| Autor: |
Mohlke, K.L., Karjalainen, T., Kuusisto, J., Boehnke, M., Scott, L.J., Latva-Rasku, A., Stringham, H., Gloyn, A.L., Nuutila, P., Manning, A.K., Guan, L., Stanc��kov��, A., Nummenmaa, L., Lindgren, C.M., Honka, M.-J., Laakso, M., Koistinen, H.A. |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| DOI: |
10.17615/djfn-sk41 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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