Abstract
BackgroundGlycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). Glucose 6-phosphate (G6P) availability has been shown to modulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an ER-bound enzyme catalyzing the local conversion of inactive cortisone into active cortisol. Adrenal cortex assessment has never been performed in GSDI. The aim of the current study was to evaluate the adrenal cortex hormones levels in GSDI patients.MethodsSeventeen GSDI (10 GSDIa and 7 GSDIb) patients and thirty-four age and sex-matched controls were enrolled. Baseline adrenal cortex hormones and biochemical markers of metabolic control serum levels were analyzed. Low dose ACTH stimulation test was also performed.ResultsBaseline cortisol serum levels were higher in GSDIa patients (p = 0.042) and lower in GSDIb patients (p = 0.041) than controls. GSDIa patients also showed higher peak cortisol response (p = 0.000) and Cortisol AUC (p = 0.029). In GSDIa patients, serum cholesterol (p = 0.000), triglycerides (p = 0.000), lactate (p = 0.000) and uric acid (p = 0.008) levels were higher and bicarbonate (p = 0.000) levels were lower than controls. In GSDIb patients, serum cholesterol levels (p = 0.016) were lower and lactate (p = 0.000) and uric acid (p = 0.000) levels were higher than controls. Baseline cortisol serum levels directly correlated with cholesterol (ρ = 0.65, p = 0.005) and triglycerides (ρ = 0.60, p = 0.012) serum levels in GSDI patients.ConclusionsThe present study showed impaired cortisol levels in GSDI patients, with opposite trend between GSDIa and GSDIb. The otherwise preserved adrenal cortex function suggests that this finding might be secondary to local deregulation rather than hypothalamo-pituitary-adrenal axis dysfunction in GSDI patients. We hypothesize that 11βHSD1 might represent the link between endocrine regulation and metabolic derangement in GSDI, constituting new potential therapeutic target in GSDI patients.
Highlights
Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb)
No significant difference in the remaining parameters was observed between GSDIa and GSDIb patients and controls
Opposite cortisol levels were found in GSDIa and GSDIb patients
Summary
Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). Glycogen storage disease type I (GSDI) is an inborn disorder of carbohydrate metabolism caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) system. It is characterized by accumulation of glycogen and fat in the liver and kidneys. Two major subtypes of GSDI have been identified: GSDIa, which is caused by mutations in the gene encoding the G6Pase alpha (G6Paseα), and GSDIb, caused by mutations in the gene encoding the glucose 6-phosphate (G6P) translocase (G6PT), which transports G6P from cytoplasm to microsomes. In GSDIa, the G6P excess in the endoplasmic reticulum (ER) (due to G6Paseα deficiency) has been associated to increased 11βHSD1 activity, while in GSDIb the lack of G6P in ER (due to G6PT deficiency) has been associated to decreased 11βHSD1 activity [2]
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