A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose-1,6-bisphosphatase deficiency

Abstract

Background: A potential role for muscle in glucose homeostasis was recently suggested based on characterization of extrahepatic and extrarenal glucose-6-phosphatase (glucose-6-phosphatase-beta). To study the role of extrahepatic tissue in glucose homeostasis during fasting glucose kinetics were studied in two patients with a deficient hepatic and renal glycogenolysis and/or gluconeogenesis.

Design: Endogenous glucose production (EGP), glycogenolysis (GGL), and gluconeogenesis (GNG) were quantified with stable isotopes in a patient with glycogen storage disease type 1a (GSD-1a) and a patient with fructose-1,6-bisphosphatase (FBPase) deficiency. The [6,6-(2)H(2)]glucose dilution method in combination with the deuterated water method was used during individualized fasting tests.

Results: Both patients became hypoglycemic after 2.5 and 14.5 h fasting, respectively. At that time, the patient with GSD-1a had EGP 3.84 micromol/kg per min (30% of normal EGP after an overnight fast), GGL 3.09 micromol/kg per min, and GNG 0.75 micromol/kg per min. The patient with FBPase deficiency had EGP 8.53 micromol/kg per min (62% of normal EGP after an overnight fast), GGL 6.89 micromol/kg per min GGL, and GNG 1.64 micromol/kg per min.

Conclusion: EGP was severely hampered in both patients, resulting in hypoglycemia. However, despite defective hepatic and renal GNG in both disorders and defective hepatic GGL in GSD-1a, both patients were still able to produce glucose via both pathways. As all necessary enzymes of these pathways have now been functionally detected in muscle, a contribution of muscle to EGP during fasting via both GGL as well as GNG is suggested.

Fig. 1

Study protocols in patients 1 [glycogen storage disease type 1a (GSD-1a)] and 2 [fructose-1,6-bisphosphatase (FBPase)] deficiency

Fig. 2

Glucose kinetics in relation to plasma glucose concentration and fasting duration in a patient with glucose-6-phosphatase deficiency (GSD-1a). Plasma glucose concentrations are depicted in the left panel (A). Endogenous glucose production (EGP; ●), glycogenolysis (GGL; ▲) and gluconeogenesis (GNG; ▼) are depicted in the right panel (B)

Fig. 3

Glucose kinetics in relation to plasma glucose concentration and fasting duration in a patient with fructose-1,6-bisphosphatase (FBPase) deficiency. Plasma glucose concentrations are depicted in theleft panel (A). Endogenous glucose production (EGP; ●), glycogenolysis (GGL; ▲) and gluconeogenesis (GNG; ▼) are depicted in theright panel (B)