The Role of Glucocorticoids in Hepatic Gluconeogenesis, Associated Pathologies, and Novel Therapeutic Approaches Glukokortikoidlerin Hepatik Glukoneogenezdeki Rolü, İlişkili Patolojiler ve Yeni Tedavi Yaklaşımları
Fabad Journal of Pharmaceutical Sciences, cilt.51, sa.1, ss.419-434, 2026 (Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 51 Sayı: 1
- Basım Tarihi: 2026
- Doi Numarası: 10.55262/fabadeczacilik.1825544
- Dergi Adı: Fabad Journal of Pharmaceutical Sciences
- Derginin Tarandığı İndeksler: Scopus, EMBASE, Health Research Premium Collection (ProQuest), Pharma Collection (ProQuest)
- Sayfa Sayıları: ss.419-434
- Anahtar Kelimeler: diabetes, Glucocorticoid, gluconeogenesis, glucose metabolism, hyperglycemia
- Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
- Atatürk Üniversitesi Adresli: Evet
Özet
Glucocorticoids are essential steroid hormones that play a pivotal role in regulating hepatic gluconeogenesis, thereby contributing to the maintenance of systemic glucose homeostasis. This review provides a comprehensive overview of the molecular mechanisms by which glucocorticoids modulate hepatic glucose production and explores their clinical implications in metabolic health and disease. Glucocorticoids exert their primary effects through genomic pathways, involving the translocation of activated glucocorticoid receptors (GRs) into the nucleus, where they bind to glucocorticoid response elements (GREs) on DNA. This interaction promotes the transcription of key gluconeogenic enzymes, notably phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Additionally, glucocorticoids enhance the expression of these enzymes by synergizing with critical transcriptional regulators such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), forkhead box protein O1 (FOXO1), and hepatocyte nuclear factor 4-alpha (HNF-4α). Beyond their hepatic effects, glucocorticoids influence systemic metabolism by stimulating proteolysis and lipolysis in peripheral tissues, thereby increasing the availability of substrates for gluconeogenesis. Furthermore, they antagonize insulin signaling, contributing to insulin resistance. The local activation of glucocorticoids via the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) adds another layer of regulation. Non-genomic effects through the cAMP/PKA/CREB signaling pathway allows for rapid metabolic responses. Chronic glucocorticoid excess, as observed in conditions like Cushing's syndrome, is linked to the development of type 2 diabetes. Emerging therapeutic strategies, including 11β-HSD1 inhibitors, selective GR modulators, and targeted inhibitors of gluconeogenic enzymes, present promising avenues for managing glucocorticoid-induced metabolic disorders.