Endocrine

, Volume 48, Issue 2, pp 371–393 | Cite as

Prediabetes and associated disorders

  • Martin Buysschaert
  • José Luís Medina
  • Michael Bergman
  • Avni Shah
  • Jaqueline Lonier
Review

Abstract

Prediabetes represents an elevation of plasma glucose above the normal range but below that of clinical diabetes. Prediabetes includes individuals with IFG, IGT, IFG with IGT and elevated HbA1c levels. Insulin resistance and β-cell dysfunction are characteristic of this disorder. The diagnosis of prediabetesis is vital as both IFG and IGT are indeed well-known risk factors for type 2 diabetes with a greater risk in the presence of combined IFG and IGT. Furthermore, as will be illustrated in this review, prediabetes is associated with associated disorders typically only considered in with established diabetes. These include cardiovascular disease, periodontal disease, cognitive dysfunction, microvascular disease, blood pressure abnormalities, obstructive sleep apnea, low testosterone, metabolic syndrome, various biomarkers, fatty liver disease, and cancer. As the vast majority of individuals with prediabetes are unaware of their diagnosis, it is therefore vital that the associated conditions are identified, particularly in the presence of mild hyperglycemia, so they may benefit from early intervention.

Keywords

Prediabetes Cardiovascular disease Testosterone deficiency Cognitive dysfunction Nonalcoholic fatty liver disease Cancer 

References

  1. 1.
    M. Buysschaert, M. Bergman, Definition of prediabetes. Med. Clin. N. Am. 95(2), 289–297 (2011)PubMedGoogle Scholar
  2. 2.
    K. Færch, K. Borch-Johnsen, J.J. Holst, A. Vaag, Pathophysiology and aetiology of impaired fasting glycemia and impaired glucose tolerance: does it matter for prevention and treatment of type 2 diabetes? Diabetologia 52, 1714–1723 (2009)PubMedGoogle Scholar
  3. 3.
    R.A. DeFronzo, M.A. Ghani, Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am. J. Cardiol. 108(Suppl), 3B–24B (2011)PubMedGoogle Scholar
  4. 4.
    M. Buysschaert, M. Bergman, Diagnosis of prediabetes and diabetes prevention, in Prevention of Diabetes, 1st edn., ed. by P. Schwarz, P. Reddy (Wiley, New York, 2013)Google Scholar
  5. 5.
    M. Buysschaert, V. Preumont, J.L. Medina, M. Bergman, Global Health Perspectives in Prediabetes and Diabetes (World Scientific Publishing, Hackensack, 2014)Google Scholar
  6. 6.
    H. Gerstein, P. Santaguida, P. Raina, K. Morrison, C. Balion, D. Hunt, H. Yazdi et al., Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic review and meta-analysis of prospective studies. Diabetes Res. Clin. Pract. 78, 305–312 (2007)PubMedGoogle Scholar
  7. 7.
    A.G. Tabák, C. Herder, W. Rathmann, E.J. Brunner, M. Kivimäki, Prediabetes: a high-risk state for diabetes development. Lancet 379, 2279–2290 (2012)PubMedCentralPubMedGoogle Scholar
  8. 8.
    E. Ferrannini: Definition of intervention points in prediabetes. Lancet (2014). doi:10.1016/s2213-8587(13)70175-x
  9. 9.
    S.M. Grundy, Pre-diabetes, metabolic syndrome and cardiovascular risk. JACC 59, 635–643 (2012)PubMedGoogle Scholar
  10. 10.
    J.L. Chiasson, S. Bernard, Reducing cardiovascular risk factors in patients with prediabetes. Diabetes Manag. 1(4), 423–438 (2011)Google Scholar
  11. 11.
    L.G. Mellbin, M. Anselmino, R. Lars, Diabetes, prediabetes and cardiovascular risk. Eur. J. Cardiovasc. Prev. Rehabil. 17, S9–S14 (2010)PubMedGoogle Scholar
  12. 12.
    A. Norhammar, A. Tenerz, G. Nilsson, A. Hamsten, S. Effendic, L. Ryden, G. Malmber, Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 359, 2140–2144 (2002)PubMedGoogle Scholar
  13. 13.
    S. Fonville, A.A.M. Zandbergen, S.E. Vermeer, D.W.J. Dippel, P.J. Koudstaal, H.M. den Hertog, Prevalence of prediabetes and newly diagnosed diabetes in patients with a transient ischemic attack or stroke. Cerebrovasc. Dis. 36, 283–289 (2013)PubMedGoogle Scholar
  14. 14.
    W.L. Lee, A.M. Cheung, D. Cape, B. Zinman, Impact of diabetes on coronary artery disease in women and men: a meta-analysis of prospective studies. Diabetes Care 23(7), 962–968 (2000)PubMedGoogle Scholar
  15. 15.
    R. Huxley, F. Barzi, M. Woodward, Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ 332(7533), 73–78 (2006)PubMedCentralPubMedGoogle Scholar
  16. 16.
    Emerging Risk Factors Collaboration, N. Sarwar, P. Gao, S.R. Seshasai, R. Gobin, S. Kaptoge, E. Di Angelantonio et al., Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375, 2215–2222 (2010)Google Scholar
  17. 17.
    E.J. Brunner, M.J. Shipley, D.R. Witte, J.H. Fuller, M.G. Marmot, Relation between blood glucose and coronary mortality over 33 years in the Whitehall Study. Diabetes Care 29(1), 26–31 (2006)PubMedGoogle Scholar
  18. 18.
    B. Balkau, M. Shipley, R.J. Jarrett, K. Pyörälä, M. Pyörälä, A. Forhan, E. Eschwège, High blood glucose concentration is a risk factor mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study. The Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care 21(3), 360–367 (1998)PubMedGoogle Scholar
  19. 19.
    M. Coutinho, H.C. Gerstein, Y. Wang, S. Yusuf, The relationship between glucose and incident cardiovascular events. Diabetes Care 22, 233–240 (1999)PubMedGoogle Scholar
  20. 20.
    E.L. Barr, P.Z. Zimmet, T.A. Welborn, D. Jolley, D.J. Magliano, D.W. Dunstan et al., Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity and lifestyle Study (AusDiab). Circulation 116(2), 151–157 (2007)PubMedGoogle Scholar
  21. 21.
    B. Hoogwerf, D. Spreche, G. Pearce, M. Alevedo, J.P. Frolkis, J.M. Foody et al., Blood glucose concentration ≤125 mg/dl and coronary heart disease risk. Am. J. Cardiol. 89, 556–559 (2002)Google Scholar
  22. 22.
    E.S. Ford, G. Zhao, C. Li, Pre-diabetes and the risk for cardiovascular disease. A systematic review of the evidence. J. Am. Coll. Cardiol. 55, 1310–1317 (2010)PubMedGoogle Scholar
  23. 23.
    E.L.M. Barr, E.J. Boyko, P.Z. Zimmet, R. Wolfe, A.M. Tonkin, J.E. Shaw, Continuous relationship between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and lifestyle (AusDiab) study. Diabetologia 52, 415–424 (2009)PubMedGoogle Scholar
  24. 24.
    E. Selvin, M.W. Steffes, H. Zhu, K. Matsushita, L. Wagenknecht, J. Pankow et al., Glycated hemoglobin, diabetes and cardiovascular risk in non diabetic adults. N. Engl. J. Med. 362(9), 800–811 (2010)PubMedCentralPubMedGoogle Scholar
  25. 25.
    M. Lee, J.L. Saver, K.S. Hong, S. Song, K.H. Chang, B. Ovbiagele, Effect of pre-diabetes on future risk of stroke: meta-analysis. BMJ 344, e3564 (2012). doi:10.1136/bmj.e3564 PubMedCentralPubMedGoogle Scholar
  26. 26.
    A. Di Pino, R. Scicali, S. Calanna, F. Urbano, C. Mantegna, A.M. Rabuazzo et al., Cardiovascular risk profile in subjects with prediabetes and new-onset type 2 diabetes identified by HbA1c according to American Diabetes Association criteria. Diabetes Care 37, 1447–1453 (2014)PubMedGoogle Scholar
  27. 27.
    J. Yeboah, A.G. Bertoni, D.M. Herrington, W.S. Post, G.L. Burke, Impaired fasting glucose and the risk of incident diabetes mellitus and cardiovascular events in an adult population. J. Am. Coll. Cardiol. 58, 140–146 (2001)Google Scholar
  28. 28.
    B. Kowall, W. Rathmann, M. Heier, G. Giani, A. Peters, B. Thorand et al., Categories of glucose tolerance and continuous glycemic measures and mortality. Eur. J. Epidemiol. 26(8), 637–645 (2011)PubMedGoogle Scholar
  29. 29.
    P. Deedwania, K. Patel, G.C. Fonarow, R.V. Desai, Y. Zhang, M.A. Feller et al., Prediabetes is not an independent risk factor for incident heart failure, other cardiovascular events or mortality in older adults: findings from a population-based cohort study. Int. J. Cardiol. 168(4), 3616–3622 (2013)PubMedCentralPubMedGoogle Scholar
  30. 30.
    K. Shaye, T. Amir, S. Shlomo, S. Yechezkel, Fasting glucose levels within the high normal range predict cardiovascular outcome. Am. Heart J. 164, 111–116 (2012)PubMedGoogle Scholar
  31. 31.
    For the DECODE Study Group, F. Ning, J. Tuomilehto, K. Pyörälä, A. Onat, S. Söderberg, Q. Qiao, Cardiovascular disease mortality in Europeans in relation to fasting and 2-h plasma glucose levels within a normoglycemic range. Diabetes Care 33, 2211–2216 (2010)PubMedCentralGoogle Scholar
  32. 32.
    K.T. Khaw, N. Wareham, R. Luben, S. Bingham, S. Oakes, A. Welch, N. Day, Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). BMJ 322, 1–6 (2001)Google Scholar
  33. 33.
    K.T. Khaw, N. Wareham, S. Bingham, R. Luben, A. Welch, N. Day, Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann. Intern. Med. 141(6), 413–420 (2004)PubMedGoogle Scholar
  34. 34.
    H.C. Gerstein, S. Islam, S. Anand, W. Almahmeed, A. Damasceno, A. Dans et al., Dysglycaemia and the risk of acute myocardial infarction in multiple ethnic groups: an analysis of 15,780 patients from the INTERHEART study. Diabetologia 53, 2509–2517 (2010)PubMedGoogle Scholar
  35. 35.
    Q. Qiao, K. Pyörälä, M. Pyörälä, A. Nissinen, J. Lindström, R. Tilvis, J. Tuomilehto, Two-hour glucose is better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose. Eur. Heart J. 23(16), 1267–1275 (2002)PubMedGoogle Scholar
  36. 36.
    The DECODE Study Group, On behalf of the European Diabetes Epidemiology Group, Glucose tolerance and cardiovascular mortality. Comparison of fasting and 2-hour diagnostic criteria. Arch. Intern. Med. 161, 397–404 (2001)Google Scholar
  37. 37.
    S.B. Meigs, D.M. Nathan, R.B. D’Agostino Sr, The Framingham Offspring Study. Fasting and postchallenge glycemic and cardiovascular disease risk. Diabetes Care. 25, 1845–1850 (2002)PubMedGoogle Scholar
  38. 38.
    F. De Vegt, J.M. Dekker, H.G. Ruhé, C.D. Stehouwer, G. Nijpels, L.M. Bouter, R.J. Heine, Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia 42(8), 926–931 (1999)PubMedGoogle Scholar
  39. 39.
    M. Tominaga, H. Eguchi, H. Manaka, K. Igarashi, T. Kato, A. Sekikawa, Impaired glucose tolerance is a risk factor for cardiovascular disease but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 22(6), 920–924 (1999)PubMedGoogle Scholar
  40. 40.
    K. Kato, T. Otsuka, N. Kobayashi, Y. Kon, T. Kawada, Two-hour post-load plasma glucose levels are associated with carotid intima-media thickness in subjects with normal glucose tolerance. Diabet. Med. 31(1), 76–83 (2014)PubMedGoogle Scholar
  41. 41.
    Emerging Risk Factors Collaboration, S.R. Seshasai, S. Kaptoge, A. Thompson, E. Di Angelantonio, P. Gao, N. Sarwar et al., Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364(9), 829–841 (2011)Google Scholar
  42. 42.
    J.A. Laukkanen, T.H. Makikallio, K. Ronkainen, J. Karppi, S. Kurl, Impaired fasting plasma glucose and type 2 diabetes are related to the risk of out-of-hospital sudden cardiac death and all-cause mortality. Diabetes Care 36, 1166–1171 (2012). doi:10.2337/dc12-0110 PubMedGoogle Scholar
  43. 43.
    Y.S. Levitzky, M.J. Pencina, R.B. D’Agostino, J.B. Meigs, J.M. Murabito, R.S. Vasan, C.S. Fox, Impact of impaired fasting glucose on cardiovascular disease. JACC 51, 264–270 (2008)PubMedGoogle Scholar
  44. 44.
    E. Selvin, J. Coresh, S.H. Golden, F.L. Brancati, A.R. Folsom, M.W. Steffes, Glycemic control and coronary heart disease risk in persons with and without diabetes: the atherosclerosis risk in communities study. Arch. Intern. Med. 165(16), 1910–1916 (2005)PubMedGoogle Scholar
  45. 45.
    N. Sarwar, T. Aspelund, G. Eiriksdottir, R. Gobin, S.R. Seshasai, N.G. Forouhi et al., Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik prospective study and systematic review. PLoS Med. 7(5), e1000278 (2010). doi:10.1371/journal.pmed.1000278 PubMedCentralPubMedGoogle Scholar
  46. 46.
    M.V. Skriver, K. Borch-Johnsen, T. Lauritzen, HbA1c as predictor of all-cause mortality in individuals at high risk of diabetes with normal glucose tolerance, identified by screening: a follow-up study of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION), Denmark. Diabetologia 53(11), 2328–2333 (2010)PubMedGoogle Scholar
  47. 47.
    K. Faerch, D. Vistisen, N. Johansen Borup, M.E. Jorgensen, Cardiovascular risk stratifications and management in prediabetes. Curr. Diab. Rep. 14, 493 (2014)PubMedGoogle Scholar
  48. 48.
    S. Kodama, K. Saito, S. Tanaka et al., Fasting and post-challenge glucose as quantitative cardiovascular risk factors: a meta-analysis. J. Atheroscler. Thromb. 19, 385–396 (2012)PubMedGoogle Scholar
  49. 49.
    A.S. Gami, B.J. Witt, D.E. Howard et al., Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J. Am. Coll. Cardiol. 49, 403–414 (2007)PubMedGoogle Scholar
  50. 50.
    S. Mottillo, K.B. Filion, J. Genest et al., The metabolic syndrome and cardiovascular risk : a systematic review and meta-analysis. J. Am. Coll. Cardiol. 56, 1113–1132 (2010)PubMedGoogle Scholar
  51. 51.
    Y. Zhang, E.T. Lee, R.B. Devereux, J. Yeh, L.G. Best, R.R. Fabsitz, B.V. Howard, Prehypertension diabetes and cardiovascular disease risk in a population-based sample: the Strong Heart Study. Hypertension 47, 410–414 (2006)PubMedGoogle Scholar
  52. 52.
    S. Milman, J.P. Crandall, Mechanisms of vascular complications in prediabetes. Med. Clin. N. Am. 95, 309–325 (2011)PubMedGoogle Scholar
  53. 53.
    J. Tuomilehto, J. Lindström, J.G. Eriksson, T.T. Valle, H. Hämäläinen, P. Ilanne-Parikka et al., Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344(18), 1343–1350 (2001)PubMedGoogle Scholar
  54. 54.
    R. Ratner, R. Goldberg, S. Haffner, S. Marcovina, T. Orchard, S. Fowler, Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes Care 28(4), 888–894 (2005)PubMedGoogle Scholar
  55. 55.
    W.C. Knowler, E. Barrett-Connor, S.E. Fowler, R.F. Hammam, J.M. Lachin, E.A. Walker et al., Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346(6), 393–403 (2002)PubMedGoogle Scholar
  56. 56.
    T. Orchard, M. Temprosa, E. Barrett-Connor et al., Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabet. Med. 30, 46–55 (2013)PubMedCentralPubMedGoogle Scholar
  57. 57.
    F.B. Hu, M.J. Stampfer, S.M. Haffner, C.G. Solomon, W.C. Willett, J.E. Manson, Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 25(7), 1129–1134 (2002)PubMedGoogle Scholar
  58. 58.
    J.L. Chiasson, R.G. Josse, R. Gomis, M. Hanefeld, A. Karasik, M. Laakso, Acarbose treatment and risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. The STOP-NIDDM trial. JAMA. 290, 486–494 (2003)PubMedGoogle Scholar
  59. 59.
    E. Lonn, H. Gerstein, P. Sheridan, For the DREAM and STARR Investigations et al., Effect of ramipril and of rosiglitazone on carotid intima-media thickness in people with impaired glucose tolerance or impaired fasting glucose: STARR (Study of Atherosclerosis with Ramipril and Rosiglitazone). J. Am. Coll. Cardiol. 53, 2028–2035 (2009)PubMedGoogle Scholar
  60. 60.
    E.M. Lonn, J. Bosch, R. Diaz, P. Lopez-Jaramillo, A. Ramachandran, N. Hâncu et al., Effect of insulin glargine and n-3FA on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events : the glucose reduction and atherosclerosis continuing evaluation study (ORIGIN-GRACE). Diabetes Care 36(9), 2466–2474 (2013)PubMedCentralPubMedGoogle Scholar
  61. 61.
    I. Hopper, B. Billah, M. Skiba, H. Krum, Prevention of diabetes and reduction in major cardiovascular events in studies of subjects with prediabetes: meta-analysis of randomised controlled clinical trials. Eur. J. Cardiovasc. Prev. Rehabil. 18(6), 813–823 (2011)PubMedGoogle Scholar
  62. 62.
    G. Li, P. Zhang, J. Wang, Y. An, Q. Gong, E.W. Gregg et al., Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet 28, 88–136 (2014). doi:10.1016/s2213-8587(14)70057-9 Google Scholar
  63. 63.
    M. Bergman, M. Buysschaert, P.E.H. Schwarz, A. Albright, V. Narayan, D. Yach, Diabetes prevention: global health policy and perspectives from the ground. Diabetes Manag. 2(4), 309–321 (2012)Google Scholar
  64. 64.
    L. Rydén et al., Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD): ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with EASD. Eur. Heart J. 34, 3035–3087 (2013)PubMedGoogle Scholar
  65. 65.
    American Diabetes Association, Standards of medical care in diabetes—2014. Diabetes Care 37(Suppl. 1), s14 (2014)Google Scholar
  66. 66.
    P.M. Kearney, L. Blackwell, R. Collins, A. Keech, J. Simes, R. Peto et al., Efficacy of cholesterol-lowering therapy in 18.686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371, 117–125 (2008)PubMedGoogle Scholar
  67. 67.
    P.M. Ridker, E. Danielson, F.A. Fonseca et al., JUPITER Study Group: rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359, 2195–2207 (2008)PubMedGoogle Scholar
  68. 68.
    P.M. Preshaw, A.L. Alba, D. Herrera, S. Jepsen, A. Konstantinidis, K. Makrilakis, R. Taylor, Periodontitis and diabetes: a two-way relationship. Diabetelogia 55, 21–31 (2012)Google Scholar
  69. 69.
    F. Javed, A.S.T. Alghamdi, T. Mikami, A. Mehmood, H.B. Ahemed, L.P. Samaranayake, H.C. Tenenbaum, Effect of glycemic control on self-perceived oral health, periodontal parameters, and alveolar bone loss among patients with prediabetes. J. Periodontol. 85, 234–241 (2014)PubMedGoogle Scholar
  70. 70.
    N. Arora, P.N. Papapanou, M. Rosenbaum, D.R. Jacobs Jr, M. Desvarieux, R.T. Demmer, Periodontal infection, impaired fasting glucose and impaired glucose tolerance: results from The Continuous National Health and Nutrition Examination Survey 2009–2010. J. Clin. Periodontol. 41, 643–652 (2014)PubMedGoogle Scholar
  71. 71.
    C.C.P. Andersen, A. Flyvbjerg, K. Buschard, P. Holmstrup, Periodontitis is associated with aggravation of prediabetes in Zucker fatty rats. J. Periodontol. 71, 1625–1631 (2007)Google Scholar
  72. 72.
    M. Manouchehr-Pour, P.J. Spagnuolo, H.M. Rodman, N.F. Bissada, Comparison of neutrophil chemotactic response in diabetic patients with mild and severe periodontal disease. J. Periodontol. 52, 410–415 (1981)PubMedGoogle Scholar
  73. 73.
    M. Altamash, S. Arledal, B. Klinge, P.-E. Engström, Pre-diabetes and diabetes: medical risk factors and periodontal conditions. Acta Odontol. Scand. 71, 1625–1631 (2013)PubMedGoogle Scholar
  74. 74.
    R. McCrimmon, C.M. Ryan, M. Frier, Diabetes and cognitive dysfunction. Lancet 379, 2291–2299 (2012)PubMedGoogle Scholar
  75. 75.
    T. Cukierman-Yaffe, Diabetes, dysglycemia & cognitive dysfunction. Diabetes Metab. Res. Rev. 30(5), 341–345 (2014)PubMedGoogle Scholar
  76. 76.
    D.D. Schwartz, M.E. Axelrad, B.J. Andersen, Neurocognitive function in children and adolescents at the time of type 1 diabetes diagnosis: associations with glycemic control 1 year after diagnosis. Diabetes Care 37(9), 2475–2482 (2014)PubMedGoogle Scholar
  77. 77.
    C. Dufouil, C. Brayne, The continuing challenge of turning promising observational evidence about risk for dementia to evidence supporting prevention. JAMA Intern. Med. 174, 333–335 (2014)PubMedGoogle Scholar
  78. 78.
    P.J.J. Spauwen, C.D.A. Stehouwer, Cognitive decline in type 2 diabetes. Lancet Diabetes Endocrinol. 2, 188–189 (2013). doi:10.1016/S2213-8587(13)70167-0 PubMedGoogle Scholar
  79. 79.
    J.S. Roriz-Filho, T.M. Sá-Roriz, I. Rosset, A.L. Camozzato, A.C. Santos, M.L.F. Chaves, J.C. Moriguti, M. Roriz-Cruz, (Pre)diabetes, brain aging, and cognition. Biochim. Biophys. Acta 1792, 432–443 (2009)Google Scholar
  80. 80.
    R.H. Tuligenga, A. Dugravot, A.G. Tabák, A. Elbaz, E.J. Brunner, M. Kivimäki, A. Singh-Manoux, Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post hoc analysis of the Whitehall II cohort study. Lancet (2013). doi:10.1016/S2213-8587(13)70192-X PubMedGoogle Scholar
  81. 81.
    G.J. Biessels, Intensive glucose lowering and cognition in type 2 diabetes. Lancet Neurol. 10, 949–950 (2011)PubMedGoogle Scholar
  82. 82.
    L. Kerti, A.V. Witte, A. Winkler, U. Grittner, D. Rujescu, A. Flöel, Higher glucose levels associated with lower memory and reduced hippocampal microstructure. Neurology 81, 1746–1753 (2013)PubMedGoogle Scholar
  83. 83.
    C. Anderson et al., Glucose intolerance and diabetes as risk factors for cognitive impairment in people at high cardiovascular risk: results from the ONTARGET/TRANSCEND Research Programme. Diabetes Res. Clin. Pract. 83(3), 387–393 (2009)PubMedGoogle Scholar
  84. 84.
    C.M. Sanz, J.-B. Ruidavets, V. Bongard, J.-C. Marquié, H. Hanaire, J. Ferrières, S. Andrieu, Relationship between markers of insulin resistance, markers of adiposity, HbA1c, and cognitive functions in a middle-aged population-based sample: the MONA LISA Study. Diabetes Care 36(6), 1512–1521 (2013)PubMedCentralPubMedGoogle Scholar
  85. 85.
    Z.S. Tan, A.S. Beiser, C.S. Fox et al., Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study. Diabetes Care 34, 1766–1770 (2011)PubMedCentralPubMedGoogle Scholar
  86. 86.
    M. Nazaribadie, K. Asgari, M. Amini, M. Ahmadpanah, M. Nazarbadie, S. Jamlipaghale, Cognitive processes and functions in patients with type 2 diabetes in comparison to pre-diabetic patients. JRHS 13(2), 208–213 (2013)PubMedGoogle Scholar
  87. 87.
    T. Ohara, Y. Doi, T. Ninomiya et al., Glucose tolerance status and risk off dementia in the community: the Hisayama Study. Neurology 77, 1126–1134 (2011)PubMedGoogle Scholar
  88. 88.
    P.K. Crane, R. Walker, R.A. Hubbard, G. Li, D.M. Nathan, H. Zheng, S. Haneuse, S. Craft, T.J. Montine, S.E. Kahn, W. McCormick, S.M. McCurry, J.D. Bowen, E.B. Larson, Glucose levels and risk of dementia. N. Engl. J. Med. 369, 540–548 (2013)PubMedCentralPubMedGoogle Scholar
  89. 89.
    P.G. Lee, C.T. Cigolle, J. Ha, L. Min, S.L. Murphy, C.S. Blaum, W.H. Herman, Physical function limitations among middle-aged and older adults with prediabetes. Diabetes Care 36(10), 3076–3083 (2013)PubMedCentralPubMedGoogle Scholar
  90. 90.
    A.L. Christman, K. Matsushita, R.F. Gottesman, T. Mosley, A. Alonso, J. Coresh, F. Hill-Briggs, A.R. Sharrett, E. Selvin, Glycated haemoglobin and cognitive decline: the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia 54, 1645–1652 (2011)PubMedCentralPubMedGoogle Scholar
  91. 91.
    A.M. Jacobson, Diabetes and cognitive performance: a story that is still unfolding. Diabetologia 54, 1593–1595 (2011)PubMedGoogle Scholar
  92. 92.
    S.G.C. van Elderen, A. deRoos, A.J.M. de Craen et al., Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology 75, 997–1002 (2010)PubMedGoogle Scholar
  93. 93.
    R.O. Roberts, D.S. Knopman, S.A. Przybelski et al., Association of type 2 diabetes with brain atrophy and cognitive impairment. Neurology (2014). doi:10.1212/WNL.0000000000000269 Google Scholar
  94. 94.
    G.J. Biessels, S. Staekenborg, E. Brunner, C. Brayne, P. Scheltens, Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 5, 64–74 (2006)PubMedGoogle Scholar
  95. 95.
    R.N. Bryan, M. Bilello, C. Davatzikos, R.M. Lazar, A. Murray, K. Horowitz, J. Lovato, M.E. Miller, J. Williamson, L.J. Launer, Effect of diabetes on brain structure: the action to control cardiovascular risk in diabetes MR imaging baseline data. Radiology 271(1), 210–216 (2014)Google Scholar
  96. 96.
    A. Kleinridders, H.A. Ferris, W. Cai, C.R. Kahn, Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63(7), 2232–2243 (2014)PubMedGoogle Scholar
  97. 97.
    A. Elbaz, M.J. Shipley, H. Nabi, E.J. Brunner, M. Kivimäki, A. Singh-Manoux, Trajectories of the Framingham general cardiovascular risk profile in midlife and poor motor function later in life: The Whitehall II study. Int. J. Cardiol. 172, 96–102 (2014). doi:10.1016/j.ijcard.2013.12.051 PubMedCentralPubMedGoogle Scholar
  98. 98.
    L.J. Launer, M.E. Miller, J.D. Williamson, R.M. Lazar, H.C. Gertsein, A.M. Murray, M. Sullivan, K.R. Horowitz, J. Ding, S. Marcovina, L.C. Lovato, J. Lovato, K.L. Margolis, P. O’Connor, E.E. Lipkin, J. Hirsch, L. Coker, J. Maldjian, J.L. Sunshine, C. Truwit, C. Davatzikos, R.N. Bryan, For the ACCORD MIND investigators, Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND):a randomized open-label substudy. Lancet Neurol. 10, 969–977 (2011)PubMedCentralPubMedGoogle Scholar
  99. 99.
    J.D. Williamson, L.J. Launer, R.N. Bryan, L.H. Coker, R.M. Lazar, H.C. Gerstein, A.M. Murray, M.D. Sullivan, K.R. Horowitz, S. Marcovina, L.C. Lovato, J. Lovato, K.L. Margolis, C. Davatzikos, J. Barzilay, H.N. Ginsberg, P.E. Linz, M.E. Miller, For the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes (MIND) investigators, Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels. JAMA Intern. Med. 174(3), 24–333 (2014)Google Scholar
  100. 100.
    C.D. Saudek, W.H. Herman, D.B. Sacks, R.M. Bergenstal, D. Edelman, M.B. Davidson, A new look at screening and diagnosing diabetes mellitus. J. Clin. Endocrinol. Metab. 93(7), 2447–2453 (2008)PubMedGoogle Scholar
  101. 101.
    S. Ghosh, A. Collier, T. Elhadd, I. Malik, Retinopathy in diabetes. Br. J. Diabetes Vasc. Dis. 10(3), 155–156 (2010)Google Scholar
  102. 102.
    T.Y. Wong, G. Liew, R.J. Tapp, M.I. Schmidt, J.J. Wang, P. Mitchell, R. Klein, B.E. Klein, P. Zimmet, J. Shaw, Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based cross-sectional studies. Lancet 371, 736–743 (2008)PubMedCentralPubMedGoogle Scholar
  103. 103.
    Y.J. Cheng, E.W. Gregg, L.S. Geiss, G. Imperatore, D.E. Williams, X. Zhang, A.L. Albright, C.C. Cowie, R. Klein, J.B. Saaddine, Association of A1c and fating plasma glucose levels with diabetic retinopathy prevalence in the U.S. population. Diabetes Care 32(11), 2027–2032 (2009)PubMedCentralPubMedGoogle Scholar
  104. 104.
    Diabetes Prevention Program Research Group, The prevalence of retinopathy un impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet. Med. 24, 137–144 (2007)PubMedCentralGoogle Scholar
  105. 105.
    T.T. Nguyen, J.J. Wang, T.Y. Wong, Reinal vascular changes in pre-diabetes and prehypertension. Diabetes Care 30(10), 2708–2715 (2007)PubMedGoogle Scholar
  106. 106.
    N. Papanas, A.I. Vinik, D. Ziegler, Neuropathy in prediabetes: does the clovk start ticking early? Nat. Rev. Endocrinol. 7, 682–690 (2011)PubMedGoogle Scholar
  107. 107.
    C.J. Sumner, S. Sheth, J.W. Griffin, D.R. Cornblath, M. Polydefkis, The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 60, 108–111 (2003)PubMedGoogle Scholar
  108. 108.
    B.W.C. Bongaerts, W. Rathmann, M. Heier, B. Kowall, C. Herder, D. Stöckl, C. Meisinger, D. Ziegler, Older subjects with diabetes and prediabetes are frequently unaware of having distal sensorimotor polyneuropathy. Diabetes Care 36(5), 1141–1146 (2013)PubMedCentralPubMedGoogle Scholar
  109. 109.
    L.C. Plantinga, D.C. Crews, J. Coresh, E.R. Miller, R. Saran, J. Yee, E. Hedgeman, M. Pavkov, M.S. Eberhardt, D.E. Williams, N.R. Powe, For the CDC CKD Surveillance team, Prevalence of chronic kidney disease in U.S. adults with undiagnosed diabetes or prediabetes. Clin. J. Am. Soc. Nephrol. 5, 673–682 (2010)PubMedCentralPubMedGoogle Scholar
  110. 110.
    H. Kramer, Screening for kidney disease in adults with diabetes and prediabetes. Curr. Opin. Nephrol. Hypertens. 14, 249–252 (2005)PubMedGoogle Scholar
  111. 111.
    G.C. Curhan, Prediabetes, prehypertension…Is it time for pre-CKD? Clin. J. Am. Soc. Nephrol. 5, 557–559 (2010)PubMedGoogle Scholar
  112. 112.
    O. Schnell, E. Standl, Impaired glucose tolerance, diabetes, and cardiovascular disease. Endocr. Pract. 12(1), 16–19 (2006)PubMedGoogle Scholar
  113. 113.
    E.J. Diamantopoulos, E.A. Andreadis, G.I. Tsourous, P.M. Katsanou, D.X. Georgiopoulos, N.C. Nestora, S.A. Raptis, Early vascular lesions in subjects with metabolic syndrome and prediabetes. Int. Angiol. 25(2), 179–183 (2006)PubMedGoogle Scholar
  114. 114.
    J.B. Meigs, M.G. Larson, R.B. D’Agostino, D. Levy, M.E. Clouse, D.M. Nathan, P.W. Wilson, C.J. O’Donnell, Coronary artery calcification in type 2 diabetes and insulin resistance: the Framingham offspring study. Diabetes Care 25(8), 1313–1319 (2002)PubMedGoogle Scholar
  115. 115.
    M.W. Millar-Craig, C.N. Bishop, E.B. Raftery, Circadian variation of blood-pressure. Lancet 1(8075), 795–797 (1978)PubMedGoogle Scholar
  116. 116.
    A.K. Gupta, F.L. Greenway, G. Cornelissen, W. Pan, F. Halberg, Prediabetes is associated with abnormal circadian blood pressure variability. J. Hum. Hypertens. 22(9), 627–633 (2008)PubMedCentralPubMedGoogle Scholar
  117. 117.
    W.B. White, Relevance of blood pressure variation in the circadian onset of cardiovascular events. J. Hypertens. 21(6), S9–S15 (2003)Google Scholar
  118. 118.
    R.C. Hermida, D.E. Ayala, F. Portaluppi, Circadian variation of blood pressure: the basis for the chronotherapy of hypertension. Adv. Drug Deliv. Rev. 59(9–10), 904–922 (2007)PubMedGoogle Scholar
  119. 119.
    W.B. White, How well does ambulatory blood pressure predict target-organ disease and clinical outcome in patients with hypertension? Blood Press. Monit. 4(2), S17–S21 (1999)PubMedGoogle Scholar
  120. 120.
    O. Torffvit, C.D. Agardh, Day and night variation in ambulatory blood pressure in type 1 diabetes mellitus with nephropathy and autonomic neuropathy. J. Intern. Med. 233(2), 131–137 (1993)PubMedGoogle Scholar
  121. 121.
    F.S. Nielsen, P. Rossing, L.E. Bang, T.L. Svendsen, M.A. Gall, U.M. Smidt, H.H. Parving, On the mechanisms of blunted nocturnal decline in arterial blood pressure in NIDDM patients with diabetic nephropathy. Diabetes 44(7), 783–789 (1995)PubMedGoogle Scholar
  122. 122.
    V. Spallone, M.R. Maiello, R. Morganti, S. Mandica, G. Frajese, Usefulness of ambulatory blood pressure monitoring in predicting the presence of autonomic neuropathy in type I diabetic patients. J. Hum. Hyperten. 21(7), 381–386 (2007)Google Scholar
  123. 123.
    S. Nakano, M. Fukuda, F. Hotta, T. Ito, T. Ishii, M. Kitazawa, M. Nishizawa, T. Kigoshi, K. Uchida, Reversed circadian blood pressure rhythm is associated with occurrence of both fatal and nonfatal vascular events in NIDDM subjects. Diabetes 47(9), 1501–1506 (1998)PubMedGoogle Scholar
  124. 124.
    A.K. Gupta, G. Cornelissen, F.L. Greenway, V. Dhoopati, F. Halberg, W.D. Johnson, Abnormalities in circadian blood pressure variability and endothelial function: pragmatic markers for adverse cardiometabolic profiles in asymptomatic obese adults. Cardiovasc. Diabetol. (2010). doi:10.1186/1475-2840-9-58 PubMedCentralPubMedGoogle Scholar
  125. 125.
    B. Isak, B. Oflazoglu, T. Tanridag, I. Yitmen, O. Us, Evaluation of peripheral and autonomic neuropathy among patients with newly diagnosed impaired glucose tolerance. Diabetes Metab. Res. Rev. 24(7), 563–569 (2008)PubMedGoogle Scholar
  126. 126.
    S. Kumarasamy, K. Gopalakrishnan, D.H. Kim, N.G. Abraham, W.D. Johnson, B. Joe, A.K. Gupta, Dysglyceia induces abnormal circadian blood pressure variability. Cardiovasc. Diabetol. (2011). doi:10.1186/1475-2840-10-104 PubMedCentralPubMedGoogle Scholar
  127. 127.
    Z. Putz, N. Németh, I. Istenes, T. Martos, R.A. Gandhi, A.E. Körei, Z. Hermányi, M. Szathmári, G. Jermendy, S. Tesfaye, Á.G. Tabák, P. Kempler, Autonomic dysfunction and circadian blood pressure variations in people with impaired glucose tolerance. Diabet. Med. 30(3), 358–362 (2013)PubMedGoogle Scholar
  128. 128.
    J.E. Shaw, N.M. Punjabi, J.P. Wilding, K.G. Alberti, P.Z. Zimmet, Sleep-disordered breathing and type 2 diabetes: a report from the International Diabetes Federation Taskforce on Epidemiology and Prevention. Diabetes Res. Clin. Pract. 81(1), 2–12 (2008)PubMedGoogle Scholar
  129. 129.
    S.R. Coughlin, L. Mawdsley, J.A. Mugarza, P.M. Calverley, J.P. Wilding, Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur. Heart J. 25(9), 735–741 (2004)PubMedGoogle Scholar
  130. 130.
    N.M. Punjabi, E. Shahar, S. Redline, D.J. Gottlieb, R. Givelber, H.E. Resnick, Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am. J. Epidemiol. 160(6), 521–530 (2004)PubMedGoogle Scholar
  131. 131.
    S. Seicean, H.L. Kirchner, D.J. Gottlieb, N.M. Punjabi, H. Resnick, M. Sanders, R. Budhiraja, M. Singer, S. Redline, Sleep-disordered breathing and impaired glucose metabolism in normal-weight and overweight/obese individuals: the Sleep Heart Health Study. Diabetes Care 31(5), 1001–1006 (2008)PubMedGoogle Scholar
  132. 132.
    I. Muraki, T. Tanigawa, K. Yamagishi, S. Sakurai, T. Ohira, H. Imano, A. Kitamura, M. Kiyama, S. Sato, T. Shimamoto, M. Konishi, H. Iso, Nocturnal intermittent hypoxia and the development of type 2 diabetes: the Circulatory Risk in Communities Study (CIRCS). Diabetologia 53(3), 481–488 (2010)PubMedGoogle Scholar
  133. 133.
    N. Botros, J. Concato, V. Mohsenin, B. Selim, K. Doctor, H.K. Yaggi, Obstructive sleep apnea as a risk factor for type 2 diabetes. Am. J. Med. 122(12), 1122–1127 (2009)PubMedCentralPubMedGoogle Scholar
  134. 134.
    T. Kendzerska, A.S. Gershon, G. Hawker, G. Tomlinson, R.S. Leung, Obstructive sleep apnea and incident diabetes. A historical cohort study. Am. J. Respir. Crit. Care Med. 190(2), 218–225 (2014)PubMedGoogle Scholar
  135. 135.
    S. Pamidi, E. Tasali, Obstructive sleep apnea and type 2 diabetes: is there a link? Front. Neurol. 3, 126 (2012). doi:10.3389/fneur.2012.00126 PubMedCentralPubMedGoogle Scholar
  136. 136.
    O. Alshaarawy, S. Teppala, A. Shankar, Markers of sleep-disordered breathing and prediabetes in US adults. Int. J. Endocrinol. (2012). doi:10.1155/2012/902324 PubMedCentralPubMedGoogle Scholar
  137. 137.
    N. Cheng, W. Cai, M. Jiang, S. Wu, Effect of hypoxia on blood glucose, hormones, and insulin receptor functions in newborn calves. Pediatr. Res. 41(6), 852–856 (1997)PubMedGoogle Scholar
  138. 138.
    J.P. Chaput, J.P. Despres, C. Bouchard, A. Tremblay, Short sleep duration is associated with reduced leptin levels and increased adiposity: results from the Quebec family study. Obesity 15(1), 253–261 (2007)PubMedGoogle Scholar
  139. 139.
    N. Peled, A. Greenberg, G. Pillar, O. Zinder, N. Levi, P. Lavie, Contributions of hypoxia and respiratory disturbance index to sympathetic activation and blood pressure in obstructive sleep apnea syndrome. Am. J. Hypertens. 11(11), 1284–1289 (1998)PubMedGoogle Scholar
  140. 140.
    D. Einhorn, D.A. Stewart, M.K. Erman, N. Gordon, A. Philis-Tsimikas, E. Casal, Prevalence of sleep apnea in a population of adults with type 2 diabetes mellitus. Endocr. Pract. 13(4), 355–362 (2007)PubMedGoogle Scholar
  141. 141.
    G.D. Foster, M.H. Sanders, R. Millman, G. Zammitt, K.E. Borradaile, A.B. Newman, T.A. Wadden, D. Kelley, R.R. Wing, F.X. Sunyer, V. Darcey, S.T. Kuna, Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care 32(6), 1017–1019 (2009)PubMedCentralPubMedGoogle Scholar
  142. 142.
    R.S. Aronsohn, H. Whitmore, E. Van Cauter, E. Tasali, Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am. J. Respir. Crit. Care Med. 181(5), 507–513 (2010)PubMedCentralPubMedGoogle Scholar
  143. 143.
    R.N. Aurora, N.M. Punjabi, Obstructive sleep apnoea and type 2 diabetes mellitus: a bidirectional association. Lancet Respir. Med. 1(4), 329–338 (2013)PubMedGoogle Scholar
  144. 144.
    J.M. Fredheim, J. Rollheim, T. Omland, D. Hofsø, J. Røislien, K. Vegsgaard, J. Hjelmesæth, Type 2 diabetes and pre-diabetes are associated with obstructive sleep apnea in extremely obese subjects: a cross-sectional study. Cardiovasc. Diabetol. (2011). doi:10.1186/1475-2840-10-84 PubMedCentralPubMedGoogle Scholar
  145. 145.
    P. Levy, M.R. Bonsignore, J. Eckel, Sleep, sleep-disordered breathing and metabolic consequences. Eur. Respir. J. 34(1), 243–260 (2009)PubMedGoogle Scholar
  146. 146.
    I.A. Harsch, S.P. Schahin, K. Brückner, M. Radespiel-Tröger, F.S. Fuchs, E.G. Hahn, P.C. Konturek, T. Lohmann, J.H. Ficker, The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes. Respiration 71(3), 252–259 (2004)PubMedGoogle Scholar
  147. 147.
    H.A. Hassaballa, A. Tulaimat, J.J. Herdegen, B. Mokhlesi, The effect of continuous positive airway pressure on glucose control in diabetic patients with severe obstructive sleep apnea. Sleep Breath. 9(4), 176–180 (2005)PubMedGoogle Scholar
  148. 148.
    A.R. Babu, J. Herdegen, L. Fogelfeld, S. Shott, T. Mazzone, Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea. Arch. Intern. Med. 165(4), 447–452 (2005)PubMedGoogle Scholar
  149. 149.
    S.D. West, D.J. Nicoll, T.M. Wallace, D.R. Matthews, J.R. Stradling, Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 62(11), 969–974 (2007)PubMedCentralPubMedGoogle Scholar
  150. 150.
    S. Surani, S. Subramanian, Effect of continuous positive airway pressure therapy on glucose control. World J. Diabetes 3(4), 65–70 (2012)PubMedCentralPubMedGoogle Scholar
  151. 151.
    S. Pamidi, Abstract #39588. American Thoracic Society 2013 International Conference, Philadelphia, May 17–22, 2013Google Scholar
  152. 152.
    D. Kapoor, H. Aldred, S. Clark, K.S. Channer, T.H. Jones, Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 30(4), 911–917 (2007)PubMedGoogle Scholar
  153. 153.
    M. Grossmann, M.C. Thomas, S. Panagiotopoulos, K. Sharpe, R.J. Macisaac, Low testosterone levels are common and associated with insulin resistance in men with diabetes. J. Clin. Endocrinol. Metab. 93(5), 1834–1840 (2008)PubMedGoogle Scholar
  154. 154.
    A.A. Al Hayek, Y.S. Khader, S. Jafal, N. Khawaja, A.A. Robert, K. Ajilouni, Prevalence of low testosterone levels in men with type 2 diabetes mellitus: a cross-sectional study. J. Fam. Community Med. 20(3), 179–186 (2013)Google Scholar
  155. 155.
    E.L. Ding, Y. Song, V.S. Malik, S. Liu, Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295(11), 1288–1299 (2006)PubMedGoogle Scholar
  156. 156.
    G. Hackett, M. Kirby, A.J. Sinclair, Testosterone deficiency, cardiac health, and older men. Int. J. Endocrinol. (2014). doi:10.1155/2014/143763 PubMedCentralPubMedGoogle Scholar
  157. 157.
    R. Pasquali, C. Macor, V. Vicennati, F.R. Delasio, P. Mesini, S. Boschi, F. Casimirri, R. Vettor, Effects of acute hyperinsulinemia on testosterone serum concentrations in adult obese and normal-weight men. Metabolism 46(5), 526–529 (1997)PubMedGoogle Scholar
  158. 158.
    S. Bhasin, G.R. Cunningham, F.J. Hayes, A.M. Matsumoto, P.J. Snyder, R.S. Swerdloff, V.M. Montori, Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 95(6), 2536–2559 (2010)PubMedGoogle Scholar
  159. 159.
    R.K. Stellato, H.A. Feldman, O. Hamdy, E.S. Horton, J.B. McKinlay, Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 23(4), 490–494 (2000)PubMedGoogle Scholar
  160. 160.
    E.C. Tsai, A.M. Matsumoto, W.Y. Fujimoto, E.J. Boyko, Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care 27(4), 861–868 (2004)PubMedGoogle Scholar
  161. 161.
    P. Marin, S. Homang, L. Jonsson, L. Sjostrom, H. Kvist, G. Holm, G. Lindstedt, P. Bjorntorp, The effects of testosterone treatment on body composition and metabolism in middle-aged obese men. Int. J. Obes. Relat. Metab. Disord. 16(12), 991–997 (1992)PubMedGoogle Scholar
  162. 162.
    S. Filippi, L. Vignozzi, A. Morelli, A.K. Chavalmane, E. Sarchielli, B. Fibbi, F. Saad, P. Sandner, P. Ruggiano, G.B. Vannelli, E. Mannucci, M. Maggi, Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 inhibitors in an animal model of male metabolic syndrome. J. Sex Med. 6(12), 3274–3288 (2009)PubMedGoogle Scholar
  163. 163.
    D. Goodman-Gruen, E. Barrett-Connor, Sex differences in the association of endogenous sex hormone levels and glucose tolerance status in older men and women. Diabetes Care 23(7), 912–918 (2000)PubMedGoogle Scholar
  164. 164.
    G. Corona, G. Rastrelli, G. Balercia, F. Lotti, A. Sforza, M. Monami, G. Forti, E. Mannucci, M. Maggi, Hormonal association and sexual dysfunction in patients with impaired fasting glucose: a cross-sectional and longitudinal study. J. Sex Med. 9(6), 1669–1680 (2012)PubMedGoogle Scholar
  165. 165.
    C.H. Ho, H.J. Yu, C.Y. Wang, F.S. Jaw, J.T. Hsieh, W.C. Liao, Y.S. Pu, S.P. Liu, Prediabetes is associated with an increased risk of testosterone deficiency, independent of obesity and metabolic syndrome. PLoS ONE (2013). doi:10.1371/journal.pone.0074173 Google Scholar
  166. 166.
    D. Kapoor, E. Goodwin, K.S. Channer, T.H. Jones, Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur. J. Endocrinol. 154(6), 899–906 (2006)PubMedGoogle Scholar
  167. 167.
    M.I. Naharci, M. Pinar, E. Bolu, A. Olgun, Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonadism. Endocr. Pract. 13(6), 629–635 (2007)PubMedGoogle Scholar
  168. 168.
    T.H. Jones, S. Arver, H.M. Behre, J. Buvat, E. Meuleman, I. Moncada, A.M. Morales, M. Volterrani, A. Yellowlees, J.D. Howell, K.S. Channer, Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 34(4), 828–837 (2011)PubMedCentralPubMedGoogle Scholar
  169. 169.
    J. Kaur, A comprehensive review on metabolic syndrome. Cardiol Res Pract. (2014). doi:10.1155/2014/943162 Google Scholar
  170. 170.
    H. Beltran-Sanchez, M.O. Harhay, M.M. Harhay, S. McElligott, Prevalance and trends of metabolic syndrome in the adult U.S. population, 1999–2010. J. Am. Coll. Cardiol. 62(8), 697–703 (2013)PubMedCentralPubMedGoogle Scholar
  171. 171.
    Expert Panel on Detection, Evaluation and treatment of high cholesterol in adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel detection, evaluation and treatment of high cholesterol in adults (Adult Treatment Panel III). JAMA 285(19), 2486–2497 (2001)Google Scholar
  172. 172.
    S.M. Grundy, J.I. Cleeman, S.R. Daniels, K.A. Donato, R.H. Eckel, B.A. Franklin, D.J. Gordon, R.M. Krauss, P.J. Savage, S.C. Smith Jr, J.A. Spertus, F. Costa, Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary. Cardiol. Rev. 13(6), 322–327 (2005)PubMedGoogle Scholar
  173. 173.
    K.G. Alberti, P. Zimmet, J. Shaw, The metabolic syndrome—a new worldwide definition. Lancet 366(9491), 1059–1062 (2005)PubMedGoogle Scholar
  174. 174.
    G.M. Reaven, The insulin resistance syndrome: definition and dietary approaches to treatment. Annu. Rev. Nutr. 25, 391–406 (2005)PubMedGoogle Scholar
  175. 175.
    R.A. DeFronzo, E. Ferrannini, Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 14(3), 173–194 (1991)PubMedGoogle Scholar
  176. 176.
    C.M. Alexander, P.B. Landsman, S.M. Grundy, Metabolic syndrome and hyperglycemia: congruence and divergence. Am. J. Cardiol. 98(7), 982–985 (2006)PubMedGoogle Scholar
  177. 177.
    E.J. Diamantopoulos, E.A. Andreadis, G.I. Tsourous, G.K. Ifanti, P.M. Katsanou, D.X. Georgiopoulos, C.V. Vassilopoulos, G. Dimitriadis, S.A. Raptis, Metabolic syndrome and prediabetes identify overlapping but not identical populations. Exp. Clin. Endocrinol. Diabetes 144(7), 377–383 (2006)Google Scholar
  178. 178.
    C. Lorenzo, K. Williams, K.J. Hunt, S.M. Haffner, The National Cholesterol Education Program—Adult Treatment Panel III, International Diabetes Federation, and World Health Organization definitions of the metabolic syndrome as predictors of incident cardiovascular disease and diabetes. Diabetes Care 30(1), 8–13 (2007)PubMedGoogle Scholar
  179. 179.
    C. Lorenzo, M. Okoloise, K. Williams, M.P. Stern, S.M. Haffner, The metabolic syndrome as predictor of type 2 diabetes: the San Antonio heart study. Diabetes Care 26(11), 3153–3159 (2003)PubMedGoogle Scholar
  180. 180.
    Q.M. Nguyen, S.R. Srinivasan, J.H. Xu, W. Chen, G.S. Berenson, Changes in risk variables of metabolic syndrome since childhood in pre-diabetic and type 2 diabetic subjects: the Bogalusa Heart Study. Diabetes Care 31(10), 2044–2049 (2008)PubMedCentralPubMedGoogle Scholar
  181. 181.
    J.A. Morrison, L.A. Friedman, P. Wang, C.J. Glueck, Metabolic syndrome in childhood predicts adult metabolic syndrome and type 2 diabetes mellitus 25 to 30 years later. J. Pediatr. 152(2), 201–206 (2008)PubMedGoogle Scholar
  182. 182.
    H. Florez, M.G. Temprosa, T.J. Orchard, K.J. Mather, S.M. Marcovina, E. Barrett-Connor, E. Horton, C. Saudek, X.F. Pi-Sunyer, R.E. Ratner, R.B. Goldberg, Metabolic syndrome components and their response to lifestyle and metformin interventions are associated with differences in diabetes risk in persons with impaired glucose tolerance. Diabetes Obese Metab. 16(4), 325–333 (2014)Google Scholar
  183. 183.
    S.M. Grundy, Pre-diabetes, metabolic syndrome, and cardiovascular risk. J. Am. Coll. Cardiol. 59(7), 635–643 (2012)PubMedGoogle Scholar
  184. 184.
    T.J. Orchard, M. Temprosa, R. Goldberg, S. Haffner, R. Ratner, S. Marcovina, S. Fowler, The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann. Intern. Med. 142(8), 611–619 (2005)PubMedCentralPubMedGoogle Scholar
  185. 185.
    J.L. Chiasson, R.G. Josse, R. Gomis, M. Hanefeld, A. Karasik, M. Laakso, Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 290(4), 486–494 (2003)PubMedGoogle Scholar
  186. 186.
    R. Rajagopalan, S. Iyer, M. Khan, Effect of pioglitazone on metabolic syndrome risk factors: results of double-blind, multicenter, randomized clinical trials. Curr. Med. Res. Opin. 21(1), 163–172 (2005)PubMedGoogle Scholar
  187. 187.
    S. Li, H.J. Shin, E.L. Ding, R.M. van Dam, Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 302(2), 179–188 (2009)PubMedGoogle Scholar
  188. 188.
    A.G. Tabak, M. Cartensen, D.R. Witte, E.J. Brunner, M.J. Shipley, M. Jokela, M. Roden, M. Kivimaki, C. Herder, Adiponectin trajectories before type 2 diabetes diagnosis. Diabetes Care 35(12), 2540–2547 (2012)PubMedCentralPubMedGoogle Scholar
  189. 189.
    H. Kim, J. Jo, J.E. Lim, Y.D. Yun, S.J. Baek, T. Lee, K.B. Huh, S.H. Jee, Adiponectin as predictor for diabetes among pre-diabetic groups. Endocrine 44(2), 411–418 (2013)PubMedGoogle Scholar
  190. 190.
    M.Y. Donath, D.M. Schumann, M. Faulenbach, H. Ellingsgaard, A. Perren, J.A. Ehses, Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Diabetes Care 31(Suppl 2), S161–S164 (2008)PubMedGoogle Scholar
  191. 191.
    C.M. Larsen, M. Faulenbach, A. Vaag, A. Volund, J.A. Ehses, B. Seifert, T. Mandrup-Poulsen, M.Y. Donath, Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356(15), 1517–1526 (2007)PubMedGoogle Scholar
  192. 192.
    M. Carstensen, C. Herder, M. Kivimaki, M. Jokela, M. Roden, M.J. Shipley, D.R. Witte, E.J. Brunner, A.G. Tabak, Accelereated increase in serum interleukin-1 receptor antagonist starts 6 years before diagnosis of type 2 diabetes: Whitehall II prospective cohort study. Diabetes 59(5), 1222–1227 (2010)PubMedCentralPubMedGoogle Scholar
  193. 193.
    T.J. Wang, M.G. Larson, R.S. Vasan, S. Cheng, E.P. Rhee, E. McCabe, G.D. Lewis, C.S. Fox, P.F. Jacques, C. Fernandez, C.J. O’Donnell, S.A. Carr, V.K. Mootha, J.C. Florez, A. Souza, O. Melander, C.B. Clish, R.E. Gerszten, Metabolite profiles and the risk of developing diabetes. Nat. Med. 17(4), 448–453 (2011)PubMedCentralPubMedGoogle Scholar
  194. 194.
    R. Wang-Sattler, Z. Yu, C. Herder, A.C. Messias, A. Floegel, Y. He, K. Heim, M. Campillos, C. Holzapfel, B. Thorand, H. Grallert, T. Xu, E. Bader, C. Huth, K. Mittelstrass, A. Doring, C. Meisinger, C. Gieger, C. Prehn, W. Roemisch-Margl, M. Carstensen, L. Xie, H. Yamanaka-Okumura, G. Xing, U. Ceglarek, J. Thiery, G. Giani, H. Lickert, X. Lin, Y. Li, H. Boeing, H. Joost, M. Hrabé de Angelis, W. Rathmann, K. Suhre, H. Prokisch, A. Peters, T. Meitinger, M. Roden, H. Wichmann, T. Pischon, J. Adamski, T. Illig, Novel biomarkers for pre-diabetes identified by metabolomics. Mol. Syst. Biol. 8, 615 (2012)PubMedCentralPubMedGoogle Scholar
  195. 195.
    A. Floegel, N. Stefan, Z. Yu, K. Mühlenbruch, D. Drogan, H. Joost, A. Fritsche, H. Häring, M. Hrabe de Angelis, A. Peters, M. Roden, C. Prehn, R. Wang-Sattler, T. Illig, M.B. Schulze, J. Adamski, H. Boeing, T. Pischon, Identifcation of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomics approach. Diabetes 62(2), 639–648 (2013)PubMedCentralPubMedGoogle Scholar
  196. 196.
    W.E. Gall, K. Beebe, K.A. Lawton, K. Adam, M.W. Mitchell, P.J. Nakhle, J.A. Ryals, M.V. Milburn, M. Nannipieri, S. Camastra, A. Natali, E. Ferrannini, RISC Study Group, α-Hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE 5(5), e10883 (2010)PubMedCentralPubMedGoogle Scholar
  197. 197.
    E. Ferranini, A. Natali, S. Camastra, M. Nannipieri, A. Mari, K. Adam, M.V. Milburn, G. Kastenmüller, J. Adamski, T. Tuomi, V. Lyssenko, L. Groop, W.E. Gall, Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance. Diabetes 62(5), 1730–1737 (2013)Google Scholar
  198. 198.
    E. Selvin, A.M. Rawlings, M. Grams, R. Klein, A.R. Sharrett, M. Steffes, J. Coresh, Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Lancet Diabetes Endocrinol. 2(4), 279–288 (2014)PubMedGoogle Scholar
  199. 199.
    J.M. Pappachan, F.A. Antonio, M.E. Edavalath, A. Mukherjee, Non-alcoholic fatty liver disease: a diabetologist’s perspective. Endocrine 45(3), 334–353 (2014)Google Scholar
  200. 200.
    C.P. Day, O.F. James, Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4), 842–845 (1998)PubMedGoogle Scholar
  201. 201.
    H. Tilg, A.R. Moschen, Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52(5), 1836–1846 (2010)PubMedGoogle Scholar
  202. 202.
    M. Sargin, O. Uygur-Bayramiçli, H. Sargin, E. Orbay, A. Yayla, Association of nonalcoholic fatty liver disease with insulin resistance: is OGTT indicated in nonalcoholic fatty liver disease? J. Clin. Gastroenterol. 37(5), 399–402 (2003)PubMedGoogle Scholar
  203. 203.
    V.W.S. Wong, A.Y. Hui, S.W.C. Tsang, J.L.Y. Chan, G.L.H. Wong, A.W.H. Chan, W.Y. So, A.Y.S. Cheng, P.C.Y. Tong, F.K.L. Chan, J.J.Y. Sung, H.L.Y. Chan, Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-aloholic fatty liver disease. Aliment. Pharmacol. Ther. 24(8), 1215–1222 (2006)PubMedGoogle Scholar
  204. 204.
    J.W. Yun, Y.K. Cho, J.H. Park, H.J. Kim, D.I. Park, C.I. Sohn, W.K. Jeon, B.I. Kim, Abnormal glucose tolerance in young male patients with nonalcoholic fatty liver disease. Liver Int. 29(4), 525–529 (2009)PubMedCentralPubMedGoogle Scholar
  205. 205.
    C. Ortiz-Lopez, R. Lomonaco, B. Orsak, J. Finch, Z. Chang, V.G. Kochunov, J. Hardies, K. Cusi, Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care 35(4), 873–878 (2012)PubMedCentralPubMedGoogle Scholar
  206. 206.
    S. Zelber-Sagi, R. Lotan, O. Shibolet, M. Webb, A. Buch, D. Nitzan-Kaluski, Z. Halpern, E. Santo, R. Oren, Non-alcoholic fatty liver disease independently predicts prediabetes during a 7-year prospective follow-up. Liver Int. 33(9), 1406–1412 (2013)PubMedGoogle Scholar
  207. 207.
    B. Vozarova, N. Stefan, R.S. Lindsay, A. Saremi, R.E. Pratley, C. Bogardus, P.A. Tataranni, High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 51(6), 1889–1895 (2002)PubMedGoogle Scholar
  208. 208.
    A.J. Hanley, K. Williams, A. Festa, L.E. Wagenknecht, R.B. D’Agostino Jr, J. Kempf, B. Zinman, S.M. Haffner, Insulin resistance atherosclerosis study, elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 53(10), 2623–2632 (2004)PubMedGoogle Scholar
  209. 209.
    M. Nannipieri, C. Gonzales, S. Baldi, R. Posadas, K. Williams, S.M. Haffner, M.P. Stern, E. Ferrannini, Mexico City Diabetes Study, liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City diabetes study. Diabetes Care 28(7), 1757–1762 (2005)PubMedGoogle Scholar
  210. 210.
    Y. Doi, M. Kubo, K. Yonemoto, T. Ninomiya, M. Iwase, Y. Tanizaki, K. Shikata, M. Iida, Y. Kiyohara, Liver enzymes as predictor for incident diabetes in a Japanese population: the Hisayama study. Obesity (Silver Spring) 15(7), 1841–1850 (2007)Google Scholar
  211. 211.
    E.S. Ford, M.B. Schulze, M.M. Bergmann, C. Thamer, H.G. Joost, H. Boeing, Liver enzymes and incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes Care 31(6), 1138–1143 (2008)PubMedGoogle Scholar
  212. 212.
    A. Fraser, R. Harris, N. Sattar, S. Ebrahim, G.D. Smith, D.A. Lawlor, Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women’s Heart and Health Study and meta-analysis. Diabetes Care 32(4), 741–750 (2009)PubMedCentralPubMedGoogle Scholar
  213. 213.
    G. Bedogni, S. Bellentani, L. Miglioli, F. Masutti, M. Passalacqua, A. Castiglione, C. Tiribelli, The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 6, 33 (2006)PubMedCentralPubMedGoogle Scholar
  214. 214.
    B. Balkau, C. Lange, S. Vol, F. Fumeron, F. Bonnet, Group Study D.E.S.I.R., Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol. 10, 56 (2010)PubMedCentralPubMedGoogle Scholar
  215. 215.
    I. Rückert, M. Heier, W. Rathmann, S.E. Baumeister, A. Döring, C. Meisinger, Association between markers of fatty liver disease and impaired glucose regulation in men and women from the general population: the KORA-F4-Study. PLoS ONE 6(8), e22932 (2011)PubMedCentralPubMedGoogle Scholar
  216. 216.
    N. Stefan, A.M. Hennige, H. Staiger, J. Machann, F. Schick, S.M. Kröber, F. Machicao, A. Fritsche, H. Häring, α2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 29(4), 853–857 (2006)PubMedGoogle Scholar
  217. 217.
    H. Ou, Y. Yang, H. Wu, J. Wu, F. Lu, C. Chang, Increased fetuin-A concentrations in impaired glucose tolerance with or without nonalcoholic fatty liver disease, but not impaired fasting glucose. J. Clin. Endocrinol. Metab. 97(12), 4717–4723 (2012)PubMedGoogle Scholar
  218. 218.
    E. Giovannucci, D.M. Harlan, M.C. Archer, R.M. Bergnestal, S.M. Gapstur, L.A. Habel, M. Pollak, J.G. Regensteiner, D. Yee, Diabetes and Cancer. A consensus report. Diabetes Care 33(7), 1674–1685 (2010)PubMedCentralPubMedGoogle Scholar
  219. 219.
    Y. Huang, X. Cai, M. Qiu, P. Chen, H. Tang, Y. Hu, Y. Huang, Prediabetes and the risk of cancer: a meta-analysis. Diabetologia (2014). doi:10.1007/s00125-014-3361-2 Google Scholar
  220. 220.
    S. Gao, A. Li, F. Liu et al., NCOA5 haploinsufficency results in glucose intolerance and subsequent heaptocellualr carcinoma. Cancer Cell 24, 725–737 (2013)PubMedCentralPubMedGoogle Scholar
  221. 221.
    A. Leone, E. DiGennaro, F. Bruzzese, A. Avallone, A. Budillon, New perspective for an old antidiabteic drug: metformin as anticancer agent. Cancer Treat Res 159, 355–376 (2014)PubMedGoogle Scholar
  222. 222.
    M. Bergman, R. Dankner, J. Roth, K.M. Venkat Narayan, Are current diagnostic guidelines delaying early detection of dysglycemic states? Time for new approaches. Endocrine 44(1), 66–69 (2013)PubMedGoogle Scholar
  223. 223.
    M. Bergman, Pathophysiology of prediabetes and treatment implications for the prevention of type 2 diabetes mellitus. Endocrine 43(3), 504–513 (2013)PubMedGoogle Scholar
  224. 224.
    M. Bergman, Inadequacies of current approaches to prediabetes and diabetes prevention. Endocrine 44(3), 623–633 (2013)PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Martin Buysschaert
    • 1
  • José Luís Medina
    • 2
  • Michael Bergman
    • 3
  • Avni Shah
    • 4
  • Jaqueline Lonier
    • 5
  1. 1.Department of Endocrinology and DiabetologyUniversity Clinic Saint-Luc, Université Catholique de LouvainBrusselsBelgium
  2. 2.Oporto Medical SchoolOporto UniversityOportoPortugal
  3. 3.Division of Endocrinology and MetabolismNYU Diabetes and Endocrine Associates, NYU School of MedicineNew YorkUSA
  4. 4.Internal MedicineSouth Shore HospitalWeymouthUSA
  5. 5.Endocrinology, Diabetes and MetabolismNYU School of MedicineNew YorkUSA

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