Current drug targets · 2026
Cytokeratin 8 as a Novel Therapeutic Target in Type 2 Diabetes Mellitus: Suppression of Hepatic Glycogen Synthesis via IRS1/PI3K/Akt/GSK3β Signaling.
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Sun Mingzhu, Li Xiuli, Sun Jin, Wang Zhidong
Аннотация
INTRODUCTION: Recent studies have established that cytokeratin 8 (CK8) is closely linked to glycogen synthesis; however, its mechanistic role in hepatic glycogen synthesis in type 2 diabetes mellitus (T2DM) remains unclear. This study aimed to elucidate the effects and underlying molecular mechanisms of CK8.
METHODS: We analyzed CK8 expression and the IRS1 (Insulin Receptor Substrate 1)/PI3K (Phosphoinositide 3-Kinase)/Akt (Protein Kinase B)/GSK3β (Glycogen Synthase Kinase 3 beta) pathway in liver samples from T2DM patients, diabetic C57BL/6J mouse models, and high glucose- treated NCTC 1469 cells using Western blotting, immunohistochemistry, and PAS staining.
RESULTS: CK8 was significantly upregulated in all T2DM models, correlating with suppressed IRS1/PI3K/Akt/GSK3β signaling and reduced glycogen synthesis. Our functional studies demonstrated that CK8 overexpression exacerbated these effects, while CK8 knockdown restored glycogen levels to near-normal.
DISCUSSION: In our study, CK8 was identified as a negative regulator of hepatic glycogen synthesis by modulating the IRS1/PI3K/Akt/GSK3β pathway.
CONCLUSION: These findings position CK8 as a promising therapeutic target for T2DM, with CK8 inhibition offering a novel strategy to improve hepatic insulin resistance and glycogen storage without requiring β-cell stimulation.
METHODS: We analyzed CK8 expression and the IRS1 (Insulin Receptor Substrate 1)/PI3K (Phosphoinositide 3-Kinase)/Akt (Protein Kinase B)/GSK3β (Glycogen Synthase Kinase 3 beta) pathway in liver samples from T2DM patients, diabetic C57BL/6J mouse models, and high glucose- treated NCTC 1469 cells using Western blotting, immunohistochemistry, and PAS staining.
RESULTS: CK8 was significantly upregulated in all T2DM models, correlating with suppressed IRS1/PI3K/Akt/GSK3β signaling and reduced glycogen synthesis. Our functional studies demonstrated that CK8 overexpression exacerbated these effects, while CK8 knockdown restored glycogen levels to near-normal.
DISCUSSION: In our study, CK8 was identified as a negative regulator of hepatic glycogen synthesis by modulating the IRS1/PI3K/Akt/GSK3β pathway.
CONCLUSION: These findings position CK8 as a promising therapeutic target for T2DM, with CK8 inhibition offering a novel strategy to improve hepatic insulin resistance and glycogen storage without requiring β-cell stimulation.