A1 Refereed original research article in a scientific journal

A Partial Loss-of-Function Variant in AKT2 is Associated with Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin Sensitive Tissues: a Genotype-Based Callback Positron Emission Tomography Study




AuthorsAino Latva-Rasku, Miikka-Juhani Honka, Alena Stančáková, Heikki A. Koistinen, Johanna Kuusisto, Li Guan, Alisa K Manning, Heather Stringham, Anna L Gloyn, Cecilia M Lindgren, the T2D-GENES Consortium, Francis S Collins, Karen L Mohlke, Laura J Scott, Tomi Karjalainen, Lauri Nummenmaa, Michael Boehnke, Pirjo Nuutila, Markku Laakso

Publication year2018

JournalDiabetes

Volume67

Issue2

First page 334

Last page342

Number of pages9

ISSN0012-1797

DOIhttps://doi.org/10.2337/db17-1142

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/27208040


Abstract


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 p.Pro50Thr 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 non-carriers (N=25) for this allele in the population-based 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 non-carriers, 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 7 tested brain regions. These data demonstrate that the 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.


Downloadable publication

This is an electronic reprint of the original article.
This reprint may differ from the original in pagination and typographic detail. Please cite the original version.





Last updated on 2024-26-11 at 20:35