Altered cortisol metabolism in individuals with HNF1A-MODY
Author(s)
Type
Journal Article
Abstract
Objective and context
Maturity onset diabetes of the young due to variants in HNF1A (HNF1A-MODY) is the most common form of monogenic diabetes. Individuals with HNF1A-MODY usually have a lean phenotype which contrasts with type 2 diabetes (T2DM). Data from hepatocytes derived from Hnf1a knock-out mice demonstrated dysregulation of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regulates glucocorticoid availability and action in target tissues, together with 11β-HSD2 and steroid A-ring reductases, 5α- and 5β-reductase. We proposed that altered glucocorticoid metabolism might underpin some of the phenotypic differences between patients with HNF1A-MODY and those with T2DM.
Design
A retrospective matched cohort study.
Patients and measurements
24-hours urine steroid metabolome profiling was carried out by gas chromatography-mass spectrometry in 35 subjects with HNF1A-MODY, 35 individuals with T2DM and 35 healthy controls matched for age, sex and BMI. The steroid metabolites were expressed as μg/L in all groups and measured in mid-morning urine in diabetic subjects and 24-hour urine collection in healthy controls. Hence, only ratios were compared not the individual steroids. Established ratios of glucocorticoid metabolites were used to estimate 11β-HSD1/2 and 5α- and 5β-reductase activities.
Results
While 11β-HSD1 activity was similar in all groups, 11β-HSD2 activity was significantly lower in subjects with HNF1A-MODY and T2DM than in healthy controls. The ratio of 5β- to 5α-metabolites of cortisol was higher in subjects with HNF1A-MODY than in T2DM and healthy controls, probably due to increased activity of the 5β-reductase (AKR1D1) in HNF1A-MODY.
Conclusions
This is the first report of steroid metabolites in HNF1A-MODY. We have identified distinct differences in steroid metabolism pathways in subjects with HNF1A-MODY that have the potential to alter steroid hormone availability. Further studies are required to explore whether these changes link to phenotype.
Maturity onset diabetes of the young due to variants in HNF1A (HNF1A-MODY) is the most common form of monogenic diabetes. Individuals with HNF1A-MODY usually have a lean phenotype which contrasts with type 2 diabetes (T2DM). Data from hepatocytes derived from Hnf1a knock-out mice demonstrated dysregulation of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regulates glucocorticoid availability and action in target tissues, together with 11β-HSD2 and steroid A-ring reductases, 5α- and 5β-reductase. We proposed that altered glucocorticoid metabolism might underpin some of the phenotypic differences between patients with HNF1A-MODY and those with T2DM.
Design
A retrospective matched cohort study.
Patients and measurements
24-hours urine steroid metabolome profiling was carried out by gas chromatography-mass spectrometry in 35 subjects with HNF1A-MODY, 35 individuals with T2DM and 35 healthy controls matched for age, sex and BMI. The steroid metabolites were expressed as μg/L in all groups and measured in mid-morning urine in diabetic subjects and 24-hour urine collection in healthy controls. Hence, only ratios were compared not the individual steroids. Established ratios of glucocorticoid metabolites were used to estimate 11β-HSD1/2 and 5α- and 5β-reductase activities.
Results
While 11β-HSD1 activity was similar in all groups, 11β-HSD2 activity was significantly lower in subjects with HNF1A-MODY and T2DM than in healthy controls. The ratio of 5β- to 5α-metabolites of cortisol was higher in subjects with HNF1A-MODY than in T2DM and healthy controls, probably due to increased activity of the 5β-reductase (AKR1D1) in HNF1A-MODY.
Conclusions
This is the first report of steroid metabolites in HNF1A-MODY. We have identified distinct differences in steroid metabolism pathways in subjects with HNF1A-MODY that have the potential to alter steroid hormone availability. Further studies are required to explore whether these changes link to phenotype.
Date Issued
2020-09-01
Date Acceptance
2020-04-20
Citation
Clinical Endocrinology, 2020, 93 (3), pp.269-279
ISSN
0300-0664
Publisher
Wiley
Start Page
269
End Page
279
Journal / Book Title
Clinical Endocrinology
Volume
93
Issue
3
Copyright Statement
© 2020 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32395877
Subjects
11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1
5-ALPHA-REDUCTASE
BETA-HYDROXYSTEROID DEHYDROGENASE
Endocrinology & Metabolism
EXPRESSION
HEPATOCYTE NUCLEAR FACTOR-1-ALPHA
HNF1A
Life Sciences & Biomedicine
MASS
MODY
Science & Technology
SELECTIVE-INHIBITION
SENSITIVITY
urinary steroids
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2020-05-12