The role of the transcription factor Sox4 in insulin secretion and impaired glucose tolerance

Abstract

Objectives: To identify, map, clone and functionally validate a novel mouse model for impaired glucose tolerance and insulin secretion.

Research Design and Methods: Haploinsufficiency of the insulin receptor (IR) and associated mild insulin resistance has been utilised to sensitise an ENU screen to identify novel mutations resulting in impaired glucose tolerance and diabetes. The new IGT4 model was selected using an intraperitoneal glucose tolerance test and inheritance of the phenotype confirmed by generation of backcross progeny. Segregation of the phenotype was correlated with genotype information to map the location of the gene and candidates sequenced for mutations. The function of the Sox4 gene in insulin secretion was tested using another ENU allele and by siRNA silencing in insulinoma cells.

Results: We describe two allelic autosomal dominant mutations in the highly conserved HMG box of the transcription factor Sox4. Previously associated with pancreas development, Sox4 mutations in the adult mouse result in an insulin secretory defect, which in association with IR^+/− induced insulin resistance exhibits impaired glucose tolerance. Elimination of the Sox4 transcript in INS1 and Min6 cells resulted in the abolition of glucose-stimulated insulin release similar to that observed for silencing of the key metabolic enzyme glucokinase. Intracellular calcium measurements in treated cells indicates that this defect lies downstream of the K_ATP channel and calcium influx.

Conclusions: IGT4 represents a novel di-genic model of insulin resistance coupled with an insulin secretory defect. The Sox4 gene has a role in insulin secretion in the adult beta cell downstream of the K_ATP channel.