, Volume 60, Issue 12, pp 2341–2351 | Cite as

Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: results from the TULIP study

  • Vera Schmid
  • Robert Wagner
  • Corinna Sailer
  • Louise Fritsche
  • Konstantinos Kantartzis
  • Andreas Peter
  • Martin Heni
  • Hans-Ulrich Häring
  • Norbert Stefan
  • Andreas Fritsche



Lifestyle intervention is effective to prevent type 2 diabetes. However, a considerable long-term non-response occurs to a standard lifestyle intervention. We investigated which risk phenotypes at baseline and their changes during the lifestyle intervention predict long-term glycaemic non-response to the intervention.


Of 300 participants at high risk for type 2 diabetes who participated in a 24 month lifestyle intervention with diet modification and increased physical activity, 190 participants could be re-examined after 8.7 ± 1.6 years. All individuals underwent a five-point 75 g OGTT and measurements of body fat compartments and liver fat content with MRI and spectroscopy at baseline, 9 and 24 months during the lifestyle intervention, and at long-term follow-up. Fasting proinsulin to insulin conversion (PI/I ratio) and insulin sensitivity and secretion were calculated from the OGTT. Non-response to lifestyle intervention was defined as no decrease in glycaemia, i.e. no decrease in AUC for glucose at 0–120 min during OGTT (AUCglucose0–120 min).


Before the lifestyle intervention, 56% of participants had normal glucose regulation and 44% individuals had impaired fasting glucose and/or impaired glucose tolerance. At long-term follow-up, 11% had developed diabetes. Multivariable regression analysis with adjustment for age, sex, BMI and change in BMI during the lifestyle intervention revealed that baseline insulin secretion and insulin sensitivity, as well as change in insulin sensitivity during the lifestyle intervention, predicted long-term glycaemic control after 9 years. In addition, increased hepatic lipid content as well as impaired fasting proinsulin conversion at baseline were newly detected phenotypes that independently predicted long-term glycaemic control.


Increased hepatic lipid content and impaired proinsulin conversion are new predictors, independent of change in body weight, for non-response to lifestyle intervention in addition to the confirmed factors, impaired insulin secretion and insulin sensitivity.


Fatty liver Insulin secretion Insulin sensitivity Lifestyle intervention Prediabetes Predictors Proinsulin 


AUCglucose0–120 min

AUC for glucose at 0–120 min during OGTT


Diabetes Prevention Program


Diabetes Prevention Program Outcome Study


Diabetes Prevention Study


Proton magnetic resonance spectroscopy


Impaired fasting glucose


Impaired glucose tolerance


Insulinogenic index


Insulin sensitivity index


Non-alcoholic fatty liver disease

PI/I ratio

Proinsulin/insulin ratio


Subcutaneous adipose tissue


total adipose tissue


Tübingen Lifestyle Intervention Program


Visceral adipose tissue



We thank all the study participants for their cooperation with this project. We gratefully acknowledge the excellent technical assistance of A. Bury, E. Kollmar, A. Vosseler and A. Dessecker (all University of Tübingen, Germany). We further thank J. Machann and F. Schick from the Section for Experimental Radiology for the excellent body imaging and cooperation within the study.

Data availability

The datasets generated during and/or analysed during the current study are not publicly available because the participants have not granted permission for this. The datasets are available from the corresponding author on reasonable request.


The study was supported in part by grants from the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research (BMBF) to the German Centre for Diabetes Research (DZD). The study was supported by a grant of the DZD to AF.

Duality of interest

The study was initiated by the authors and there are no other sponsors other than those acknowledged. The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

All authors provided substantial contributions to the conception and design, acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content. They all gave final approval of the version to be published. The most important contributions of each author were as follows. VS and AF researched data and wrote the manuscript. RW, CS, LF, KK, AP and MH researched data and edited the manuscript. AF, NS and HUH designed the study, contributed to the discussion and reviewed the manuscript. AF is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Supplementary material

125_2017_4407_MOESM1_ESM.pdf (322 kb)
ESM Table 1 (PDF 321 kb)


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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Vera Schmid
    • 1
    • 2
  • Robert Wagner
    • 1
    • 3
    • 4
  • Corinna Sailer
    • 1
    • 3
    • 4
  • Louise Fritsche
    • 1
    • 3
    • 4
  • Konstantinos Kantartzis
    • 1
    • 3
    • 4
  • Andreas Peter
    • 1
    • 3
    • 4
  • Martin Heni
    • 1
    • 3
    • 4
  • Hans-Ulrich Häring
    • 1
    • 3
    • 4
  • Norbert Stefan
    • 1
    • 3
    • 4
  • Andreas Fritsche
    • 1
    • 3
    • 4
  1. 1.Department of Internal Medicine IVUniversity Hospital of TübingenTübingenGermany
  2. 2.International Research Training Group 1302University of TübingenTübingenGermany
  3. 3.Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of TübingenTübingenGermany
  4. 4.German Centre for Diabetes Research (DZD)TübingenGermany

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