Fig. 1

Proposed pathomechanism linking endocrine regulation and metabolic imbalance in GSDI. In GSDIa G6P accumulates in both cytosol and ER within the hepatocytes. Increased G6P availability in the ER upregulates 11βHSD1 activity resulting in increased cortisol regeneration. Increased G6P in the cytosol enhances glycolysis and lipid load to mitochondria resulting in mitochondrial stress and increased cortisol synthesis (secondary to increased substrate availability). Together, these secondary metabolic disturbances lead to increased risk of insulin-resistance and metabolic syndrome. In GSDIb G6PT defect results in disrupted ER cycling in immune cells (e.g. neutrophils, lymphocytes) and subsequently decreased cortisol regeneration with the ER and potentially reduced substrates to mitochondria for cortisol synthesis. Reduced cortisol availability might contribute to chronic inflammation and higher risk for autoimmune disorders. G6P: glucose 6-phosphate, 6PG:6-phosphogluconactone, 11βHSD1:11β-hydroxysteroid dehydrogenase type 1, H6PDH: hexose-6-phosphate dehydrogenase, FAO: fatty acid oxidation