk for type 2 diabetes.
        N Engl J Med. 2018; 378: 1302-1312
        • Baker J.L.
        • Olsen L.W.
        • Sorensen T.I.A.
        Childhood body-mass index and the risk of coronary heart disease in adulthood.
        N Engl J Med. 2007; 357: 2329-2337
        • Juonala M.
        • Magnussen C.
        • Berenson G.
        • et al.
        Childhood adiposity, adult adiposity, and cardiovascular risk factors.
        N Engl J Med. 2011; 365: 1876-1885
        • Li S.
        • Chen W.
        • Srinivasan S.
        • et al.
        Relation of childhood obesity/cardiometabolic phenotypes to adult cardiometabolic profile: the Bogalusa Heart Study.
        Am J Epidemiol. 2012; 176: S142-S149
        • Tirosh A.
        • Shai I.
        • Afek A.
        • et al.
        Adolescent BMI trajectory and risk of diabetes versus coronary disease.
        N Engl J Med. 2011; 364: 1315-1325
        • Hu Y.
        • Bhupathiraju S.N.
        • de Koning L.
        • Hu F.B.
        Duration of obesity and overweight and risk of type 2 diabetes among US women.
        Obesity (Silver Spring). 2014; 22: 2267-2273
        • Abdullah A.
        • Stoelwinder J.
        • Shortreed S.
        • et al.
        The duration of obesity and the risk of type 2 diabetes.
        Public Health Nutr. 2011; 14: 119-126
        • Twig T.
        • Yaniv G.
        • Levine H.
        • et al.
        Body mass index in 2.3 million adolescents and cardiovascular death in adulthood.
        N Engl J Med. 2016; 374: 2430-2440
        • World Cancer Research Fund (WCRF)
        2014 UK preventability estimates from the.
        ([Last accessed 20.09.2018])
        • Renehan A.G.
        • Soerjomataram I.
        • Tyson M.
        • Egger M.
        • Zwahlen M.
        • Coebergh J.W.
        • et al.
        Incident cancer burden attributable to excess body mass index in 30 European countries.
        Int J Cancer. 2010; 126: 692-702
        • Renehan A.G.
        • Tyson M.
        • Egger M.
        • Heller R.F.
        • Zwahlen M.
        Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.
        Lancet. 2008; 371: 569-578
        • Chen Y.
        • Liu L.
        • Wang X.
        • Wang J.
        • Yan Z.
        • Cheng J.
        • et al.
        Body mass index and risk of gastric cancer: a meta-analysis of a population with more than ten million from 24 prospective studies.
        CEBP. 2013; 22: 1395-1408
        • Castillo J.J.
        • Reagan J.L.
        • Ingham R.R.
        • et al.
        Obesity but not overweight increases the incidence and mortality of leukemia in adults: a meta-analysis of prospective cohort studies.
        Leuk Res. 2012; 36: 868-875
        • Gredner T.
        • Behrens G.
        • Stock C.
        • Brenner H.
        • Mons U.
        Cancers due to infection and selected environmental factors – estimation of the attributable cancer burden in Germany.
        Dtsch Arztebl Int. 2018; 115: 586-593
        • Anderson A.S.
        • Key T.J.
        • Norat T.
        • Scoccianti C.
        • Cecchini M.
        • Berrino F.
        • et al.
        European code against cancer 4th edition: obesity, body fatness and cancer.
        Cancer Epidemiol. 2015; 39/1: 34-45
        • Schillinger D.
        • Ling P.M.
        • Fine S.
        • Boyer C.B.
        • Rogers E.
        • Vargas R.A.
        • et al.
        Reducing cancer and cancer disparities: lessons from a youth-generated diabetes prevention campaign.
        Am J Prev Med. 2017; 53: S103-S113
        • Jefferys M.
        • Smith G.D.
        • Martin R.M.
        • Frankel S.
        • Gunnell D.
        Childhood body mass index and later cancer risk: a 50-year follow-up of the Boyd Orr study.
        Int J Cancer. 2004; 112: 348-353
        • Park M.H.
        • Falconer C.
        • Viner R.M.
        • Kinra S.
        The impact of childhood obesity on morbidity and mortality in adulthood: a systematic review.
        Obes Rev. 2012; 13: 985-1000
        • Leiba M.
        • Leiba A.
        • Keinan-Boker L.
        • et al.
        Adolescent weight and height are predictors of specific non-Hodgkin lymphoma subtypes among a cohort of 2,352,988 individuals aged 16–19 years.
        Cancer. 2016; 122: 1068-1077
        • Levi Z.
        • Kark J.D.
        • Afek A.
        • et al.
        Measured body mass index in adolescence and the incidence of pancreatic cancer in a cohort of 720,000 Jewish men.
        Cancer Causes Control. 2012; 23: 371-378
        • Levi Z.
        • Kark J.D.
        • Shamiss A.
        • et al.
        Body mass index and socioeconomic status measured in adolescence, country of origin, and the incidence of gastroesophageal adenocarcinoma in a cohort of 1 million men.
        Cancer. 2013; 119: 4086-4093
        • Levi Z.
        • Kark J.D.
        • Barchana M.
        • et al.
        Measured body mass index in adolescence and the incidence of colorectal cancer in a cohort of 1.1 million males.
        Cancer Epidemiol Biomarkers Prev. 2011; 20: 2524-2531
        • Leiba A.
        • Kark J.D.
        • Afek A.
        • et al.
        Adolescent obesity and paternal country of origin predict renal cell carcinoma: a cohort study of 1.1 million 16 to 19-year-old males.
        J Urol. 2013; 189: 25-29
        • Poynter J.N.
        • Richardson M.
        • Blair C.K.
        • Roesler M.A.
        • Hirsch B.A.
        • Nguyen P.
        • et al.
        Obesity over the life course and risk of acute myeloid leukemia and myelodysplastic syndromes.
        Cancer Epidemiol. 2016; 40: 134-140
        • NCD-Risk-Factor-Collaboration
        Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults.
        Lancet. 2017; https://doi.org/10.1016/S0140-6736(17)32129-3
        • Waters E.
        • de Silva-Sanigorski A.
        • Hall B.
        • et al.
        Interventions for preventing obesity in children.
        Cochrane Database Syst Rev. 2011; (001810.001002/14651858. CD14001871.pub14651853)CD001871
        • Plachta-Danielzik S.
        • Kehden B.
        • Landsberg B.
        • et al.
        Attributable risks for childhood overweight: evidence for limited effectiveness of prevention.
        Pediatrics. 2012; 130: e865-e871
        • Weihrauch-Blüher S.
        • Kromeyer-Hauschild K.
        • Graf C.
        • Widhalm K.
        • Korsten-Reck U.
        • Jödicke B.
        • et al.
        Current guidelines for obesity prevention in childhood and adolescence.
        Obes Facts. 2018; 11: 263-276
        • World Health Organisation
        Global action plan for the prevention and control of NCDs 2013–2020.
        ([assessed Nov. 26, 2018])
        • Hawkes C.
        • Smith T.G.
        • Jewell J.
        • et al.
        Smart food policies for obesity prevention.
        Lancet. 2015; 385: 2410-2421
        • Roberto C.A.
        • Swinburn B.
        • Hawkes C.
        • et al.
        Patchy progress on obesity prevention: emerging examples, entrenched barriers, and new thinking.
        Lancet. 2015; 385: 2400-2409
        • Sherafat-Kazemzadeh R.
        • Yanovski S.Z.
        • Yanovski J.A.
        Pharmacotherapy for childhood obesity: present and future prospects.
        Int J Obes (Lond). 2013; 37: 1-15
        • Mühlig Y.
        • Wabitsch M.
        • Moss A.
        • et al.
        Weight loss in children and adolescents.
        Dtsch Arztebl Int. 2014; 111: 818-824
        • Oude Luttikhuis H.
        • Baur L.
        • Jansen H.
        • et al.
        Interventions for treating obesity in children.
        Cochrane Database Syst Rev. 2009; CD001872https://doi.org/10.1002/14651858.CD001872.pub2
        • McDonagh M.S.
        • Selph S.
        • Ozpinar A.
        • Foley C.
        Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger.
        JAMA Pediatr. 2014; 168: 178-184
        • Yanovski J.A.
        • Krakoff J.
        • Salaita C.G.
        • et al.
        Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial.
        Diabetes. 2011; 60: 477-485
        • Evia-Viscarra M.L.
        • Rodea-Montero E.R.
        • Apolinar-Jiménez E.
        • et al.
        The effects of metformin on inflammatory mediators in obese adolescents with insulin resistance: controlled randomized clinical trial.
        J Pediatr Endocrinol Metab. 2012; 25: 41-49
        • Gómez-Díaz R.A.
        • Talavera J.O.
        • Pool E.C.
        • et al.
        Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial.
        Metabolism. 2012; 61: 1247-1255
        • Mauras N.
        • Delgiorno C.
        • Hossain J.
        • et al.
        Metformin use in children with obesity and normal glucose tolerance–effects on cardiovascular markers and intrahepatic fat.
        J Pediatr Endocrinol Metab. 2012; 25: 33-40
        • Kendall D.
        • Vail A.
        • Amin R.
        • et al.
        Metformin in obese children and adolescents: the MOCA trial.
        J Clin Endocrinol Metab. 2013; 98: 322-329
        • Pastor-Villaescusa B.
        • Cañete M.D.
        • Caballero-Villarraso J.
        • Hoyos R.
        • Latorre M.
        • Vázquez-Cobela R.
        • et al.
        Metformin for obesity in prepubertal and pubertal children: a randomized controlled trial.
        Pediatrics. 2017; 140: e20164285
        • Astrup A.
        • Rossner S.
        • Van Gaal L.
        • Rissanen A.
        • Niskanen L.
        • Al Hakim M.
        • et al.
        Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study.
        Lancet. 2009; 374: 1606-1616
        • Kelly A.S.
        • Metzig A.M.
        • Rudser K.D.
        • Fitch A.K.
        • Fox C.K.
        • Nathan B.M.
        • et al.
        Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study.
        Obesity (Silver Spring). 2012; 20: 364-370
        • Inge T.H.
        • Laffel L.M.
        • Jenkins T.M.
        • Marcus M.D.
        • Leibel N.I.
        • Brandt M.L.
        • et al.
        Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) consortia. Comparison of surgical and medical therapy for type 2 diabetes in severely obese adolescents.
        JAMA Pediatr. 2018; 172: 452-460
        • Weiss R.
        • Dziura J.
        • Burgert T.S.
        • et al.
        Obesity and the metabolic syndrome in children and adolescents.
        N Engl J Med. 2004; 350: 2362-2374
        • Norat T.
        • Scoccianti C.
        • Boutron-Ruault M.C.
        • et al.
        European code against cancer 4th edition: diet and cancer.
        Cancer Epidemiol. 2015; 39/1: 56-66
        • Leitzmann M.
        • Powers H.
        • Anderson A.S.
        • et al.
        European code against cancer 4th edition: physical activity and cancer.
        Cancer Epidemiol. 2015; 39/1: 46-55
        • Calle E.E.
        • Kaaks R.
        Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms.
        Nat Rev Cancer. 2004; 8: 579-591
        • Gallagher E.J.
        • Leroith D.
        Minireview: IGF, insulin, and cancer.
        Endocrinology. 2011; 152: 2546-2551
        • Thakkar B.
        • Aronis K.N.
        • Vamvini M.T.
        • Shields K.
        • Mantzoros C.S.
        Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies.
        Metabolism. 2013; 62: 922-934
        • Mantovani A.
        • Allavena P.
        • Sica A.
        • Balkwill F.
        Cancer-related inflammation.
        Nature. 2008; 454: 436-444
        • Eckel N.
        • Li Y.
        • Kuxhaus O.
        • Stefan N.
        • Hu F.B.
        • Schulze M.B.
        Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the nurses' health study): 30 year follow-up from a prospective cohort study.
        Lancet Diabetes Endocrinol. 2018; 6: 714-724
        • Schwarz P.E.H.
        • Riemenschneider H.
        Slowing down the progression of type 2 diabetes: we need fair, innovative, and disruptive action on environmental and policy levels!.
        Diabetes Care. 2016; 39: S121-S126