Glucocorticoid Receptor Signaling in Diabetes
Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn,...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/20/11173 |
| _version_ | 1797514346702569472 |
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| author | Ioanna Kokkinopoulou Andriana Diakoumi Paraskevi Moutsatsou |
| author_facet | Ioanna Kokkinopoulou Andriana Diakoumi Paraskevi Moutsatsou |
| author_sort | Ioanna Kokkinopoulou |
| collection | DOAJ |
| description | Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation. |
| first_indexed | 2024-03-10T06:30:11Z |
| format | Article |
| id | doaj.art-d7de1a3898bd47108ac2249272c7be03 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:30:11Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d7de1a3898bd47108ac2249272c7be032023-11-22T18:35:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122201117310.3390/ijms222011173Glucocorticoid Receptor Signaling in DiabetesIoanna Kokkinopoulou0Andriana Diakoumi1Paraskevi Moutsatsou2Department of Clinical Biochemistry, Medical School, National and Kapodistrian University of Athens, University General Hospital “ATTIKON”, 12462 Athens, GreeceDepartment of Clinical Biochemistry, Medical School, National and Kapodistrian University of Athens, University General Hospital “ATTIKON”, 12462 Athens, GreeceDepartment of Clinical Biochemistry, Medical School, National and Kapodistrian University of Athens, University General Hospital “ATTIKON”, 12462 Athens, GreeceStress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation.https://www.mdpi.com/1422-0067/22/20/11173glucocorticoidsglucocorticoid receptorGRdiabetes mellitusstress |
| spellingShingle | Ioanna Kokkinopoulou Andriana Diakoumi Paraskevi Moutsatsou Glucocorticoid Receptor Signaling in Diabetes International Journal of Molecular Sciences glucocorticoids glucocorticoid receptor GR diabetes mellitus stress |
| title | Glucocorticoid Receptor Signaling in Diabetes |
| title_full | Glucocorticoid Receptor Signaling in Diabetes |
| title_fullStr | Glucocorticoid Receptor Signaling in Diabetes |
| title_full_unstemmed | Glucocorticoid Receptor Signaling in Diabetes |
| title_short | Glucocorticoid Receptor Signaling in Diabetes |
| title_sort | glucocorticoid receptor signaling in diabetes |
| topic | glucocorticoids glucocorticoid receptor GR diabetes mellitus stress |
| url | https://www.mdpi.com/1422-0067/22/20/11173 |
| work_keys_str_mv | AT ioannakokkinopoulou glucocorticoidreceptorsignalingindiabetes AT andrianadiakoumi glucocorticoidreceptorsignalingindiabetes AT paraskevimoutsatsou glucocorticoidreceptorsignalingindiabetes |