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

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Abstract

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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.

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Abbreviations

ALT:

Alanine aminotransferase

BW:

Body weight

FI:

Food intake

FL:

Fatty liver

GH:

Growth hormone

GI:

Glycaemic index

GIP:

Glucose-dependent insulinotropic polypeptide

GLP-1:

Glucagon like peptide 1

GTT:

Glucose tolerance test

HFD:

High fat diet

IR:

Insulin resistance

NAFL:

Non-alcoholic fatty liver

SOCS2:

Suppressor of cytokine signalling 2

TG:

Triacylglycerol

TEE:

Total energy expenditure

References

  1. Williams CD, Stengel J, Asike MI et al (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140:124–131

    Article  PubMed  Google Scholar 

  2. Krawczyk M, Bonfrate L, Portincasa P (2010) Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 24:695–708

    Article  CAS  PubMed  Google Scholar 

  3. Marchesini G, Bugianesi E, Forlani G et al (2003) Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:917–923

    Article  PubMed  Google Scholar 

  4. Birkenfeld AL, Shulman GI (2014) Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 59:713–723

    Article  PubMed  Google Scholar 

  5. Rudovich NN, Weickert MO, Machann J, Pfeiffer AF (2010) Combination of acarbose and ezetimibe prevents non-alcoholic fatty liver disease: a break of intestinal insulin resistance? J Hepatol 52:952–953

    Article  PubMed  Google Scholar 

  6. Sato K, Arai H, Mizuno A et al (2007) Dietary palatinose and oleic acid ameliorate disorders of glucose and lipid metabolism in Zucker fatty rats. J Nutr 137:1908–1915

    CAS  PubMed  Google Scholar 

  7. Daly M (2003) Sugars, insulin sensitivity, and the postprandial state. Am J Clin Nutr 78:865S–872S

    CAS  PubMed  Google Scholar 

  8. Kawai K, Yoshikawa H, Murayama Y, Okuda Y, Yamashita K (1989) Usefulness of palatinose as a caloric sweetener for diabetic patients. Horm Metab Res 21:338–340

    Article  CAS  PubMed  Google Scholar 

  9. Isken F, Klaus S, Petzke KJ, Loddenkemper C, Pfeiffer AF, Weickert MO (2010) Impairment of fat oxidation under high- vs. low-glycemic index diet occurs before the development of an obese phenotype. Am J Physiol Endocrinol Metab 298:E287–E295

    Article  CAS  PubMed  Google Scholar 

  10. Mortensen K, Christensen LL, Holst JJ, Orskov C (2003) GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul Pept 114:189–196

    Article  CAS  PubMed  Google Scholar 

  11. Yip RG, Wolfe MM (2000) GIP biology and fat metabolism. Life Sci 66:91–103

    Article  CAS  PubMed  Google Scholar 

  12. Shimotoyodome A, Suzuki J, Fukuoka D, Tokimitsu I, Hase T (2010) RS4-type resistant starch prevents high-fat diet-induced obesity via increased hepatic fatty acid oxidation and decreased postprandial GIP in C57BL/6J mice. Am J Physiol Endocrinol Metab 298:E652–E662

    Article  CAS  PubMed  Google Scholar 

  13. Musso G, Gambino R, Pacini G, De Michieli F, Cassader M (2009) Prolonged saturated fat-induced, glucose-dependent insulinotropic polypeptide elevation is associated with adipokine imbalance and liver injury in nonalcoholic steatohepatitis: dysregulated enteroadipocyte axis as a novel feature of fatty liver. Am J Clin Nutr 89:558–567

    Article  CAS  PubMed  Google Scholar 

  14. Isken F, Weickert MO, Tschop MH et al (2009) Metabolic effects of diets differing in glycaemic index depend on age and endogenous glucose-dependent insulinotrophic polypeptide in mice. Diabetologia 52:2159–2168

    Article  CAS  PubMed  Google Scholar 

  15. Haberer D, Thibault L, Langhans W, Geary N (2009) Beneficial effects on glucose metabolism of chronic feeding of isomaltulose versus sucrose in rats. Ann Nutr Metab 54:75–82

    Article  CAS  PubMed  Google Scholar 

  16. Matsuo K, Arai H, Muto K et al (2007) The anti-obesity effect of the palatinose-based formula Inslow is likely due to an increase in the hepatic PPAR-alpha and adipocyte PPAR-gamma gene expressions. J Clin Biochem Nutr 40:234–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Rico-Bautista E, Flores-Morales A, Fernandez-Perez L (2006) Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine Growth Factor Rev 17:431–439

    Article  CAS  PubMed  Google Scholar 

  18. Zadjali F, Santana-Farre R, Vesterlund M et al (2012) SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice. FASEB J 26:3282–3291

    Article  CAS  PubMed  Google Scholar 

  19. Preitner F, Ibberson M, Franklin I et al (2004) Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J Clin Invest 113:635–645

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Isken F, Klaus S, Osterhoff M, Pfeiffer AF, Weickert MO (2010) Effects of long-term soluble vs. insoluble dietary fiber intake on high-fat diet-induced obesity in C57BL/6J mice. J Nutr Biochem 21:278–284

    Article  CAS  PubMed  Google Scholar 

  21. Valentini L, Wirth EK, Schweizer U et al (2009) Circulating adipokines and the protective effects of hyperinsulinemia in inflammatory bowel disease. Nutrition 25:172–181

    Article  CAS  PubMed  Google Scholar 

  22. Rainer J, Sanchez-Cabo F, Stocker G, Sturn A, Trajanoski Z (2006) CARMAweb: comprehensive R- and bioconductor-based web service for microarray data analysis. Nucleic Acids Res 34:W498–W503

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Tollet-Egnell P, Flores-Morales A, Stavreus-Evers A, Sahlin L, Norstedt G (1999) Growth hormone regulation of SOCS-2, SOCS-3, and CIS messenger ribonucleic acid expression in the rat. Endocrinology 140:3693–3704

    CAS  PubMed  Google Scholar 

  24. Lina BA, Jonker D, Kozianowski G (2002) Isomaltulose (Palatinose): a review of biological and toxicological studies. Food Chem Toxicol 40:1375–1381

    Article  CAS  PubMed  Google Scholar 

  25. Arai H, Mizuno A, Matsuo K et al (2004) Effect of a novel palatinose-based liquid balanced formula (MHN-01) on glucose and lipid metabolism in male Sprague-Dawley rats after short- and long-term ingestion. Metabolism 53:977–983

    Article  CAS  PubMed  Google Scholar 

  26. Takeda E, Arai H, Yamamoto H, Okumura H, Taketani Y (2005) Control of oxidative stress and metabolic homeostasis by the suppression of postprandial hyperglycemia. J Med Invest 52(Suppl):259–265

    Article  PubMed  Google Scholar 

  27. Park JH, Kwon OD, Ahn SH, Lee S, Choi BK, Jung KY (2013) Fatty diets retarded the propulsive function of and attenuated motility in the gastrointestinal tract of rats. Nutr Res 33:228–234

    Article  CAS  PubMed  Google Scholar 

  28. Goff LM, Cowland DE, Hooper L, Frost GS (2013) Low glycaemic index diets and blood lipids: a systematic review and meta-analysis of randomised controlled trials. Nutrition, metabolism, and cardiovascular diseases. Nutr Metab Cardiovasc Dis 23:1–10

    Article  CAS  PubMed  Google Scholar 

  29. Kendall DM, Sobel BE, Coulston AM et al (2003) The insulin resistance syndrome and coronary artery disease. Coron Artery Dis 14:335–348

    Article  PubMed  Google Scholar 

  30. Cummings JH, Englyst HN (1995) Gastrointestinal effects of food carbohydrate. Am J Clin Nutr 61:938S–945S

    CAS  PubMed  Google Scholar 

  31. Chinda D, Nakaji S, Fukuda S et al (2004) The fermentation of different dietary fibers is associated with fecal clostridia levels in men. J Nutr 134:1881–1886

    CAS  PubMed  Google Scholar 

  32. Tonouchi H, Yamaji T, Uchida M et al (2011) Studies on absorption and metabolism of palatinose (isomaltulose) in rats. Br J Nutr 105:10–14

    Article  CAS  PubMed  Google Scholar 

  33. Naitoh R, Miyawaki K, Harada N et al (2008) Inhibition of GIP signaling modulates adiponectin levels under high-fat diet in mice. Biochem Biophys Res Commun 376:21–25

    Article  CAS  PubMed  Google Scholar 

  34. McClean PL, Irwin N, Cassidy RS, Holst JJ, Gault VA, Flatt PR (2007) GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am J Physiol Endocrinol Metab 293:E1746–E1755

    Article  CAS  PubMed  Google Scholar 

  35. Knight ZA, Hannan KS, Greenberg ML, Friedman JM (2010) Hyperleptinemia is required for the development of leptin resistance. PLoS One 5:e11376

    Article  PubMed Central  PubMed  Google Scholar 

  36. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS (1995) Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1:1311–1314

    Article  CAS  PubMed  Google Scholar 

  37. Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451

    Article  CAS  PubMed  Google Scholar 

  38. Shimabukuro M, Koyama K, Chen G et al (1997) Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A 94:4637–4641

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Elam MB, Cowan GS Jr, Rooney RJ et al (2009) Hepatic gene expression in morbidly obese women: implications for disease susceptibility. Obesity (Silver Spring) 17:1563–1573

    Article  CAS  Google Scholar 

  40. Tateno C, Kataoka M, Utoh R et al (2011) Growth hormone-dependent pathogenesis of human hepatic steatosis in a novel mouse model bearing a human hepatocyte-repopulated liver. Endocrinology 152:1479–1491

    Article  CAS  PubMed  Google Scholar 

  41. Fan Y, Menon RK, Cohen P et al (2009) Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J Biol Chem 284:19937–19944

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Umahara M, Okada S, Ohshima K, Mori M (2003) Glucose-dependent insulinotropic polypeptide induced growth hormone secretion in acromegaly. Endocr J 50:643–650

    Article  CAS  PubMed  Google Scholar 

  43. Occhi G, Losa M, Albiger N et al (2011) The glucose-dependent insulinotropic polypeptide receptor is overexpressed amongst GNAS1 mutation-negative somatotropinomas and drives growth hormone (GH)-promoter activity in GH3 cells. J Neuroendocrinol 23:641–649

    Article  CAS  PubMed  Google Scholar 

  44. Kraus D, Yang Q, Kong D et al (2014) Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508:258–262

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Department of Clinical Nutrition, German Institute of Human Nutrition, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany

    Farnaz Keyhani-Nejad, Frank Isken & Andreas F. H. Pfeiffer

  2. Department for Endocrinology, Diabetes and Nutrition, Charité – University of Medicine, Berlin, Germany

    Farnaz Keyhani-Nejad, Frank Isken, Andreas L. Birkenfeld & Andreas F. H. Pfeiffer

  3. German Center for Diabetes Research (DZD), Munich, Germany

    Farnaz Keyhani-Nejad, Johannes Beckers & Andreas F. H. Pfeiffer

  4. Institute of Experimental Genetics and German Mouse Clinic, Helmholtz Zentrum München GmbH, Neuherberg, Germany

    Martin Irmler & Johannes Beckers

  5. Institute of Experimental Endochrinology, Charité – University of Medicine, Berlin, Germany

    Eva K. Wirth

  6. Department of Experimental Genetics, Technical University Munich, Freising-Weihenstephan, Germany

    Johannes Beckers

  7. Medical Department III and Paul Langerhans Institute, Dresden University School of Medicine, Dresden, Germany

    Andreas L. Birkenfeld

Authors
  1. Farnaz Keyhani-Nejad
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  2. Martin Irmler
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  3. Frank Isken
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  4. Eva K. Wirth
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  5. Johannes Beckers
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  6. Andreas L. Birkenfeld
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  7. Andreas F. H. Pfeiffer
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Corresponding author

Correspondence to Andreas F. H. Pfeiffer.

Additional information

Dr Frank Isken, who contributed to this research, passed away on 4 October 2010 prior to the publication of this work.

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Keyhani-Nejad, F., Irmler, M., Isken, F. et al. Nutritional strategy to prevent fatty liver and insulin resistance independent of obesity by reducing glucose-dependent insulinotropic polypeptide responses in mice. Diabetologia 58, 374–383 (2015). https://doi.org/10.1007/s00125-014-3423-5

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