Characterization of hepatic and brain metabolism in young adults with glycogen storage disease type 1: a magnetic resonance spectroscopy study

In glycogen storage disease type 1 (GSD1), children present with severe hypoglycemia, whereas the propensity for hypoglycemia may decrease with age in these patients. It was the aim of this study to elucidate the mechanisms for milder hypoglycemia symptoms in young adult GSD1 patients. Four patients with GSD1 body mass index (BMI) 23.2 +/- 6.3 kg/m, age 21.3 +/- 2.9 yr] and four healthy controls matched for BMI (23.1 +/- 3.0 kg/m) and age (24.0 +/- 3.1 yr) were studied. Combined (1)H/(31)P nuclear magnetic resonance spectroscopy (NMRS) was used to assess brain metabolism. Before and after administration of 1 mg glucagon, endogenous glucose production (EGP) was measured with d-6,6-(2)H(2)]glucose and hepatic glucose metabolism was examined by (1)H/(13)C/(31)P NMRS. At baseline, GSD1 patients exhibited significantly lower rates of EGP (0.53 +/- 0.04 vs. 1.74 +/- 0.03 mg.kg(-1).min(-1); P < 0.01) but an increased intrahepatic glycogen (502 +/- 89 vs. 236 +/- 11 mmol/l; P = 0.05) and lipid content (16.3 +/- 1.1 vs. 1.4 +/- 0.4%; P < 0.001). After glucagon challenge, EGP did not change in GSD1 patients (0.53 +/- 0.04 vs. 0.59 +/- 0.24 mg.kg(-1).min(-1); P = not significant) but increased in healthy controls (1.74 +/- 0.03 vs. 3.95 +/- 1.34; P < 0.0001). In GSD1 patients, we found an exaggerated increase of intrahepatic phosphomonoesters (0.23 +/- 0.08 vs. 0.86 +/- 0.19 arbitrary units; P < 0.001), whereas inorganic phosphate decreased (0.36 +/- 0.08 vs. -0.43 +/- 0.17 arbitrary units; P < 0.01). Intracerebral ratios of glucose and lactate to creatine were higher in GSD1 patients (P < 0.05 vs. control). Therefore, hepatic defects of glucose metabolism persist in young adult GSD1 patients. Upregulation of the glucose and lactate transport at the blood-brain barrier could be responsible for the amelioration of hypoglycemic symptoms.