Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with
reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but
inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and
imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced
insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of
glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and
possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also
emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.