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Proinsulin to insulin ratio is associated with incident type 2 diabetes but not with vascular complications in the KORA F4/FF4 study
  1. Cornelia Then1,
  2. Christina Gar1,2,
  3. Barbara Thorand3,4,
  4. Cornelia Huth3,4,
  5. Holger Then5,
  6. Christa Meisinger3,6,
  7. Margit Heier3,7,
  8. Annette Peters3,4,
  9. Wolfgang Koenig8,9,
  10. Wolfgang Rathmann10,
  11. Andreas Lechner1,2,
  12. Jochen Seissler1,2
  1. 1Medizinische Klinik und Poliklinik IV, LMU Klinikum der Universität München, Munich, Germany
  2. 2Clinical Cooperation Group Diabetes, Ludwig-Maximilians-Universität München and Helmholtz Zentrum München, Munich, Germany
  3. 3Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
  4. 4Deutsches Zentrum für Diabetesforschung (DZD), German Center for Diabetes Research, München-Neuherberg, Germany
  5. 5Department of Mathematics, Freie Waldorfschule Augsburg, Augsburg, Germany
  6. 6Chair of Epidemiology at UNIKA-T Augsburg, Ludwig-Maximilians-Universität München, Munich, Germany
  7. 7KORA Study Centre, University Hospital Augsburg, Augsburg, Germany
  8. 8Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
  9. 9Technische Universität München, Deutsches Herzzentrum München, München, Germany
  10. 10German Diabetes Center, Institute of Biometrics and Epidemiology, Leibniz Institute at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  1. Correspondence to Dr Cornelia Then; cornelia.then{at}


Introduction We investigated the association of the proinsulin to insulin ratio (PIR) with prevalent and incident type 2 diabetes (T2D), components of the metabolic syndrome, and renal and cardiovascular outcomes in the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (2006–2008)/FF4 study (2013–2014).

Research design and methods The analyses included 1514 participants of the KORA F4 study at baseline and 1132 participants of the KORA FF4 study after a median follow-up time of 6.6 years. All-cause and cardiovascular mortality as well as cardiovascular events were analyzed after a median time of 9.1 and 8.6 years, respectively. The association of PIR with T2D, renal and cardiovascular characteristics and mortality were assessed using logistic regression models. Linear regression analyses were used to assess the association of PIR with components of the metabolic syndrome.

Results After adjustment for sex, age, body mass index (BMI), and physical activity, PIR was associated with prevalent (OR: 2.24; 95% CI 1.81 to 2.77; p<0.001) and incident T2D (OR: 1.66; 95% CI 1.26 to 2.17; p<0.001). PIR was associated with fasting glucose (β per SD: 0.11±0.02; p<0.001) and HbA1c (β: 0.21±0.02; p<0.001). However, PIR was not positively associated with other components of the metabolic syndrome and was even inversely associated with waist circumference (β: −0.22±0.03; p<0.001), BMI (β: −0.11±0.03; p<0.001) and homeostatic model assessment of insulin resistance (β: −0.22±0.02; p<0.001). PIR was not significantly associated with the intima-media thickness (IMT), decline of kidney function, incident albuminuria, myocardial infarction, stroke, cardiovascular or all-cause mortality.

Conclusions In the KORA F4/FF4 cohort, PIR was positively associated with prevalent and incident T2D, but inversely associated with waist circumference, BMI and insulin resistance, suggesting that PIR might serve as a biomarker for T2D risk independently of the metabolic syndrome, but not for microvascular or macrovascular complications.

  • diabetes mellitus, type 2
  • proinsulin
  • metabolic syndrome
  • mortality

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  • Contributors Conception and design of the study: BT, CM, CH, MH, AP, WK, WR, JS. Collection of data: BT, CT, CM, CH, MH, AP, WK, WR, AL, JS. Data analysis, interpretation of results, writing of the manuscript: CT, CG, HT, BT, CH, AL, JS. All authors revised the manuscript critically for important intellectual content and approved the final version.

  • Funding The KORA study was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. The study was supported by a research grant from the Virtual Diabetes Institute (Helmholtz Zentrum München) and the Clinical Cooperation Group Diabetes, Ludwig-Maximilians-University München and Helmholtz Zentrum München, and by the German Diabetes Center. The German Diabetes Center was supported by the Federal Ministry of Health (Berlin, Germany) and the Ministry of Culture and Science of the state North Rhine Westphalia (Düsseldorf, Germany). Further support was obtained from the Deutsche Diabetes Gesellschaft (DDG). The KORA F4 study was partly funded by a grant from the German Research Foundation (DFG) (RA-45913/3-1).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Ethics Committees of the Bavarian Medical Association (approval number 06068) in adherence to the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request from the corresponding author.

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