A Partial Loss-of-Function Variant in <i>AKT2</i> Is Associated With Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A Genotype-Based Callback Positron Emission Tomography Study

Abstract

Rare fully penetrant mutations in <i>AKT2</i> are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function <i>AKT2</i> coding 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.Pro50Thr <i>AKT2</i> variant (p.P50T/<i>AKT2</i>) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers (<i>N</i> = 20) and matched noncarriers (<i>N</i> = 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/<i>AKT2</i> carriers to noncarriers, we found a 39.4% reduction in whole-body GU (<i>P</i> = 0.006) and a 55.6% increase in the rate of endogenous glucose production (<i>P</i> = 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 of <i>AKT2</i> influences 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/<i>AKT2</i> carriers.