Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 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 AKT2 variant (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/AKT2 carriers 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 of AKT2 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/AKT2 carriers.

Original publication

DOI

10.2337/db17-1142

Type

Journal article

Journal

Diabetes

Publication Date

02/2018

Volume

67

Pages

334 - 342

Addresses

Turku PET Centre, University of Turku, Turku, Finland.

Keywords

T2D-GENES Consortium, Humans, Diabetes Mellitus, Type 2, Insulin Resistance, Genetic Predisposition to Disease, Insulin, Fluorodeoxyglucose F18, Blood Glucose, Hypoglycemic Agents, Positron-Emission Tomography, Early Diagnosis, Follow-Up Studies, Amino Acid Substitution, Heterozygote, Alleles, Aged, Middle Aged, Finland, Male, Proto-Oncogene Proteins c-akt, Genetic Variation, Genetic Association Studies, Absorption, Physiological, Loss of Function Mutation