Skeletal muscle overexpression of sAnk1.5 in transgenic mice does not predispose to type 2 diabetes

Genome-wide association studies (GWAS) and cis-expression quantitative trait locus (cis-eQTL) analyses indicated an association of the rs508419 single nucleotide polymorphism (SNP) with type 2 diabetes (T2D). rs508419 is localized in the muscle-specific internal promoter (P2) of the ANK1 gene, which drives the expression of the sAnk1.5 isoform. Functional studies showed that the rs508419 C/C variant results in increased transcriptional activity of the P2 promoter, leading to higher levels of sAnk1.5 mRNA and protein in skeletal muscle biopsies of individuals carrying the C/C genotype. To investigate whether sAnk1.5 overexpression in skeletal muscle might predispose to T2D development, we generated transgenic mice (Tg(sAnk1.5/+)) in which the sAnk1.5 coding sequence was selectively overexpressed in skeletal muscle tissue. Tg(sAnk1.5/+) mice expressed up to 50% as much sAnk1.5 protein as wild-type (WT) muscles, mirroring the difference reported between individuals with the C/C or T/T genotype at rs508419. However, fasting glucose levels, glucose tolerance, insulin levels and insulin response in Tg(sAnk1.5/+) mice did not differ from those of age-matched WT mice monitored over a 12-month period. Even when fed a high-fat diet, Tg(sAnk1.5/+) mice only presented increased caloric intake, but glucose disposal, insulin tolerance and weight gain were comparable to those of WT mice fed a similar diet. Altogether, these data indicate that sAnk1.5 overexpression in skeletal muscle does not predispose mice to T2D susceptibility.

Automated summary

Genome-wide association studies and cis-expression quantitative trait locus analyses identified an association between the rs508419 SNP and type 2 diabetes. Functional studies showed that the C/C variant of rs508419 increases the activity of the P2 promoter, leading to higher levels of sAnk1.5 expression. However, overexpression of sAnk1.5 in skeletal muscle does not predispose mice to susceptibility to type 2 diabetes.