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

Abstract

Weghuber D, Mandl M, Krššák M, Roden M, Nowotny P, Brehm A, Krebs M, Widhalm K, Bischof MG. Characterization of hepatic and brain metabolism in young adults with glycogen storage disease type 1: a magnetic resonance spectroscopy study. Am J Physiol Endocrinol Metab 293: E1378-E1384, 2007. First published September 4, 2007; doi:10.1152/ajpendo.00658.2006.-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 Ϯ 6.3 kg/m, age 21.3 Ϯ 2.9 yr] and four healthy controls matched for BMI (23.1 Ϯ 3.0 kg/m) and age (24.0 Ϯ 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 H2]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 Ϯ 0.04 vs. 1.74 Ϯ 0.03 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ; P Ͻ 0.01) but an increased intrahepatic glycogen (502 Ϯ 89 vs. 236 Ϯ 11 mmol/l; P ϭ 0.05) and lipid content (16.3 Ϯ 1.1 vs. 1.4 Ϯ 0.4%; P Ͻ 0.001). After glucagon challenge, EGP did not change in GSD1 patients (0.53 Ϯ 0.04 vs. 0.59 Ϯ 0.24 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ; P ϭ not significant) but increased in healthy controls (1.74 Ϯ 0.03 vs. 3.95 Ϯ 1.34; P Ͻ 0.0001). In GSD1 patients, we found an exaggerated increase of intrahepatic phosphomonoesters (0.23 Ϯ 0.08 vs. 0.86 Ϯ 0.19 arbitrary units; P Ͻ 0.001), whereas inorganic phosphate decreased (0.36 Ϯ 0.08 vs. Ϫ0.43 Ϯ 0.17 arbitrary units; P Ͻ 0.01). Intracerebral ratios of glucose and lactate to creatine were higher in GSD1 patients (P Ͻ 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. endogenous glucose production; glucose-6-phospate; intrahepatocellular lipid content; hypoglycemia GLYCOGEN STORAGE DISEASE (GSD) type 1 is an inherited defect of endogenous glucose production (EGP) occurring approximately once in every 100,000 live births (44). Two forms of GSD1 are known at present: GSD1a, caused by a defect of the glucose-6-phosphatase hydrolase, and GSD1b, caused by nonfunctioning mutations of the glucose-6-phosphatase translocase. Both known defects of GSD1 inactivate the multienzyme complex of glucose-6-phosphatase, which is necessary for the terminal step of gluconeogenesis, the conversion of glucose-6-phosphate (G6P) to glucose. Thus G6P is trapped inside the cell and cannot be released into the circulation, resulting in susceptibility to hypoglycemia during periods of fasting. Mutation search in liver biopsies is the gold standard for diagnosis of ...

Flux analysis of inborn errors of metabolism

“…At the highest exogenous glucose infusion rate of 33.3 μmol.kg −1 .min −1 endogenous glucose production could still be measured, although the rate was decreased to 7.1 ± 0.4 μmol.kg −1 .min −1 . Comparable observations were made by Wengler et al ( 2007 ) and Huidekoper et al (Huidekoper et al 2010 ). Kalderon and coworkers (Kalderon et al 1989a , Kalderon et al 1988 , Kalderon et al 1989b ) studied glucose production with [ 13 C 6 ]-glucose and measure isotope dilution and ‘scrambling’ of 13 C–labeling in glucose by NMR.…”

Glucose metabolism in children: influence of age, fasting, and infectious diseases

“…Because a change in the plasma glucose concentration is not necessarily a good parameter for a change in EGP, more insight in glucose kinetics must be obtained by combining the glucagon test with stable isotope studies [103]. This technique was used to measure EGP in response to glucagon in (preterm) infants [104][105][106][107] and in adults [97,[108][109][110], showing a 4.5-and 9-fold increase in EGP, respectively. In children, merely case reports have been published on this subject [111,112].…”

Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia

“…Several studies have reported residual endogenous glucose production (EGP) in GSD I patients. (4)(5)(6)(7)(8) For instance, in a GSD I patient with complete loss of G6Pase activity a 30% retention of systemic EGP was observed in comparison to healthy subjects. (9) Although the origin of residual EGP in GSD I is unknown, several hypotheses have been proposed.…”

“…Hypoglycemia imposes a primary and life‐threatening risk in GSD Ia patients. Several studies have reported residual endogenous glucose production (EGP) in GSD I patients . For instance, in a GSD I patient with complete loss of G6Pase activity a 30% retention of systemic EGP was observed in comparison to healthy subjects .…”