Glycogenin-2 Is Dispensable for Liver Glycogen Synthesis and Glucagon-Stimulated Glucose Release

CONTEXT: The synthesis of glycogen is initiated by glycogenin. In humans, glycogenin-1 is expressed ubiquitously, whereas glycogenin-2 (GN2) is highly expressed in liver. It has therefore been suggested that GN2 is a liver isoform of glycogenin. In a search for possible copy number variations associated with monogenic diabetes, we identified a 102-kb deletion of the X chromosome involving the entire GYG2 gene (encoding GN2) in 2 families. OBJECTIVE: The purpose of this study was to test whether male GYG2 deletion carriers had abnormal glucose metabolism and/or glycogen synthesis. DESIGN, SETTING, AND PATIENTS: Two families with diabetes and a GYG2 deletion were investigated with medical history and examination, glucagon stimulation tests, and liver biopsies. RESULTS: We identified a GYG2 deletion in 3 members of family 1, 8 members of family 2, and 1 blood donor. The deletion showed no clear cosegregation with diabetes. Deletion carriers reported no symptoms related to fasting. Results of cardiac examination and abdominal ultrasound imaging were normal. A glucagon stimulation test in 4 male deletion carriers showed a mean rise in plasma glucose of 3.6 mmol/L (95% confidence interval, 2.9-4.2) compared with 2.8 mmol/L (95% confidence interval, 2.2-3.4) in control subjects. Liver biopsy specimens did not show clear morphologic changes by light microscopy and showed the presence of both α- and β-glycogen by electron microscopy. We detected GYG1 but not GYG2 mRNA expression in the liver biopsy specimens. CONCLUSIONS: This is the first evaluation of humans without GN2 expression. Our data indicate that GN2 is not required for liver glycogen synthesis and glucagon-stimulated glucose release.