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Hepatic 11β-hydroxysteroid dehydrogenase type 1 activity in obesity and type 2 diabetes using a novel triple tracer cortisol technique

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Abstract

Aims/hypothesis

Dysregulation of 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme activities are implicated in the pathogenesis of obesity and insulin resistance. The aim of the study was to determine whether hepatic 11β-HSD type 1 (11β-HSD-1) enzyme activity differs in people with and without obesity and type 2 diabetes.

Methods

We measured hepatic 11β-HSD-1 activity in the overnight fasted state in 20 lean non-diabetic participants (LND), 21 overweight/obese non-diabetic participants (OND) and 20 overweight/obese participants with type 2 diabetes (ODM) using a non-invasive approach. One mg doses of [9,12,12-2H3]cortisol (D cortisol) and [4-13C]cortisone ([13C]cortisone) were ingested, while [1,2,6,7-3H]cortisol ([3H] cortisol) was infused intravenously to enable concurrent measurements of first-pass hepatic extraction of ingested D cortisol and hepatic conversion of ingested [13C]cortisone to C13 cortisol derived from the ingested cortisone (a measure of 11β-HSD-1 activity in the liver) using an isotope dilution technique. One-way ANOVA models and Kruskal–Wallis tests were used to test the hypothesis.

Results

Plasma D cortisol and C13 cortisol concentrations were lower in OND than in LND (p < 0.05) over 6 h of the study. There was no difference (p = 0.15) in C13 and D cortisol concentrations between OND and ODM and between LND and ODM for the same study period. Hepatic conversion of [13C]cortisone to C13 cortisol was similar between groups.

Conclusions/interpretation

Hepatic conversion of [13C]cortisone to C13 cortisol did not differ between the groups studied. We conclude that hepatic 11β-HSD-1 activity is similar in individuals who are overweight/obese or who have type 2 diabetes.

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Abbreviations

[13C]Cortisone:

[4-13C]Cortisone

[3H]Cortisol:

[1,2,6,7-3H]Cortisol

C13 Cortisol:

Cortisol derived from ingested [13C]cortisone

CTSA:

Mayo Clinic Center for Translational Science Activities

D Cortisol:

[9,12,12-2H3]Cortisol

D Cortisone:

[9,12,12-2H3]Cortisone

dpm:

Disintegrations per minute

11β-HSD:

11β-Hydroxysteroid dehydrogenase

11β-HSD-1:

11β-Hydroxysteroid dehydrogenase type 1

LND:

Lean non-diabetic participants

MPE:

Mole per cent enrichment

MR:

Molar ratio

OND:

Overweight/obese non-diabetic participants

ODM:

Overweight/obese participants with type 2 diabetes

Ra:

Rate of appearance

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Acknowledgements

We give our deepest appreciation and thanks to R. A. Rizza (Mayo Clinic) for his valuable and constructive suggestions. We are deeply indebted to the research participants. Our sincere thanks go to the staff of the CTSA, the Clinical Research Unit, the CTSA Immunochemical Core Laboratory, and the CTSA Metabolomics Core Facility (M. Persson). We wish to thank Mayo Clinic staff; C. Shonkwiler (research nurse), P. Reich (research assistant), B. Dicke (laboratory technician) and M. Slama (laboratory technician) for their technical assistance; B. McConahey (laboratory technician) for technical assistance and graphic design; and C. Speltz (medical secretary) and L. Kvall Boynton (secretary) for assistance with preparation of the manuscript.

Funding

The work was supported by National Institutes of Health grants R01 DK29953 and UL1 TR000135 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health.

Duality of interest

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

Contribution statement

SD researched the data, managed the data handling and data analyses, and assisted with writing the manuscript. BN assisted with the acquisition of data and conduct of the study. VP assisted with the conduct of the study and the acquisition and analyses of data. REC and RKL assisted with the acquisition of data and the statistical analyses. RJS assisted with the mass spectrometry data acquisition and analyses. AB assisted with the study design, data analyses and manuscript editing. RB assisted with the study design, researched the data, assisted with the conduct of the study, data analyses and writing the manuscript. All authors were involved with editing the manuscript and approving the final version to be published. RB is the guarantor of this manuscript and is responsible for the integrity of this work.

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Authors and Affiliations

  1. Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo College of Medicine, Joseph 5-194, 200 First Street, SW, Rochester, MN, 55905, USA

    Simmi Dube, Barbara Norby, Vishwanath Pattan, Ananda Basu & Rita Basu

  2. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Ravi K. Lingineni & Rickey E. Carter

  3. Division of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Ravinder J. Singh

Authors
  1. Simmi Dube
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  2. Barbara Norby
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  3. Vishwanath Pattan
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  4. Ravi K. Lingineni
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  5. Ravinder J. Singh
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  6. Rickey E. Carter
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  7. Ananda Basu
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  8. Rita Basu
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Corresponding author

Correspondence to Rita Basu.

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Dube, S., Norby, B., Pattan, V. et al. Hepatic 11β-hydroxysteroid dehydrogenase type 1 activity in obesity and type 2 diabetes using a novel triple tracer cortisol technique. Diabetologia 57, 1446–1455 (2014). https://doi.org/10.1007/s00125-014-3240-x

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  • DOI: https://doi.org/10.1007/s00125-014-3240-x

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