, Volume 58, Issue 2, pp 374–383 | Cite as

Nutritional strategy to prevent fatty liver and insulin resistance independent of obesity by reducing glucose-dependent insulinotropic polypeptide responses in mice

  • Farnaz Keyhani-Nejad
  • Martin Irmler
  • Frank Isken
  • Eva K. Wirth
  • Johannes Beckers
  • Andreas L. Birkenfeld
  • Andreas F. H. PfeifferEmail author



High intake of carbohydrates, particularly sucrose, in western societies is associated with the development of non-alcoholic fatty liver (NAFL) and diabetes mellitus. It is unclear whether this is related primarily to the carbohydrate quantity or to the hormonal responses, particularly glucose-dependent insulinotropic polypeptide (GIP), which is released in the proximal intestine. Therefore, we investigated the role of GIP by comparing two glucose–fructose dimers, sucrose and Palatinose (isomaltulose), resorbed proximally or distally.


The glycaemic and incretin responses to sucrose and Palatinose were studied by oral gavage and meal tests. We then analysed phenotypic and metabolic diet-induced changes in C57Bl/6J mice exposed to isoenergetic diets differing in carbohydrate type. Studies were repeated in GIP receptor knockout (Gipr −/−) mice and their wild-type littermates.


Compared with sucrose, Palatinose intake resulted in slower glucose absorption and reduced postprandial insulin and GIP levels. After 22 weeks, Palatinose feeding prevented hepatic steatosis (48.5%) compared with sucrose and improved glucose tolerance, without differences in body composition and food intake. Ablation of GIP signalling in Gipr −/− mice completely prevented the deleterious metabolic effects of sucrose feeding. Furthermore, our microarray analysis indicated that sucrose increased 2.3-fold the hepatic expression of Socs2, which is involved in the growth hormone signalling pathway and participates in the development of NAFL.


Our results suggest that the site of glucose absorption and the GIP response determine liver fat accumulation and insulin resistance. GIP may play a role in sucrose induced fatty liver by regulating the expression of Socs2.


Fatty liver GIP response Palatinose 



Alanine aminotransferase


Body weight


Food intake


Fatty liver


Growth hormone


Glycaemic index


Glucose-dependent insulinotropic polypeptide


Glucagon like peptide 1


Glucose tolerance test


High fat diet


Insulin resistance


Non-alcoholic fatty liver


Suppressor of cytokine signalling 2




Total energy expenditure



The authors would like to acknowledge the excellent technical assistance of S. Richter and K. Sprengel (Department of Clinical Nutrition, German Institute of Human Nutrition, Nuthetal, Germany) for metabolite measurements, A. Bettenbrock (Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München GmbH, Neuherberg, Germany) for performing microarray experiments.


This study was partially supported by a grant from the German Research Foundation (PF164/14-2) to AFHP, by a grant from the German Research Foundation (BI1292/4-1) to ALB, and by a grant from the Helmholtz Alliance ICEMED to JB.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

FKN designed experiments, researched data, wrote and edited the manuscript. FI designed experiments and researched data. MI researched and analysed microarray data, wrote and edited the manuscript. EKW researched data, wrote and edited the manuscript. JB researched and analysed microarray data, wrote and edited the manuscript. ALB researched data, wrote and edited the manuscript. AFHP designed experiments, wrote and edited the manuscript and obtained funding supporting the research. AFHP has full access to all data in the study and takes responsibility for the integrity of data and the accuracy of the data analysis. All authors approved the final version of the manuscript.

FI passed away and was not involved in drafting the paper.

Supplementary material

125_2014_3423_MOESM1_ESM.pdf (7 kb)
ESM Methods (PDF 6 kb)
125_2014_3423_MOESM2_ESM.pdf (88 kb)
ESM Table 1 (PDF 87 kb)
125_2014_3423_MOESM3_ESM.xls (158 kb)
ESM Table 2 (XLS 158 kb)
125_2014_3423_MOESM4_ESM.pdf (167 kb)
ESM Table 3 (PDF 167 kb)
125_2014_3423_MOESM5_ESM.pdf (17 kb)
ESM Fig. 1 (PDF 17 kb)
125_2014_3423_MOESM6_ESM.pdf (23 kb)
ESM Fig. 2 (PDF 23 kb)
125_2014_3423_MOESM7_ESM.pdf (11 kb)
ESM Fig. 3 (PDF 10 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Farnaz Keyhani-Nejad
    • 1
    • 2
    • 3
  • Martin Irmler
    • 4
  • Frank Isken
    • 1
    • 2
  • Eva K. Wirth
    • 5
  • Johannes Beckers
    • 3
    • 4
    • 6
  • Andreas L. Birkenfeld
    • 2
    • 7
  • Andreas F. H. Pfeiffer
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Clinical NutritionGerman Institute of Human NutritionNuthetalGermany
  2. 2.Department for Endocrinology, Diabetes and NutritionCharité – University of MedicineBerlinGermany
  3. 3.German Center for Diabetes Research (DZD)MunichGermany
  4. 4.Institute of Experimental Genetics and German Mouse ClinicHelmholtz Zentrum München GmbHNeuherbergGermany
  5. 5.Institute of Experimental EndochrinologyCharité – University of MedicineBerlinGermany
  6. 6.Department of Experimental GeneticsTechnical University MunichFreising-WeihenstephanGermany
  7. 7.Medical Department III and Paul Langerhans InstituteDresden University School of MedicineDresdenGermany

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