The Role of TBC1D4 in Exercise- and Insulin-induced Glucose Metabolism in Human Skeletal Muscle

Recently a common Greenlandic nonsense p.Arg684erTer variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 was discovered. The variant has an allele frequency of 17%. Homozygous carriers of this TBC1D4 variant have impaired glucose tolerance and a 10-fold enhanced risk of developing type 2 diabetes (T2D). The investigators propose to carry out comprehensive metabolic phenotyping of adult Inuits carrying zero or two alleles of the TBC1D4 variant. The investigators hypothesise that regulation of TBC1D4 in skeletal muscle is pivotal in regulating glucose uptake during exercise, during physiological insulin stimulation, and for the ability of an acute bout of exercise to improve insulin sensitivity to regulate glucose metabolism in humans. The overall aims in the present project are to: 1. Determine whether the TBC1D4 p.Arg684Ter variant affects the regulation of glucose uptake in skeletal muscle during exercise and during physiological insulin stimulation. 2. Determine the effect of the TBC1D4 p.Arg684Ter variant for the ability of acute exercise to insulin sensitize skeletal muscle to regulate glucose metabolism. 3. Define the metabolic pathways affected by the p.Arg684Ter variant in order to identify causal factors responsible for the diabetic phenotype of Inuit carriers. The knowledge generated will contribute to additional explanatory clues to the increased frequency of T2D in the carriers.