Regulation of Glucocorticoid Receptor Signaling and the Diabetogenic Effects of Glucocorticoid Excess

Ortsäter, Henrik; Sjöholm, Åke; Rafacho, Alex

doi:10.5772/51759

Cited by 8 publications

(18 citation statements)

References 141 publications

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“…This hypothesis remains to be proven in humans but is supported by the observation that patients with Cushing's syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue . In Addition, GC-induced attenuation of insulin signalling in the adipose tissue has been associated with reduced glucose uptake (Ortsäter et al 2012). In summary, GCs exposure leads to impaired insulin signalling and a systemic elevation of fatty acids and triglycerides which contributes to IR.…”

Section: Adipose Tissuementioning

confidence: 99%

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Rafacho¹,

Ortsäter²,

Nadal³

et al. 2014

Journal of Endocrinology

Self Cite

177

114

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Glucocorticoids (GCs) are broadly prescribed for numerous pathological conditions because of their anti-inflammatory, antiallergic and immunosuppressive effects, among other actions. Nevertheless, GCs can produce undesired diabetogenic side effects through interactions with the regulation of glucose homeostasis. Under conditions of excess and/or long-term treatment, GCs can induce peripheral insulin resistance (IR) by impairing insulin signalling, which results in reduced glucose disposal and augmented endogenous glucose production. In addition, GCs can promote abdominal obesity, elevate plasma fatty acids and triglycerides, and suppress osteocalcin synthesis in bone tissue. In response to GC-induced peripheral IR and in an attempt to maintain normoglycaemia, pancreatic b-cells undergo several morphofunctional adaptations that result in hyperinsulinaemia. Failure of b-cells to compensate for this situation favours glucose homeostasis disruption, which can result in hyperglycaemia, particularly in susceptible individuals. GC treatment does not only alter pancreatic b-cell function but also affect them by their actions that can lead to hyperglucagonaemia, further contributing to glucose homeostasis imbalance and hyperglycaemia. In addition, the release of other islet hormones, such as somatostatin, amylin and ghrelin, is also affected by GC administration. These undesired GC actions merit further consideration for the design of improved GC therapies without diabetogenic effects. In summary, in this review, we consider the implication of GC treatment on peripheral IR, islet function and glucose homeostasis.

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Section: Adipose Tissuementioning

confidence: 99%

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Rafacho¹,

Ortsäter²,

Nadal³

et al. 2014

Journal of Endocrinology

Self Cite

177

114

View full text Add to dashboard Cite

show abstract

“…Both CRH and ACTH release is negatively influenced by GC secretion, leading to a negative feedback loop where GCs inhibit their own release. The central nervous system is thus the commander-in-chief of GC responses, providing an excellent example of close integration between the nervous and endocrine systems (neuroendocrine) [179][180][181]. Cortisol levels vary in diurnal cycles with the lowest levels between 10 in the evening and 4 in the morning.…”

Section: Regulation Of Glucocorticoid Secretionmentioning

confidence: 99%

“…Other adverse effects of GC excess include skin atrophy and delayed wound healing, osteoporosis, muscle atrophy, glaucoma and cataract, central nervous system complications such as disturbances in mood, behavior, cognition and memory, menstrual irregularity, hypertension, increased risk of infection and re-activation of viruses, peptic ulcer and pancreatitis [172,181,213,228,229]. The effect of GCs on hypertension is partly due to the GC-induced activation of the MR, leading to increased sodium and water reabsorption in the kidneys, and partly due to actual GR activation in tissues involved in blood pressure regulation, including kidney, brain and the vasculature [230].…”

Section: Adverse Effects Of Glucocorticoid Excessmentioning

confidence: 99%

Mitogen-activated protein kinases and protein phosphatase 5 mediate glucocorticoid-induced cytotoxicity in pancreatic islets and β-cells

Fransson

Rosengren

Saha

et al. 2014

Molecular and Cellular Endocrinology

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“…Despite their potent anti-inflammatory effects, steroids cause relevant side effects when used for longer periods and at high doses ( 13 – 16 ), limiting their use and reducing adherence to treatment. Therefore, understanding the signaling mechanisms and pathways related to GC and their receptor [glucocorticoid receptor (GR)] is essential to provide the basis for the development of new selective glucocorticoid receptor modulators (SEGRMs) ( 17 , 18 ).…”

Section: Introductionmentioning

confidence: 99%

New Insights in Glucocorticoid Receptor Signaling—More Than Just a Ligand-Binding Receptor

2017

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The clinical use of classical glucocorticoids (GC) is narrowed by the many side effects it causes and the resistance to GC observed in some diseases. Since the great majority of GC effects depend on the activation of a glucocorticoid receptor (GR), many research groups had focused to better understand the signaling pathways involving those receptors. Transgenic animal models and genetic modifications of the receptor brought a huge insight into GR mechanisms of action. This in turn opened a new window for the search of selective GR modulators that ideally may have agonistic and antagonistic combined effects and activate one specific signaling pathway, inducing mostly transrepression or transactivation mechanisms. Another important research field concerns to posttranslational modifications that affect the GR and consequently also affect its signaling and function. In this mini review, we discuss many of those aspects of GR signaling, as well as findings like the ligand-independent activation of GR, which add another layer of complexity in GR signaling pathways. Although several recent data have been added to the GR field, much work has yet to be done, especially to find out the biological relevance of those alternative GR signaling pathways. Improving the knowledge about alternative GR signaling pathways and understanding how these pathways intercommunicate and in which situations they are relevant might help to develop new strategies to take benefit of it and to improve GC or other compounds efficacy causing minimal side effects.

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Regulation of Glucocorticoid Receptor Signaling and the Diabetogenic Effects of Glucocorticoid Excess

Cited by 8 publications

References 141 publications

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

Mitogen-activated protein kinases and protein phosphatase 5 mediate glucocorticoid-induced cytotoxicity in pancreatic islets and β-cells

New Insights in Glucocorticoid Receptor Signaling—More Than Just a Ligand-Binding Receptor

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