G6PC1 and G6PC2 influence G6P flux but not HSD11B1 activity

Area of Science:

• Biochemistry and Molecular Biology
• Endocrinology and Metabolism

Background:

• Glucose-6-phosphatase catalytic subunits 1 and 2 (G6PC1; G6PC2) and hexose-6-phosphate dehydrogenase (H6PD) are ER lumen enzymes involved in glucose metabolism.
• 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) uses NADPH generated by H6PD to convert cortisone to cortisol, impacting insulin sensitivity.
• HSD11B1 inhibitors improve insulin sensitivity, while G6PC inhibitors are predicted to lower fasting blood glucose (FBG).

Purpose of the Study:

• To investigate the interplay between G6PC1/G6PC2 and H6PD in regulating glucose-6-phosphate (G6P) flux.
• To determine if G6PC1/G6PC2 influence HSD11B1 activity and glucocorticoid signaling.
• To assess the potential therapeutic implications of G6PC inhibitors for metabolic disorders.

Main Methods:

• Utilized a novel transcriptional assay with separate fusion genes to quantify glucocorticoid and glucose signaling.
• Overexpressed H6PD, HSD11B1, G6PC1, and G6PC2 in islet-derived 832/13 and liver-derived HepG2 cell lines.
• Studied metabolic changes in wild-type and G6pc2 knockout mice treated with 11-dehydrocorticosterone (11-DHC).

Main Results:

• Overexpression of H6PD and HSD11B1 activated glucocorticoid signaling in both cell lines.
• Overexpression of HSD11B1 blunted glucose-stimulated gene expression independently of G6P flux.
• Overexpression of G6PC1/G6PC2 blunted glucose signaling but minimally affected glucocorticoid signaling; G6PC1/2 had no effect in HepG2 cells.
• Rodent studies showed metabolic changes were unaffected by the absence of G6PC2, indicating HSD11B1 activity is independent of G6PC1/G6PC2.

Conclusions:

• HSD11B1 activity is not significantly influenced by the presence or absence of G6PC1 or G6PC2.
• G6PC1 and G6PC2 inhibitors are predicted to effectively lower FBG without adverse effects on glucocorticoid signaling.
• These findings support the development of G6PC inhibitors as a therapeutic strategy for managing metabolic diseases like type 2 diabetes.