A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

Diabetes. 2017 Jul;66(7):2019-2032. doi: 10.2337/db16-1329. Epub 2017 Mar 24.

Abstract

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Americans / genetics
  • Alleles
  • Asian Continental Ancestry Group / genetics
  • Case-Control Studies
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • European Continental Ancestry Group / genetics*
  • Fasting / metabolism*
  • Finland
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Hispanic Americans / genetics
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance / genetics*
  • Odds Ratio
  • Proto-Oncogene Proteins c-akt / genetics*

Substances

  • Insulin
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt

Grant support