We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A Partial Loss-of-Function Variant in Is Associated With Reduced Insulin-Mediated Glucose Uptake in Multiple Insulin-Sensitive Tissues: A Genotype-Based Callback Positron Emission Tomography Study.
- Authors
Latva-Rasku, Aino; Honka, Miikka-Juhani; Stancáková, Alena; Koistinen, Heikki A.; Kuusisto, Johanna; Li Guan; Manning, Alisa K.; Stringham, Heather; Gloyn, Anna L.; Lindgren, Cecilia M.; Collins, Francis S.; Mohlke, Karen L.; Scott, Laura J.; Karjalainen, Tomi; Nummenmaa, Lauri; Boehnke, Michael; Nuutila, Pirjo; Laakso, Markku; Stančáková, Alena; Guan, Li
- 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 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.
- Subjects
GENETICS of type 2 diabetes; TYPE 2 diabetes risk factors; GLUCOSE metabolism; MONOGENIC & polygenic inheritance (Genetics); POSITRON emission tomography; HYPERINSULINISM
- Publication
Diabetes, 2018, Vol 67, Issue 2, p334
- ISSN
0012-1797
- Publication type
Academic Journal
- DOI
10.2337/db17-1142