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Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study

  • Gyuri Kim
  • Sang-Guk Lee
  • Byung-Wan Lee
  • Eun Seok Kang
  • Bong-Soo Cha
  • Ele Ferrannini
  • Yong-ho LeeEmail author
  • Nam H. ChoEmail author



Ketones may be regarded as a thrifty fuel for peripheral tissues, but their clinical prognostic significance remains unclear. We investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic variables in a large population-based observational study.


We analysed 8703 individuals free of diabetes at baseline enrolled in the Korean Genome and Epidemiology Study, a community-based 12 year prospective study. Individuals with (n = 195) or without fasting ketonuria were matched 1:4 by propensity score. Incident diabetes was defined as fasting plasma glucose ≥7.0 mmol/l, post-load 2 h glucose ≥11.1 mmol/l on biennial OGTTs, or current use of glucose-lowering medication. Using Cox regression models, HRs for developing diabetes associated with the presence of ketonuria at baseline were analysed.


Over 12 years, of the 925 participants in the propensity score-matched cohort, 190 (20.5%) developed diabetes. The incidence rate of diabetes was significantly lower in participants with spontaneous ketonuria compared with those without ketonuria (HR 0.63; 95% CI 0.41, 0.97). Results were virtually identical when participants with fasting ketonuria were compared against all participants without ketonuria (after multivariate adjustment, HR 0.66; 95% CI 0.45, 0.96). During follow-up, participants with baseline ketonuria maintained lower post-load 1 h and 2 h glucose levels and a higher insulinogenic index despite comparable baseline values.


The presence of spontaneous fasting ketonuria was significantly associated with a reduced risk of diabetes, independently of metabolic variables. Our findings suggest that spontaneous fasting ketonuria may have a potential preventive role in the development of diabetes.


Cohort Diabetes Ketone Risk 





Fibroblast growth factor 21


3-Hydroxy-3-methylglutaryl-CoA synthase 2


Insulinogenic index


Korean Genome and Epidemiology Study


Peroxisome proliferator-activated receptor, alpha


Sodium–glucose cotransporter 2



Data in this study were from the KoGES (4851-302), National Research Institute of Health, Centers for Disease Control and Prevention, Ministry for Health and Welfare, Republic of Korea.

Contribution statement

GK and Y-hL conceived and designed the study and performed the analyses. GK, NHC, S-GL and Y-hL acquired the data. GK, EF and Y-hL wrote the first draft of the manuscript. All authors interpreted the data, contributed to the writing of the manuscript and read and approved the final version. Y-hL and NHC are responsible for the integrity of the work as a whole.


This research was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2016R1A5A1010764) and from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI17C0913).

Duality of interest

The authors declare that they have no competing interests.

Supplementary material

125_2019_4829_MOESM1_ESM.pdf (369 kb)
ESM (PDF 368 kb)


  1. 1.
    Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46(1):3–19. CrossRefPubMedGoogle Scholar
  2. 2.
    Han CY (2016) Roles of reactive oxygen species on insulin resistance in adipose tissue. Diabetes Metab J 40(4):272–279. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    McGarry JD, Foster DW (1980) Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem 49(1):395–420. CrossRefPubMedGoogle Scholar
  4. 4.
    Cotter DG, Ercal B, Huang X et al (2014) Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia. J Clin Invest 124(12):5175–5190. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Beisswenger BG, Delucia EM, Lapoint N, Sanford RJ, Beisswenger PJ (2005) Ketosis leads to increased methylglyoxal production on the Atkins diet. Ann N Y Acad Sci 1043(1):201–210. CrossRefPubMedGoogle Scholar
  6. 6.
    Cotter DG, Schugar RC, Crawford PA (2013) Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 304(8):H1060–H1076. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Newman JC, Verdin E (2014) Ketone bodies as signaling metabolites. Trends Endocrinol Metab 25(1):42–52. CrossRefPubMedGoogle Scholar
  8. 8.
    Ferrannini E, Mark M, Mayoux E (2016) CV protection in the EMPA-REG outcome trial: a ‘thrifty substrate’ hypothesis. Diabetes Care 39(7):1108–1114. CrossRefPubMedGoogle Scholar
  9. 9.
    Ferrannini E, Baldi S, Frascerra S et al (2016) Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 siabetes. Diabetes 65(5):1190–1195. CrossRefPubMedGoogle Scholar
  10. 10.
    Joo NS, Lee DJ, Kim KM et al (2010) Ketonuria after fasting may be related to the metabolic superiority. J Korean Med Sci 25(12):1771–1776. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ferrannini E (2017) Sodium–glucose co-transporters and their inhibition: clinical physiology. Cell Metab 26(1):27–38. CrossRefPubMedGoogle Scholar
  12. 12.
    Kim Y, Han BG (2017) Cohort profile: the Korean Genome and Epidemiology Study (KoGES) Consortium. Int J Epidemiol 46(4):1350. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kim G, Lee YH, Jeon JY et al (2017) Increase in resting heart rate over 2 years predicts incidence of diabetes: a 10-year prospective study. Diabetes Metab 43(1):25–32. CrossRefPubMedGoogle Scholar
  14. 14.
    Ahn Y, Park SJ, Kwack HK, Kim MK, Ko KP, Kim SS (2013) Rice-eating pattern and the risk of metabolic syndrome especially waist circumference in Korean Genome and Epidemiology Study (KoGES). BMC Public Health 13(1):61. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cho NH, Cho AK, Kim HK et al (2017) Carbohydrate composition associated with the 2-year incidence of metabolic syndrome in Korean adults. Clin Nutr Res 6(2):122–129. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Son JW, Lee SS, Kim SR et al (2017) Low muscle mass and risk of type 2 diabetes in middle-aged and older adults: findings from the KoGES. Diabetologia 60(5):865–872. CrossRefPubMedGoogle Scholar
  17. 17.
    Ahn Y, Kwon E, Shim JE et al (2007) Validation and reproducibility of food frequency questionnaire for Korean genome epidemiologic study. Eur J Clin Nutr 61(12):1435–1441. CrossRefPubMedGoogle Scholar
  18. 18.
    Ahn Y, Lee JE, Paik HY, Lee HK, Jo I, Kimm K (2003) Development of a semi-quantitative food frequency questionnaire based on dietary data from the Korea National Health and Nutrition Examination Survey. Nutr Sci 6:173–184Google Scholar
  19. 19.
    World Health Organization. Regional Office for the Western Pacific (2000) The Asian-Pacific perspective: redefining obesity and its treatment. Health Communications Australia, SydneyGoogle Scholar
  20. 20.
    Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18(6):499–502Google Scholar
  21. 21.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefGoogle Scholar
  22. 22.
    Tura A, Kautzky-Willer A, Pacini G (2006) Insulinogenic indices from insulin and C-peptide: comparison of beta-cell function from OGTT and IVGTT. Diabetes Res Clin Pract 72:298–301CrossRefGoogle Scholar
  23. 23.
    American Diabetes Association (2004) Diagnosis and classification of diabetes mellitus. Diabetes Care 27(suppl 1):s5–s10Google Scholar
  24. 24.
    Grundy SM, Cleeman JI, Daniels SR et al (2005) Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 112(17):2735–2752. CrossRefGoogle Scholar
  25. 25.
    Lim S, Kim JH, Yoon JW et al (2010) Sarcopenic obesity: prevalence and association with metabolic syndrome in the Korean Longitudinal Study on Health and Aging (KLoSHA). Diabetes Care 33(7):1652–1654. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Musa-Veloso K, Likhodii SS, Cunnane SC (2002) Breath acetone is a reliable indicator of ketosis in adults consuming ketogenic meals. Am J Clin Nutr 76(1):65–70. CrossRefPubMedGoogle Scholar
  27. 27.
    Yancy WS Jr, Olsen MK, Guyton JR, Bakst RP, Westman EC (2004) A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med 140(10):769–777. CrossRefPubMedGoogle Scholar
  28. 28.
    Perez-Guisado J (2008) Ketogenic diets: additional benefits to the weight loss and unfounded secondary effects. Arch Latinoam Nutr 58:323–329 [article in Spanish]PubMedGoogle Scholar
  29. 29.
    Tendler D, Lin S, Yancy WS Jr et al (2007) The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci 52(2):589–593. CrossRefPubMedGoogle Scholar
  30. 30.
    Horne BD, Muhlestein JB, Anderson JL (2015) Health effects of intermittent fasting: hormesis or harm? A systematic review. Am J Clin Nutr 102(2):464–470. CrossRefPubMedGoogle Scholar
  31. 31.
    Patterson RE, Laughlin GA, LaCroix AZ et al (2015) Intermittent fasting and human metabolic health. J Acad Nutr Diet 115(8):1203–1212. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Marinac CR, Sears DD, Natarajan L, Gallo LC, Breen CI, Patterson RE (2015) Frequency and circadian timing of eating may influence biomarkers of inflammation and insulin resistance associated with breast cancer risk. PLoS One 10(8):e0136240. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Gallant A, Drapeau V, Allison KC et al (2014) Night eating behavior and metabolic heath in mothers and fathers enrolled in the QUALITY cohort study. Eat Behav 15(2):186–191. CrossRefPubMedGoogle Scholar
  34. 34.
    Tilg H, Kaser A (2011) Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest 121(6):2126–2132. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Rodriguez JC, Gil-Gomez G, Hegardt FG, Haro D (1994) Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem 269(29):18767–18772PubMedGoogle Scholar
  36. 36.
    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E (2007) Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5(6):426–437. CrossRefPubMedGoogle Scholar
  37. 37.
    Kim JH, Lee M, Kim SH et al (2018) Sodium–glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk. Diabetes Obes Metab.
  38. 38.
    Bae KH, Kim JG, Park KG (2014) Transcriptional regulation of fibroblast growth factor 21 expression. Endocrinol Metab (Seoul) 29(2):105–111. CrossRefGoogle Scholar
  39. 39.
    Vila-Brau A, De Sousa-Coelho AL, Mayordomo C, Haro D, Marrero PF (2011) Human HMGCS2 regulates mitochondrial fatty acid oxidation and FGF21 expression in HepG2 cell line. J Biol Chem 286(23):20423–20430. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Degirolamo C, Sabba C, Moschetta A (2016) Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat Rev Drug Discov 15(1):51–69. CrossRefGoogle Scholar
  41. 41.
    Kim KH, Lee MS (2014) FGF21 as a stress hormone: the roles of FGF21 in stress adaptation and the treatment of metabolic diseases. Diabetes Metab J 38(4):245–251. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lee JM (2017) Nuclear receptors resolve endoplasmic reticulum stress to improve hepatic insulin resistance. Diabetes Metab J 41(1):10–19. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Satapati S, Sunny NE, Kucejova B et al (2012) Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J Lipid Res 53(6):1080–1092. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bae HR, Kim DH, Park MH et al (2016) β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget 7(41):66444–66454. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Gao Z, Yin J, Zhang J et al (2009) Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58(7):1509–1517. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mihaylova MM, Vasquez DS, Ravnskjaer K et al (2011) Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145(4):607–621. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Knutson SK, Chyla BJ, Amann JM, Bhaskara S, Huppert SS, Hiebert SW (2008) Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J 27(7):1017–1028. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Veech RL (2013) Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat. Ann N Y Acad Sci 1302(1):42–48. CrossRefPubMedGoogle Scholar
  49. 49.
    Holland AM, Kephart WC, Mumford PW et al (2016) Effects of a ketogenic diet on adipose tissue, liver, and serum biomarkers in sedentary rats and rats that exercised via resisted voluntary wheel running. Am J Physiol Regul Integr Comp Physiol 311(2):R337–R351. CrossRefPubMedGoogle Scholar
  50. 50.
    Cox PJ, Kirk T, Ashmore T et al (2016) Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab 24(2):256–268. CrossRefPubMedGoogle Scholar
  51. 51.
    Kimura I, Inoue D, Maeda T et al (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A 108(19):8030–8035. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Laeger T, Metges CC, Kuhla B (2010) Role of beta-hydroxybutyric acid in the central regulation of energy balance. Appetite 54(3):450–455. CrossRefPubMedGoogle Scholar
  53. 53.
    Le Foll C, Dunn-Meynell AA, Miziorko HM, Levin BE (2014) Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acids. Diabetes 63(4):1259–1269. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Madison LL, Mebane D, Unger RH, Lochner A (1964) The hypoglycemic action of ketones. II. Evidence for a stimulatory feedback of ketones on the pancreatic beta cells. J Clin Invest 43(3):408–415. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Jenkins DJ, Hunter WM, Goff DV (1970) Ketone bodies and evidence for increased insulin secretion. Nature 227(5256):384–385. CrossRefPubMedGoogle Scholar
  56. 56.
    Balasse EO, Ooms HA, Lambilliotte JP (1970) Evidence for a stimulatory effect of ketone bodies on insulin secretion in man. Horm Metab Res 2(06):371–372. CrossRefPubMedGoogle Scholar
  57. 57.
    Shimazu T, Hirschey MD, Newman J et al (2013) Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339(6116):211–214. CrossRefPubMedGoogle Scholar
  58. 58.
    Rahman M, Muhammad S, Khan MA et al (2014) The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat Commun 5(1):3944. CrossRefPubMedGoogle Scholar
  59. 59.
    Youm YH, Nguyen KY, Grant RW et al (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21(3):263–269. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Robinson AM, Williamson DH (1980) Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 60(1):143–187. CrossRefPubMedGoogle Scholar
  61. 61.
    Klocker AA, Phelan H, Twigg SM, Craig ME (2013) Blood β-hydroxybutyrate vs. urine acetoacetate testing for the prevention and management of ketoacidosis in type 1 diabetes: a systematic review. Diabet Med 30(7):818–824. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Gyuri Kim
    • 1
  • Sang-Guk Lee
    • 2
  • Byung-Wan Lee
    • 3
    • 4
  • Eun Seok Kang
    • 3
    • 4
  • Bong-Soo Cha
    • 3
    • 4
  • Ele Ferrannini
    • 5
  • Yong-ho Lee
    • 3
    • 4
    • 6
    Email author
  • Nam H. Cho
    • 7
    Email author
  1. 1.Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea
  2. 2.Department of Laboratory MedicineYonsei University College of MedicineSeoulRepublic of Korea
  3. 3.Department of Internal MedicineYonsei University College of MedicineSeoulRepublic of Korea
  4. 4.Institute of Endocrine ResearchYonsei University College of MedicineSeoulRepublic of Korea
  5. 5.CNR Institute of Clinical PhysiologyPisaItaly
  6. 6.Department of Systems Biology, Glycosylation Network Research CenterYonsei UniversitySeoulRepublic of Korea
  7. 7.Department of Preventive MedicineAjou University School of MedicineSuwonRepublic of Korea

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