A type IV P-type ATPase affects insulin-mediated glucose uptake in adipose tissue and skeletal muscle in mice

Mice carrying two pink-eyed dilution (p) locus heterozygous deletions represent a novel polygenic mouse model of type 2 diabetes associated with obesity. Atp10c, a putative aminophospholipid transporter on mouse chromosome 7, is a candidate for the phenotype. The phenotype is diet-induced. As a next logical step in the validation and characterization of the model, experiments to analyze metabolic abnormalities associated with these mice were carried out. Results demonstrate that mutants (inheriting the p deletion maternally) heterozygous for Atp10c are hyperinsulinemic, insulin-resistant and have an altered insulin-stimulated response in peripheral tissues. Adipose tissue and the skeletal muscle are the targets, and GLUT4-mediated glucose uptake is the specific metabolic pathway associated with Atp10c deletion. Insulin resistance primarily affects the adipose tissue and the skeletal muscle, and the effect in the liver is secondary. Gene expression profiling using microarray and real-time PCR show significant changes in the expression of four genes — Vamp2, Dok1, Glut4 and Mapk14 — involved in insulin signaling. The expression of Atp10c is also significantly altered in the adipose tissue and the soleus muscle. The most striking observation is the loss of Atp10c expression in the mutants, specifically in the soleus muscle, after eating the high-fat diet for 12 weeks. In conclusion, experiments suggest that the target genes and/or their cognate factors in conjunction with Atp10c presumably affect the normal translocation and sequestration of GLUT4 in both the target tissues.