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Rare fully penetrant mutations in are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function 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 variant (p.P50T/) on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated. We identified carriers ( = 20) and matched noncarriers ( = 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 [F]-fluorodeoxyglucose during euglycemic hyperinsulinemia. When we compared p.P50T/ carriers to noncarriers, we found a 39.4% reduction in whole-body GU ( = 0.006) and a 55.6% increase in the rate of endogenous glucose production ( = 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 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/ carriers.