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
Year: 2017
Type: article
Study design: Observational Study
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.
Source: Diabetes
DOI: 10.2337/db17-1142
Authors: Aino 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, Francis S. Collins, Karen L. Mohlke, Laura J. Scott, Tomi Karjalainen, Lauri Nummenmaa, Michael Boehnke, Pirjo Nuutila, Markku Laakso
Institutions: University of Turku, Turku PET Centre, University of Eastern Finland, University of Helsinki, Helsinki University Hospital, Minerva Foundation, Kuopio University Hospital, University of Michigan, Broad Institute, Harvard University, Massachusetts General Hospital, Centre for Human Genetics, National Institute for Health and Care Research, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals NHS Trust, National Institutes of Health, National Human Genome Research Institute, University of North Carolina at Chapel Hill, Turku University Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Li Ka Shing Foundation, Foundation for Cardiovascular Research, Wellcome Trust, National Institute for Health and Care Research, Academy of Finland, Kuopion Yliopistollinen Sairaala, Sydäntutkimussäätiö, National Institutes of Health, Medical Research Council, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, NHLBI Division of Intramural Research
Awards: G1181497844, G1327835149, G1335979935, G1891855903, G2199983953, G2478079187, Bridging the gap from type 2 diabetes genetics to functional mechanisms of disease., G2970981986, Discovery of Functional Variants in Type 2 Diabetes Genes in Mexican Americans, G2988741787, G301048564, G3226476464, G3750575142, G3791769672, G3804353902, G4426574518, Bridging the gap from type 2 diabetes genetics to functional mechanisms of disease., G5088787922, Functional genetic variants for type 2 diabetes, General Clinical Research Center, G574117291, Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes, G7543358569, Defining mechanisms for pancreatic beta-cell dysfunction in type 2 diabetes, G8028352506, G9000019908, G9000023558, G9000033359, G9000051584, G9000073520, G9000078064, G9000141698, G9000156922, G9000182967, G9000206245, G9000267977, Michigan Diabetes Research Center (MDRC)
OpenAlex ID: W2770760191