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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.

Original publication

DOI

10.1371/journal.pgen.1004235

Type

Journal article

Journal

PLoS Genet

Publication Date

04/2014

Volume

10

Keywords

Alleles, Diabetes Mellitus, Type 2, Fasting, GRB10 Adaptor Protein, Genome-Wide Association Study, Glucose, Humans, Insulin, Insulin Resistance, Islets of Langerhans, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptor, Insulin, Signal Transduction