Novel insights into glucocorticoid‐mediated diabetogenic effects: towards expansion of therapeutic options?

Van Raalte, D. H.; Ouwens, D. M.; Diamant, M.

doi:10.1111/j.1365-2362.2008.02067.x

Cited by 439Adrenal Hormones and DisordersAdipokines, Inflammation, and Metabolic DiseasesEstrogen and related hormone effects

Novel insights into glucocorticoid‐mediated diabetogenic effects: towards expansion of therapeutic options?

Van Raalte, D. H., Ouwens, D. M., Diamant, M.·2009·European Journal of Clinical Investigation

DOI 10.1111/j.1365-2362.2008.02067.x

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Abstract

At pharmacological concentrations, glucocorticoids (GCs) display potent anti‐inflammatory effects, and are therefore frequently prescribed by physicians to treat a wide variety of diseases. Despite excellent efficacy, GC therapy is hampered by their notorious metabolic side effect profile. Chronic exposure to increased levels of circulating GCs is associated with central adiposity, dyslipidaemia, skeletal muscle wasting, insulin resistance, glucose intolerance and overt diabetes. Remarkably, many of these side‐effects of GC treatment resemble the various components of the metabolic syndrome (MetS), in which indeed subtle disturbances in the hypothalamic‐pituitary‐adrenal (HPA) axis and/or increased tissue sensitivity to GCs have been reported. Recent developments have led to renewed interest in the mechanisms of GC's diabetogenic effects. First, ‘selective dissociating glucocorticoid receptor (GR) ligands’, which aim to segregate GC's anti‐inflammatory and metabolic actions, are currently being developed. Second, at present, selective 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) inhibitors, which may reduce local GC concentrations by inhibiting cortisone to cortisol conversion, are evaluated in clinical trials as a novel treatment modality for the MetS. In this review, we provide an update of the current knowledge on the mechanisms that underlie GC‐induced dysmetabolic effects. In particular, recent progress in research into the role of GCs in the pathogenesis of insulin resistance and beta‐cell dysfunction will be discussed.

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GC treatment is accompanied by significant metabolic adverse effects, including insulin resistance, glucose intolerance and diabetes, visceral adiposity, dyslipidaemia and skeletal muscle atrophy.
“GC treatment is accompanied by significant metabolic adverse effects, including insulin resistance, glucose intolerance and diabetes, visceral adiposity, dyslipidaemia and skeletal muscle atrophy [6].”
From Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial (2011) · cites this paper as [6]
Key driving mechanisms of secondary diabetes under hypercortisolism include stimulation of gluconeogenesis, development of insulin resistance, and impairment of pancreatic insulin secretion.
“some key driving mechanisms have been identified such as the stimulation of gluconeogenesis and development of insulin resistance, together with the impairment of pancreatic insulin secretion ( 23, 24 ).”
From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [23]
GCs impaired glucose transport into skeletal muscle independent of changes in insulin signalling.
“GCs impaired glucose transport into skeletal muscle independent of changes in insulin signalling [6].”
From Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial (2011) · cites this paper as [6]

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Abnormalities of Insulin Responses After Ambient and Previous Exposure to Glucose in Streptozocin-diabetic and Dexamethasone-treated Rats: Role of Hyperglycemia and Increased B-Cell Demands
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Discovery of Novel, Potent Benzamide Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model▽
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How glucocorticoid receptors modulate the activity of other transcription factors: A scope beyond tethering
Ratman, D., Vanden Berghe, W., Dejager, L., Libert, C., Tavernier, J., Beck, I. M., & De Bosscher, K. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.12.014 · Cited by 411 · see citing works
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Circadian control of glucose metabolism
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New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation
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Molecular Mechanisms of Glucocorticoid-Induced Insulin Resistance
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Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals
Kumar Jha, P., Challet, E., & Kalsbeek, A. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.01.024 · Cited by 235 · see citing works
Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes
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Pathophysiology of Diabetes Mellitus in Cushing’s Syndrome
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Acute and 2-week exposure to prednisolone impair different aspects of β-cell function in healthy men
van Raalte, D. H., Nofrate, V., Bunck, M. C., van Iersel, T., Elassaiss Schaap, J., Nässander, U. K., Heine, R. J., Mari, A., Dokter, W. H. A., & Diamant, M. (2010) · European Journal of Endocrinology · doi:10.1530/eje-09-1034 · Cited by 170 · see citing works
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Glucocorticoids and Type 2 Diabetes: From Physiology to Pathology
Di Dalmazi, G., Pagotto, U., Pasquali, R., & Vicennati, V. (2012) · Journal of Nutrition and Metabolism · doi:10.1155/2012/525093 · Cited by 168 · see citing works
Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management
Scaroni, C., Zilio, M., Foti, M., & Boscaro, M. (2017) · Endocrine Reviews · doi:10.1210/er.2016-1105 · Cited by 140 · see citing works
Chronic Stress and Diabetes Mellitus: Interwoven Pathologies
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Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial
van Raalte, D. H., Brands, M., van der Zijl, N. J., Muskiet, M. H., Pouwels, P. J. W., Ackermans, M. T., Sauerwein, H. P., Serlie, M. J., & Diamant, M. (2011) · Diabetologia · doi:10.1007/s00125-011-2174-9 · Cited by 109 · see citing works
“GC treatment is accompanied by significant metabolic adverse effects, including insulin resistance, glucose intolerance and diabetes, visceral adiposity, dyslipidaemia and skeletal muscle atrophy [ 6 ].”
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Steroid-induced hyperglycemia: An underdiagnosed problem or clinical inertia? A narrative review
Bonaventura, A., & Montecucco, F. (2018) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2018.03.006 · Cited by 108 · see citing works
Cortisol Is Negatively Associated with Insulin Sensitivity in Overweight Latino Youth
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Is diabetes in Cushing’s syndrome only a consequence of hypercortisolism?
Giordano, C., Guarnotta, V., Pivonello, R., Amato, M. C., Simeoli, C., Ciresi, A., Cozzolino, A., & Colao, A. (2014) · European Journal of Endocrinology · doi:10.1530/eje-13-0754 · Cited by 79 · see citing works
A rodent model of rapid-onset diabetes (ROD) induced by glucocorticoids and high-fat feeding
Shpilberg, Y., Beaudry, J. L., D'Souza, A., Campbell, J. E., Peckett, A., & Riddell, M. C. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.008912 · Cited by 77 · see citing works
Glucocorticoid-Induced Hyperglycemia: A Neglected Problem
Cho, J.-H., & Suh, S. (2024) · Endocrinology and Metabolism · doi:10.3803/enm.2024.1951 · Cited by 63 · see citing works
Twenty‐four‐hour profiles of plasma glucose, insulin, C‐peptide and free fatty acid in subjects with varying degrees of glucose tolerance following short‐term, medium‐dose prednisone (20 mg/day) treatment: evidence for differing effects on insulin secretion and action
Yuen, K. C. J., McDaniel, P. A., & Riddle, M. C. (2012) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04242.x · Cited by 58 · see citing works
Pros and cons of screening for occult Cushing syndrome
Tabarin, A., & Perez, P. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.51 · Cited by 57 · see citing works
Diabetes Care After Transplant
Wallia, A., Illuri, V., & Molitch, M. E. (2016) · Medical Clinics of North America · doi:10.1016/j.mcna.2016.01.005 · Cited by 50 · see citing works
Italian Society for the Study of Diabetes (SID)/Italian Endocrinological Society (SIE) guidelines on the treatment of hyperglycemia in Cushing’s syndrome and acromegaly
Baroni, M. G., Giorgino, F., Pezzino, V., Scaroni, C., & Avogaro, A. (2016) · Journal of Endocrinological Investigation · doi:10.1007/s40618-015-0404-6 · Cited by 41 · see citing works
Management of steroid-induced hyperglycemia in hospitalized patients with cancer: a review
Brady, V. J., Grimes, D., Armstrong, T., & LoBiondo-Wood, G. (2014) · Oncology nursing forum · doi:10.1188/14.onf.e355-e365 · Cited by 31 · see citing works
Mortality in patients with diabetes mellitus and Addison's disease: a nationwide, matched, observational cohort study
Chantzichristos, D., Persson, A., Eliasson, B., Miftaraj, M., Franzén, S., Bergthorsdottir, R., Gudbjörnsdottir, S., Svensson, A.-M., & Johannsson, G. (2017) · European Journal of Endocrinology · doi:10.1530/eje-16-0657 · Cited by 30 · see citing works
Glucocorticoid treatment impairs microvascular function in healthy men in association with its adverse effects on glucose metabolism and blood pressure: A randomised controlled trial
van Raalte, D. H., Diamant, M., Ouwens, D. M., Ijzerman, R. G., Linssen, M. M. L., Guigas, B., Eringa, E. C., & Serné, E. H. (2013) · Diabetologia · doi:10.1007/s00125-013-3016-8 · Cited by 33 · see citing works
Self-citation
Management of hyperglycaemia in persons with non-insulin-dependent type 2 diabetes mellitus who are started on systemic glucocorticoid therapy: a systematic review
Tatalovic, M., Lehmann, R., Cheetham, M., Nowak, A., Battegay, E., & Rampini, S. K. (2019) · BMJ Open · doi:10.1136/bmjopen-2019-028914 · Cited by 27 · see citing works
“28 We updated the protocol once on 21 October 2016 to broaden inclusion criteria.”
Method
MANAGEMENT OF ENDOCRINE DISEASE disease burden and treatment challenges in patients with both Addison's disease and type 1 diabetes mellitus
Chantzichristos, D., Eliasson, B., & Johannsson, G. (2020) · European Journal of Endocrinology · doi:10.1530/eje-20-0052 · Cited by 21 · see citing works
Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: management of steroid-exacerbated hyperglycemia
Cheng, Y.-C., Guerra, Y., Morkos, M., Tahsin, B., Onyenwenyi, C., Fogg, L., & Fogelfeld, L. (2021) · PLOS ONE · doi:10.1371/journal.pone.0256682 · Cited by 12 · see citing works
Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease
Zavala, E., Gil-Gómez, C. A., Wedgwood, K. C. A., Burgess, R., Tsaneva-Atanasova, K., & Herrera-Valdez, M. A. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.27.968354 · Cited by 8 · see citing works

Authors: Van Raalte, D. H., Ouwens, D. M., & Diamant, M.
Affiliations: Leiden University Medical Center (NL)
Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
ORCID: Ouwens, D. M.
Venue: European Journal of Clinical Investigation
Publisher: Wiley
Published: 2009-01-20
Volume: 39
Issue: 2
Pages: 81-93
ISSN: 0014-2972 (ISSN-L)
1365-2362
DOI: 10.1111/j.1365-2362.2008.02067.x
OpenAlex: W2171303876
Semantic Scholar: 05ad8ec2c5299fe0f127322507ef3082c543e927
Cited by: 439
References: 139
Citations by year: 2026: 11 · 2025: 20 · 2024: 19 · 2023: 27 · 2022: 23 · 2021: 25 · 2020: 16 · 2019: 34 · 2018: 23 · 2017: 26 · 2016: 27 · 2015: 30 · 2014: 31 · 2013: 31 · 2012: 34
FWCI: 4.21
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: European Journal of Clinical Investigation (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords: glucocorticoids, glucocorticoid-induced diabetes, insulin resistance, beta-cell dysfunction, metabolic syndrome, hypothalamic-pituitary-adrenal axis, cortisone to cortisol conversion, glucocorticoid adverse effects, dyslipidemia, abdominal obesity, skeletal muscle atrophy
MeSH terms: Animals, Cortisone, Glucocorticoids, Humans, Hydrocortisone, Insulin, Insulin Resistance, Receptors, Glucocorticoid, Muscle, Skeletal, Metabolic Syndrome, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Body Fat Distribution, Lipid Metabolism, Mice, Rats

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Novel insights into glucocorticoid‐mediated diabetogenic effects: towards expansion of therapeutic options?

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