期刊
DIABETES
卷 67, 期 2, 页码 334-342出版社
AMER DIABETES ASSOC
DOI: 10.2337/db17-1142
关键词
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资金
- National Institutes of Health National Heart, Lung, and Blood Institute [NIH/NHLBI 5K01DK107836]
- Wellcome Trust [095101/Z/10/Z, 200837/Z/16/Z]
- Medical Research Council [MR/L020149/1]
- Li Ka Shing Foundation
- National Institute for Health Research Oxford Biomedical Research Centre
- Widenlife
- National Institutes of Health [CRR00070 CR00.01, R01DK093757, R01DK072193, U01DK062370]
- National Human Genome Research Institute Division of Intramural Research [Z01HG000024]
- National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [U01DK085501, U01DK085524, U01DK085526, U01DK085545, U01DK085584]
- Suomen Akatemia (Academy of Finland) [321428]
- Juselius Foundation
- Sydantutkimussaatio (Finnish Foundation for Cardiovascular Research)
- European Medical Information Framework [IMI JU GA 115372-2]
- Kuopion Yliopistollinen Sairaala (Kuopio University Hospital) VTR grant
- Academy of Finland
- Centre of Excellence of Cardiovascular and Metabolic Diseases
- Wellcome Trust [200837/Z/16/Z, 095101/Z/10/Z] Funding Source: Wellcome Trust
- MRC [MR/L020149/1] Funding Source: UKRI
- Medical Research Council [MR/L020149/1] Funding Source: researchfish
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 [F-18]-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 tissuesskeletal 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.
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