A Partial Loss-of-Function Variant inAKT2Is Associated With Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A Genotype-Based Callback Positron Emission Tomography Study.
Latva-Rasku A., Honka M-J., Stančáková A., Koistinen HA., Kuusisto J., Guan L., Manning AK., Stringham H., Gloyn AL., Lindgren CM., T2D-GENES Consortium None., Collins FS., Mohlke KL., Scott LJ., Karjalainen T., Nummenmaa L., Boehnke M., Nuutila P., Laakso M.
Rare fully penetrant mutations inAKT2are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-functionAKT2coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of the p.Pro50ThrAKT2variant (p.P50T/AKT2) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (N= 20) and matched noncarriers (N= 25) for this allele in the population-based Metabolic Syndrome in Men (METSIM)study and invited these individuals back for positron emission tomography study with [18F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/AKT2carriers to noncarriers, we found a 39.4% reduction in whole-body GU (P= 0.006) and a 55.6% increase in the rate of endogenous glucose production (P= 0.038). We found significant reductions in GU in multiple tissues-skeletal muscle (36.4%), liver (16.1%), brown adipose (29.7%), and bone marrow (32.9%)-and increases of 16.8-19.1% in seven tested brain regions. These data demonstrate that the p.P50T substitution ofAKT2influences insulin-mediated GU in multiple insulin-sensitive tissues and may explain, at least in part, the increased risk of type 2 diabetes in p.P50T/AKT2carriers.