Glycogen storage disease type 1 (GSD1) is a rare inherited defect of endogenous glucose production. While children present with severe hypoglycemia 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 grown up GSD1 patients. Four patients with GSD1 (BMI: 23.2±6.3 kg/m2, age: 21±3 yr) and four healthy controls matched for BMI (23.1±3.0 kg/m2) and age (24±3 yr) were studied. Combined 1H/31P-nuclear-magnetic-resonance-spectroscopy was used to assess brain metabolism. Before and after administration of 1 mg glucagon endogen glucose production (EGP) was measured with D-[6,6-2H2]glucose while hepatic glucose metabolism was examined by 1H/13C/31P-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 vs. control) but an increased intrahepatic glycogen (502±89 vs. 236±11 mmol/l, P=0.05 vs. control) and lipid content (16.3±1.1 vs. 1.4±0.4%, P<0.001 vs. control). 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=n.s.) 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 (PME) (0.23±0.08 vs. 0.86±0.19AU, P<0.001) while inorganic phosphate (Pi) even decreased (0.36±0.08 vs. −0.43±0.17AU, P<0.01). Intracerebral ratios of glucose, glutamate, and myo-inositol:creatine were higher in GSD1 patients (at least P<0.05 vs. control, respectively). Hepatic defects of glucose metabolism persist in grown up GSD1 patients. Upregulation of the glucose and lactate transport at the blood-brain barrier could be responsible for the amelioration of hypoglycemic symptoms.