Reduced Glucocorticoid Production Rate, Decreased 5α-Reductase Activity, and Adipose Tissue Insulin Sensitization After Weight Loss
Open accessAbstract
OBJECTIVE: The epidemics of obesity, insulin resistance, and type 2 diabetes have heightened the need to understand mechanisms that contribute to their pathogenesis. Increased endogenous glucocorticoid production has been implicated based on parallels with Cushing's syndrome. We have assessed the impact of weight loss on glucocorticoid secretion and metabolism (notably 11beta-hydroxysteroid dehydrogenase type 1 and 5alpha-reductase [5alphaR] activity) and insulin sensitivity. RESEARCH DESIGN AND METHODS: Twenty obese volunteers were investigated before and after weight loss. Patients underwent hyperinsulinemic-euglycemic clamps with simultaneous adipose microdialysis and oral cortisone acetate administration. Changes in glucocorticoid secretion and metabolism were assessed using 24-h urine collections. RESULTS: Before weight loss, fat mass correlated with glucocorticoid secretion rate (total fat, r = 0.46, P < 0.05; trunk fat, r = 0.52, P < 0.05); however, glucocorticoid secretion rate was inversely related to insulin sensitivity (r = -0.51, P < 0.05). Hyperinsulinemia failed to suppress adipose tissue interstitial fluid glycerol release (180 +/- 50 micromol [basal] vs. 153 +/- 10 micromol [steady state], NS). After oral cortisone (25 mg), cortisol concentrations within adipose interstitial fluid increased (4.3 +/- 1.1 vs. 14.2 +/- 2.6 nmol/l, P < 0.01), but glycerol concentrations did not change. After weight loss, insulin sensitivity increased. Consistent with insulin sensitization, adipose tissue interstitial fluid glycerol concentrations fell under hyperinsulinemic conditions (186 +/- 16 vs. 117 +/- 9 micromol, P < 0.05). Glucocorticoid secretion decreased (11,751 +/- 1,520 vs. 7,464 +/- 937 microg/24 h, P < 0.05) as did 5alphaR activity (5alpha-tetrahydrocortisol-to-tetrahydrocortisol ratio 1.41 +/- 0.16 vs. 1.12 +/- 0.17, P < 0.005). CONCLUSIONS: Obesity is associated with insulin resistance within adipose tissue and increased cortisol secretion rates; both are reversed with weight loss. Reduced 5alphaR activity after weight loss may decrease hypothalamo-pituitary-adrenal axis activation and reduce glucocorticoid metabolite production.
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Adrenal steroid production and metabolism are affected by sex, age, and BMI.
“Adrenal steroid production and metabolism are affected by sex, age, and BMI (342,345,346).”
From Adrenal incidentaloma (2020) · cites this paper as [346]
Glucocorticoid metabolites are higher in men than in women and in obese than in lean persons.
“Glucocorticoid metabolites are higher in men than in women and in obese than in lean persons (345,346).”
From Adrenal incidentaloma (2020) · cites this paper as [346]
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References 39 · Cited by 91
- Authors
- Tomlinson, J. W., Finney, J., Hughes, B. A., Hughes, S. V., & Stewart, P. M.
- Affiliations
- University of Birmingham (GB)
- National Health Service (GB)
- Corresponding author
- Tomlinson, Jeremy W.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-06-01
- Volume
- 57
- Issue
- 6
- Pages
- 1536-1543
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC7611651
- OpenAlex
- W2137686969
- Cited by
- 91
- References
- 39
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 10 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 10 · 2013: 3 · 2012: 5
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust (066357, 075322)
- Medical Research Council
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- glucocorticoid secretion, 5alpha-reductase activity, 11β-hydroxysteroid dehydrogenase type 1, adipose tissue insulin sensitivity, weight loss, obesity, insulin resistance, type 2 diabetes, hyperinsulinemic-euglycemic clamp, cortisone acetate, glycerol release
- MeSH terms
- Adipose Tissue, Adult, Body Composition, Energy Intake, Diet, Reducing, Female, Glucocorticoids, Humans, Hyperinsulinism, Insulin, Kinetics, Male, Middle Aged, Obesity, Glucose Clamp Technique, Weight Loss, Body Mass Index, Cholestenone 5 alpha-Reductase
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