Glycogenin-2 is dispensable for liver glycogen synthesis and glucagon-stimulated glucose release.

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. The purpose of this study was to test whether male GYG2 deletion carriers had abnormal glucose metabolism and/or glycogen synthesis. Two families with diabetes and a GYG2 deletion were investigated with medical history and examination, glucagon stimulation tests, and liver biopsies. 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. 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.