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Digestive Diseases and Sciences

, Volume 57, Issue 11, pp 3017–3025 | Cite as

Elevation of Alanine Transaminase and Markers of Liver Fibrosis After a Mixed Meal Challenge in Individuals with Type 2 Diabetes

  • E. Y. H. KhooEmail author
  • M. C. Stevenson
  • E. Leverton
  • R. Cross
  • J. W. Eriksson
  • S. M. Poucher
  • I. Spendlove
  • P. G. Morris
  • I. A. Macdonald
  • P. Mansell
  • G. P. Aithal
Original Article

Abstract

Background

Hyperalimentation for 4 weeks is associated with raised liver enzymes and liver fat content (LFC), which are two common features found in individuals with diabetes.

Aim

We evaluated the effect of two mixed meal challenges on LFC, liver enzymes and serum bio-markers of liver injury and fibrosis in 16 healthy volunteers (HV) and subjects with type 2 diabetes (T2DM).

Methods

Subjects (HV: 9 male, 7 female, aged 57.9 ± 1.7 years, body mass index (BMI) 27.1 kg/m2; and T2DM: 11 male, 5 female, aged 62.1 ± 1.3 years, BMI 28.0 ± 0.4 kg/m2) consumed two meals at 1 h (884 kcal) and at 6 h (1,096 kcal). LFC determined by 1H magnetic resonance spectroscopy, serum levels of liver enzymes, hyaluronic acid (HA), procollagen III N-terminal peptide (P3NP) and tissue inhibitor metalloproteinase-1 (TIMP-1) were estimated at time 0 (fasting) and 9 h (postprandial).

Results

Fasting LFC was higher in the T2DM group 7.6 % (4.9, 15.4) [median (inter-quartile range)] than in the HV group 2.3 % (0.8, 5.1) (p < 0.05) while levels of HA, P3NP and TIMP-1 were similar. Following the meal challenge there was no significant change in LFC. Subjects with T2DM had higher post-prandial rise in alanine transaminase (ALT) (p = 0.014), serum HA (p = 0.007) and P3NP (p = 0.015) compared with HV. Fasting LFC correlated with a greater post-prandial increase in P3NP levels in all subjects (Pearson correlation r = 0.53, p = 0.001).

Conclusions

In subjects with T2DM, a mixed meal challenge is associated with a significant elevation in the serum levels of ALT, HA and P3NP without significant changes in LFC. These markers should be performed in the fasted state.

Keywords

Diabetes mellitus Hyper-alimentation Liver fat content Liver fibrosis Magnetic resonance spectroscopy Obesity 

Abbreviations

LFC

Liver fat content

BMI

Body mass index

T2DM

Type 2 diabetes mellitus

HA

Hyaluronic acid

P3NP

Procollagen III N-terminal peptide

TIMP-1

Tissue inhibitor metalloproteinase-1

ALT

Alanine aminotransferase

HV

Healthy volunteers

NAFLD

Nonalcoholic fatty liver disease

1H MRS

Magnetic resonance spectroscopy

MR

Magnetic resonance

TG

Triglyceride

FFA

Free fatty acid

THRIVE

T-1 (weighted) high resolution isotropic volume excitation image

TFE

Turbo field echo

PRESS

Point resolved spectroscopy

TE/TR

Echo time for PRESS sequence/repetition time

GGT

Gamma-glutamyl transpeptidase

ALP

Alkaline phosphatase

Bil

Bilirubin

HDL-cholesterol

High density lipoprotein-cholesterol

LDL-c

Low density lipoprotein-cholesterol

IL

Interleukin

MCP-1

Monocyte chemoattractant

TNFα

Tumor necrosis factor alpha

TGFβ

Transforming growth factor-beta

HbA1c

Glycated hemoglobin A1c

HOMA-IR

Homeostatic model assessment

Notes

Acknowledgments

This work was supported by AstraZeneca, Europe. The study was investigator led and the authors had complete independence from the funder.

Conflict of interest

RC is an employee of iQur Ltd and his role was the analysis of serum HA, amino-terminal P3NP, and TIMP-1 as well as editing the manuscript. JWE and SMP are employees of Astrazeneca, Europe.

References

  1. 1.
    Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98:960–967.PubMedCrossRefGoogle Scholar
  2. 2.
    Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol. 2001;35:195–199.PubMedCrossRefGoogle Scholar
  3. 3.
    Hyeon CK, Chung MN, Sun HJ, et al. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983.CrossRefGoogle Scholar
  4. 4.
    Ruhl CE, Everhart JE. Elevated serum alanine aminotransferase and G-glutamyltransferase and mortality in the United States population. Gastroenterology. 2009;136:477–485.PubMedCrossRefGoogle Scholar
  5. 5.
    Adams LA, Waters OR, Knuiman MW, et al. NAFLD as a risk factor for the development of diabetes and the metabolic syndrome: an eleven-year follow-up study. Am J Gastroenterol. 2009;104:861–867.PubMedCrossRefGoogle Scholar
  6. 6.
    Guha I, Parkes J, Roderick P, et al. Non-invasive markers associated with liver fibrosis in non-alcoholic fatty liver disease. Gut. 2006;55:1650–1660.PubMedCrossRefGoogle Scholar
  7. 7.
    Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–845.PubMedCrossRefGoogle Scholar
  8. 8.
    Tiikkainen M, Bergholm R, Vehkavaara S, et al. Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes. 2003;52:701–707.PubMedCrossRefGoogle Scholar
  9. 9.
    Kechagias S, Ernersson A, Dahlqvist O, et al. Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut. 2008;57:649–654.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Eahceioglu IH, Yalniz M, Ataseven H, et al. Levels of serum hyaluronic acid, TNF- and IL-8 in patients with nonalcoholic steatohepatitis. Hepatogastroenterology. 2005;52:1549–1553.Google Scholar
  11. 11.
    Siri W. Body composition from fluid space and density: analysis of methods. In: Brozek J, Henschel A, eds. Techniques for measuring body composition. Washington, DC: National Academy of Science; 1961. pp. 223–224.Google Scholar
  12. 12.
    Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man [see comment]. Diabetologia. 1985;28:412–419.PubMedCrossRefGoogle Scholar
  13. 13.
    Fabbrini E, Magkos F, Mohammed BS, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Nat Acad Sci. 2009;106:15430–15435.PubMedCrossRefGoogle Scholar
  14. 14.
    Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–1351.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Kirk E, Reeds DN, Finck BN, et al. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology. 2009;136:1552–1560.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Horton TJ, Drougas H, Brachey A, et al. Fat and carbohydrate overfeeding in humans: different effects on energy storage. Am J Clin Nutr. 1995;62:19–29.PubMedGoogle Scholar
  17. 17.
    Bortolotti M, Kreis R, Debard C, et al. High protein intake reduces intrahepatocellular lipid deposition in humans. Am J Clin Nutr. 2009;90:1002–1010.PubMedCrossRefGoogle Scholar
  18. 18.
    Johnson NA, Sachinwalla T, Walton DW, et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology. 2009;50:1105–1112.PubMedCrossRefGoogle Scholar
  19. 19.
    Lawlor DA, Sattar N, Smith GD, et al. The associations of physical activity and adiposity with alanine aminotransferase and gamma-glutamyltransferase. Am J Epidemiol. 2005;161:1081–1088.PubMedCrossRefGoogle Scholar
  20. 20.
    Rosenberg W, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127:1704–1713.PubMedCrossRefGoogle Scholar
  21. 21.
    Guha IN, Parkes J, Roderick P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47:455–460.PubMedCrossRefGoogle Scholar
  22. 22.
    Horslev-Petersen K, Bentsen K, Halberg P, et al. Connective tissue metabolites in serum as markers of disease activity in patients with rheumatoid arthritis. Clin Exp Rheumatol. 1988;6:129–134.PubMedGoogle Scholar
  23. 23.
    Montazeri G, Estakhri A, Mohamadnejad M, et al. Serum hyaluronate as a non-invasive marker of hepatic fibrosis and inflammation in HBeAg-negative chronic hepatitis B. BMC Gastroenterol. 2005;5:32.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–1669.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Parsons CJ, Takashima M, Rippe RA. Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol. 2007;22:S79–S84.PubMedCrossRefGoogle Scholar
  26. 26.
    Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointest Liver Dis. 2007;16:39–46.Google Scholar
  27. 27.
    Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis. 2004;174:193–196.PubMedCrossRefGoogle Scholar
  28. 28.
    Nelson A, Torres DM, Morgan AE, et al. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol. 2009;43:990–994.PubMedCrossRefGoogle Scholar
  29. 29.
    Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation. 2002;106:2067–2072.PubMedCrossRefGoogle Scholar
  30. 30.
    Mayo MJ, Parkes J. Prediction of clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology. 2008;48:1549–1557.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • E. Y. H. Khoo
    • 1
    Email author
  • M. C. Stevenson
    • 2
  • E. Leverton
    • 2
  • R. Cross
    • 3
  • J. W. Eriksson
    • 4
    • 5
  • S. M. Poucher
    • 6
  • I. Spendlove
    • 7
  • P. G. Morris
    • 2
  • I. A. Macdonald
    • 7
  • P. Mansell
    • 7
    • 8
  • G. P. Aithal
    • 9
  1. 1.Division of Endocrinology, Department of Medicine, Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
  2. 2.Sir Peter Mansfield Magnetic Resonance CentreUniversity of NottinghamNottinghamUK
  3. 3.iQur LtdSouthamptonUK
  4. 4.AstraZeneca R&DMölndalSweden
  5. 5.Institute of MedicineSahlgrenska University HospitalGothenburgSweden
  6. 6.Discovery DepartmentAstrazeneca PharmaceuticalsMacclesfieldUK
  7. 7.School of Biomedical SciencesUniversity of NottinghamNottinghamUK
  8. 8.Department of Diabetes and EndocrinologyNottingham University HospitalsNottinghamUK
  9. 9.National Institute for Health Research Biomedical UnitNottingham University HospitalsNottinghamUK

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